β-Glucuronidase levels in patients with fibrocystic breast disease

Certain enzymes in tissues and body fluids may, through reversal of the detoxification process, influence the composition and availability of steroid hormones, toxins, and carcinogens. The ubiquitous enzyme -glucuronidase, which hydrolyzes glucuronide conjugates, thereby reversing one of the main detoxification and excretion pathways, was found to vary in concentration in different cysts over a 300-fold range. The distribution was a continuum, devoid of discrete sub-populations. Evidence obtained on selected cyst fluids of high and low -glucuronidase activities indicated that the level of the enzyme significantly influenced the ratio of unconjugated: glucuronidated estradiol. The patients with fibrocystic breast disease fell into 2 distinct subpopulations on the basis of their serum -glucuronidase activity. In one group the activity was near normal, while in the second group the average serum -glucuronidase activity was 3-fold higher than in the women who did not have benign breast disease.     

Can core biopsy be used instead of surgical biopsy in the diagnosis and prognostic factor analysis of breast carcinoma?

PURPOSE: The aim of this article was to investigate the efficacy of ultrasonography-guided core needle biopsy and prognostic factor analysis of breast cancer to plan overall treatment strategy. PATIENTS AND METHODS: A consecutive series of nonpalpable and palpable breast cancers constituted our study group (n= 201 lesions; mean size, 20.4 mm) Mean number of core samples was 3.4. Malignant lesions diagnosed with core biopsy underwent therapeutic surgical excision. Core biopsy and surgical excisions were compared for histologic type, grade, estrogen receptors (ERs), progesterone receptors (PgRs), and c-erbB2 levels. Cutoff values for ER, PgR, and c-erbB2 affecting the management strategy were selected as 10%, 10%, and 50%, respectively. RESULTS: Eighty-five lesions (42.3%) were malignant in core biopsy (mean size, 18.4 mm). Among these, 11 were inoperable and 13 were surgically excised at other institutions. In 61 lesions, core and surgical excision specimens were evaluated in the same institution (mean tumor size, 18.6 mm; range 6-60 mm). Concordance between the 2 biopsy methods was 85.2% (52 of 61) for histologic type of tumor, 68.8% (33 of 48) for tumor grade, 90% (27 of 30) for ER, 86.7% (26 of 30) for PgR, and 79.3% (23 of 29) for c-erbB2 levels. Appropriate site selection for sampling was indicated to be of paramount importance, especially in determining reliable ER, PgR, and c-erbB2 levels. CONCLUSION: Core needle biopsy of breast cancer is equally effective compared with surgical biopsy and can be used in overall treatment planning. However, appropriate site selection for sampling should be guaranteed using ultrasonographic guidance.     

The impact of sentinel lymph node biopsy in patients with a core biopsy diagnosis of ductal carcinoma in situ

Background  

When ductal carcinoma in situ (DCIS) is found on core biopsy, histological underestimation can occur due to sampling error. When an invasive cancer is subsequently found, another operation is required for nodal staging. Sentinel lymph node biopsy (SLNB) enables nodal staging at the same operation. We examine the value of SLNB in patients with a preoperative diagnosis of DCIS focusing on the need for reoperation.     

Expression of TGF-β1 and the mechanism of invasiveness and metastasis induced by TGF-β1 in breast cancer

Objective To investigate the expression of MMP-2,TIMP-2,TGF-β1 and TGF-βRI and the relationship among them in breast cancer.Methods The protein expression of MMP-2,TIMP-2,TGF-β1 and TGF-β1R1 was detected on tissue chips by S-P immunohistochemical staining in 160 cases of breast carcinoma.Results The positive rates of TGF-β1,TGF-β1 mRNA,MMP-2,MMP-9,TIMP-1 and TIMP-2 expression were 73.7%,56.2%,96.9%,95.0%,87.5% and 89.4%,respectively.Axillary lymph node metastasis and TNM staging(P ＜0.01 and P ＜0.01,respectively)were positively correlated to the expression of TGF-β1.Relase-free survival of TGF-β1 positive group was lower than that of TGF-β1 negative group(P = 0.023).The expression of M MP-2 or M M P-9 was positively correlated to that of TGF-β1 (r=0.170,P＜0.05;r =0.221,P＜0.01)and was negatively correlated to that of TGF-β1 mRNA(r =-0.126,P ＞0.05;r = 0.019,P ＞ 0.05).Conclusion The expression of TGF-β1 may be closely correlated with the invasion and metastasis of breast cancer.TGF-β1-induced invasiveness and metastasis of breast cancer cells are mediated by MMP-2 and MMP-9.     

