Women with familial risk for breast cancer have an increased frequency of aldehyde dehydrogenase expressing cells in breast ductules

Background

Knowledge is limited regarding the association between stem cells in histologically benign breast tissue and risk factors for breast cancer, and hence we addressed this issue in the present study. Recently, we assessed the histology of benign breast tissue from cancer and non-cancer patients for cells positive for the putative stem cell marker aldehyde dehydrogenase 1 A1 (ALDH), and the findings indicated an association between expression of ALDH and the hormonal factors menopause and hormone therapy. The current investigation examined possible associations between various known clinical and genetic risk factors for breast cancer and cellular expression of ALDH in ductules in benign human breast tissue.

Methods

The study included breast surgery patients that were BRCA1/2 mutation carriers without breast cancer (n?=?23), had BRCA1/2 (n?=?28) or sporadic (n?=?21) breast cancer, or required non-cancer-related mammoplasty (n?=?34). The distribution and frequency of ALDH-immunolabelled cells were correlated to patient subgroups with different risk factors, using mammoplasty patients as a control group. Statistical analyses comprised linear and logistic regression, Spearman’s rank test, Pearson’s test, and Fisher’s exact test. In two-tailed tests, p?<?0.05 was considered significant.

Results

A strong association was found between family history of breast cancer and a high frequency of ALDH+ cells (p?=?0.001) at all ductular levels in all groups, regardless of BRCA status, age, parity, or occurrence of cancer. In pre-menopausal non-BRCA cancer patients, the frequency of ALDH+ cells increased with age (p?<?0.01) but decreased with increasing parity (p?<?0.03). High frequencies of ALDH+ cells were found in the non-basal ductular levels in BRCA1 mutation carriers (p?=?0.03), but in the basal ductular level in BRCA2 cancer patients (p?=?0.02). Among post-menopausal patients, only on-going hormone replacement therapy was correlated with a high number of ALDH+ cells (p?<?0.03).

Conclusion

In histologically normal breast tissue, we found a positive association between the frequency of ductular ALDH+ cells and several breast cancer risk factors, particularly family history of this disease, which supports previous evidence that ALDH plays a role in breast cancer.

     

In human invasive breast ductal carcinoma, tumor stromal macrophages and tumor nest macrophages have distinct relationships with clinicopathological parameters and tumor angiogenesis

Tumor-associated macrophages play a crucial role in breast cancer progression and tumor angiogenesis. However, evaluation of tumor-associated macrophages incorporating their histological locations is lacking. The aim of this study was to clarify whether macrophages in tumor stroma and macrophages in tumor cell nests have distinctive properties in relation to pertinent breast cancer clinicopathological parameters and tumor angiogenesis. In 94 human invasive breast ductal carcinomas, tumor-associated macrophages were immunostained with anti-CD68 antibody and counted or graded according to these histological locations. Microvessels were immunostained with anti-CD34 antibody and counted for microvessel density. We found that the presence of tumor stromal and tumor nest macrophages was closely correlated (p?=?0.001). Both tumor stromal and tumor nest macrophages were associated with mitotic count (p?=?0.001 and p?=?0.037, respectively). However, only higher tumor stromal macrophage grades were associated with higher tumor grades (p?=?0.004) and negative estrogen receptor status (p?=?0.007). Multivariate analysis showed that tumors with a high mitotic count score (score 3 vs. scores 1 and 2) had a higher tumor stromal macrophage density (Grades III and IV) when adjusted for tumor size, tubule formation, and estrogen receptor status (odds ratio 3.41, p?=?0.010). The tumor nest macrophage count significantly correlated with the microvessel density (p?<?0.001). These results imply that tumor stromal macrophages and tumor nest macrophages residing in different tumor microenvironments have distinctive roles.     

