The presence of circulating total DNA and methylated genes is associated with circulating tumour cells in blood from breast cancer patients

Circulating tumour cells (CTC) and tumour-related methylated DNA in blood have been separately assessed for their utility as a marker for subclinical metastasis in breast cancer. However, no studies have looked into the relation between the both molecular markers in this type of cancer. In this study, we investigated the correlations between total/methylated DNA and CTC in the blood from metastatic breast cancer patients. We simultaneously obtained whole blood, plasma and serum samples from 80 patients and 20 controls. The CellSearch System was used to enumerate CTC in blood samples. Plasma total DNA levels were determined by a QPCR method. Sera were analysed by methylation-specific QPCR for three markers: adenomatous polyposis coli (APC), ras association domain family protein 1A (RASSF1A) and oestrogen receptor 1 (ESR1). Total DNA levels in patients were significantly increased when compared with controls (P<0.001) and correlated with the number of CTC (r=0.418, P<0.001). Hypermethylation of one or more genes was detected in 42 (53%) serum samples from breast cancer patients and in three (16%) serum samples from controls (P=0.003). APC was hypermethylated in 29%, RASSF1A in 35% and ESR1 in 20% of breast cancer cases. Detection of a methylated gene in serum was associated with the detection of CTC in blood (P=0.03). The detection of large amounts of circulating total/methylated DNA correlated with the presence of CTC in the blood from patients with breast cancer. This can be interpreted in two ways: (a) CTC are a potential source of circulating tumour-specific DNA; (b) high numbers of CTC and circulating methylated DNA are both a phenotypic feature of more aggressive tumour biology.     

Clinical utility of RASSF1A methylation in human malignancies

The high frequency of RASSF1A methylation has been noted in a vast number of patients in a broad spectrum of malignancies, suggesting that RASSF1A inactivation is associated with cancer pathogenesis. However, whether this recurrent incidence of RASSF1A hypermethylation in human malignancies and its association with more aggressive tumour phenotype is a frequent event across different cancer types has not yet been discussed. In this review, we interrogated existing evidence for association of RASSF1A hypermethylation with clinicopathological characteristics that can indicate more invasive lesions.     

Ras association domain family 1A: a promising prognostic marker in recurrent nonmuscle invasive bladder cancer

IntroductionAberrant methylation of promoter CpG islands is an important inactivation mechanism of tumor suppressors and tumor-related genes. Ras association domain family 1A (RASSF1A) promoter hypermethylation was shown to be associated with bladder cancer (BC), but its prognostic value remains unclear. The aim of the present study was to investigate the value of RASSF1A methylation as a prognostic marker in BC.Materials and MethodsPrimary BC tissues were obtained from 301 patients and included 186 specimens of nonmuscle invasive bladder cancer (NMIBC) and 115 specimens of muscle invasive bladder cancers (MIBC). RASSF1A hypermethylation was assessed using methylation-specific polymerase chain reaction (MS-PCR). The association between RASSF1A hypermethylation and clinicopathologic features, and the prognostic significance of RASSF1A hypermethylation were evaluated by Kaplan-Meier and multivariate Cox regression analyses.ResultsRASSF1A promoter hypermethylation was detected in 33.6% of BCs and occurred more frequently in MIBC (46.1%) than in NMIBC (25.8%) (P < .001). In NMIBC, RASSF1A methylation was associated with advanced tumor stage (P = .026) and high grade (P < .001). Among patients with recurrent NMIBC, RASSF1A methylation was associated with shorter time to progression by Kaplan-Meier analysis (log-rank test; P = .004) and identified as an independent predictor of cancer progression by multivariate Cox regression analysis (hazard ratio [HR], 8.559; P = .014).ConclusionsOur results suggest that methylated RASSF1A may be a potential prognostic marker in patients with recurrent NMIBC.     

Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis

Background

Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive disease with no evidence of effect from adjuvant therapy. It is further associated with the hereditary syndrome neurofibromatosis type 1 (NF1). Silencing of the tumor suppressor gene RASSF1A through DNA promoter hypermethylation is known to be involved in cancer development, but its impact in MPNSTs remains unsettled.

Methods

The RASSF1A promoter was analyzed by methylation-specific PCR in 113 specimens, including 44 NF1-associated MPNSTs, 47 sporadic MPNSTs, 21 benign neurofibromas, and 1 nonneoplastic nerve sheath control.

