Detection of oesophageal cancer biomarkers by plasma proteomic profiling of human cell line xenografts in response to chemotherapy

Background:

The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy may improve survival, but targeting treatment to patients who respond to chemotherapy could be improved by the availability of markers of response. This study sought proteomic markers of therapeutic response using an adenocarcinoma xenograft model.

Methods:

Epirubicin, cisplatin or 5-fluorouracil was administered to severe combined immune-deficient mice bearing OE19 oesophageal adenocarcinoma xenografts. Murine plasma samples from treated and untreated xenografts were analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectroscopy, and panels of peaks were found using class prediction models that distinguished treatment groups. Proteins in these peaks were identified by mass spectroscopy in tryptic digests of purified fractions. Five paired samples from oesophageal cancer patients before and after chemotherapy were analysed using the same methodology.

Results:

Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the treated xenograft and control groups. Marker panels predicted treated vs untreated xenografts with sensitivities of 100%, specificities of 86–100% and test efficiencies of 89–100%. Three of the proteins identified in these panels, apolipoprotein A-I, serum amyloid A and transthyretin were confirmed in the clinical samples.

Conclusion:

Plasma protein markers can be detected in response to chemotherapy in oesophageal adenocarcinoma xenografts and in clinical samples, and have the potential to monitor response and guide chemotherapy in oesophageal adenocarcinoma.     

Improved survival in both histologic types of oesophageal cancer in Sweden

The prognosis among patients diagnosed with oesophageal cancer is poor with an overall 5-year survival close to 5% in most countries. Improved diagnostic and surgical strategies might influence the survival, however. We investigated the observed and relative survival among all patients in Sweden diagnosed with oesophageal adenocarcinoma (n = 1,441) or squamous cell carcinoma (n = 6395) from 1961-1996 with follow-up to December 1997. Observed survival rates were calculated by the life-table method. Relative survival rates were computed as the ratio of the observed to the expected survival. The expected survival was inferred from the survival among the entire Swedish population in the same age, sex and calendar year strata. The 5-year observed survival rate for adenocarcinoma increased from a stable figure close to 4% during the entire period 1961-1989 to 10.5% during 1990-1996. Similarly, the 5-year relative survival rate was stable around 5% during 1961-1989, but during 1990-1996 the survival was increased to 13.7%. For squamous cell carcinoma, the survival improved slightly by each decade, starting with 3.8% 5-year observed survival in 1961-1969 to 7.0% during 1990-1996. Similarly, the 5-year relative survival improved from 5.0% to 8.9% during the study period. In conclusion, the survival rates for both oesophageal adenocarcinoma and squamous cell carcinoma have increased significantly during the 1990s compared to those in the previous 3 decades (p < 0.001).     

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

Squamous cell carcinoma of the oesophagus (SCCO) is still a pathology of bad prognosis. Specific therapies are now developed against epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, c-kit receptor (CD117), vascular endothelial growth factor (VEGF) and p53 protein. This study was aimed at assessing their expression in a large series of SCCO, as well as their potential therapeutic interest in this pathology. Immunohistochemical expression of these factors was assessed retrospectively in 107 cases of SCCO with primary surgery, as well as their relationships to recurrence, metastasis and overall survival on a long-term follow-up. Human epidermal growth factor receptor 2 and CD117 were expressed in less than 3% of the cases. Epidermal growth factor receptor and p53 were overexpressed in 68.2 and 66.4% of the cases, and VEGF in 38.3%. Epidermal growth factor receptor overexpression was significantly related to vascular invasion (P=0.023). Its diffuse positivity was significantly related in multivariate analysis to higher local recurrence (P=0.006) and lower overall survival (P=0.003), in a subgroup of patients of poor outcome who had received postoperative adjuvant treatment. These results highlight the great potential prognostic and therapeutic interest of evaluating EGFR diffuse positivity in locally advanced SCCO.     

Risk of betel chewing for oesophageal cancer in Taiwan

Among 104 cases of squamous-cell oesophageal carcinoma patients and 277 controls in Taiwan, after adjusting for cigarette smoking, alcohol consumption, and other confounders, we found that subjects who chewed from 1 to 495 betel-year and more than 495 betel-years (about 20 betel quid per day for 20 years) had 3.6-fold (95% Cl = 1.3-10.1) and 9.2-fold risk (95% Cl = 1.8-46.7), respectively, of developing oesophageal cancer, compared to those who did not chew betel.     

Factors affecting the survival of patients with oesophageal carcinoma under radiotherapy in the north of Iran.