Cancer stem cell characteristics, ALDH1 expression in the invasive front of nasopharyngeal carcinoma

The invasive tumor front underlies the biological aggressiveness and epithelial–mesenchymal transition (EMT) in various human malignances. However, the molecular and biological characteristics of invasive tumor front in NPC have rarely been described. Additionally, the features of cancer stem cells (CSCs) in the invasive front of tumors and its correlation with EMT also remain elusive. Our study was to investigate the expression of CSCs marker aldehyde dehydrogenase 1 (ALDH1) in the invasive front of nasopharyngeal carcinoma (NPC) and its clinical significance. Immunohistochemistry was mainly used to detect ALDH1 expression in the invasive front of NPC. The relationship between ALDH1 expression and EMT-associated markers was also examined. ALDH1 expression in the invasive front correlated strongly with lymphatic invasion (p?<?0.001), T classification (p?=?0.001), M classification (p?<?0.001), clinical stage (p?<?0.001), and local recurrence (p?=?0.008). ALDH1 overexpression in the invasive front contributed to worse survival of NPC, particularly in patients with early stage (T1-T2 or N0-N1) (p?<?0.001 and p?=?0.002, respectively), though it was not an independent prognostic factor (p?=?0.196). Furthermore, in the invasive front of NPC, ALDH1 expression correlated significantly with EMT-related biomarkers E-cadherin (p?=?0.026), Vimentin (p?<?0.001), Periostin (p?<?0.001), and Snail (p?<?0.001), but not with β-catenin (p?=?0.143). Our findings demonstrate first that ALDH1 expression in the invasive front links closely with EMT characteristics and tumor aggressiveness, which might provide a useful prognostic marker for NPC patients.     

The presence of sinusoidal CD163+ macrophages in lymph nodes is associated with favorable nodal status in patients with breast cancer

As macrophages are some of the first cells to encounter metastatic tumor cells in sentinel lymph nodes (SLN) and natural killer (NK) cells are critical to the cytotoxicity of abnormal cells, we sought to determine if these cell populations were altered in the presence of nodal metastasis. We used immunohistochemistry to assess the SLN of 47 patients with breast cancer (36 with nodal metastasis and 11 without nodal metastasis) and 10 control lymph nodes. We assessed metastatic areas and nonmetastatic areas separately for CD163, a marker of macrophages, and ANK-1, a marker for precursors of activated NK cells. Positively stained cells were manually counted in multiple high-power fields and averaged. Groups were compared with the Kruskal?CWallis test. Spearman rank order test was used for correlations. There was a lower frequency of CD163⁺ macrophages in the SLN of patients with breast cancer (median, 11.0?%; range, 4.1?C20.4?%) than controls (median, 16.5?%; range, 8.9?C19.6?%; p?=?0.002). There were no differences in the expression of ANK between patients with cancer (median, 1.4?%; range, 0.23?C6.3?%) and controls (median, 1.5?%; range, 0.60?C5.4?%; p?=?0.5). In patients with nodal metastasis, the accumulation of CD163⁺ cells in the sinuses correlated negatively with CD8⁺ tumor-infiltrating lymphocytes (r ²?=?0.23; p?=?0.001). These results suggest that the reduction of CD163⁺ macrophages in the sinuses of the SLN is associated with nodal metastasis and may have a role in regional immunity.     

Loss of nuclear prothymosin-α expression is associated with disease progression in human superficial bladder cancer

In this paper, we report a study on the clinical relevance of prothymosin-α expression and its correlation with intratumoral Foxp3⁺ and CD8⁺ lymphocytes (Foxp3⁺TIL and CD8⁺TIL) in bladder cancer patients. We used immunohistochemical staining for prothymosin-α, Foxp3, and CD8 on 101 tumor specimens harvested by endoscopic resection. The results were correlated with clinicopathological variables and clinical outcome in bladder cancer patients, particularly in 73 patients with superficial disease, using the log-rank test and Cox proportional hazard model. Overall, of the tumors, 30 % were negative, 34 % showed nuclear, and 37 % showed cytoplasmic prothymosin-α expression. Foxp3⁺TILs were detected in 11 % of patients (nonnuclear vs. nuclear, p?=?0.096). Patients with a history of urothelial carcinoma have a higher frequency of nonnuclear prothymosin-α expression than those without (p?=?0.016, chi-square test). By univariate and multivariate analyses of cases with superficial disease, grade and stage were identified as independent predictors for recurrence-free survival (p?=?0.016 and 0.016, respectively). Higher stage and nonnuclear prothymosin-α expression independently predict shorter progression-free survival (p?=?0.006 and 0.043, respectively). The presence of Foxp3⁺TILs was significantly associated with disease progression by univariate analysis (p?=?0.022), but not by multivariate analysis (p?=?0.147). In vitro assays showed that J82 cells which express ectopically nuclear prothymosin-α exhibit higher growth rate and secrete less TGF-β1 than those with cytoplasmic expression or control cells. Altogether, prothymosin-α expression is a determinant of disease progression in superficial bladder cancer. Foxp3⁺TILs tend to be found more often in bladder cancer with nonnuclear prothymosin-α expression. Future study is required to unravel their interaction.     

