BRCA1 promoter methylation is a marker of better response to platinum–taxane-based therapy in sporadic epithelial ovarian cancer

Background

The aim of the current study was to investigate the role of BRCA1 promoter methylation as predictive factor of response to platinum–taxane-based therapy in sporadic ovarian cancer.

Patients and methods

BRCA1 promoter methylation was analyzed in 42 sporadic epithelial ovarian cancers. The results were validated in a second cohort of 137 ovarian cancer patients.

Results

BRCA1 promoter methylation was observed in 35.7 % of patients in the first group and in 33.6 % in the second group. BRCA1 promoter methylation was associated with significant increase in median progression-free survival (PFS) of ovarian cancer patients receiving adjuvant platinum–taxane-based chemotherapy (P = 0.008). Multivariate analysis revealed that BRCA1 promoter methylation remains a favorable factor in regard to PFS (HR 0.52; 95 % CI 0.32–0.85, P = 0.009) after adjustment for other prognostic factors. Under the patients with recurrent disease, BRCA1 promoter methylation was associated with significant longer median PFS of 18.5 months in comparison with 12.8 months PFS for patients without BRCA1 promoter methylation.

Conclusions

BRCA1 promoter methylation is predictive for better response to platinum–taxane-based therapy in EOC.     

TFAP2E hypermethylation was associated with survival advantage in patients with colorectal cancer

Purpose

Hypermethylation of TFAP2E (AP-2E) is associated with the chemotherapy-resistant in patients with colorectal cancer (CRC), but its implications on prognosis directly remain unknown. This study was aimed to investigate the role of AP-2E methylation status and other clinicopathologic parameters as predictors of prognosis.

Methods

We detected the methylation status of AP-2E in tumor and adjacent non-tumor tissues from 311 sporadic CRC patients by methylation-sensitive high-resolution melting analysis. Log-rank tests and multivariate Cox analyses were performed to evaluate the role of AP-2E methylation status and other clinicopathologic parameters as predictors of prognosis.

Results

Hypermethylation of AP-2E was detected in 61 % (190/311) tumor tissues. It occurred more frequently in tumors in earlier stages (I/II; P = 0.02), lower levels of tumor invasion (T1–T3; P = 0.04), fewer lymph nodes involved (N0; P < 0.01), and higher histologic grades (G1/G2; P < 0.01). The overall 5-year survival rates in hypermethylation and hypomethylation group were 76.91 and 47.17 % (P < 0.0001), respectively. AP-2E hypermethylation was significantly associated with a favorable clinical outcome with a hazard ratio of 0.486 (95 % CI 0.342–0.692, P < 0.0001) after controlling for age, gender, tumor location, histologic type, TNM staging, and histologic grade.

Conclusions

AP-2E was frequently hypermethylated in tumors from patients with CRC. Aberrant hypermethylation of AP-2E occurred more frequently in tumors with earlier stages, lower levels of tumor invasion, fewer lymph nodes involved, and higher histologic grades. AP-2E hypermethylation might be an independent predictor of survival advantage in patients with CRC.     

DNA Methylation in the Rectal Mucosa Is Associated with Crypt Proliferation and Fecal Short-Chain Fatty Acids

Background

DNA methylation varies throughout the normal colorectal mucosa and DNA methylation in normal appearing mucosa is associated with serrated and adenomatous neoplasia elsewhere within the colorectum.

Aims

The purpose of this study was to measure luminal chemistry, rectal proliferation and mucosal DNA methylation and thus determine whether regional and pathological patterns of DNA methylation could be explained by luminal and epithelial factors.

Methods

Twenty healthy subjects had normal rectal mucosal biopsies and a 24-h fecal collection. Rectal biopsies were analyzed for epithelial proliferation (Ki67 immunohistochemistry) and DNA methylation at 17 different markers, including ??type A?? markers (ESR1, GATA5, HIC1, HPP1, SFRP1), ??type C?? markers (MGMT, MLH1, CDKN2A, MINT1, MINT2, MINT31, IGF2, CACNA1G, NEUROG1, SOCS1, RUNX3), and LINE-1. Fecal analysis included short-chain fatty acids (SCFA), pH and ammonia. Mean ??type A?? and CIMP panel methylation Z-scores were calculated.

