Elevated cyclooxygenase-2 expression correlates with diminished survival in carcinoma of the cervix treated with radiotherapy

Purpose: The purpose of this study was to examine the relationship between overall survival and prognostic factors in carcinoma of the cervix treated with radiation therapy. A clinicopathologic study was performed on 24 patients.

Methods and Materials: Formalin-fixed, paraffin-embedded tumor biopsies were stained for Cyclooxygenase-2 (COX-2), Topoisomerase I, Topoisomerase II, and p53. Clinical factors such as stage, grade, tumor size, pre- and post-treatment hemoglobin level, and radiotherapy dose were also evaluated.

Results: Median follow-up was 75 months for living patients. The only immunohistochemical or clinical factor that was associated with improved survival was decreased COX-2 distribution staining. High COX-2 distribution staining was associated with decreased overall survival (p = 0.021) and decreased disease-free survival (p = 0.015) by log-rank comparison of Kaplan-Meier survival curves. The 5-year overall survival rates for tumors with low vs. high COX-2 distribution values were 75% and 35%, respectively. COX-2 staining intensity was found to correlate positively with tumor size (p = 0.022).

Conclusion: These findings indicate that increased expression of COX-2 portends a diminished survival in patients with invasive carcinoma of the cervix treated with radiotherapy. Because COX-2 is an early-response gene involved in angiogenesis and inducible by different stimuli, these data may indicate opportunity to intervene with specific inhibitors of COX-2 in carcinoma of the cervix.     

Topoisomerase IIα expression correlates with diminished disease-free survival in invasive breast cancer

PURPOSE: Topoisomerase II alpha (Topo II alpha) plays a role in DNA replication and is the molecular target for anthracyline-based chemotherapy. The purpose of this study was to evaluate the relationship between Topo II alpha expression and survival in patients with invasive breast cancer. METHODS AND MATERIALS: Formalin-fixed, paraffin-embedded tumor specimens from 24 women with invasive breast cancer were stained for Topo II alpha expression. All women underwent mastectomy. Radiotherapy was given at the University of Utah Department of Radiation Oncology. Of the patients, 23 (96%) received chemotherapy. The level of Topo II alpha expression within tumor cells was compared with clinical factors and overall survival. RESULTS: The median percentage of tumor cells expressing Topo II alpha was 70%. Increased Topo II alpha tumor expression significantly correlated with diminished disease-free survival. Five-year disease-free survival was 100% for patients with <70% of breast cancer cells expressing Topo II alpha compared with 42% for patients with > or =70% Topo II alpha expression (p = 0.008). The level of Topo II alpha expression within tumor cells correlated with T stage (p = 0.008) but not with other pathologic factors. CONCLUSIONS: Increased Topo II alpha expression significantly correlated with diminished disease-free survival in patients with invasive breast cancer. These findings may indicate a role for Topo II alpha expression as a prognostic factor in breast cancer.     

The survival of inoperable breast cancer treated with radiotherapy and radiotherapy followed by mastectomy

Forty-five patients with locally advanced breast carcinoma were treated by radiotherapy. Twelve of them became operable and were operated. After 3 and 4 years in comparable clinical stage the rate of metastases in the nonoperated group was 78.6% and in the operated 75%. The survival after 3 and 4 years in comparable clinical stages was similar. In more advanced stages the survival was worse. Considering the trauma of mastectomy and the similar survival obtained in our material, an international trial should be performed to decide whether inoperable breast cancer becoming operable after radiotherapy should be operated.     

Thymidine phosphorylase expression correlates with tumor differentiation and bcl-2 in invasive breast cancer

BACKGROUND: Angiogenesis plays an important role in the growth and metastasis of solid tumors. Several angiogenic factors have been identified, and thymidine phosphorylase (TP) is thought to be one such factor. To date, little information is available on the relationship between TP and other clinicopathological variables. METHODS: Formalin-fixed, paraffin-embedded materials from 116 primary breast carcinomas were used. The expression of TP, estrogen receptor, Bcl-2, Bax, p53, c-erbB-2 and MIB-1 was examined by immunohistochemical methods. RESULTS: Nuclear and/or cytoplasmic TP expression was observed in the neoplastic cells, and accentuation of TP was often present at the infiltrating tumor edge and intraductal spread region. Tumor cell TP expression was significantly inversely correlated with histological grade (p< 0.05) and positively correlated with Bcl-2 expression, but no association with other tumor variables was found. CONCLUSIONS: TP is associated with Bcl-2 expression and tumor differentiation in breast cancer. TP may be a new prognostic parameter for breast cancer.     