肿瘤间质比和肿瘤浸润淋巴细胞对淋巴结转移乳腺癌预后的影响

目的探讨肿瘤间质比(tumor-stroma ratio,TSR)和肿瘤浸润淋巴细胞(tumor-infiltrating lymphocytes,TIL)对淋巴结阳性非特殊型浸润性乳腺癌预后的影响。方法采用HE染色法评估260例乳腺原发癌和相应淋巴结转移癌中TSR和原发癌中的TIL对患者预后的影响。结果乳腺原发癌中TSR≥50%(低间质组)148例,TSR<50%(高间质组)112例,低间质组患者总生存率和无瘤生存率明显高于高间质组(P均<0.05);TIL低表达组(TIL<10%)155例,高表达组(TIL≥10%)105例,两组患者总生存率和无瘤生存率差异无统计学意义(P均>0.05)。淋巴结转移癌中TSR≥50%(低间质组)163例,TSR<50%(高间质组)97例,低间质组患者无瘤生存率明显高于高间质组(P<0.05);原发癌和淋巴结转移癌同为低间质组时,原发癌低间质组提示预后更好(P<0.05)。原发癌与淋巴结转移癌中TSR呈明显的正相关(r=0.726,P<0.01)。原发癌低间质组中TIL的表达对预后影响,差异无统计学意义(P均>0.05);高间质组中TIL高表达组无瘤生存率明显高于TIL低表达组(P=0.012)。患者总生存率和无瘤生存率与年龄、肿块直径、组织学分级和阳性淋巴结个数无关(P均>0.05)。结论TSR是判断淋巴结转移的乳腺癌患者预后重要指标,且在原发癌和转移癌之间呈正相关,但原发癌TSR对判断预后更有意义。联合TSR和TIL分析,可为淋巴结阳性的乳腺癌患者预后和临床治疗提供帮助。     

Predictive and prognostic factors in locally advanced breast cancer: effect of intratumoral FOXP3+ Tregs

This study aimed to investigate the prognostic and predictive effect of FOXP3+ Tregs together with clinicopathologic factors in locally advanced breast cancer (LABC) patients. The medical records of 101 LABC patients who received neoadjuvant chemotherapy (NAC) between 2005 and 2012 were evaluated retrospectively. The density of intratumoral FOXP3+ lymphocytes in paraffin-embedded tissues was assessed by immunohistochemical analyses in appropriate cases. The relationship with clinicopathologic features, prognosis and chemotherapy response was investigated. HR(–) and HER2(+) tumors tended to have higher pre-chemotherapy Tregs than HR(+) tumors, and significantly higher pathologic complete response (PCR) rates were observed in these patients. Treg decline after NAC was associated with better pathological response rates. Lower intratumoral infiltration of FOXP3+ Tregs after NAC (<3.4/HPF) was significantly associated with higher PCR rates for breast, and close to the significance limit for total (or both for breast and axillary) PCR rates (PCR for breast: 25 vs. 2.9 % for low vs. high Treg, p = 0.001; PCR for breast + axillary tissue: 13.9 vs. 0 %, p = 0.05). Despite better PCR rates, patients with high intratumoral Treg infiltrates (≥11.5/HPF) before chemotherapy had significantly shorter overall survival than patients with low Treg infiltrates (<11.5/HPF). Cox multivariate regression analyses demonstrated that the density of Treg infiltration before chemotherapy was the strongest predictor for survival. This study established the predictive and prognostic effect of intratumoral FOXP3+ Tregs in LABC patients. To predict clinical outcome, evaluation of FOXP3+ Tregs in tumoral tissues before and after NAC should be considered for these high-risk patients.     