Results

Rectal proliferation was significantly correlated with methylation at ESR1 (?? = 0.81, P = 0.003) and GATA5 (?? = 0.78, P = 0.012). LINE-1 methylation was 71.7 vs. 74.1%, in patients with ??low?? and ??high?? fecal total SCFA concentration (defined by the median value), respectively (P = 0.0019). On multivariate linear regression ??type A?? methylation was independently associated with rectal proliferation (P = 0.001). LINE-1 methylation was directly associated with rectal proliferation (P = 0.038) and total fecal SCFA concentration (P = 0.002), and inversely associated with fecal NH₃ concentrations (P = 0.003).

Conclusions

DNA methylation in normal rectal mucosa is associated with crypt proliferation and fecal SCFA concentration. These associations may help to explain regional differences in DNA methylation as well as providing a possible link between the colorectal lumen and carcinogenesis.     

Methylation of PITX2, HOXD3, RASSF1 and TDRD1 predicts biochemical recurrence in high-risk prostate cancer

Purpose

To explore differential methylation of HAAO, HOXD3, LGALS3, PITX2, RASSF1 and TDRD1 as a molecular tool to predict biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa).

Methods

A multiplexed nested methylation-specific PCR was applied to quantify promoter methylation of the selected markers in five cell lines, 42 benign prostatic hyperplasia (BPH) and 71 high-risk PCa tumor samples. Uni- and multivariate Cox regression models were used to assess the importance of the methylation level in predicting BCR.

Results

A PCa-specific methylation marker HAAO in combination with HOXD3 and a hypomethylation marker TDRD1 distinguished PCa samples (>90 % of tumor cells each) from BPH with a sensitivity of 0.99 and a specificity of 0.95. High methylation of PITX2, HOXD3 and RASSF1, as well as low methylation of TDRD1, appeared to be significantly associated with a higher risk for BCR (HR 3.96, 3.44, 2.80 and 2.85, correspondingly) after correcting for established risk factors. When DNA methylation was treated as a continuous variable, a two-gene model PITX2 × 0.020677 + HOXD3 × 0.0043132 proved to be the best predictor of BCR (HR 4.85) compared with the individual markers. This finding was confirmed in an independent set of 52 high-risk PCa tumor samples (HR 11.89).

Conclusions

Differential promoter methylation of HOXD3, PITX2, RASSF1 and TDRD1 emerges as an independent predictor of BCR in high-risk PCa patients. A two-gene continuous DNA methylation model “PITX2 × 0.020677 + HOXD3 × 0.0043132” is a better predictor of BCR compared with individual markers.     

BCL-2, topoisomerase IIα, microvessel density and prognosis of early advanced breast cancer patients after adjuvant anthracycline-based chemotherapy

Purpose

The aim of this retrospective study was to investigate the effect of B cell lymphoma 2 (BCL-2) expression on disease-free survival (DFS) in 172 early breast cancer (BC) patients treated with anthracycline-based adjuvant chemotherapy. We have reanalysed follow-up data in these patient groups, and therefore, the relation between DFS and other tumour biological features [expression of oestrogen (ER) and progesterone (PgR) receptors, cytokeratin 5/6 (CK5/6), HER2, topoisomerase IIα (TOPOIIα), Ki-67, P53 and microvessel density (MVD)] studied previously (Biesaga et al. in Breast 20(4):338–350, 2011, doi:10.1016/j.breast.2011.03.002, Pathol Oncol Res 18(4): 949–960, 2012, doi:10.1007/s12253-012-9525-9) was also investigated.

Method

Tumour biological features were assessed immunohistochemically on paraffin-embedded sections obtained before treatment from 172 women with BC in stage T1–T2, N1–N2, M0.