浸润性乳腺癌乳房切除术联合Ⅰ期重建后放疗相关问题研究现状

随着对外形美观的要求越来越高,越来越多患者在乳房切除术后会选择不同类型重建手术。对于这部分患者,怎样的综合治疗时序可以让患者在外形美观和抗肿瘤治疗疗效间取得平衡、得到最大获益,是目前多学科治疗关注的重要问题。本文从术后放疗对乳房重建的美容影响、组织扩张器和永久性假体置换与术后放疗的时序关系以及乳房重建手术和放疗技术的最新进展做一综述。笔者综合现有文献报道以及临床实践总结了重建手术与辅助治疗的整体决策推荐流程图,为临床实践提供参考。     

Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival

Angiogenic factors produced by tumor cells are essential for tumor growth and metastasis. In our study, the expression of Angiopoietin-1 (ANG1) and Angiopoietin-2 (ANG2) mRNA in archival human breast cancer tumor samples and in 6 breast cancer cell lines was investigated. Total RNA from biopsies of 38 breast cancer patients was extracted and ANG1 and ANG2 mRNA expression was measured by means of quantitative real-time RT-PCR (Taqman). Matching data with available clinicopathologic and biochemical data revealed a significant association between ANG2 expression and axillary lymph node invasion. Univariate and multivariate survival analysis, by means of Kaplan-Meier method and Cox's proportional hazards model, showed significant and independent association between ANG2 mRNA level and both disease-free (p < 0.0001) and overall survival (p < 0.0003). An important fact is that, notwithstanding the small number of cases examined, this association was confirmed also in the group of lymph node-negative patients (DFS, p < 0.003; OS, p < 0.020). Immunohistochemical analysis demonstrated that Ang2 is expressed by both tumor cells and endothelial elements. Expression in tumor cells was confirmed by studying a panel of human breast carcinoma cell lines in culture by RT-PCR. In ZR75.1 and T47D cells, expression of ANG2 mRNA was increased up to 10-fold by treatment with estrogen within 24 hr. Although preliminary, these data suggest a possible role of ANG2 as a prognostic factor for primary breast cancer.     

Cyclooxygenase-2 gene expression in human breast cancer

Expression of the inducible isoform of the cyclooxygenase gene (PGHS-2, COX-2) which codes for the enzyme that catalyzes formation of prostaglandins, was detected in 13/13 human breast tumors of high grade but not in samples of normal breast tissue. There was a statistically significant linear association between COX-2 gene expression and high (>50%) tumor cell density (p<0.01), with COX-2 protein localized to tumor cells. These results indicate that COX-2 gene expression may be useful as a molecular biomarker for human breast tumors and may also predict sensitivity to treatment with nonsteroidal anti-inflammatory drugs.     

Three cases of breast cancer with skin metastasis after mastectomy treated by radiotherapy

We reported three cases of patient with triple negative skin metastasis after mastectomy of breast cancer. All three cases had received radiotherapy for skin metastasis. Radiation therapy was effective for recurrent sites, and could improve patient's QOL. After radiotherapy, 2 patients died due to a distant metastasis. Case 1 was resistant to chemotherapy. Case 2 was no indication of chemotherapy because of dementia metastases. Case 3 was the only one continued chemotherapy. It appears that a further consideration was needed for the timing of radiotherapy to be performed among the treatments of locoregional recurrence and distant metastasis of breast cancer.     

Locoregional recurrence risks in elderly breast cancer patients treated with mastectomy without adjuvant radiotherapy

This study examined tumour and treatment characteristics in elderly women treated with mastectomy without radiotherapy and compared their outcomes to younger counterparts. Data were analysed for 2362 women aged 50 years and older referred to the British Columbia Cancer Agency, Canada between 1989 and 1997. The women had invasive T1-4, N0-N3, M0 breast cancer treated with mastectomy without adjuvant radiotherapy. Clinical characteristics and patient outcomes were compared between two age cohorts: 50-69 (n = 1423) and 70+ years (n = 939). Median follow-up was 8.3 years. Tumours > 5 cm were present in 5% of women aged 50-69 and 3.5% of women aged 70+, respectively. The distribution of nodal stage was similar in the two age cohorts but older women were more likely to have fewer axillary nodes removed (P = 0.009). Fewer women aged 70+ had grade III histology (P = 0.002) and estrogen receptor (ER)-negative status (P < 0.001). The rates of systemic therapy use were comparable in the two age groups. With tumours > 5 cm, locoregional recurrence (LRR) were 13.7% and 30.0% in women aged 50-69 and 70+, respectively. With 1-3 positive nodes (N+), LRR were 14.8% and 13.0% in women aged 50-69 and 70+. In the presence of 4 N+, LRR were 16.8% and 30.8% in women aged 50-69 and 70+. On multivariate analysis, age was not significantly associated with LRR (P = 0.62). Independent prognostic factors for LRR were grade III histology, lymphovascular invasion and positive nodal status. This study suggests that despite more favourable tumour characteristics and comparable systemic therapy use, women aged 70+ years have similar or higher postmastectomy LRR risks compared to younger women. Chronologic age alone should not preclude these women from consideration of adjuvant radiotherapy.     