Validation of a simple resazurin-based promastigote assay for the routine monitoring of miltefosine susceptibility in clinical isolates of Leishmania donovani

Simple, cost-effective approach for routine surveillance of parasite susceptibility to antileishmanial drug miltefosine (MIL) is highly desirable for controlling emergence of drug resistance in visceral leishmaniasis (VL). We validated a simple resazurin-based fluorimetric assay using promastigotes to track natural MIL tolerance in Leishmania donovani parasites from VL cases (n?=?17) against standard amastigote assay, in two different labs in India. The inter-stage MIL susceptibility correlated strongly (r?=?0.70, p?=?0.0018) using J774.A.1 macrophage cell line-based amastigote assay and fluorescence-based resazurin assay for promastigotes. Investigation of inter-stage MIL susceptibility for the same set of clinical isolates in another lab also showed a strong correlation (r?=?0.72, p?=?0.0012) using mouse peritoneal macrophages for amastigote assay and resazurin-based alamar blue assay for promastigotes. Additionally, parasites from post-kala-azar dermal leishmaniasis (PKDL) lesions (n?=?7, r?=?0.78, p?=?0.046) and MIL-induced parasites (r?=?0.92, p?=?0.0001; n?=?3) also exhibited a strongly correlated inter-stage miltefosine susceptibility. Thus, our results support the utility of resazurin assay as a simplified biological tool for MIL susceptibility monitoring in clinical isolates from MIL-treated VL/PKDL patients.     

Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer

Purpose

Decreased expression of p27^kip1 and p57^kip2 is considered as a prognostic indicator in patients with breast cancer receiving adjuvant chemotherapy. Previous in vitro studies have reported that reduced expression of p27^kip1 and p57^kip2 is associated with resistance to taxane, which is one of the most effective chemotherapeutic agents. In this study, we investigated the association of low p27^kip1 and p57^kip2 expression with outcomes in patients with breast cancer.

Immune tumoral microenvironment in gliomas: focus on CD3+ T cells,Vδ1+ T cells,and microglia/macrophages

Gliomas are histologically defined as low-grade gliomas (LGG) and high-grade gliomas (HGG). The most common type of HGG is the glioblastoma (GBM). We aimed to determine the immunological characteristics of CD3 T-cells, Vδ1 T-cells, and microglia/macrophages infiltrating brain gliomas. We collected 24 formalin-fixed paraffin-embedded samples issued from 19 cases of GBM and 5 cases of LGG. An immunohistochemical analysis was performed using anti-CD3, anti-Vδ1, and anti-iba-1 antibodies. Labelling indexes (LI) of CD3 and Vδ1 were evaluated quantitatively, and other CD3, Vδ1, and iba-1 staining characteristics were evaluated qualitatively. The median age of patients was 49 years in GBM and 52 years in LGG. The sex ratio was 1.4 and GBM predominated in males (p?=?0.05). In GBM, the medians of CD3-LI and Vδ1-LI were 30 and 3.5 respectively. CD3-LI inversely correlated with survival in GBM cases (r?=????0.543; p?=?0.016). CD3 staining intensity correlated with CD3-LI (p?<?0.0001) and with the survival in GBM cases (p?=?0.003). Compared to LGG, the CD3-LI, the intensity of intra-tumoral Vδ1 staining, and the amount of iba-1 were higher in GBM (p?=?0.042; p?=?0.014; and p?=?0.001 respectively). The iba-1 organization was more amoeboid in older patients and more branched in younger patients (p?=?0.028) and tended to be more amoeboid in cases with high iba-1 amount (p?=?0.09). Our results suggest that a high level of CD3-LI and a strong intra-tumoral infiltration of Vδ1 T-cells as well as a high involvement of TAM can be considered potential markers of poor prognosis of GBM. However, this requires further studies on more balanced GBM-LGG sample, including an expanded panel of biomarkers.

     

Clinicopathological significance of the immunologic signature (PDL1, FOXP3+ Tregs,TILs) in early stage triple-negative breast cancer treated with neoadjuvant chemotherapy

Patients with breast cancer are appropriate candidates for neoadjuvant chemotherapy (NAC) to facilitate conservative surgery. The chemotherapeutic agents may exert their action by inducing the anti-tumor immune response. This study aimed to evaluate the tumor immune microenvironment including PD-L1, Foxp3+ Tregs, and TILs count in early stages TNBC patients (stage T1, T2) before and after neoadjuvant chemotherapy and their correlation with the clinical and pathological response. Fifty patients of TNBC patients were enrolled in this study; all of them received neoadjuvant chemotherapy. TILs count, Foxp3+ Tregs, and PD-L1 immunohistochemical expression were investigated in all cases before NAC and then evaluated in residual masses after surgery. Data on the clinical and pathological response to NAC were collected and then statistically analyzed. PDL1 expression was detected in 24% of all studied cases, all of them were node-positive (P < 0.002); while Foxp3+ Tregs expressed in 50% and high TILs in 28%. Pathological complete response (pCR) was achieved in 40% of patients and was associated with high TILs expression (P < 0.02) and absence of Foxp3+ Tregs and PDL1 (P < 0.001 for each). In conclusion, Pathologic complete response to NAC was associated with the immunological profile of TNBC. High TILs expression with concomitant decreased PD-L1 expression and low FOXP3+ Tregs is associated with favorable tumor prognosis. Combined therapeutic approaches aiming to PD-L1 block and Tregs depletion might improve treatment efficacy in TNBC.     