Association of TGF-β1 -509C/T polymorphisms with breast cancer risk: evidence from an updated meta-analysis

Epidemiological studies have evaluated the association between transforming growth factor-β1 (TGF-β1) -509C/T polymorphisms and breast cancer risk. However, the results remain conflicting rather than conclusive. The aim of this study was to comprehensively clarify the association between TGF-β1 -509C/T polymorphisms and breast cancer risk. All relevant studies were searched in the electronic databases. The potential sources of heterogeneity were detected with the chi-square-based Q test. The strength of associations between TGF-β1 -509C/T polymorphisms and breast cancer risk was measured by odds ratio (OR) and 95 % confidence intervals (CI). Publication bias was tested by Begg’s test and Egger’s test. A total of 10 studies including 10,913 cases and 14,187 controls were included in the meta-analysis. Overall, there was no evidence of significant association of TGF-β1 -509C/T polymorphisms with breast cancer risk (TT vs. CC [OR?=?0.97, 95 % CI?=?0.83–1.14]; CT vs. CC [OR?=?1.05, 95 % CI?=?0.90–1.22]; TT?+?CT vs. CC [OR?=?0.99, 95 % CI?=?0.91–1.08]; T allele vs. C allele [OR?=?0.99, 95 % CI?=?0.93–1.06]). Similar results were also found in the subgroup analyses by ethnicity and source of control. When stratified by estrogen receptor (ER) status, TT genotype and T allele were associated with a decreased ER-positive breast cancer risk (OR?=?0.66, 95 % CI?=?0.49–0.90 and OR?=?0.85, 95 % CI?=?0.75–0.96, respectively). The present meta-analysis results suggest that TGF-β1 -509C/T variants may not contribute to the risk of breast cancer overall. However, T allele may be a potential protective factor for developing ER-positive breast cancer. Well-designed studies with larger sample size were required to verify our findings further.     

Relationship of serum levels of VEGF and TGF-β1 with radiosensitivity of elderly patients with unresectable non-small cell lung cancer

This study aimed to evaluate the relationship of serum levels of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) with radiosensitivity of elderly patients with unresectable non-small cell lung cancer (NSCLC) receiving three-dimensional conformal radiation therapy (3D-CRT). Fifty-eight elderly patients with unresectable NSCLC and 40 healthy controls were enrolled in this study. Serum levels of VEGF and TGF-β1 were detected by the enzyme-linked immunosorbent assay (ELISA) method before and after 3D-CRT. Clinical performances of serum VEGF and TGF-β1 levels in predicting radiosensitivity of NSCLC patients with 3D-CRT were evaluated. Serum VEGF and TGF-β1 levels of NSCLC patients were higher than those of health controls (all p?<?0.05). After 3D-CRT treatment, 41 patients achieved effective clinical response (complete response (CR)?+?partial response (PR)) and 17 patients were ineffective clinical response (stable disease (SD)?+?progressive disease (PD)). There was no significant difference in the VEGF and TGF-β1 levels between the effective and ineffective groups before 3D-CRT (all p?>?0.05). Serum levels of VEGF and TGF-β1 after 3D-CRT in the effective group were lower compared with the levels before 3D-CRT treatment (p?<?0.001 and 0.027, respectively). However, no significant differences in serum VEGF and TGF-β1 levels between before and after 3D-CRT in the ineffective group were observed (p?=?0.196 and 0.517, respectively). We observed significant differences in serum VEGF and TGF-β1 levels between the effective and ineffective groups after 3D-CRT (p?<?0.001 and 0.013, respectively). Sensitivity and specificity of VEGF combined with TGF-β1 in predicting radiosensitivity of NSCLC patients with 3D-CRT were 87.8 and 94.1 %, respectively. In conclusion, our results indicate that serum VEGF and TGF-β1 levels may accurately predict radiosensitivity of elderly patients with unresectable NSCLC receiving 3D-CRT.     