Results

RASSF1A methylation was found only in the malignant samples (60%) and identified a subgroup among patients with NF1-associated MPNST with a poor prognosis. These patients had a mean 5-year disease-specific survival of 27.3 months (95% CI: 17.2–37.4) versus 47.4 months (95% CI: 37.5–57.2) for NF1 patients with unmethylated promoters, P = 0.014. In multivariate Cox regression analysis, methylated RASSF1A remained an adverse prognostic factor independent of clinical risk factors, P = .013 (hazard ratio: 5.2; 95% CI: 1.4–19.4).

Conclusion

A considerable number of MPNST samples display hypermethylation of the RASSF1A gene promoter, and for these tumors, this is the first molecular marker that if validated can characterize a subgroup of patients with inferior prognosis, restricted to individuals with NF1.     

Hypoxia-inducible factor-1�� and -2�� are expressed in most rectal cancers but only hypoxia-inducible factor-1�� is associated with prognosis

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1α and HIF-2α expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1α and HIF-2α, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1α and -2α were expressed in >50% of rectal cancers (HIF-1α, 54%, 48/90; HIF-2α, 64%, 58/90). HIF-1α positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2α expression and any pathological features, and HIF-1α positivity had no effect on outcome. The study showed an independent association between HIF-1α expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1α, but not HIF-2α, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management.     

Molecular heterogeneity and prognostic implications of synchronous advanced colorectal neoplasia

Background:

It is uncertain whether synchronous colorectal cancers (S-CRCs) preferentially develop through widespread DNA methylation and whether they have a prognosis worse than solitary CRC. As tumours with microsatellite instability (MSI) may confound the effect of S-CRC methylation on outcome, we addressed this issue in a series of CRC characterised by BRAF and MS status.

Methods:

Demographics, clinicopathological records and disease-specific survival (DSS) were assessed in 881 consecutively resected CRC undergoing complete colonoscopy. All tumours were typed for BRAF^c.1799T>A mutation and MS status, followed by search of germ-line mutation in patients with MSI CRC.

Results:

Synchronous colorectal cancers (50/881, 5.7%) were associated with stage IV microsatellite-stable (MSS) CRC (19/205, 9.3%, P=0.001) and with HNPCC (9/32, 28%, P<0.001). BRAF mutation (60/881, 6.8%) was associated with sporadic MSI CRC (37/62, 60%, P<0.001) but not with S-CRC (3/50, 6.0%, P=0.96). Synchronous colorectal cancer (HR 1.82; 95% CI 1.15–2.87; P=0.01), synchronous advanced adenoma (HR 1.81; 95% CI 1.27–2.58; P=0.001), and BRAF^c.1799T>A mutation (HR 2.16; 95% CI 1.25–3.73; P=0.01) were stage-independent predictors of death from MSS CRC. Disease-specific survival of MSI CRC patients was not affected by S-CRC (HR 0.74; 95% CI 0.09–5.75; P=0.77).

Conclusion:

Microsatellite-stable CRCs have a worse prognosis if S-CRC or synchronous advanced adenoma are diagnosed. The occurrence and the enhanced aggressiveness of synchronous MSS advanced neoplasia are not associated with BRAF mutation.     

The key hypoxia regulated gene CAIX is upregulated in basal-like breast tumours and is associated with resistance to chemotherapy

Basal-like tumours account for 15% of invasive breast carcinomas and are associated with a poorer prognosis and resistance to therapy. We hypothesised that this aggressive phenotype is because of an intrinsically elevated hypoxic response. Microarrayed tumours from 188 patients were stained for hypoxia-inducible factor (HIF)-1α, prolyl hydroxylase (PHD)1, PHD2, PHD3 and factor inhibiting HIF (FIH)-1, and carbonic anhydrase (CA) IX stained in 456 breast tumours. Tumour subtypes were correlated with standard clincopathological parameters as well as hypoxic markers. Out of 456 tumours 62 (14%) tumours were basal-like. These tumours were positively correlated with high tumour grade (P<0.001) and were associated with a significantly worse disease-free survival compared with luminal tumours (P<0.001). Fifty percent of basal-like tumours expressed HIF-1α, and more than half expressed at least one of the PHD enzymes and FIH-1. Basal-like tumours were nine times more likely to be associated with CAIX expression (P<0.001) in a multivariate analysis. Carbonic anhydrase IX expression was positively correlated with tumour size (P=0.005), tumour grade (P<0.001) and oestrogen receptor (ER) negativity (P<0.001). Patients with any CAIX-positive breast tumour phenotype and in the basal tumour group had a significantly worse prognosis than CAIX-negative tumours when treated with chemotherapy (P<0.001 and P=0.03, respectively). The association between basal phenotype and CAIX suggests that the more aggressive behaviour of these tumours is partly due to an enhanced hypoxic response. Further, the association with chemoresistance in CAIX-positive breast tumours and basal-like tumours in particular raises the possibility that targeted therapy against HIF pathway or downstream genes such as CAs may be an approach to investigate for these patients.     