Loco-regional recurrence in 2064 patients with breast cancer treated with mastectomy without adjuvant radiotherapy.

INTRODUCTION: We investigated the incidence of loco-regional recurrence in a sub-group of patients who underwent mastectomy without adjuvant radiotherapy to evaluate the effect of each specific clinical or pathological parameter that could be associated with a higher local relapse rate. PATIENTS AND METHODS: Two thousand and sixty-four patients were treated from January 1971 to December 2003 at the University of Florence. RESULTS: At the time of analysis 18.3% of patients (378/2064) had isolated loco-regional failures. Univariate analysis showed an association of borderline statistical significance with pathological tumour size. Elderly age at diagnosis had a low incidence of local recurrence but the results did not reach statistical significant. The number of positive axillary lymph node did not show any influence for local recurrence. CONCLUSION: In our series we noted a higher relapse rate only related to the pathological tumour size without any correlation with number of positive axillary nodes. Radiotherapy after mastectomy still remains controversial, but in our series the number of positive axillary lymph node did not seem enough to justify adjuvant treatment.     

Cyclooxygenase-2 expression during immortalization and breast cancer progression

Identification of molecular aberrations in premalignant human mammary epithelial cells (hMEC), the precursors for breast cancers, is a central goal in breast cancer biology. Recent studies implicated expression of cyclooxygenase 2 (COX-2) as a marker to identify precursor cells for breast cancer. In this study, we analyzed COX-2 expression in preselection and postselection hMEC cells and observed similar COX-2 levels in both cells. Interestingly, immortalization of postselection cells using various methods leads to a dramatic decrease in COX-2 expression. Similar to immortal cells, the majority of breast cancer cell lines expressed low levels of COX-2 protein. Finally, analyses of COX-2 expression in a series of specimens from reduction mammoplasty, adenosis, ductal carcinoma in situ, and infiltrating ductal carcinoma showed down-regulation of COX-2 expression during tumor progression. Importantly, down-regulation of COX-2 using small interfering RNA in cells showed no effect on cell proliferation, anchorage-independent growth, migration, or invasion. These results show that (a) COX-2 overexpression does not seem to predict a breast cancer precursor cell and does not provide advantage for the cell to be transformed; (b) inhibition of COX-2 does not affect hMEC growth and oncogenic behavior in the conditions analyzed; and (c) COX-2 expression is decreased in breast cancer cell lines and cancer specimens as compared with normal mammary epithelial cells.     

Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy

PURPOSE: The purpose of this study was to describe regional nodal failure patterns in patients who had undergone mastectomy with axillary dissection to define subgroups of patients who might benefit from supplemental regional nodal radiation to the axilla or supraclavicular fossa/axillary apex. METHODS AND MATERIALS: The cohort consisted of 1031 patients treated with mastectomy (including a level I-II axillary dissection) and doxorubicin-based systemic therapy without radiation on five clinical trials at M.D. Anderson Cancer Center. Patient records, including pathology reports, were retrospectively reviewed. All regional recurrences (with or without distant metastasis) were recorded. Median follow-up was 116 months (range, 6-262 months). RESULTS: Twenty-one patients recurred within the low-mid axilla (10-year actuarial rate 3%). Of these, 16 were isolated regional failures (no chest wall failure). The risk of failure in the low-mid axilla was not significantly higher for patients with increasing numbers of involved nodes, increasing percentage of involved nodes, larger nodal size or gross extranodal extension. Only 3 of 100 patients with <10 nodes examined recurred in the low-mid axilla. Seventy-seven patients had a recurrence in the supraclavicular fossa/axillary apex (10-year actuarial rate 8%). Forty-nine were isolated regional recurrences. Significant predictors of failures in this region included > or = 4 involved axillary lymph nodes, >20% involved axillary nodes, and the presence of gross extranodal extension (10-year actuarial rates 15%, 14%, and 19%, respectively, p < 0.0005). The extent of axillary dissection and the size of the largest involved node were not predictive of failure within the supraclavicular fossa/axillary apex. CONCLUSIONS: These results suggest that failure in the level I-II axilla is an uncommon occurrence after modified radical mastectomy and chemotherapy. Therefore, supplemental radiotherapy to the dissected axilla is not warranted for most patients. However, patients with > or = 4 involved axillary lymph nodes, >20% involved axillary nodes, or gross extranodal extension are at increased risk of failure in the supraclavicular fossa/axillary apex and should receive radiation to undissected regions in addition to the chest wall.     