Results

In univariate analysis, longer DFS was found for patients having tumours with BCL-2 positivity (P = 0.005), low grade (P = 0.001), ER (P = 0.017) and PgR (P = 0.045) positivity, CK5/6 negativity (P = 0.021), low TOPOIIα expression (P = 0.003) and high MVD (P = 0.000). In multivariate analysis, BCL-2, TOPOIIα and MVD were independent parameters indicating patient prognosis. All patients (n = 18) characterized by tumour BCL-2 positivity, low TOPOIIα expression and high MVD survived 80 months without any evidence of cancer disease, whereas DFS for all other patients was significantly (P = 0.022) lower (76.5 %).

Conclusion

Combination of three parameters: BCL-2 positivity, low topoisomerase IIα expression and high MVD, allows to identify subgroup of BC patients with very good prognosis after adjuvant anthracycline-based chemotherapy.     

Improved oncologic outcomes with image-guided intensity-modulated radiation therapy using helical tomotherapy in locally advanced hepatocellular carcinoma

Aim

To investigate whether image-guided intensity-modulated radiation therapy (IG-IMRT) improves survival in hepatocellular carcinoma (HCC) relative to 3-dimensional conformal radiotherapy (3D-CRT).

Methods

Between 2006 and 2011, 187 HCC patients treated with definitive RT were reviewed. Median age was 53(range 51–83). All patients were stage III or IV-A. Concurrent chemoradiation was received by 178 patients (95.2 %). Overall actuarial survival (OS), progression-free survival (PFS), and infield-failure-free survival (IFFS) analyses were performed by Kaplan–Meier method. A Cox proportional hazards model was used for univariate and multivariate analysis. Pearson’s chi-square test or Fisher’s exact test was used to compare patient characteristics and treatment-related toxicity between the groups.

Results

Sixty-five patients were treated with IG-IMRT and 122 patients with 3D-CRT. No significant differences were seen between the groups for all patient characteristics. IG-IMRT delivered higher doses than 3D-CRT (median biological effective dose 62.5 vs 53.1 Gy, P < 0.001). IG-IMRT showed significantly higher 3-year OS (33.4 vs 13.5 %, P < 0.001), PFS (11.1 vs 6.0 %, P = 0.004), and IFFS (46.8 vs 28.2 %, P = 0.007) than 3D-CRT. On univariate and multivariate analysis, RT modality was significant prognostic factor for OS (HR 2.18; 95 % CI 1.45–3.25; P < 0.001), PFS (HR 1.64; 95 % CI 1.17–2.29; P = 0.004). There was no significant difference between the two modalities for radiation-induced liver disease (P = 0.716).

Conclusion

Our findings suggest that IG-IMRT could be an effective treatment that provides survival benefit without increasing severe toxicity in locally advanced HCC.     

Esophageal Intraepithelial Eosinophils in Dysphagic Patients with Gastroesophageal Reflux Disease

Background

Patients with gastroesophageal reflux disease (GERD) often complain of dysphagia and are frequently found to have intraepithelial eosinophils on esophageal biopsy.

Aim

The aim of this study was to investigate the relationship between dysphagia and the number of intraepithelial eosinophils in patients with GERD.

Methods

Review of all patients studied in our esophageal function laboratory from 1999 to 2007 identified 1,533 patients with increased esophageal acid exposure. Patients who complained of dysphagia without mechanical or motor causes were identified and divided into three groups based on whether dysphagia was their primary, secondary or tertiary symptom. A control group consisted of randomly selected GERD patients with no dysphagia. The highest number of intraepithelial eosinophils per high-power field (HPF) in biopsies from the squamocolumnar junction (SCJ) and esophageal body was compared across groups.

Results

There were 71 patients with unexplained dysphagia. Dysphagia was the primary symptom in 13 (18%), secondary symptom in 34 (48%), and tertiary symptom in 24 (34%) patients. The number of eosinophils differed between the four groups, with the highest number in those with dysphagia as the primary symptom (P = 0.0007). This relationship persisted whether biopsies were from the SCJ (P = 0.0057) or esophageal body (P = 0.0096).

