Polypeptide N-acetylgalactosaminyltransferase 6 expression in pancreatic cancer is an independent prognostic factor indicating better overall survival

Background:

The family of polypeptide N-acetylgalactosaminyltransferases (GalNAc-Ts) is responsible for the altered glycosylation in cancer. The purpose of our study was to investigate the clinical significance of two isoforms, GalNAc-T6 and -T3, and their correlation with the prognosis of pancreatic cancer.

Methods:

Immunohistochemistry was used to analyse GalNAc-T6 and -T3 expressions in 70 clinicopathologically characterised pancreatic cancer cases.

Results:

Positive expressions of GalNAc-T6 and -T3 were immunohistochemically identified in 51% (36 of 70) and in 77% (54 of 70) of patients, respectively. A close relationship was noted between GalNAc-T6 positive expression and pathological well/moderate differentiated type (P=0.001), small tumour size (P=0.044), absence of vascular invasion (P=0.009), and low stage of the American Joint Committee on Cancer systems (P=0.043). The expression of GalNAc-T3 significantly correlated with good differentiation (P=0.001), but not with other clinicopathologic features. Furthermore, univariate and multivariate analyses revealed that GalNAc-T6 expression was an independent prognosis indicator for the disease, whereas GalNAc-T3 expression had no impact on clinical outcome, even though 33 of 36 GalNAc-T6-positive cases also had a positive expression of GalNAc-T3 (P=0.001, r=0.356).

Conclusion:

Both GalNAc-T6 and -T3 expressions correlated significantly with tumour differentiation, whereas only GalNAc-T6 expression predicted prognosis in pancreatic cancer.     

Heparanase expression is a prognostic indicator for postoperative survival in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma has a median survival of less than 6 months from diagnosis. This is due to the difficulty in early diagnosis, the aggressive biological behaviour of the tumour and a lack of effective therapies for advanced disease. Mammalian heparanase is a heparan-sulphate proteoglycan cleaving enzyme. It helps to degrade the extracellular matrix and basement membranes and is involved in angiogenesis. Degradation of extracellular matrix and basement membranes as well as angiogenesis are key conditions for tumour cell spreading. Therefore, we have analysed the expression of heparanase in human pancreatic cancer tissue and cell lines. Heparanase is expressed in cell lines derived from primary tumours as well as from metastatic sites. By immunohistochemical analysis, it is preferentially expressed at the invading edge of a tumour at both metastatic and primary tumour sites. There is a trend towards heparanase expression in metastasising tumours as compared to locally growing tumours. Postoperative survival correlates inversely with heparanase expression of the tumour reflected by a median survival of 34 and 17 month for heparanase negative and positive tumours, respectively. Our results suggest, that heparanase promotes cancer cell invasion in pancreatic carcinoma and could be used as a prognostic indicator for postoperative survival of patients.     

Prognostic nomogram for nonresectable pancreatic cancer treated with gemcitabine-based chemotherapy

Background:

A nomogram is progressively being used as a useful predictive tool for cancer prognosis. A nomogram to predict survival in nonresectable pancreatic cancer treated with chemotherapy has not been reported.

Methods:

Using prospectively collected data on patients with nonresectable pancreatic cancer receiving gemcitabine-based chemotherapy at five Japanese hospitals, we derived a predictive nomogram and internally validated it using a concordance index and calibration plots.

Results:

In total, 531 patients were included between June 2001 and February 2013. The American Joint Committee on Cancer (AJCC) TNM stages were III and IV in 204 and 327 patients, respectively. The median survival time of the total cohort was 11.3 months. A nomogram was generated to predict survival probabilities at 6, 12, and 18 months and median survival time, based on the following six variables: age; sex; performance status; tumour size; regional lymph node metastasis; and distant metastasis. The concordance index of the present nomogram was higher than that of the AJCC TNM staging system at 12 months (0.686 vs 0.612). The calibration plots demonstrated good fitness of the nomogram for survival prediction.

Conclusions:

The present nomogram can provide valuable information for tailored decision-making early after the diagnosis of nonresectable pancreatic cancer.     

Paclitaxel-based chemotherapy for advanced pancreatic cancer after gemcitabine-based therapy failure: a case series of 5 patients

Background/Objectives

Gemcitabine (GEM) is a gold-standard chemotherapy agent for advanced pancreatic cancer. Because of the malignant character of the disease, nearly all patients show disease progression despite treatment with GEM-based chemotherapy; therefore, second-line chemotherapy may be beneficial for these patients. We report a retrospective analysis of 5 patients with advanced pancreatic cancer, treated with a paclitaxel-containing regimen as second-, third- or fourth-line chemotherapy after various therapies, such as a GEM-based regimen, S-1 regimen, and chemoradiation. We retrospectively analyzed the efficacy and adverse events, and evaluated the paclitaxel-containing regimens. A review of the literature is also discussed.