Frequent hypermethylation of RASSF1A tumour suppressor gene promoter and presence of Merkel cell polyomavirus in small cell lung cancer

In small cell lung cancer (SCLC), hypermethylation of the tumour suppressor Ras association domain family 1A (RASSF1A) is frequent. It is associated with SV40 polyomaviral infection in other tumours. Merkel cell polyomavirus (MCPyV) infection has been reported in Merkel cell carcinoma (MCC), a neuroendocrine carcinoma with biological similarity to SCLC. In our study, we investigated polyomavirus infection (SV40 and MCPyV) and promoter hypermethylation of the tumour suppressors RASSF1A and p16 in 18 SCLCs (14 primaries and 4 regional lymph node metastases) and 18 blood control samples. MCPyV was found in 39% (7 of 18) of the tumour tissues but not observed in controls. SV40 was not observed in the tumour tissue. RASSF1A promoter hypermethylation (94%; 17 of 18) was more frequent compared to p16 methylation (56%, 10 of 18). We found no significant correlation between RASSF1A or p16 promoter hypermethylation and infection with the investigated polyoma viruses. Our results show a high frequency of hypermethylation of the RASSF1A promoter and occurrence of MCPyV infection in the tumour tissue of SCLC. These events may contribute to the pathogenesis of SCLC.     

Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer

Background:

We explored the predictive significance of BRCA1, TXR1 and TSP1 expression in non-small-cell lung cancer (NSCLC) patients treated with docetaxel in association with cisplatin or gemcitabine.

Methods:

To analyse BRCA1, TXR1 and TSP1 mRNA expression from microdissected primary tumours of 131 patients with stage IIIB (wet) and IV NSCLC, RT–qPCR was used.

Results:

The mRNA levels of TXR1/TSP1 were inversely correlated (Spearman''s test: −0.37; P=0.001). Low TXR1 mRNA levels were associated with higher response rate (RR; P=0.018), longer median progression-free survival (PFS; P=0.029) and median overall survival (mOS P=0.003), whereas high TSP1 expression was correlated with higher RR (P=0.035), longer PFS (P<0.001) and mOS (P<0.001). Higher BRCA1 mRNA expression was associated with higher RR (P=0.028) and increased PFS (P=0.021), but not mOS (P=0.4). Multivariate analysis demonstrated that low TXR1/high TSP1 expression was an independent factor for increased PFS (HR 0.49; 95% CI 0.32–0.76; P<0.001) and mOS (HR 0.37; 95% CI 0.2–0.58; P<0.001), whereas high BRCA1 expression was correlated with increased PFS (HR 0.53; 95% CI 0.37–0.78; P=0.001).

Conclusions:

These data indicate that TXR1/TSP1 and BRCA1 expression could be used for the prediction of taxanes'' resistance in the treatment of NSCLC.     

Elevated preoperative CEA is associated with worse survival in stage I-III rectal cancer patients

Background:

The objective of this investigation was to assess whether preoperative carcinoembryonic antigen (CEA) level is an independent predictor of overall survival in rectal cancer patients.

Methods:

All patients (n=504) undergoing a resection for stage I–III rectal cancer at the Kantonsspital St Gallen were included into a database between 1991 and 2008. The impact of preoperative CEA level on overall survival was assessed using risk-adjusted Cox proportional hazard regression models and propensity score methods.

Results:

In risk-adjusted Cox proportional hazard regression analyses, preoperative CEA level (hazard ratio (HR): 1.98, 95% confidence interval (CI): 1.36–2.90, P<0.001), distance from anal verge (<5 cm: HR: 1.93, 95% CI: 1.11–3.37; P=0.039), older age (HR: 1.07, 95% CI: 1.05–1.09; P<0.001), lower body mass index (HR: 0.94, 95% CI: 0.89–0.98; P=0.006), advanced tumour stage (stage II HR: 1.41, 95% CI: 0.85–2.32; stage III HR: 2.08, 95% CI: 1.31–3.31; P=0.004), R 1 resection (HR: 5.65, 95% CI: 1.59–20.1; P=0.005) and chronic kidney disease (HR: 2.28, 95% CI: 1.03–5.04; P=0.049) were all predictors for poor overall survival.