Conclusion

An association exists between the number of intraepithelial eosinophils and dysphagia in GERD patients, with the highest number of eosinophils in those with the primary symptom of dysphagia.     

GH secretion reserve in subclinical hypercortisolism

Purpose

In overt hypercortisolism, growth hormone (GH) secretion is decreased and normalizes after surgery. In subclinical hypercortisolism (SH), GH secretion has been scarcely investigated. We assessed GH reserve in patients with and without SH and, in the former, also after recovery.

Methods

We enrolled 24 patients with adrenal adenomas, 12 with SH (SH+, 8 females, 58.3 ± 6.5 years) and 12 without SH (SH?; 11 females, 61.8 ± 10.6 years). SH was diagnosed in the presence of ≥2 out of: 1 mg overnight dexamethasone suppression test >83 nmol/L, urinary free cortisol (UFC) >193 nmol/day and ACTH levels <2.2 pmol/L. GH secretion was assessed by GHRH + Arginine test (GHRH–ARG) and age-adjusted serum IGF-I levels, expressed as SDS (IGF-I SDS). Eight SH+ patients were re-evaluated after the recovery from SH.

Results

Age, gender, body mass index (BMI) and IGF-I SDS were comparable between SH+ and SH? patients. After GHRH–ARG the mean GH peak levels (GH-P) and GH response (as Area Under Curve, GH-AUC) were lower in SH+ than in SH? patients (15.2 ± 8.1 vs 44.5 ± 30.9 μg/L, P = 0.004 and 1,418 ± 803 vs 4,028 ± 2,476 μg/L/120 min, P = 0.002, respectively), after adjusting for age and BMI. The GH-AUC and GH-P levels were negatively associated with UFC after adjusting for age and BMI (β = ?0.39, P = 0.02 and β = ?0.4, P = 0.020 respectively). After recovery, GH-P levels and GH-AUC increased as compared to baseline (23.7 ± 16.3 vs 15.8 ± 10.2 μg/L, P = 0.036 and 2,549 ± 1,982 vs 1,618 ± 911 μg/L/120 min, P = 0.012, respectively).

Conclusions

GH secretion reserve is decreased in SH patients and increases after the recovery.     

Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis

Purpose

To investigate and clarify the relationship between circulating 25-hydroxyvitamin D level and prostate cancer risk.

Methods

We conducted the meta-analysis to better evaluate the association. Terms “25-Hydroxyvitamin D”/“vitamin D” and “prostate cancer” were used for literature search.

Results

We identified 21 relevant publications from databases of PubMed and MEDLINE and included 11,941 cases and 13,870 controls in the meta-analysis. Overall studies revealed a significant 17 % elevated risk of prostate cancer for individuals with higher level of 25-hydroxyvitamin D (OR = 1.17, 95 % CI = 1.05–1.30, P  = 0.004), and no publication bias was found in the calculations (P  = 0.629). Subgroup analysis confirmed the association from nested case–control study group, studies from USA group and studies using serum samples group (nested case–control studies: OR = 1.17, 95 % CI = 1.08–1.27, P < 0.001; USA: OR = 1.15, 95 % CI = 1.03–1.29, P = 0.017; serum: OR = 1.20, 95 % CI = 1.01–1.42, P = 0.042); moreover, sensitivity tests also indicated significant results in studies from Europe and studies conducting with plasma samples after exclusion of some influential single study from the analysis, respectively (Europe: OR = 1.21, 95 % CI = 1.04–1.40, P = 0.014; plasma: OR = 1.13, 95 % CI = 1.00–1.27, P = 0.05).

Conclusions

Our meta-analysis, for the first time, suggested significant positive relationship between high level of 25-hydroxyvitamin D and increased risk of prostate cancer, reminding us that more concern should be taken into account during assessing the effect of 25-hydroxyvitamin D.     