Results

The median overall survival from the start of salvage therapy was 10.7 months. The disease control rate of the paclitaxel-containing regimen according to RECIST criteria was 60%, including complete response in 0 patients, partial response in 3, and stable disease in 2. Two patients had malignant ascites at the start of this salvage therapy, and in both of them the ascites and clinical complaints improved. Grade 3 and 4 hematological adverse events were observed in 2 patients and 1 patient, respectively.

Conclusion

Salvage paclitaxel-based therapy could be beneficial to advanced pancreatic cancer patients who maintain good performance status after several chemotherapy failures.Key words: Pancreatic cancer, Paclitaxel, Chemotherapy, Gemcitabine failure, Second-line therapy     

Role of EGFR as a prognostic factor for survival in head and neck cancer: a meta-analysis

The prognostic role of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma (HNSCC) remains controversial. The goal of this study was to summarize existing evidence regarding whether EGFR overexpression is a prognostic factor in HNSCC. Relevant studies were identified using Pubmed, Ovid, and Web of Science databases. A meta-analysis was conducted on the prognostic value of EGFR expression for overall survival (OS) and disease-free survival (DFS). Thirty-seven studies were included. Primary analysis indicated that EGFR overexpression was associated with reduced OS (hazard ratio [HR]: 1.694, 95 % confidence interval [CI]: 1.432–2.004). DFS, on the other hand, was not associated with EGFR expression after adjusting for publication bias (HR: 1.084, 95 % CI: 0.910–1.290). Subgroup analysis gave a statistically significant pooled HR for OS in laryngeal carcinoma (HR: 2.519, 95 % CI: 1.615–3.928) and in oropharyngeal carcinoma (HR: 2.078, 95 % CI: 1.605–2.690). The pooled HR was statistically significant for DFS with respect to oropharyngeal carcinoma (HR: 1.055, 95 % CI: 1.020–1.092), but not laryngeal carcinoma (HR: 1.750, 95 % CI: 0.911–3.360). When dividing studies based on the immunohistochemistry (IHC) scoring system, only the group that evaluated EGFR expression according to the intensity and extent of staining showed no between-study heterogeneity for both OS and DFS. Overall, EGFR overexpression was associated with shortened OS, but not DFS. Future studies are needed that stratify patients by specific tumor sites. Furthermore, when estimating protein level by the IHC method, it is advisable to consider both intensity and extent of staining.     

BRCA1 mRNA expression levels predict for overall survival in ovarian cancer after chemotherapy.

PURPOSE: We investigated whether BRCA1 mRNA expression levels may represent a biomarker of survival in sporadic epithelial ovarian cancer following chemotherapy treatment. EXPERIMENTAL DESIGN: The effect of loss of BRCA1 expression on chemotherapy response in ovarian cancer was measured in vitro using dose inhibition assays and Annexin V flow cytometry. Univariate and multivariate analyses were done to evaluate the relationship between BRCA1 mRNA expression levels and survival after chemotherapy treatment in 70 fresh frozen ovarian tumors. RESULTS: We show that inhibition of endogenous BRCA1 expression in ovarian cancer cell lines results in increased sensitivity to platinum therapy and decreased sensitivity to antimicrotubule agents. In addition, we show that patients with low/intermediate levels of BRCA1 mRNA have a significantly improved overall survival following treatment with platinum-based chemotherapy in comparison with patients with high levels of BRCA1 mRNA (57.2 versus 18.2 months; P = 0.0017; hazard ratio, 2.9). Furthermore, overall median survival for higher-BRCA1-expressing patients was found to increase following taxane-containing chemotherapy (23.0 versus 18.2 months; P = 0.12; hazard ratio, 0.53). CONCLUSIONS: We provide evidence to support a role for BRCA1 mRNA expression as a predictive marker of survival in sporadic epithelial ovarian cancer.     