Expression of ALDH1 and TGFβ2 in benign and malignant breast tumors and their prognostic implications

The specific mechanism underlying the role of putative stem cell marker aldehyde dehydrogenase 1 (ALDH1) playing in development and progression of breast cancer is currently unclear. Transforming growth factor β (TGFβ) signaling pathway is reported to be activated in most cancers. Thus a study was initiated to explore possible differences and correlation of ALDH1 and TGFβ2 expression in the most common malignant and benign tumors of the breast in Chinese women. Samples of 75 breast cancer tissues, 30 paracancerous normal tissues, and 39 fibroadenoma breast tissues were investigated for the expression of ALDH1 and TGFβ2 using immunohistochemistry. The positive rates of ALDH1 and TGFβ2 protein were 62.67% and 66.67%, respectively, in breast cancer tissues, which were significantly higher than that in normal fibroadenoma breast (P<0.05) and paracancerous tissues (P<0.01). ALDH1 and TGFβ2 status were significantly associated with tumor histological grade and receptor status (P<0.05). Expression of ALDH1 was found to be positively correlative to TGFβ2 in breast cancer (r = 0.33, P<0.01). Expression of both proteins remained significantly associated with reduced overall survival (OS) by univariate analysis (P<0.05). Multivariate Cox regression analysis showed that ALDH1 expression, tumor stage, and lymph node status are independent prognostic factors in invasive breast cancer patients. Thus ALDH1 and TGFβ2 play important roles in the development of breast cancer. The ALDH1 phenotype is an independent predictor of poor prognosis, and TGFβ2 signaling pathway activation might be involved in the pathological regulation of ALDH1 in breast cancer.     

Real-world effectiveness of peginterferon α-2b plus ribavirin in a Canadian cohort of treatment-naïve chronic hepatitis C patients with genotypes 2 or 3: results of the PoWer and RediPEN studies

The purpose of this investigation was to assess the real-life effectiveness of pegylated interferon (peg-IFN) α-2b with ribavirin (RBV) in a cohort of treatment-naïve patients with chronic genotypes 2 (G2) or 3 (G3) hepatitis C virus (HCV) infection. A post-hoc pooled analysis of two Canadian multicenter, observational studies, RediPEN and PoWer, was carried out. A total of 1242 G2- or G3-infected patients were included. The primary outcome was sustained virologic response (SVR). Secondary endpoints included early virologic response (EVR), end-of-treatment (EOT) response, and relapse. Multivariate logistic regression was used to identify independent predictors of treatment response. SVR in G2 and G3 was 74.4 % and 63.6 %, respectively. Relapse occurred in 12.7 % and 19.1 % of G2- and G3-infected patients achieving EOT response, respectively. Overall, G3 was found to independently predict reduced SVR [odds ratio (OR)?=?0.20; p?=?0.007] and increased relapse (OR?=?6.84; p?=?0.022). Among G3-infected patients, increasing fibrosis score was the most important factor predicting reduced SVR [F2 vs. F0/F1 (OR?=?0.41; p?=?0.009); F3 vs. F0/F1 (OR?=?0.72; p?=?0.338); F4 vs. F0/F1 (OR?=?0.27; p?=?0.001)]. Male gender (OR?=?13.16; p?=?0.020) and higher fibrosis score [F2 vs. F0/F1 (OR?=?9.72; p?=?0.016); F3/F4 vs. F0/F1 (OR?=?4.23; p?=?0.113)] were associated with increased relapse in G3 patients. These results support the real-life effectiveness of peg-IFN α-2b plus ribavirin in HCV G2- and G3-infected patients. Overall, genotype was identified as the most significant predictor of treatment outcome. Fibrosis score and gender were key outcome predictors in the G3-infected population. In clinical settings, peg-INF/RBV offers an alternative for patients without access to all oral direct-acting antivirals.     