Effects of mosapride on esophageal motor activity and esophagogastric junction compliance in healthy volunteers

Background

The effects of the prokinetic drug mosapride on esophageal motor activity vary at standard doses. In addition to esophageal motor activities, compliance of the esophagogastric junction (EGJ) is important for prevention of gastroesophageal reflux. However, the effects of mosapride on EGJ compliance have not been reported. Here, we investigated the effects of high-dose mosapride on esophageal motor activities and EGJ compliance.

Methods

Nine healthy volunteers were enrolled in the study. Peristaltic esophageal contraction and lower esophageal sphincter pressures before and after administration of 40 mg mosapride were examined by high resolution esophageal manometry. Esophageal compliance was also investigated by intra-esophageal impedance planimetry (EndoFLIP^®).

Results

High-dose mosapride augmented peristaltic contractions, especially in the distal esophageal segments (P < 0.05). The mean resting lower esophageal sphincter pressure was elevated from 25.0 mmHg before administration to 28.9 mmHg after (P < 0.05). In addition, mosapride significantly reduced EGJ compliance (P < 0.05).

Conclusions

Mosapride at 40 mg augmented esophageal motor activities and reduced EGJ compliance in healthy volunteers.     

Genetic association of osteopontin (OPN) and its receptor CD44 genes with susceptibility to Chinese gastric cancer patients

Purpose

(1) To investigate associations between single nucleotide polymorphisms (SNPs) in osteopontin (OPN) and its receptor—cluster of differentiation 44 (CD44) genes and gastric cancer susceptibility. (2) To explore the correlation of OPN and CD44 expression of gastric cancer.

Methods

We detected 26 SNPs of the genes in gastric cancer patients from the Chinese Han population by Sequenom technique and performed expression of OPN in combination with CD44 in 243 tissues samples of the cases by tissue microarray and immunohistochemistry (IHC).

Results

We found that the minor alleles of OPN rs4754C>T and OPN rs9138C>A remained strongly associated with decreased gastric cancer risk (P = 1.53 × 10^?4, odds ratio (OR) 0.642, 95 % confidence interval (CI) 0.511–0.808 and P = 1.59 × 10^?4, OR 0.642, 95 %CI 0.510–0.809). OPN variant rs1126772A>G and CD44 variant rs353639A>C significantly contributed to elevated risk of gastric cancer (P = 0.042, OR 1.279, 95 % CI 1.008–1.622 and P = 0.047, OR 1.334, 95 % CI 1.003–1.772). Haplotypes of OPN and CD44 variants significantly influenced risk of gastric cancer. Clinical data indicated that rs4754 and rs9138 of OPN were significantly associated with smoking (P = 0.029, OR 0.343, 95 % CI 0.127–0.926 and P = 0.029, OR 0.343, 95 %CI 0.127–0.926) and OPN rs1126772 revealed associations with tumor–node–metastasis (TNM) stage (P = 0.025, OR 1.765, 95 % CI 1.073–2.905) and tumor differentiation (P = 0.031, OR 1.722, 95 % CI 1.049–2.825). OPN expression was observed in 133 of the 243 cases (54.7 %) by IHC and was correlated with serosa invasion (P = 0.013), TNM stage (P = 0.003) and lymph node metastasis (P = 0.002). CD44 expression was found in 92 of the 243 cases (37.9 %) and was associated with tumor size (P = 0.005) and lymph node metastasis (P = 0.023), respectively. The OPN expression displayed a positive association with CD44 (P = 0.01, r _s = 0.164).

Conclusions

We found that the polymorphisms rs4754, rs9138 and rs1126772 of OPN gene and rs353639 of CD44 gene were significantly associated with gastric cancer. Our IHC data indicated that interaction of OPN and CD44 protein would promote progression and metastasis of gastric cancer.     

Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist,in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised,double-blind,placebo-controlled trial

Purpose

This phase II study evaluated the synthetic DNA-based immunomodulator and Toll-like receptor 9 agonist MGN1703 as maintenance treatment in metastatic colorectal carcinoma (mCRC).

Methods

Fifty-nine patients with mCRC and disease control after standard first-line chemotherapy were randomised to MGN1703 60 mg (N = 43) or placebo (N = 16).