胰腺癌辅助化疗的预后与复发因素分析

目的 探讨影响胰腺癌辅助化疗者预后及复发的因素,以期早期发现复发来提高远期生存。方法 回顾性分析2008年1月至2015年9月77例胰腺癌切除术后行辅助化疗患者的资料,分析影响胰腺癌辅助化疗的预后及复发的因素。结果 单因素分析显示分化程度、切缘情况、肿瘤最大径、脉管内癌栓、血管侵犯、淋巴结转移、术前癌胚抗原（CEA）水平、中性粒细胞与淋巴细胞比值（NLR）及是否完成辅助化疗与预后有关（P＜0.05）;多因素分析显示淋巴结转移、低分化、R1切除及未完成辅助化疗是胰腺癌预后差的独立危险因素。肿瘤最大径、T分期、血管侵犯及术前CEA水平与胰腺癌复发有关,Logistic回归分析显示血管侵犯及术前CEA水平升高是胰腺癌复发的独立危险因素,且复发者复发后生存时间更短。结论 对于胰腺癌辅助化疗患者,淋巴结转移、低分化、R1切除及未完成辅助化疗是影响预后的危险因素。血管侵犯及术前CEA水平升高者更易复发,且复发后生存时间更短,对这些易早期复发患者术前应重视评估病情及慎重考虑是否需要术前治疗。     

Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer

BackgroundWe investigated the relationship between resumption or persistence of menstruation after cytotoxic chemotherapy (RM) and disease-free survival (DFS) in premenopausal patients with early breast cancer.MethodsMedical records from 872 patients who received cytotoxic chemotherapy for stage I to III breast cancer were retrospectively reviewed.ResultsThe median patient age was 41 years (range, 21–54) and the median follow-up duration was 6.2 years (range, 0.7–10.4). Six hundred ninety-two patients (79.4%) were hormone receptor (HR) positive and the majority of these received tamoxifen therapy after completing chemotherapy. The chemotherapy-induced amenorrhea (CIA) rate was 76.7% (n = 669), and 51.8% (n = 452) experienced RM during the follow-up period. One hundred twenty-one (13.9%) patients had persistent menstruation without CIA. DFS was significantly affected by younger age at diagnosis (≤35 years) (P = 0.013), tumor size > 2 cm (P < 0.001), node positivity (P < 0.001), HR negativity (P < 0.001), HER2 positivity (P = 0.010), and RM (P < 0.001). HR negativity [hazard ratio 1.7, 95% confidence interval (CI) 1.2–2.4, P = 0.006], tumor size > 2 cm (hazard ratio 2.1, 95% CI 1.4–3.0, P < 0.001), node positivity (hazard ratio 3.0, 95% CI 2.0–4.7, P < 0.001), and RM (hazard ratio 1.8, 95% CI 1.2–2.7, P = 0.004) remained significant factors for DFS on multivariate analysis.ConclusionsA considerable proportion of premenopausal patients treated with chemotherapy experienced RM after CIA. RM was a poor prognostic factor for DFS in premenopausal patients with early breast cancer.     

Serum apolipoprotein C-II is prognostic for survival after pancreatic resection for adenocarcinoma

Background:

Pancreaticoduodenectomy remains a major undertaking. A preoperative blood test, which could confidently predict the benefits of surgery would improve the selection of pancreatic cancer patients for surgery. This study aimed to identify protein biomarkers prognostic for long-term survival and to validate them with clinico-pathological information.

Methods:

Serum from 40 preoperative patients was used to train for predictive biomarkers using surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI), and the results were verified on 21 independent samples. Two predictive proteins were identified by tryptic peptide mass fingerprinting and sequencing, and validated on serum from another 57 patients by enzyme-linked immunosorbent assay (ELISA). The influence of these proteins on growth and invasion of two cancer cell lines was tested in-vitro.

Results:

The SELDI panel of m/z 3700, 8222 and 11 522 peaks predicted <12 months'' survival (ROC AUC: 0.79, 0.64–0.90; P<0.039). When CA19-9 was added, the ROC AUC increased to 0.95 (0.84–0.99; P<0.0001). The six subjects in the verification group who died within 12 months were correctly classified. The m/z 8222 and 11 522 proteins were identified as Serum ApoC-II and SAA-1, respectively. In the validation samples, ELISA results confirmed that ApoC-II was predictive of survival (Kaplan–Meier P<0.009), but not SAA-I. ApoC-II, CA19-9 and major-vessel involvement independently predicted survival. ApoC-II and SAA-1 increased cell growth and invasion of both cancer cell lines.

Conclusion:

Serum ApoC-II, CA19-9 and major-vessel invasion independently predict survival and improves selection of patients for pancreaticoduodenectomy.     

Changes in the immune cell population and cell proliferation in peripheral blood after gemcitabine-based chemotherapy for pancreatic cancer

Purpose

Regulatory T cells (Tregs) play a role in the immunosuppressive state in pancreatic cancer patients. We aimed to evaluate the changes of immune cells population including Tregs caused by gemcitabine (GEM)-based chemotherapy.