The expression of programmed death-ligand 1 and programmed death-ligand 2 in endometrial carcinosarcoma: Correlation with mismatch repair protein expression status,tumor-infiltrating lymphocyte infiltration,and clinical outcomes

BackgroundEndometrial carcinosarcomas have high malignant potential with a high recurrence rate and poor prognosis. Immunotherapy may be a promising treatment option. The aim of this study is to evaluate the expression of PD-L1/PD-L2 and its relationship to mismatch repair (MMR) protein status and tumor-infiltrating lymphocyte (TIL) density.MethodsWe performed immunohistochemical analyses of PD-L1 (clone 22C3), PD-L2 (clone TY25), MSH-2, MSH-6, PMS-2, and MLH-1 in 77 tumors. We count TILs using CD8 antibody. Clinicopathologic features were recorded and statistically correlated with immunohistochemical results. Kaplan-Meier analyses were used to analyze the prognosis.ResultsWhile PD-L1 positivity was seen more commonly in MMR protein deficient tumors (p = 0.010), PD-L2 positivity was seen more commonly in MMR protein proficient tumors (p = 0.003). PD-L1 positivity was also found to be more common in carcinosarcoma with high TIL infiltration. PD-L2 positivity was associated with decreased overall survival (OS) rates (p = 0.043, p = 0.043, respectively), whereas the PD-L1 positivity and TIL density were not significantly associated with OS rate. The OS rate of patients with MMR protein proficient tumors was significantly lower compared with those with MMR protein deficient tumors (p = 0.042). The lower TILs infiltration was associated with a shorter disease-free survival (DFS) rate. PD-L1 and PD-L2 positivity did not affect the DFS rate.ConclusionsPD-L1/PD-L2 might be a better target for immunotherapy in endometrial carcinosarcoma. PD-L2 positivity was also associated with a worse clinical outcome in patients with endometrial carcinosarcoma, suggesting that PD-L2 status can be used to predict clinical behavior. Further studies are needed to elucidate the relationship between PD-L1/PD-L2 expression and therapeutic response.     

AZGP1 and SPDEF mRNA expression differentiates breast carcinoma from ovarian serous carcinoma

The ANPEP, AZGP1, and SPDEF genes were previously found to be overexpressed in breast compared to ovarian carcinoma effusions. The present study validated this finding in a larger cohort consisting of both primary and metastatic tumors. ANPEP, AZGP1, and SPDEF mRNA expression was investigated in 83 breast carcinomas (57 primary carcinomas and 26 effusions) and 40 ovarian carcinomas (20 primary carcinomas and 20 effusions) using qPCR. ANPEP protein expression was immunohistochemically analyzed in 53 breast carcinoma effusions and patient-matched primary carcinomas (n?=?25) and lymph node metastases (n?=?16). mRNA and protein levels were studied for association with tumor type and anatomic site, and for clinical role in breast carcinoma. AZGP1 and SPDEF mRNA was overexpressed in breast compared to ovarian carcinoma (both p?<?0.001). AZGP1 mRNA was overexpressed in primary breast carcinoma compared to effusions (p?<?0.001), with opposite findings for ANPEP (p?=?0.044). AZGP1 mRNA expression correlated with positive ER status (p?=?0.032) and grade 1 histology (p?=?0.011), whereas SPDEF mRNA levels were associated with positive ER (p?=?0.002) and PR (p?=?0.013) status and tamoxifen treatment (p?=?0.004). ANPEP protein expression was higher in breast carcinoma effusions compared to primary tumors and lymph node metastases (both p?=?0.001). ANPEP, AZGP1, and SPDEF levels were unrelated to disease-free or overall survival. This is the first study documenting ANPEP, AZGP1, and SPDEF expression in breast carcinoma effusions. AZGP1 and SPDEF may be novel molecular markers for the differentiation of breast from ovarian carcinoma. ANPEP may be involved in breast carcinoma progression in view of its overexpression in effusions compared to solid specimens.     