Results

The hazard ratio (HR) for the primary endpoint [progression-free survival (PFS) from the start of maintenance] was 0.56 (95 % CI 0.29–1.08; P = 0.07) and 0.55 (95 % CI 0.3–1.0; P = 0.04) by independent and investigator review, respectively. MGN1703 significantly improved PFS measured from the start of induction therapy versus placebo on independent (HR 0.49; 95 % CI 0.26–0.94; P = 0.03) and investigator review (HR 0.50; 95 % CI 0.31–1.02; P = 0.02). Overall survival (OS) data remain immature (HR 95 %; 95 % CI 0.3–1.5; P = 0.29) with 28/43 patients alive after a medium follow-up of >17 months. Retrospective subgroup analysis showed a significant effect of MGN1703 on PFS versus placebo in patients with greater than median tumour size reduction and normalised carcinoembryonic antigen concentrations following induction therapy, and in patients with elevated activated NKT cells ≥3.08 %. Adverse events were mild to moderate and limited to injection-site reactions or linked to general immune system activation.

Conclusions

MGN1703 maintenance treatment was well tolerated and appears to induce durable and prolonged PFS and disease control in a subgroup of patients with mCRC following induction therapy. Activated NKT cells may be a predictive biomarker for selecting patients likely to benefit more from MGN1703.     

Effect of Omeprazole Dose,Nonsteroidal Anti-inflammatory Agents,and Smoking on Repair Mechanisms in Acute Peptic Ulcer Bleeding

Background

Peptic ulcer bleeding (PUB) is a major cause of upper gastrointestinal bleeding. The effect of omeprazole on mucosal repair is unknown.

Aims

We studied the effect of omeprazole, nonsteroidal anti-inflammatory agents, and smoking on PUB.

Methods

There were 43 PUB patients who received regular or high dose of omeprazole for 72 h. Biopsies from antrum and corpus were taken before and after treatment. Biopsy samples from 20 celiac disease patients worked as controls. The expression of Ki-67, Bcl-2, COX-2, Hsp27, and Hsp70 was analyzed from patients and controls.

Results

Bcl-2 expression in PUB patients was lower than in controls. However, Bcl-2 increased significantly from 5.0 (SD 4.5) to 9.1 % (SD 6.7), p = 0.0004, in the antrum after omeprazole. In univariate analysis, a high omeprazole dose caused a more profound increase in Ki-67 expression in the corpus: 35.3 % (SD 54.8) than a regular dose: ?10.1 % (SD 40.6), p = 0.022. In multivariate analysis, Ki-67 decreased significantly in the corpus between the pre- and posttreatment period (p = 0.011), while a high omeprazole dose (p = 0.0265), the use of NSAIDs (p = 0.0208), and smoking (p = 0.0296) significantly increased Ki-67 expression. Bcl-2 in the corpus increased significantly (p = 0.0003) after treatment.

Conclusions

Our findings suggest that Bcl-2 may be an important factor in the pathogenesis of a peptic ulcer and PUB. In addition, high-dose omeprazole increased the expression of Ki-67, which may enhance the healing process of a peptic ulcer.     

Association between promoters polymorphisms of matrix metalloproteinases and risk of digestive cancers: a meta-analysis

Purpose

A variety of studies have been performed to elucidate the polymorphisms in promoter regions of matrix metalloproteinases (MMPs) associated with the risk of digestive cancers, and yet, results remain conflicting and heterogeneous. Thus, we undertook a systematic meta-analysis to determine the genetic susceptibility of MMPs to digestive cancers.

Methods

A computerized literature search was conducted in databases of PubMed, Embase, and ISI Web of Knowledge till October 2012 for any MMP genetic association study in oral squamous, gastric, esophageal, and colorectal carcinomas. Odds ratios (OR) and 95 % confidence interval (CI) were estimated for each gene under dominant and recessive models, and the heterogeneity between studies was assessed using Q test and I ² value. Overall and subgroup analysis according to anatomical sites and ethnicity was carried out. Statistical analysis was performed with Review Manager 5.0.