Staging the axilla in women with breast cancer： the utility of preoperative ultrasound-guided needle biopsy

Preoperative staging of the axilla in women with invasive breast cancer using ultrasound-guided needle biopsy（UNB） identifies approximately 50% of patients with axillary nodal metastases prior to surgical intervention. Although moderately sensitive, it is a highly specific staging strategy that is rarely falsely-positive, hence a positive UNB allows patients to be triaged to axillary lymph-node dissection（ALND） avoiding potentially unnecessary sentinel node biopsy（SNB）. In this review, we extend our previous work through an updated literature search, focusing on studies that report data on UNB utility. Based on data for 10,934 breast cancer patients, sourced from 35 studies, a positive UNB allowed triage of 1,745 cases（simple proportion 16%） to axillary surgical treatment： the utility of UNB was a median 19.8% [interquartile range（IQR） 11.6%-26.7%] across these studies. We also modelled data from a subgroup of studies, and estimated that amongst patients with metastases to axillary nodes, the odds ratio（OR） for high nodal disease burden for a positive UNB versus a negative UNB was 4.38 [95% confidence interval（95% CI）： 3.13, 6.13], P〈0.001. From this model, the estimated proportion with high nodal disease burden was 58.9%（95% CI： 50.2%, 67.0%） for a positive UNB, whereas the estimated proportion with high nodal disease burden was 24.6%（95% CI： 17.7%, 33.2%） if UNB was negative. Overall, axillary UNB has good clinical utility and a positive UNB can effectively triage to ALND. However, the evolving landscape of axillary surgical treatment means that UNB will have relatively less utility where surgeons have modified their practice to omission of ALND for minimal nodal metastatic disease.     

Clinical significance of serum transforming growth factor-beta 1 (TGF-β1) levels in patients with epithelial ovarian cancer

Transforming growth factor-beta 1 (TGF-β1) plays an important role in the pathogenesis of multiple malignancies, and its expression also strongly affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of TGF-β1 in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum TGF-β1 concentrations were determined by the solid-phase sandwich ELISA method. Thirty age- and sex-matched healthy controls were included in the analysis. Median age of patients was 56.5 years old (range 22 to 83 years). Majority of the patients had advanced disease (FIGO stage III–IV; 90 %). There was no significant difference in baseline serum TGF-β1 levels between EOC patients and the controls (p?=?0.39). A trend to significant relationship was found between the serum levels of TGF-β1 and stage of disease (p?=?0.06). The elevated serum TGF-β1 level was associated with metastatic disease. The other known clinical variables including histology, grade of histology, debulking surgery, and serum CA 125 levels were not found to be correlated with serum TGF-β1 concentrations (p?>?0.05). Only the chemotherapy-unresponsive patients had higher serum TGF-β1 levels compared with responsive ones (p?=?0.02). Serum TGF-β1 concentration was found to have no prognostic role for both progression-free and overall survivals (p?=?0.42 and p?=?0.09, respectively). In conclusion, although the serum level of TGF-β1 has no diagnostic and prognostic role, it is associated with sensitivity to standard chemotherapy in EOC patients.     

Association of tissue promoter methylation levels of APC, TGFβ2, HOXD3 and RASSF1A with prostate cancer progression

Aberrant promoter methylation is known to silence tumor-suppressor genes in prostate cancer (PCa). We correlated quantitative promoter methylation levels of APC, TGFβ2 and RASSF1A in 219 radical prostatectomies diagnosed between 1998 and 2001 with clinicopathological follow-up data available including Gleason Pattern (GP), Gleason Score (GS) and pathological stage and explored their potential in predicting biochemical recurrence using univariate and multivariate analyses. We observed that the average methylation levels of APC increased significantly from GS ≤ 6 to GS7, and pT2 to pT3a, and that of TGFβ2 increased from GS ≤ 6 to GS7, but not for RASSF1A. PCa samples were also stratified into high methylation (HM) and low methylation (LM) groups based on the PMR scores of all cases analyzed for each marker. The HM frequency of APC was greater in pT3a than pT2, and in GS ≥ 8 than GS ≤ 6. The HM frequency also increased significantly from GP3 to GP4 for APC, TGFβ2 and RASSF1A. APC methylation level was a significant predictor of biochemical recurrence in univariate analysis (p-value = 0.028). Finally, we combined methylation data of these three genes with the previously reported novel methylation biomarker HOXD3. Quantitative methylation assessment of a multiplex panel of markers, consisting of APC, HOXD3 and TGFβ2, outperforms any single marker for the prediction of biochemical recurrence (p-value = 0.017). Our study demonstrated that quantitative increase in promoter methylation levels of APC, HOXD3 and TGFβ2 are associated with PCa progression.     

Cost–utility of adjuvant zoledronic acid in patients with breast cancer and low estrogen levels

Background

Adjuvant zoledronic acid (za) appears to improve disease-free survival (dfs) in women with early-stage breast cancer and low levels of estrogen (lle) because of induced or natural menopause. Characterizing the cost–utility (cu) of this therapy could help to determine its role in clinical practice.