Factors relevant to the survival of patients with oesophageal cancer under radiotherapy have been studied in northern Iran where its incidence is high. We conducted an analytical study using a historical cohort and information from the medical charts of patients with oesophageal cancer. Out of 523 patients referred to the Shahid Rajaii radiotherapy centre in Babolsar from 1992 to 1996, we followed 230 patients for whom an address was available in 1998. The frequency of prognostic factors among those not contacted was very similar to those included in the study. The data were analysed using survival analysis by the nonparametric method of Kaplan Meier and the Cox regression model to determine risk ratios (RR) of prognostic factors. Survival rates were 42% at 1 year, 21% at 2 years, and 8% at 5 years after diagnosis. Patients aged 50-64 were found to have poorer survival compared with those less than 50 (RR = 1.73, P = 0.03); the risk ratio for ages f = 65 was 1.88 (P = 0.03). Females had significantly better survival than males (RR = 0.71, P = 0.02). For each 100 rads dose of radiotherapy, the risk ratio was significantly decreased by 1% (RR = 0.99, P = 0.05); for each session of radiotherapy, the risk ratio was significantly decreased by 4% (RR = 0.96, P = 0.0001); for each square centimetre size of surface under radiotherapy, the risk ratio significantly increased (RR = 1.002, P = 0.04). We did not observe a significant difference on survival by histology, anatomical location of tumours, or type of treatment (P > 0.05). Prognosis is extremely poor.     

The impact of body mass index on complication and survival in resected oesophageal cancer: a clinical-based cohort and meta-analysis

Background:

Body mass index (BMI) has been associated with the risk of oesophageal cancer. But the influence of BMI on postoperative complication and prognosis has always been controversial.

Methods:

In total, 2031 consecutive patients who underwent oesophagectomy between 1998 and 2008 were classified according to Asian-specific BMI (kg m⁻²) cutoff values. The impact of BMI on overall survival (OS) was estimated using the Kaplan–Meier method and Cox proportional hazard models. We performed a meta-analysis to examine the association of BMI with OS and postoperative complication.

Results:

Patients with higher BMI had more postoperative complication (P=0.002), such as anastomotic leakage (P=0.016) and cardiovascular diseases (P<0.001), but less incidence of chylous leakage (P=0.010). Logistic regression analysis showed that BMI (P=0.005) was a confounding factor associated with postoperative complication. Multivariate analysis showed that overweight and obese patients had a more favourable survival than normal weight patients (HR (hazard ratio) = 0.80, 95% CI (confidence interval): 0.70–0.92, P=0.001). Subgroup analysis showed that the association with higher BMI and increased OS was observed in patients with oesophageal squamous cell carcinoma (ESCC) (P<0.001), oesophageal adenocarcinoma (EA) (P=0.034), never-smoking (P=0.035), ever-smoking (P=0.035), never alcohol consumption (P=0.005), weight loss (P=0.003) and advanced pathological stage (P<0.001). The meta-analysis further corroborated that higher BMI was associated with increased complication of anastomotic leakage (RR (risk ratio)=1.04, 95% CI: 1.02–1.06, P=0.001), wound infection (RR=1.03, 95% CI: 1.00–1.05, P=0.031) and cardiovascular diseases (RR=1.02, 95% CI: 1.00–1.05, P=0.039), but decreased incidence of chylous leakage (RR=0.98, 95% CI: 0.96–0.99, P<0.001). In addition, high BMI could significantly improved OS (HR=0.78, 95% CI: 0.71–0.85, P<0.001).

Conclusion:

Preoperative BMI was an independent prognostic factor for survival, and strongly associated with postoperative complications in oesophageal cancer.     

Primary small-cell carcinoma of the oesophagus with spontaneous oesophageal perforation following chemotherapy

The authors describe a 66 year old woman with small-cell carcinoma of the oesophagus who developed a perforation following chemotherapy. Small-cell carcinoma of the oesophagus is a rare neoplasm, varying in appearance from a small mucosal lesion to a larger fungating mass, which in our patient presented as a bulky soft-tissue mass causing stricture. Pleural fluid collections which developed via a spontaneous oesophageal-pleural fistula were subsequently drained using percutaneously placed catheters. Radiologic management of this condition provided a successful and cost-effective means of patient care.     

Correlation of changes between 2-year disease-free survival and 5-year overall survival in adjuvant breast cancer trials from 1966 to 2006.