Conclusion:

This is one of the first investigations based on a large cohort of exclusively rectal cancer patients demonstrating that preoperative CEA level is a strong predictor of decreased overall survival. Preoperative CEA should be used as a prognostic factor in the preoperative assessment of rectal cancer patients.     

KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer

This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II (P<0.001), and p-ERK1/2 (P<0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P=0.2460, P=0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. Cl-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.     

Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m⁻² at week 1 and 250 mg m⁻² weekly thereafter until disease progression. Oxaliplatin (100 mg m⁻²) and leucovorin (100 mg m⁻²) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m⁻²) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1–65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5–6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-α levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.     

Survival from childhood cancer in northern England, 1968-2005

Background:

Cancer is the second most common cause of death in children in the developed world. The study investigated patterns and trends in survival from childhood cancer in patients from northern England diagnosed 1968–2005.

Methods:

Five-year survival was analysed using Kaplan–Meier estimation for four successive time periods. Cox regression analysis was used to explore associations with age and demographic factors.

Results:

The study included 2958 cases (1659 males and 1299 females). Five-year survival for all cancers improved significantly from 39% in 1968–1977 to 79% in 1998–2005 (P<0.001). Five-year survival for leukaemia increased from 24% to 81% (P<0.001), lymphoma from 46% to 87% (P<0.001), central nervous system tumours from 43% to 73% (P<0.001), bone tumours from 21% to 75% (P<0.001), soft tissue sarcoma from 30% to 58% (P<0.001) and germ cell tumours from 59% to 97% (P<0.001). Survival was worse for cases of acute lymphoblastic leukaemia (P<0.001) and astrocytoma (P<0.001) aged 10–14 years compared with 0–4-year olds.

Conclusion:

There were marked improvements in survival over a 38-year time span. Future work should examine factors that could influence further improvement in survival such as diagnosis delays.     

Breast-conserving surgery with or without radiotherapy vs mastectomy for ductal carcinoma in situ: French Survey experience

From March 2003 to April 2004, 77 physicians throughout France prospectively recruited 1289 ductal carcinoma in situ (DCIS) patients and collected data on diagnosis, patient and tumour characteristics, and treatments. Median age was 56 years (range, 30–84). Ductal carcinoma in situ was diagnosed by mammography in 87.6% of patients. Mastectomy, conservative surgery alone (CS) and CS with radiotherapy (CS+RT) were performed in 30.5, 7.8 and 61.7% of patients, respectively. Thus, 89% of patients treated by CS received adjuvant RT. Sentinel node biopsy (SNB) and axillary dissection (AD) were performed in 21.3 and 10.4% of patients, respectively. Hormone therapy was administered to 13.4% of the patients (80% tamoxifen). Median tumour size was 14.5 mm (6, 11 and 35 mm for CS, CS+RT and mastectomy, respectively, P<0.0001). Nuclear grade was high in 21% of patients, intermediate in 38.5% and low in 40.5%. Excision was considered complete in 92% (CS) and 88.3% (CS+RT) of patients. Oestrogen receptors were positive in 69.8% of assessed cases (31%). Treatment modalities varied widely according to region: mastectomy rate, 20–37%; adjuvant RT, 84–96%; hormone treatment, 6–34%. Our survey on current DCIS management in France has highlighted correlations between pathological features (tumour size, margin and grade) and treatment options, with several similar variations to those observed in recent UK and US studies.     

The impact of young age on cancer-specific and non-cancer-related survival after surgery for colorectal cancer: 10-year follow-up

Background:

It has been reported that although young patients present with more advanced disease, when adjusted for stage, cancer-specific survival is not different after surgery for colorectal cancer. However, few studies have examined non-cancer survival in young patients and 10-year survival has rarely been reported. Moreover, the largest study included patients of old age as a comparator. The aim of this study was to compare cancer-specific and non-cancer-related survival at 10 years in a young age cohort and a middle age cohort in patients undergoing surgery for colorectal cancer.

Methods:

Two thousand and seventy seven patients who underwent surgery for colorectal cancer between 1991 and 1994 in 11 hospitals in Scotland were included in the study. Ten-year cancer-specific and non-cancer-related survival and the hazard ratios (HR) were calculated according to age groups (<45/45–54/55–64/65–74 years).