Methods

Using the perspective of the Canadian health care system, we examined the cu of adjuvant endocrine therapy with or without za in women with early-stage endocrine-sensitive breast cancer and lle. A Markov model was used to compute the cumulative costs in Canadian dollars and the quality-adjusted life-years (qalys) gained from each adjuvant strategy, discounted at a rate of 5% annually. The model incorporated the dfs and fracture benefits of adjuvant za. Probabilistic and one-way sensitivity analyses were conducted to examine key model parameters.

Results

Compared with a no-za strategy, adjuvant za in the induced and natural menopause groups was associated with, respectively, $7,825 and $7,789 in incremental costs and 0.46 and 0.34 in qaly gains for cu ratios of $17,007 and $23,093 per qaly gained. In one-way sensitivity analyses, the results were most sensitive to changes in the za dfs benefit. Probabilistic sensitivity analysis suggested a 100% probability of adjuvant za being a cost-effective strategy at a threshold of $100,000 per qaly gained.

Conclusions

Based on available data, adjuvant za appears to be a cost-effective strategy in women with endocrine-sensitive breast cancer and lle, having cu ratios well below accepted thresholds.     

Association of ErbB1–4 expression in invasive breast cancer with clinicopathological characteristics and prognosis

Background

Human epidermal growth factor receptor type 2 (Her2)/ErbB2 plays a key role in the initiation and progression of invasive breast cancer. However, the prognostic relevance to breast cancer patients of the other ErbB family members has long been a matter of debate.

Methods

In a series of 250 primary invasive breast cancer patients, we performed a comprehensive analysis of ErbB1–4 at the levels of mRNA expression and gene copy number using real-time quantitative PCR. The relationship between the status of ErbB1–4 and the clinicopathological characteristics or prognosis was evaluated.

Results

The mRNA expression of ErbB2, but not the other ErbB genes, was significantly correlated to copy number (P = 0.0005). ErbB3 and ErbB4 mRNA expression were positively correlated to each other (P < 0.0001). The mRNA expression of ErbB1/2 was inversely correlated to estrogen receptor (ER) and progesterone receptor (PgR) positivity, although mRNA expression of ErbB3/4 was positively correlated to ER and PgR positivity. Kaplan-Meier survival analysis showed that ErbB1 mRNA expression was associated with reduced survival. Neither ErbB2 nor ErbB3 mRNA expression had any association with survival, because half of the patients with Her2-positive tumors were treated with trastuzumab. High ErbB4 mRNA expression showed good prognosis with respect to breast cancer-specific survival

Conclusions

ErbB3 and ErbB4 mRNA expression, as well as well as that of ErbB1 and ErbB2, could be histopathological factors. ErbB3 mRNA was highly expressed in ER-positive tumors and has controversial prognostic value. ErbB4 mRNA expression was well correlated with ER positivity and good prognosis, indicating that ErbB4 may contribute to ER-dependent growth.     

Is sextant biopsy a valid method in diagnosis of prostatic cancer?

We evaluated effectiveness of a laterally directed sextant biopsy on large prostates and analysed the results of this biopsy technique in a group of men with obstructive voiding symptoms and suspected prostatic cancer (PC). Biopsy was performed in 386 men because of elevated PSA and/or abnormality in digital rectal examinations (DRE). The mean prostate volume was 79.6 +/- 39.1 cm3, and in 72.3% of the cases the volume of the prostate was > or = 50 cm3. PC was diagnosed in 107 of 386 cases (27.7%). In groups of patients with < 50 cm3 (small), 50 to 79 cm3 (medium) and > or = 80 cm3 (large) prostate volume and normal DRE, PC was detected in 27.5, 19.4 and 9.5% of cases, respectively (p < 0.018). PC detection rate was statistically insignificant (SI) in the same groups of patients with abnormal findings at DRE, 49.2, 54.2 and 51.9%, respectively (SI). Repeat sextant biopsy revealed PC in 14.5% patients. After TURP prostatic cancer was found in 7.7% patients who had undergone biopsy two times before. Thus, our results show that laterally directed sextant biopsy is an effective method of PC detection among suspected patients (PSA > 4 ng/ml) with large volume prostates and abnormal findings at DRE. An extensive biopsy protocol should be considered as a more appropriate method for markedly enlarged prostates with normal DRE findings but also for repeat biopsies.     

Ultrasound-guided core needle biopsy of the breast: does frozen section give an accurate diagnosis?