Results

A total of 40 eligible publications with 68 comparisons were included in this study. For MMP1 nt-1607, individuals with 2G state could increase risk of digestive cancers in total analysis (dominant: OR = 1.31, 95 % CI = 1.16–1.48, P < 0.00001; recessive: OR = 1.29, 95 % CI = 1.11–1.50, P = 0.0009). In the subgroup of tumor sites, significant associations were also observed in esophageal cancer and colorectal cancer under both genetic models. For MMP2 nt-1306, CT or TT carriers performed significant protection against digestive cancer in the dominant model (OR = 0.69, 95 % CI = 0.55–0.85, P = 0.0007) of the overall. In the subgroup analysis, significant association was found in esophageal cancer, with borderline effects in gastric cancer and oral squamous cell carcinoma. For MMP7 ?181 A/G, significant association was observed under two genetic models in the overall (dominant: OR = 1.26, 95 % CI = 1.10–1.43, P = 0.0009; recessive: OR = 1.33, 95 % CI = 1.11–1.60, P = 0.002) and in the individual cancer subgroup of esophageal cancer and gastric cancer. For MMP9 ?1,562 C/T, a borderline effect was found with digestive cancers in the total and stratified analysis of the colorectal cancer under dominant model. No association was observed in either the overall or subgroup analysis for MMP3 ?1,171 5A/6A.

Conclusions

Our meta-analysis demonstrated the fact that polymorphisms in promoter regions of MMP genes might be related to the susceptibility of digestive cancers, with cancer development for MMP1 and MMP7, and a protection against cancer for MMP2 and MMP9. Further evidences with adequate sample sizes need to be conducted.     

Association of the GNB3 825T-allele with better survival in patients with glioblastoma multiforme

Purpose

Genotypes of the C825T polymorphism of the GNB3 gene encoding the G protein β3 subunit were recently associated with the prognosis of different malignomas. We investigated potential associations of GNB3 genotypes with survival of patients with glioblastoma multiforme (GBM).

Methods

One hundred and sixty-one patients suffering from GBM were retrospectively investigated. Inclusion criteria were availability of DNA and a follow-up of at least 24 months. The results were evaluated with respect to the basic clinical data, type of surgical intervention, MGMT promoter methylation, adjuvant therapy, and survival.

Results

After 2 years of first diagnosis, 128 (79.5%) of the 161 patients had died, 33 (20.5%) were alive. Kaplan–Meier curves revealed a significant higher rate of survival for homo- and heterozygous T-allele carriers (P = 0.019) with 38.5 and 25.3%, respectively, but only 11.6% for homozygous C-allele carriers. Multivariable Cox regression identified the heterozygous (hazard ratio 3.3, 95% CI 1.3–8.0, P = 0.010), as well as homozygous GNB3 825 C-allele (hazard ratio 3.7, 95% CI 1.5–9.1, P = 0.004) as an independent negative prognostic factor for 2-year survival according to the GNB3 825 TT genotype reference group.

Conclusions

Our data suggest an association of the GNB3 825TT genotype and better survival in patients with GBM.     

Preventing Stricture Formation by Covered Esophageal Stent Placement After Endoscopic Submucosal Dissection for Early Esophageal Cancer

Objective

We aimed to evaluate the efficacy and safety of fully covered esophageal stent placement for preventing esophageal strictures after endoscopic submucosal dissection (ESD).

Methods

Twenty-two patients with a mucosal defects that exceeded 75 % of the circumference of the esophagus after ESD treatment for superficial esophageal squamous cell carcinomas were grouped according to the type of mucosal defect and randomized to undergo fully covered esophageal stent placement post-ESD (group A, n = 11) or no stent placement (group B, n = 11). In group A, the esophageal stents were removed 8 weeks post-ESD. Endoscopy was performed when patients reported dysphagia symptoms and at 12 weeks post-ESD in patients without symptoms. Savary–Gilliard dilators were used for bougie dilation in patients experiencing esophageal stricture in both groups, and we compared the rates of post-ESD strictures and the need for bougie dilation procedures.