Mammographic breast density and survival in women with invasive breast cancer

Cancer Causes & Control - We explored the under-debate association between mammographic breast density (MBD) and survival. From the Piedmont Cancer Registry, we identified 693 invasive breast...     

局部晚期乳腺癌新辅助化疗和改良根治术后放疗价值分析

目的 分析局部晚期乳腺癌患者neoCT和改良根治术后放疗的价值,以及探讨能否根据化疗疗效进行个体化放疗。 方法 选取本院1999—2013年收治的临床Ⅲ_A、Ⅲ_B期乳腺癌病例,完成neoCT和改良根治术的 523例纳入分析,其中 404例术后行放疗,119例未行放疗。用Kaplan-Meier法计算复发率和生存率,Logrank法单因素预后分析,Cox模型多因素预后分析。 结果 放疗组患者 5年LRR显著低于未放疗组(13.9%∶24.8%,P=0.013),DFS显著高于未放疗组(64.1%∶53.9%,P=0.048),OS相近(83.2%∶78.2%,P=0.389)。ypT₃—T₄、ypN₂—N₃以及病理Ⅲ期亚组中放疗患者 5年LRR显著低于未放疗患者(P<0.05),放疗患者 5年OS显著高于未放疗患者(P<0.05)。158例ypN₀期放疗患者 5年LRR显著低于未放疗患者(P=0.004)。41例ypCR患者仅 2例LRR,均未放疗。多因素分析显示放疗是影响全组及ypN₀期患者LRR的因素。 结论 放疗显著降低临Ⅲ_A、Ⅲ_B期乳腺癌neoCT和改良根治术后患者LRR,同时降低ypT₃—T₄、ypN₂—N₃和病理Ⅲ期亚组患者复发率、死亡率。目前尚无充足证据可以根据化疗反应免除ypN₀期和pCR患者术后放疗。     

非小细胞肺癌环氧合酶-2表达与血管生成之间的关系

背景与目的:我们以前的研究发现,环氧合酶-2(COX-2)在非小细胞肺癌(NSCLC)上调表达是患者独立预后的不良因素。COX-2参加结肠癌等实体瘤的血管生成,是否参与NSCLC血管生成目前尚有争议。本研究的目的是探讨COX-2表达与血管生成和血管内皮细胞生长因子(VEGF)-A表达之间的关系。方法:用脂质体将表达COX-2反义核酸的质粒和空质粒分别稳定转染H1299细胞(H1299-AS和H1299-P),采用RT-PCT和W esternB lot法检测细胞株COX-2和VEGF-A的水平。应用免疫组织化学染色法检测60例NSCLC肿瘤组织COX-2、VEGF-A和CD31表达情况,用χ2检验分析这些参数间相互关系。结果:H1299-AS细胞株COX-2 mRNA和蛋白水平较H1299-P细胞明显下降;VEGF-A蛋白表达水平亦同步下降。肺腺癌COX-2表达率为77%,显著高于肺鳞癌的37%(P<0.05)。NSCLC中COX-2和VEGF-A表达与肿瘤微血管密度明显相关(r分别为0.55和0.42,P<0.05)。COX-2表达阴性患者肿瘤微血管密度为45.7±15.6根/200×视野,显著高于不表达患者的37.4±9.7根/200×视野(P<0.05)。NSCLC组织中COX-2表达水平和微血管密度与患者术后生存期明显相关(P<0.05)。结论:NSCLC存在COX-2和VEGF-A共表达,COX-2可能通过诱导VEGF-A表达来发挥促血管生成样作用。     