BACKGROUND: Although disease-free survival (DFS) is accepted as a valid end point in adjuvant breast cancer trials, improvement in 2-year DFS has never been formally established as an adequate correlate for 5-year overall survival (OS). We set out to ascertain if changes in 2-year DFS can be used to accurately predict 5-year OS changes. DESIGN: We conducted a systematic Medline search (1966-2006) for randomized adjuvant breast cancer trials of >100 patients per arm with 2-year DFS and 5-year OS data. A univariate regression model weighted by trial sample size was constructed to determine whether 2-year DFS differences between treatment arms within trials were predictive of 5-year OS differences. RESULTS: A total of 126 studies containing 149 treatment comparisons met the inclusion criteria. Difference in 2-year DFS was a significant predictor of difference in 5-year OS. For every 1% increase in 2-year DFS difference, the 5-year OS difference increased by 0.5%-0.55%. The proportion of variation explained ranged from 0.38 to 0.42, with a wide prediction interval. CONCLUSION: There is a statistically significant correlation, of moderate strength, between difference in 2-year DFS between treatment comparisons and difference in 5-year OS but the correlation is not strong enough to be used as a predictor.     

Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer

The association between cell proliferation and the malignant potential of colon cancer is not well understood. Here, we evaluated this association using a colon-specific gene proliferation signature (GPS). The GPS was derived by combining gene expression data obtained from the analysis of a cancer cell line model and a published colon crypt profile. The GPS was overexpressed in both actively cycling cells in vitro and the proliferate compartment of colon crypts. K-means clustering was used to independantly stratify two cohorts of colon tumours into two groups with high and low GPS expression. Notably, we observed a significant association between reduced GPS expression and an increased likelihood of recurrence (P<0.05), leading to shorter disease-free survival in both cohorts. This finding was not a result of methodological bias as we verified the well-established association between breast cancer malignancy and increased proliferation, by applying our GPS to public breast cancer data. In this study, we show that reduced proliferation is a biological feature characterizing the majority of aggressive colon cancers. This contrasts with many other carcinomas such as breast cancer. Investigating the reasons underlying this unusual observation may provide important insight into the biology of colon cancer progression and putative novel therapy options.     

The contribution of smoking and smokeless tobacco to oesophageal squamous cell carcinoma risk in the African oesophageal cancer corridor: Results from the ESCCAPE multicentre case-control studies

Tobacco use is a well-established risk factor for oesophageal squamous cell carcinoma (ESCC) but the extent of its contribution to the disease burden in the African oesophageal cancer corridor has not been comprehensively elucidated, including by type of tobacco use. We investigated the contribution of tobacco use (smoking and smokeless) to ESCC in Tanzania, Malawi and Kenya. Hospital-based ESCC case-control studies were conducted in the three countries. Incident cases and controls were interviewed using a comprehensive questionnaire which included questions on tobacco smoking and smokeless tobacco use. Logistic regression models were used to estimate odds ratios (OR) and their 95% confidence intervals (CI) of ESCC associated with tobacco, adjusted for age, sex, alcohol use, religion, education and area of residence. One thousand two hundred seventy-nine cases and 1345 controls were recruited between August 5, 2013, and May 24, 2020. Ever-tobacco use was associated with increased ESCC risk in all countries: Tanzania (OR 3.09, 95%CI 1.83-5.23), and in Malawi (OR 2.45, 95%CI 1.80-3.33) and lesser in Kenya (OR 1.37, 95%CI 0.94-2.00). Exclusive smokeless tobacco use was positively associated with ESCC risk, in Tanzania, Malawi and Kenya combined (OR 1.92, 95%CI 1.26-2.92). ESCC risk increased with tobacco smoking intensity and duration of smoking. Tobacco use is an important risk factor of ESCC in Tanzania, Malawi and Kenya. Our study provides evidence that smoking and smokeless tobacco cessation are imperative in reducing ESCC risk.     