Co-expression of receptors of the HER family correlates with clinical outcome in non-small cell lung cancer (NSCLC)

HER family receptors play a critical role in lung carcinogenesis. There is a growing body of evidence showing that cooperation between them contributes to a more aggressive tumor phenotype and impacts on their response to targeted therapy. We explored immunohistochemical co-expression of HER family receptors (HER1, HER2, HER3, HER4) and its potential role as prognostic factor in resected non-small cell lung cancer (NSCLC). Expression of HER family receptors was assessed by immunohistochemistry on 125 surgically resected NSCLC. Kaplan–Meier estimates of overall survival (OS), disease-free survival (DFS), and time to recurrence were calculated for clinical variables and HER expression, using the Cox model for multivariate analysis. HER1 and HER3 expression was detected more frequently in squamous cell carcinoma (p?=?0.002 and p?=?<0.001, respectively). HER4 was more often expressed in patients older than 60 years (p?=?0.02) and in tumors of low histological grade (p?=?0.04). Cases which expressed only HER1 had a worse DFS (p?=?0.01) and OS (p?=?0.01) compared to cases expressing HER1 and one or more of the other family members and to cases which did not express HER1 but one of the other HERs. By multivariate analysis, stage was an independent prognostic factor for DFS and OS. Furthermore, different patterns of co-expression of HER family receptors showed a statistically significant correlation with a shorter DFS (p?=?0.03) and OS (p?=?0.02). Our findings suggest that expression of HER1 only is correlated with worse DFS and OS. A better understanding of the functional relationships between these receptors may lead to a useful predictive indicator of response to targeted therapy.     

The role of ALDH1A1 in contributing to breast tumour aggressiveness: A study conducted in an African population

Aldehyde dehydrogenase 1 member A1 (ALDH1A1) is one of the most well studied breast cancer stem cells. Its expression has been associated with poor clinicopathological features and clinical outcomes in several studies. This paper studies the expression of ALDH1A1 and its combination with CD44⁺/CD24^−/low breast cancer stem cell and their association with clinicopathological parameters and molecular subtypes.MethodTissue Microarray was constructed from 222 Formalin Fixed Paraffin Embedded (FFPE) breast cancer tissues. The expression of ALDH1A1, CD44 and CD24 were assessed by Immunohistochemistry (IHC). The association of ALDH1A1 and its association with clinicopathological parameters, molecular subtypes, CD44 and CD24 were studied in an African population. The association between CD44⁺/CD24^−/low/ALDH1⁺ and the clinicopathological phenotypes were also studied.ResultsA high ALDH1A1 expression of 90% was recorded in this study. No association was found between ALDH1A1 and clinicopathological parameters. ALDH1A1 was positively associated with CD24 (r = 0.228, OR-4.599 95% CI- 1.751–12.076, p = 0.001) and CD44 (r = 0.228, OR-5.538 95%CI- 1.841–16.662, p = 0.001) but not associated with CD44⁺/CD24^−/low (r = 0.134, OR- 2.720 95%CI- 0.959–7.710, p = 0.052). CD44⁺/CD24⁻/ALDH1⁺ however had significant associations with Age (p- 0.020, r = 0.161, OR- 2.771, 95%CI 1.147–6.697), Gender (p = 0.004, OR- 15.333 95%CI 1.339–175.54), Tumour grade (p = 0.005, r = 0.197, OR-3.913 95%CI 1.421–10.776) and clinical prognostic staging (p = 0.014, r = 0.182, OR-3.028 95%CI- 1.217–7.536). There was no association between CD44⁺/CD24⁻/ALDH1⁺ and the molecular subtypes.ConclusionThe high expression of ALDH1A1 in breast cancer makes it an important target for targeted therapy. This study further confirms the increased tumourigenicity of CD44⁺/CD24⁻/ALDH1⁺ combination phenotype and its association with increased tumour grade and clinical prognostic stage. Survival studies of ALDH1A1 and other breast cancer stem cells in African populations are strongly recommended to help further understand their effect on tumour aggressiveness.     