Results

The proportion of patients who developed a stricture was significantly lower in group A (18.2 %, n = 2) than in group B (72.7 %, n = 8) (P < 0.05). Moreover, the number of bougie dilation procedures was significantly lower in group A (mean 0.45, range 0–3) than in group B (mean 3.9, range 0–17) (P < 0.05). The two patients in group A who experienced stricture also had stent displacement.

Conclusions

Esophageal stents are a safe and effective method of preventing esophageal strictures in cases where >75 % of the circumference of the esophagus has mucosal defects after ESD treatment for early esophageal cancer.     

Clinical significance of peritumoral mast cells in esophageal squamous cell carcinoma with neoadjuvant chemoradiotherapy

Background

Neoadjuvant chemoradiotherapy (CRT) followed by surgery is the standard approach for locally advanced esophageal cancer. Recently, the microenvironment (including the host immune response) after conventional chemo- and/or radiotherapy has been highlighted. The aim of this preliminary study was to evaluate peritumoral mast cells (MCs) in esophageal squamous cell carcinoma (ESCC) after neoadjuvant CRT.

Methods

We obtained a total of twenty specimens from patients with ESCC who underwent neoadjuvant CRT (30–40 Gy; 5-fluorouracil plus cisplatin) followed by surgery. We evaluated the expression of tryptase by MCs, Foxp3 by regulatory T cells, CD8 by cytotoxic T cells, and microvessel density (MVD) using immunohistochemistry. We investigated the correlation between the sizes of these marker-positive cell populations surrounding residual tumor nests, MVD and CRP, and clinical outcome.

Results

Patients with a low number of peritumoral MCs more frequently had lymphatic invasion (P = 0.0191). There was no significant correlation among the sizes of the marker-positive cell populations. We observed a significant negative correlation between the number of MCs and preoperative CRP levels (P = 0.009). Low numbers of peritumoral MCs, high MVD, and a preoperative C-reactive protein of >0.5 mg/dL were significantly associated with poor overall survival (MCs: P = 0.0239; MVD: P = 0.0317; CRP: P = 0.0395).

Conclusion

Our results suggest that peritumoral MCs may be associated with prognosis in patients with ESCC after neoadjuvant CRT.     

The gefitinib dose reduction on survival outcomes in epidermal growth factor receptor mutant non-small cell lung cancer

Purpose

Gefitinib is safe for the treatment of non-small cell lung cancer (NSCLC), but some patients experience toxicities and require dose reduction. The purpose of this study was to evaluate the effect of gefitinib dose reduction on survival.

Methods

We retrospectively analyzed 263 patients with NSCLC harboring sensitive epidermal growth factor receptor (EGFR) mutation. All patients had recurred or metastatic disease and received gefitinib 250 mg daily as palliative chemotherapy.

Results

Of the 263 patients, 23 had gefitinib dose reduction due to toxicities (1 due to mucositis, 5 due to skin rash, 11 due to hepatotoxicity and 6 for both skin and hepatotoxicity). In the dose reduction group, the mean dose intensity was 0.84 (range 0.48–0.98). Patients with dose reduction showed significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to those receiving the standard dose (median PFS: 14.0 vs. 10.6 months, P = 0.042, median OS: 54.5 vs. 29.6, P = 0.020). In multivariate analysis, the effect of dose reduction was not significantly associated with prolonged PFS [hazard ratio (HR) 0.619, 95 % confidence interval (CI) 0.357–1.073, P = 0.085], or OS (HR 0.625, 95 % CI 0.287–1.362, P = 0.237). However, patients receiving low-dose gefitinib tended to have superior survival outcomes compared to those receiving standard-dose gefitinib.

Conclusions

The patients experiencing gefitinib dose reduction or short-term treatment interruption due to toxicities did not show inferior survival, compared to those receiving full dose of gefitinib in NSCLC patients with EGFR mutation.