Methods

Fifty-three patients with pancreatic cancer were enrolled in this study, of which 32 received GEM- based chemotherapy. Blood samples were collected before and at least 2 weeks after the last dose of chemotherapy. The peripheral blood mononuclear cells (PBMCs) were subjected to flow cytometry analysis after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Other lymphocytes and NK cell markers were also measured. The proliferative capacity of PBMCs stimulated with anti-CD3 was analyzed using H³ thymidine.

Results

The percentage and number of Tregs were significantly decreased after chemotherapy (p = 0.032, p = 0.003, respectively). The other immune cells and the proliferative capacity did not change.

Conclusion

This study showed that GEM-based chemotherapy produced an immunomodulatory effect via the depletion of Tregs.     

Endometriosis as a prognostic factor for cancer survival

Studies have shown an increased risk of malignancies in women with endometriosis. Little is known about the impact of endometriosis on cancer survival. We investigated whether the survival after a diagnosis of a malignancy differs in women with a previously diagnosed endometriosis compared to other women. Women with a first time diagnosis of a malignancy in 1969-2005, were identified using the National Swedish Cancer Register (NSCR). By use of the National Swedish Patient Register (NSPR) we identified all women with a diagnosis of endometriosis during the same period and linked these patients with the data from the NSCR. The cohort comprised 4,278 women with endometriosis and a malignancy, and 41,831 randomly selected matched women without endometriosis. Cox regression was used for all calculations to obtain crude and adjusted cause specific mortality rates, measured as hazard ratios (HR) with 95% confidence intervals (CI). A total of 46,109 women entered the study. There was a statistically significant better survival for women with endometriosis for all malignancies combined (HR=0.92) and for breast cancer (HR=0.86) and ovarian cancer (HR=0.81) specifically. For breast cancer the survival enhancing effect in women with endometriosis decreased with increasing parity. There was poorer survival in malignant melanoma for women with endometriosis (HR=1.52). The survival in a malignancy is better in women with a previously diagnosed endometriosis compared to women without endometriosis especially for breast and ovarian cancers. The prognosis of malignant melanoma is poorer in women with endometriosis.     

ADAM9 expression in pancreatic cancer is associated with tumour type and is a prognostic factor in ductal adenocarcinoma

Gene expression profiling revealed ADAM9 to be distinctly overexpressed in pancreatic ductal adenocarcinoma (PDAC). We examined the relevance of ADAM9 expression in PDAC diagnosis and prognosis. A total of 59 infiltrating PDACs, 32 specimens from patients with chronic pancreatitis, 11 endocrine tumours and 24 acinar cell carcinomas were immunohistochemically analysed for ADAM9 expression. Staining for ADAM9 was detected in 58 out of 59 (98.3%) PDACs and in two out of 24 (8.3%) acinar cell carcinomas, but not in endocrine tumours. In the non-neoplastic pancreas, whether normal or chronically inflamed, ADAM9 was expressed in centroacinar and intralobular duct cells, but not in interlobular duct cells and their hyperplastic lesions. Pancreatic ductal adenocarcinomas showing cytoplasmic ADAM9 expression correlated with poor tumour differentiation and also with shorter overall survival than in cases showing only an apical membranous staining pattern (P=0.001). Multivariate analysis identified cytoplasmic ADAM9 expression as an independent marker of shortened survival in a set of 42 curatively (R0) resected PDAC (P<0.05, hazard ratio 2.85, 95% confidence interval: 1.21-6.71). The results show that ADAM9 expression distinguishes PDACs from other solid pancreatic tumours. In addition, cytoplasmic ADAM9 overexpression is associated with poor differentiation and shortened survival. Therefore, ADAM9 overexpression might contribute to the aggressiveness of PDACs.     

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

IntroductionPancreatic 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.AimTo assess the frequency and prognostic impact of tumour budding in PDAC.MethodsWhole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10 buds across 10 HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines.ResultsInter-observer agreement was considered strong (ICC = 0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p = 0.0463), lymphatic invasion (p = 0.0192) and decreased disease-free (p = 0.0005) and overall survival (p < 0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p < 0.0001; HR (95% CI): 3.65 (2.1–6.4)).ConclusionsOur results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches.     

ERCC1对胃癌患者手术及化疗后生存预测的意义

Objective  

The aim of this study was to evaluate the effect of the excision repair cross-complementing (ERCC1) expression on survival in advanced gastric cancer patients who underwent surgical resection and treated with oxaliplatinbased adjuvant chemotherapy.