Continuing rising trend in oesophageal adenocarcinoma

Our study provides an update of the incidence of oesophageal cancer in the West Midland region of England and Wales from 1992-96. A total of 2,671 cases of oesophageal cancer were identified during the 5-year study period, with an age-standardised annual incidence (ASR) of 5.24 per 100,000 (95% CI: 5.02, 5.45). Similar numbers of adenocarcinoma and squamous cell carcinoma were found. Only 152 (5.6%) had no histology. There was a 5-fold difference in age-standardised annual incidence rates between males and females for adenocarcinoma of oesophagus, but no gender difference for squamous cell carcinoma. The parallel but higher ASR in males compared to females for adenocarcinoma of both oesophagus and cardia merits further investigation. The similarities in the patterns of age- and sex-specific rates and in the socioeconomic profiles could indicate a common aetiology for adenocarcinoma of oesophagus and gastric cardia. Quality control in Cancer Registries needs to focus on the accuracy and consistency of subsite classification to ensure that trends in incidence are identified. In the absence of accurate subsite classification of stomach cancers, the proportions of adenocarcinoma and squamous cell carcinoma of oesophagus (or the absolute rate of adenocarcinoma of oesophagus) may provide a useful tool in indicating whether adenocarcinoma of gastric cardia is likely to be increasing in incidence.     

Dietary intake of flavonoids and oesophageal and gastric cancer: incidence and survival in the United States of America (USA)

Background:

Flavonoids, polyphenolic compounds concentrated in fruits and vegetables, have experimentally demonstrated chemopreventive effects against oesophageal and gastric cancer. Few epidemiologic studies have examined flavonoid intake and incidence of these cancers, and none have considered survival.

Methods:

In this USA multicentre population-based study, case participants (diagnosed during 1993–1995 with oesophageal adenocarcinoma (OEA, n=274), gastric cardia adenocarcinoma (GCA, n=248), oesophageal squamous cell carcinoma (OES, n=191), and other gastric adenocarcinoma (OGA, n=341)) and frequency-matched controls (n=662) were interviewed. Food frequency questionnaire responses were linked with USDA Flavonoid Databases and available literature for six flavonoid classes and lignans. Case participants were followed until 2000 for vital status. Multivariable-adjusted odds ratios (ORs) and hazard ratios (HRs) (95% confidence intervals (CIs)) were estimated, comparing highest with lowest intake quartiles, using polytomous logistic and proportional hazards regressions, respectively.

Results:

Little or no consistent association was found for total flavonoid intake (main population sources: black tea, orange/grapefruit juice, and wine) and incidence or survival for any tumour type. Intake of anthocyanidins, common in wine and fruit juice, was associated with a 57% reduction in the risk of incident OEA (OR=0.43, 95% CI=0.29–0.66) and OES (OR=0.43, 95% CI=0.26–0.70). The ORs for isoflavones, for which coffee was the main source, were increased for all tumours, except OES. Anthocyanidins were associated with decreased risk of mortality for GCA (HR=0.63, 95% CI=0.42–0.95) and modestly for OEA (HR=0.87, 95% CI=0.60–1.26), but CIs were wide.

Conclusions:

Our findings, if confirmed, suggest that increased dietary anthocyanidin intake may reduce incidence and improve survival for these cancers.     

Definitive chemoradiation for oesophageal cancer--a standard of care in patients with non-metastatic oesophageal cancer

Aims

A retrospective analysis was carried out of 291 cases of oesophageal cancer treated with definitive chemoradiotherapy (dCRT) at a single UK cancer centre between 1995 and 2009. Our protocol consisted of two cycles of neoadjuvant platinum-based chemotherapy followed by two further cycles given concurrently with 50 Gy of external beam radiotherapy delivered in 25 fractions over 5 weeks.

Materials and methods

Demographic, patient and outcome data were recorded prospectively through an electronic health record and retrospectively analysed, using appropriate statistical tools.

Results

Data on 266 patients were available for analysis. The median age was 66.6 years, 53% were adenocarcinomas. dCRT was used instead of surgery because of age/co-morbidity in 44% and disease extent in 39%. Ninety-three per cent of patients completed treatment according to protocol. Grade 3 and 4 toxicities were seen in 42 and 7%, respectively. Median survival was 20.6 months; 2, 3 and 5 year survival rates were 43.6, 32.9 and 19.5%, respectively. Advanced disease was associated with a worse outcome. Shorter disease length was associated with a better median survival, but some patients with disease >10 cm had long-term disease control. The effect of other patient- and disease-related factors was also analysed.

Conclusion

We present data showing that dCRT is well tolerated and should be considered as an alternative to surgery for all patients with locally advanced oesophageal cancer, not only those with co-morbidity. Furthermore, the benefits of dCRT are not confined to carcinomas with squamous histology.     