Impact of serum soluble programed death ligand 1 on end of treatment metabolic response of diffuse large B cell lymphoma patients

Programmed death ligand-1 (PD-L1) plays an important role in the immune evasion of cancer cells and, in turn, can influence the outcome of many malignancies. The serum soluble PD-L1 (sPD-L1) levels were measured in diffuse large B cell lymphoma (DLBCL) patients at diagnosis and at end of treatment. Their impact on end of treatment metabolic response was analyzed. Serum sPD-L1 level was significantly elevated in DLBCL patients at diagnosis than in controls (P?<?0.001). Also, serum sPD-L1 level at diagnosis was significantly higher than that at end of treatment (P?<?0.001). Patients who achieved partial response (PR) had significantly higher serum sPD-L1 level at end of treatment than controls (P?<?0.001). In contrast, all patients especially those who achieved complete response (CR) had insignificantly different serum sPD-L1 level at end of treatment than controls (P?=?0.354 and P?=?0.090, respectively). There was a significant difference between serum sPD-L1 level at diagnosis and that at end of treatment in patients who achieved PR and CR (P?=?0.023 and P?<?0.001, respectively). On univariate analysis, presence of comorbidities, Ann Arbor stage IV, high serum sPD-L1 level at diagnosis and high serum sPD-L1 level at end of treatment were significantly associated with achievement of PR (P?=?0.018 and P?=?0.043, P?=?0.045 and P?<?0.001, respectively). On multivariate analysis, serum sPD-L1 levels at diagnosis and at end of treatment were still influencing metabolic response significantly (P?=?0.014 and P?=?0.007, respectively). Serum sPD-L1 is a predictor for metabolic response to immunochemotherapy in DLBCL patients.     

Impact of IL-28B polymorphisms on pegylated interferon plus ribavirin treatment response in children and adolescents infected with HCV genotypes 1 and 4

IL-28B polymorphisms are predictors of response to therapy in adults infected with hepatitis C. We do not know whether they are markers of response to therapy in children and adolescents. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the IL-28B gene could influence the probability of response to therapy compared with other known baseline prognostic factors and correlate with clinical findings in pediatric patients infected with hepatitis C virus (HCV) genotypes 1 or 4. We determined three SNPs of IL-28B (rs12979860, rs12980275, and rs8099917) in 82 patients with chronic HCV infection treated with pegylated interferon alpha and ribavirin (peg-IFNα/RBV). Treatment response and clinical data were analyzed. Overall, sustained virological response (SVR) was achieved by 45 % of patients infected with difficult-to-treat HCV genotypes 1 and 4. Except for IL-28B polymorphisms, there was no association of SVR with any other clinical data. IL-28B rs12979860 CC [odds ratio (OR), 6.81; p?=?0.001] and rs8099917 TT (OR,?3.14; p?=?0.013) genotypes were associated with higher SVR rates. IL-28B rs12980275 was not significantly associated with SVR (p?=?0.058). Only the distribution between CC and CT–TT genotypes of rs12979860 significantly differentiated patients achieving early virological response (EVR) (OR,?10.0; p?=?0.011). Children with the rs12979860 CC genotype had significantly higher baseline viral load compared with CT–TT patients (p?=?0.010). In children and adolescents chronically infected with HCV genotypes 1 and 4, IL-28B rs12979860 and rs8099917 polymorphisms were the only predictors of response to peg-IFN/RBV.     

Prognostic value of c-FLIPL/s,HIF-1α, and NF-κβ in stage II and III rectal cancer

Locally advanced rectal cancer (LARC) is associated with a 25 % rate of metastases. The prognostic and predictive relevances of the expression of five proteins (c-FLIP_L/s, HIF-1α, β-catenin, p65, and p105/p50 NF-κβ) were assessed. This is a retrospective study. From 1998 to 2009, 152 patients with stage II/III rectal cancer were treated with radio-chemotherapy. TMAs constructed with tumor and normal tissue from the diagnostic endoscopic biopsy and the surgical specimen after chemoradiotherapy were subjected to immunohistochemical (IHC) analysis. Results were correlated with clinical and pathological data, including progression-free survival (PFS). Four different IHC conditions were independent prognostic parameters for PFS: (1) cytoplasmic c-FLIP_L/s (p?=?0.007), (2) nuclear HIF-1α (p?=?0.020), (3) a change in the cytoplasmic p65 between the diagnostic biopsy and the post-treatment specimen (p?=?0.004), and (4) a change in the cytoplasmic c-FLIP_L/s between the diagnostic biopsy and the post-treatment specimen (p?=?0.021). Three different protein expression profiles, combining biomarkers, showed prognostic significance. IHC evaluation of these biomarkers in our three protein expression profiles may help to identify patients with worse prognosis and design more effective therapeutic strategies to personalize the treatment of rectal cancer.