改良根治术后腋窝淋巴结阳性乳腺癌放疗效果与ER、PR及HER2相关性分析

目的 探讨改良根治术后腋窝淋巴结阳性乳腺癌放疗效果与雌激素受体（ER）、孕激素受体（PR）及人类表皮生长因子受体2（HER2）的相关性.方法 选取福建医科大学附属漳州市医院2008年1月至2013年1月乳腺外科收治的进行改良根治术的腋窝淋巴结阳性的乳腺癌患者350例,其中216例接受了放疗,134例未接受放疗,根据ER、PR及HER2的免疫组织化学结果,将所有患者分为三阴性乳腺癌（ER-/PR-/HER2-）、HER2阳性（ER-/PR-/HER2＋）、Luminal B（ER ＋/PR＋/HER2＋）及Luminal A（ER ＋/PR ＋/HER2-）4组,比较放疗对4组患者局部复发率、远处转移率和无瘤生存率的影响.结果 中位随访48个月,放疗降低了三阴性乳腺癌、HER2阳性、Luminal B及Luminal A 4组患者的局部复发率（x2=6.23,P=0.01;x2=8.02,P=0.00;x2=15.43,P=0.00;x2 =4.47,P=0.03）,且前3组放疗患者的远处转移率（x2=4.18,P=0.04;x2 =6.35,P=0.01;x2=43.31,P=0.00）和无瘤生存率（x2=9.78,P=0.00;x2=10.83,P=0.00;x2=16.95,P=0.00）相对于未放疗患者差异具有统计学意义.但放疗对Luminal A组患者的远处转移率和无瘤生存率无影响（P＞0.05）.结论 不同的ER、PR和HER2状态对于改良根治术后腋窝淋巴结阳性乳腺癌患者的放疗结果具有一定影响.     

Contralateral mastectomy improves survival in women with BRCA1/2-associated breast cancer

BRCA1/2 mutation carriers with breast cancer are at high risk of contralateral disease. Such women often elect to have contralateral risk-reducing mastectomy (CRRM) to reduce the likelihood of recurrence. This study considers whether CRRM improves overall survival. 105 female BRCA1/2 mutation carriers with unilateral breast cancer who underwent CRRM were compared to controls (593 mutation carriers and 105 specifically matched) not undergoing CRRM and diagnosed between 1985 and 2010. Survival was assessed by proportional hazards models, and extended to a matched analysis using stratification by risk-reducing bilateral salpingo-oophorectomy (RRBSO), gene, grade and stage. Median time to CRRM was 1.1 years after the primary diagnosis (range 0.0–13.3). Median follow-up was 9.7 years in the CRRM group and 8.6 in the non-CRRM group. The 10-year overall survival was 89 % in women electing for CRRM (n = 105) compared to 71 % in the non-CRRM group (n = 593); p < 0.001. The survival advantage remained after matching for oophorectomy, gene, grade and stage: HR 0.37 (0.17–0.80, p = 0.008)—CRRM appeared to act independently of RRBSO. CRRM appears to confer a survival advantage. If this finding is confirmed in a larger series it should form part of the counselling procedure at diagnosis of the primary tumour. The indication for CRRM in women who have had RRBSO also requires further research.     

Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer.

PURPOSE: Chronic inflammation is linked to the development of cancer in several organs, including the prostate. Up-regulated cyclooxygenase-2 (COX-2) may play a role in influencing cell proliferation, differentiation, apoptosis, or angiogenesis. This study aimed to derive data from human prostate cancer to investigate whether chronic inflammation and angiogenesis were correlated with the expression of COX-2. EXPERIMENTAL DESIGN: In this study, we did double-immunohistochemical analysis of a set of 43 human prostate cancer for COX-2 expression and the correlation with T-lymphocyte and macrophage densities and CD31-marked microvessel density (MVD) in situ. RESULTS: COX-2 positive staining was detected in 40/43 cancer samples with the very heterogeneous expression. Elevated COX-2 expression was associated with high Gleason score (P = 0.002). Foci of chronic inflammation were found in all 43 samples. COX-2-positive areas were noted with high T-lymphocyte and macrophage densities than COX-2-negative tumor areas (P < 0.0001 and P = 0.001, respectively). MVD were also found higher in COX-2-positive areas than in COX-2-negative tumor areas (P = 0.001). CONCLUSIONS: This study shows a novel relationship between COX-2 expression and the local chronic inflammation within prostate cancer and the increased angiogenesis. It is likely that the proinflammatory cytokines, released by T-lymphocytes and macrophages, up-regulate COX-2 in adjacent tumor cells and stimulate the angiogenesis in stromal tissues. These findings suggest that COX-2 may be an effective therapeutic target in prostate cancer treatment.