Results:

On follow-up, 1066 patients died of their cancer and 369 died of non-cancer-related causes. At 10 years, overall survival was 32%, cancer-specific was 45%, and non-cancer-related survival was 72%. On multivariate analysis of all factors, sex (HR 0.77, 95% CI 0.68–0.88, P<0.001), mode of presentation (HR 1.64, 95% CI 1.44–1.87, P<0.01), Dukes'' stage (HR 2.69, 95% CI 2.49–2.90, P<0.001), and specialisation (HR 1.24, 95% CI 1.04–1.44, P<0.01) were independently associated with cancer-specific survival. On multivariate analysis of all factors, age (HR 2.46, 2.04–2.97, P<0.001), sex (HR 0.56, 0.45–0.70, P<0.001), and deprivation (HR 1.16, 1.10–1.24, P<0.001) were independently associated with non-cancer-related survival.

Conclusion:

The results of this study confirm that young age does not have a negative impact on cancer-specific survival. Moreover, they show that, with 10-year follow-up, young age does not have a negative impact on non-cancer-related survival.     

Role of histological type on surgical outcome and survival following radical primary tumour debulking of epithelial ovarian, fallopian tube and peritoneal cancers

Background:

To assess the clinical impact of the two histological types as designated in the proposed model for ovarian tumourigenesis in primary epithelial ovarian, fallopian tube or peritoneal cancer (EOC) patients.

Methods:

All consecutive EOC patients (n=632) after primary tumour debulking in our institution (09/2000–08/2010) were classified into one of two groups: type I tumours (n=100; 15.8%) composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional carcinomas; and Type II tumours (n=532; 84.1%) composed of high-grade serous, high-grade endometrioid, undifferentiated and malignant mixed-mesodermal tumours. Kaplan–Meier and logistic/Cox-regression analyses were performed to assess the impact of histological type on surgical outcome and survival.

Results:

Type II patients had a significantly higher incidence of advanced disease (FIGO III/IV) than Type I patients (79.8% vs 38%, respectively; P<0.001). Median CA125 values (438 vs 93 U ml⁻¹; P=0.001); operative time (258 vs 237 min; P=0.001); and incidence of incomplete tumour resection (34.4% vs 15% P<0.001) were significantly higher in patients with Type II. During a mean follow-up time of 23 months (range: 1–106), 17% of patients with type I vs 34.8% of patients with type II tumours relapsed and/or died (P<0.001). Overall survival (P=0.021) and progression-free survival (P=0.003) were also significantly higher in patients with type I tumours. Multivariate analysis, while identifying postoperative tumour residuals, positive lymph nodes and extrapelvic dissemination as independent predictors of survival, failed to demonstrate any prognostic significance of histological type.

Conclusion:

Type I EOC patients appear to present at earlier stages have significantly higher survival and more optimal surgical outcome compared with type II patients. However, in advanced stages, histology loses significance as an independent prognosticator.     

The relationship between tumour necrosis, tumour proliferation, local and systemic inflammation, microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma

Background:

There is increasing evidence that the local and systemic inflammatory responses are associated with survival in oesophageal cancer. The aim of this study was to examine the relationship between tumour necrosis, tumour proliferation, local and systemic inflammation and microvessel density and survival in patients undergoing potentially curative resection of oesophageal adenocarcinoma.

Methods:

The interrelationship between tumour necrosis, tumour proliferation, local inflammatory response (Klintrup–Makinen criteria, intra-tumoural CD8+ lymphocyte and macrophage infiltration), systemic inflammatory response (modified Glasgow Prognostic score (mGPS)), and microvessel density was examined in 121 patients undergoing potentially curative resection for oesophageal adenocarcinoma (including type I and II tumours of the gastro-oesophageal junction).

Results:

Tumour necrosis was not significantly associated with any tumour measure other than the degree of differentiation. On multivariate analysis, only age (HR 1.93, 95% CI 1.23–3.04, P=0.004), mGPS (HR 2.91, 95% CI 1.51–5.62, P=0.001), positive to total lymph node ratio (HR 2.38, 95% CI 1.60–3.52, P<0.001) and macrophage infiltration (HR 1.49, 95% CI 1.02–2.18, P=0.041) were independently associated with cancer-specific survival in oesophageal adenocarcinoma. Intra-tumoural macrophages were associated with tumour proliferation (P<0.001) and CD8+ lymphocytes infiltration (P<0.01).

Conclusion:

The results of this study suggest that tumour necrosis does not link local and systemic inflammatory responses and is not significantly associated with survival. In contrast, tumour macrophage infiltration appears to have a central role in the proliferative activity and the coordination of the inflammatory cell infiltrate and is independently associated with poorer survival in patients with oesophageal adenocarcinoma.