紫杉醇、异环磷酰胺和顺铂新辅助化疗治疗局部晚期宫颈癌的临床疗效

目的:评估新辅助疗法TIP方案对局部晚期宫颈癌患者的有效性和耐受性.方法:回顾性分析89例晚期宫颈癌患者,其中给予TIP方案治疗患者37例,给予PVB方案治疗患者52例,化疗3周期,4周内行广泛性子宫切除术和盆腔淋巴结清扫术,统计学分析两组治疗方案疗效和不良反应的差异.结果:TIP组和PVB组在近期疗效上差异无统计学意义(P>0.05);TIP组5年总生存率(OS)和无进展生存率(PFS)显著性高于PVB组(86.4% vs 69.2%,X2=12.09,P=0.008;72.9% vs 57.6%,X2=8.15,P=0.020);TIP组在白细胞减少、中性粒细胞减少、血小板减少和贫血方面明显高于PVB组,差异有统计学意义(P<0.05).结论:在治疗局部晚期宫颈癌患者时新辅助疗法TIP方案具有可行性和有效性,同时也应谨慎预防血液学毒性.     

Brachytherapy in oesophageal carcinoma

Patients with recurrent or locally advanced oesophageal carcinoma have a poor prognosis. Relief of dysphagia is often the goal of any further treatment. Several methods, including laser re-canalization, prosthetic intubation, dilatation, external beam irradiation (EBI) and intraluminal brachytherapy (IBT) can be used to alleviate dysphagia. In this retrospective review of 11 patients, eight with recurrent tumour and three newly diagnosed patients were treated with low dose rate IBT. Relief of dysphagia was achieved in nine patients, all of whom were able to maintain swallowing of at least a semi-solid diet until death or last follow-up. Toxicity was minimal, but survival was poor, with a median survival of only 3 months. IBT presents several advantages over other palliative methods, especially in recurrent tumours where re-treatment with EBI is often difficult because of normal tissue tolerance. Low dose rate IBT takes only 1–2 days to deliver, is highly effective, has little morbidity and the palliation achieved is relatively durable.     

Long-term survival of young women receiving fertility-sparing surgery for ovarian cancer in comparison with those undergoing radical surgery

Objectives:

To compare the clinical outcome of patients with stage I epithelial ovarian cancer (EOC) who received with fertility-sparing surgery (FSS) with those who underwent radical surgery (RS).

Methods:

After a central pathological review and search of the medical records from multiple institutions, a total of 572 patients were retrospectively evaluated. All patients were divided into three groups: group A {FSS (n=74); age, ⩽40} groups B and C [RS; age, 40⩾{(B), n=52} 40<{(C), n=446}].

Results:

Five-year overall survival (OS) and disease-free survival (DFS) rates of patients in the groups were as follows: group A, 90.8% (OS)/87.9% (DFS); group B, 88.3% (OS)/84.4% (DFS); group C, 90.6% (OS)/85.3% (DFS), respectively (OS, P=0.802; DFS, P=0.765). Additionally, there was no significant difference in OS and DFS among the three groups stratified to stage IA or IC (OS (IA), P=0.387; DFS (IA), P=0.314; OS (IC), P=0.993; DFS (IC), P=0.990, respectively). Furthermore, patients with a grade 1–2 or 3 tumours in the FSS group did not have a poorer prognosis than those in the RS group.

Conclusions:

Stage I EOC patients treated with FSS showed an acceptable prognosis compared with those who underwent RS.     

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m(-2) and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3-4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.     

Downregulation of HLA Class I molecules in the tumour is associated with a poor prognosis in patients with oesophageal squamous cell carcinoma

As antigenic peptides in the context of human leukocyte antigen (HLA) class I molecules are recognised by cytotoxic T lymphocytes (CTL), the downregulation of HLA class I molecules is one of the reasons why tumour cells can evade CTL-mediated anti-tumour immunity. In this study, we investigated HLA class I expression in oesophageal squamous cell carcinoma (ESCC) (n=70) and in their metastatic lesions (lymph nodes (n=40) and liver (n=3)), by immunohistochemistry with anti-HLA class I monoclonal antibody (EMR8-5). As a result, the downregulation of HLA class I expression in primary lesions of ESCC was observed in 43%, and that in metastatic lymph nodes was noted in 90%. Furthermore, patients with preserved HLA class I expression in primary tumours showed a better survival in comparison to those with downregulated HLA class I molecules (P<0.01). Furthermore, multivariate analysis using Cox's proportional hazards model revealed that the downregulated expression of HLA class I in primary lesions was an independent, unfavourable prognostic factor (P<0.01). In conclusion, the downregulation of HLA class I expression frequently occurred in primary tumour and, to a greater extent, in metastatic lesions of patients with ESCC and was associated with patient survival.