Reducing the period of uncertainty between the discovery of a breast tumor and histological diagnosis alleviates the psychological impact of breast cancer to an important degree. We aimed to verify whether histological results obtained with frozen sections of core needle biopsies (CNBs) offer an accurate and reliable tool for minimising this period. In 2619 cases we compared histological diagnosis on frozen sections with those on paraffin sections of CNB and finally with the results of open biopsies. Of the cases 49% were proved malignant and 51% benign. In 99.3% of the malignant lesions preceding CNB was correctly classified as B5 (n = 1185, 92.9%) or at least B4 (n = 82, 6.4%) in frozen and in paraffin sections. There were seven false-negative cases in frozen (false-negative rate = 0.5%) and five false-negative cases (false-negative rate = 0.4%) in paraffin sections of CNB. On frozen sections complete sensitivity was 99.5% and the positive predictive value of B5 was 99.9%. There was one false-positive case in frozen sections and one in paraffin sections. False-positive rate = 0.08%, negative predictive value for B2 = 99.4% for frozen and 99.6% for paraffin sections; full specificity was 85.9 for frozen and 85.8 for paraffin sections of CNBs. Immediate investigation of CNB in frozen sections is an accurate diagnostic method and an important step in reducing psychological strain on patients with breast tumors and may be offered by specialised Breast Assessment Units.     

Different associations of estrogen receptor β isoforms, ERβ1 and ERβ2, expression levels with tumor size and survival in early- and late-onset breast cancer

Background

In breast cancer, little is known about the consequences of co-expression of ERα with the second estrogen receptor, ERβ, and its isoforms in light of their joint prognostic value. Previously reported correlations have been based mostly on independent ERα and ERβ expression levels in breast tumors.

Purpose

To address whether the expression ratio of ERα and ERβ and its isoforms may be a more important parameter than their absolute levels, we analyzed relative mRNA expression ratios of ERβ1 to ERβ2 and ERα in 74 clinical samples of invasive breast cancer including 39 early-onset and 35 late-onset breast cancers. Expression levels were correlated with clinical and histopathological parameters and disease-free interval.

Results

A specific correlation of ERβ1 expression levels with tumor size was detected in early-onset breast cancer patients and of ERβ2 levels with tumor size in late-onset patients. Expression of both ERβ isoforms inversely correlated with expression of the two estrogen regulated genes, progesterone receptor and pS2 in both groups. Higher levels of ERβ2 than ERβ1 isoform were associated with a better outcome in late-onset patients.

Conclusions

Our results suggest that different isoforms of ERβ may be involved in suppression of tumor growth in young and elder patients and may have different prognostic values.     

The clinical impact of breast scintigraphy acquired with a breast specific γ-camera (BSGC) in the diagnosis of breast cancer: incremental value versus mammography

We investigated the clinical impact of breast scintigraphy acquired with a breast specific γ-camera (BSGC) in the diagnosis of breast cancer (BC) and assessed its incremental value over mammography (Mx). A consecutive series of 467 patients underwent BSGC scintigraphy for different indications: suspicious lesions on physical examination and/or on US/MRI negative at Mx (BI-RADS 1 or 3), characterization of lesions suspicious at Mx (BI-RADS 4), preoperative staging in lesions highly suggestive of malignancy at Mx (BI-RADS 5). Definitive histopathological findings were obtained in all cases after scintigraphy: 420/467 patients had BC, while 47/467 patients had benign lesions. The scintigraphic data were correlated to Mx BI-RADS category findings and to histology. The incremental value of scintigraphy over Mx was calculated. Scintigraphy was true-positive in 97.1% BC patients, detecting 96.2% of overall tumor foci, including 91.5% of carcinomas ≤10 mm, and it was true-negative in 85.1% of patients with benign lesions. Scintigraphy gave an additional value over Mx in 141/467 cases (30.2%). In particular, scintigraphy ascertained BC missed at Mx in 31 patients with BI-RADS 1 or 3, including 26 patients with heterogeneously/high dense breast (19/26 with tumors ≤10 mm) and detected additional clinically occult ipsilateral or controlateral tumor foci (all <10 mm) or the in situ component sited around invasive tumors in 77 BC patients with BI-RADS 4 or 5, changing surgical management in 18.2% of these cases; moreover, scintigraphy ruled out malignancy in 33 patients with BI-RADS 4. BSGC scintigraphy proved a highly sensitive diagnostic tool, even in small size carcinoma detection, while maintaining a high specificity. The procedure increased both the sensitivity of Mx, especially in dense breast and in multifocal/multicentric disease, and the specificity as well as it better defined local tumor extension, thus guiding the surgeon to a more appropriate surgical treatment.