The complex between urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-I) independently predicts response to first-line endocrine therapy in advanced breast cancer

It has been shown that urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-I) have predictive value for therapy success in advanced breast cancer. Levels of the complex between uPA and PAI-I, formed when both molecules are in their active form, might have superior predictive power. Here, we investigate the association between levels of uPA:PAI-I complex and rate of response to first-line systemic therapy for advanced breast cancer. Tumor tissues of 170 patients with advanced breast cancer were analyzed for uPA:PAI-I complex concentrations using a quantitative enzyme-linked immunosorbent assay. The patients received either endocrine therapy (n=96) or chemotherapy (n=74) as first-line treatment after diagnosis of advanced disease. Of the endocrine treated patients, those with high levels of uPA:PAI-I complex showed a shorter progression-free survival (PFS) compared to patients with lower uPA:PAI-I complex levels (P=0.035). Furthermore, in the multivariate regression analysis a significant lower rate of response to first-line endocrine therapy was found in patients with high uPA:PAI-I complex levels compared to patients with low uPA:PAI-I complex levels (odds ratio (OR)=0.27, 95% CI, 0.09-0.59, P=0.018), in addition to the predictive impact of the steroid hormone receptor (ER/PgR) status (OR=2.68, 95% CI, 1.08-6.63, P=0.033). Complex levels did not predict efficacy of chemotherapy in patients with advanced breast cancer. The results show that the plasminogen activation system affects the response to endocrine therapy independent of steroid hormone receptor status and may be of help to further refine the indication for this treatment in individual patients. Further studies are warranted to explain this underlying resistance to endocrine therapy when uPA:PAI-I levels are high.     

Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients

In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-1 survival analyses, reflecting the interaction between nodal status and uPA/PAI-1. The estimates for uPA and PAI-1 were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-1 were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-1 are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.     

Expression of plasminogen activator inhibitors type 1 and type 3 and urokinase plasminogen activator protein and mRNA in breast cancer

BACKGROUND: The urokinase plasminogen activator (uPA) system has been involved in cancer cell invasion and in metastasis. uPA activity is controlled by its principal inhibitor, the PA inhibitor type-1 (PAI-1), but it can also be inhibited by PAI-3. Increased levels of uPA and PAI-1 are known to be associated with a poor prognosis in breast cancer. To our knowledge this is the first study of the expression and role of PAI-3 in human breast cancer tissue. MATERIALS AND METHODS: Protein and mRNA levels were evaluated for uPA, PAI-1 and PAI-3 in breast cancer tissues from 70 different patients. The localization of antigen and mRNA of these proteins was studied by immunohistochemistry and in situ hybridization, respectively. RESULTS: No significant differences were observed for PAI-3 mRNA or protein levels between the nodal status groups or the different post-surgical tumor-node-metastasis (pTNM) stages. However, uPA and PAI-1 mRNA and antigen levels significantly increased at the pTNM stage and in node-positive patients. PAI-3 antigen levels were significantly higher in early relapse-free patients, whereas PAI-1 antigen levels were significantly higher in patients who suffered a relapse. PAI-3 protein and mRNA were localized in stromal cells. PAI-1 and uPA protein were detected in cancer, endothelial and stromal cells and their mRNA mainly in stromal cells. CONCLUSIONS: Our results indicate that PAI-3 is expressed in human breast cancer tissues, and that elevated levels of PAI-3 could be a positive prognostic factor in this disease. A potential mechanism for the contribution of PAI-3 to a positive long-term outcome may involve suppression of tumor invasion through protease inhibition in stroma.     

Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis

In recent decades, evidence has been accumulating showing the important role of urokinase-type plasminogen activator (uPA) in growth, invasion, and metastasis of malignant tumours. The evidence comes from results with animal tumour models and from the observation that a high level of uPA in human tumours is associated with a poor patient prognosis. It therefore initially came as a surprise that a high tumour level of the uPA inhibitor plasminogen activator inhibitor-I (PAI-I) is also associated with a poor prognosis, the PAI-I level in fact being one of the most informative biochemical prognostic markers. We review here recent investigations into the possible tumour biological role of PAI-I, performed by animal tumour models, histological examination of human tumours, and new knowledge about the molecular interactions of PAI-I possibly underlying its tumour biological functions. The exact tumour biological functions of PAI-I remain uncertain but PAI-I seems to be multifunctional as PAI-I is expressed by multiple cell types and has multiple molecular interactions. The potential utilisation of PAI-I as a target for anti-cancer therapy depends on further mapping of these functions.     

ERP amplitude and latency in breast cancer survivors treated with adjuvant chemotherapy.

OBJECTIVE: Neurocognitive problems that were observed in a number of breast cancer survivors treated with adjuvant chemotherapy initiated a series of EEG studies to examine the neurophysiological basis of these deficits. The aim of the present study was to examine the effects of various regimens of adjuvant chemotherapy on the N1 and P3 component of the event-related potential (ERP) in breast cancer patients 3-6 years after treatment. METHODS: Fifty-three breast cancer patients treated with various chemotherapy regimens were compared to 23 stage I breast cancer patients not treated with chemotherapy. An auditory oddball task was used to study the amplitude, latency and structure of the potential field of the N1 and P3. RESULTS: Patients treated with chemotherapy showed lower P3 amplitudes than patients not treated with chemotherapy. Differences were also observed in P3 latency between patients treated with different chemotherapy regimens. CONCLUSIONS: Our results indicate a general effect of all chemotherapy regimens under study on P3 amplitude and a more specific chemotherapeutic effect on P3 latency. SIGNIFICANCE: The present study provides evidence for the notion that different chemotherapy regimens have different effects on brain functioning.     

Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen

The primary aim of the current study was to examine whether neurocognitive functioning among breast cancer survivors (BCS) exposed to systemic adjuvant chemotherapy differs from that seen among BCS who did not receive chemotherapy. The performance of each of these BCS groups was compared to a demographically matched comparison group without history of breast cancer, a group not included in the majority of previous cognitive functioning studies. We also sought to explore whether usage of the anti-estrogen drug tamoxifen, a common component of breast cancer treatment, was related to neurocognitive functioning. Finally, we wished to examine the relationship between subjective report of cognitive functioning and objective performance on neurocognitive measures among BCS. Fifty-three survivors of breast cancer (all between 2-5 years after diagnosis and initial surgical removal of cancerous tissue) and 19 healthy non-BCS comparison subjects were administered a comprehensive neurocognitive battery, and measures of mood, energy level, and self-reported cognitive functioning. Those BCS who received adjuvant chemotherapy performed significantly worse in the domains of verbal learning, visuospatial functioning, and visual memory than BCS treated with surgery only. Those who received both chemotherapy and tamoxifen showed the greatest compromise. Although patients who received chemotherapy (with and without tamoxifen) performed worse than those treated with surgery only on several domains, neither group was significantly different from demographically matched comparison subjects without a history of breast cancer. Finally, we found no relationship between subjective cognitive complaints and objective performance, although cognitive complaints were associated with measures of psychological distress and fatigue. We highlight ways in which these data converge with other recent studies to suggest that systemic chemotherapy, especially in combination with tamoxifen, can have adverse yet subtle effects on cognitive functioning.     

乳腺癌化疗后轻度认知功能障碍的行为干预

目的探讨认知行为干预对乳腺癌化疗患者认知功能的影响。方法选取2015-01—2015-12我科收治的乳腺癌术后化疗患者60例为研究对象,随机分为干预组30例和对照组30例。对照组行常规治疗,干预组在常规治疗的基础上给予认知行为干预。应用蒙特利尔评估量表(MoCA)分别测试2组化疗前后的认知功能情况。结果 2组年龄、文化程度、病理分期及化疗前认知功能比较,差异无统计学意义(P0.05)。干预组化疗后MoCA评分高于对照组,记忆能力、注意力、执行能力比较差异有统计学意义(P0.05)。结论认知行为干预能显著提高乳腺癌术后化疗患者的认知功能。     

Depression and abnormal illness behavior in cancer patients

Evaluation of the incidence of depression among cancer patients has been the object of a number of studies. Recent reports of medically ill patients have indicated that depression is related to several dimensions of abnormal illness behavior (e.g., hypochondriasis, irritability, denial, disease conviction). To investigate the relationship between depression and abnormal illness behavior in cancer patients, a study was conducted of 196 patients with a recent diagnosis of cancer and with a good performance status (Karnofsky score > 80). The Hamilton Depression Rating Scale (HDRS) and the Illness Behavior Questionnaire (IBQ) were administered in their validated Italian forms. A cutoff point of 17 on the HDRS revealed 38.26% of the patients as having symptoms of depression, whereas a more conservative cutoff point of 21 indicated a depressive state in 23.97% of the patients. Depressed patients had higher scores on all the IBQ dimensions except that of psychologic versus somatic perception of illness. The results were confirmed by the correlation between the parameters. Higher levels of denial were reported by females and by patients receiving adjuvant or palliative chemotherapy, who had, however, lower levels of dysphoria than patients not receiving treatment. Higher levels of irritability were shown in hospitalized patients. No relationship was found between medical status variables (Karnofsky score, tumor status, and disease extent) and psychologic measures, except for denial. The findings seem to confirm the importance of assessment of depression and illness behavior in cancer patients and suggest the need for more thorough investigation of the psychosocial variables associated with them.     

Late effects of high‐dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: Converging results from multimodal magnetic resonance imaging

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high‐dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract‐based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H‐MRS) in the left centrum semiovale (white matter) showed a reduction of N‐acetylasparate/creatine indicative of axonal injury. Voxel‐based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H‐MRS only in the chemotherapy group. These results converge to suggest that high‐dose adjuvant chemotherapy for breast cancer is associated with long‐term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Predictors of inflammation in response to anthracycline-based chemotherapy for breast cancer

Although chemotherapy for breast cancer can increase inflammation, few studies have examined predictors of this phenomenon. This study examined potential contributions of demographics, disease characteristics, and treatment regimens to markers of inflammation in response to chemotherapy for breast cancer. Thirty-five women with stage I-III-A breast cancer (mean age 50 years) were studied prior to cycle 1 and prior to cycle 4 of anthracycline-based chemotherapy. Circulating levels of inflammatory markers with high relevance to breast cancer were examined, including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), Interleukin-1 receptor antagonist (IL1-RA), vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), Interleukin- (IL-6), soluble P-selectin (sP-selectin), and von Willebrand factor (vWf). Chemotherapy was associated with elevations in VEGF (p < or = 0.01), sICAM-1 (p < or = 0.01), sP-selectin (p < or = 0.02) and vWf (p < or = 0.05). Multiple regression analysis controlling for age and body mass index (BMI) showed that higher post-chemotherapy levels of inflammation were consistently related to higher pre-chemotherapy levels of inflammation (ps < or =0.05) as well as to certain disease characteristics. Post-chemotherapy IL-6 levels were higher in patients who had larger tumors (p < or = 0.05) while post-chemotherapy VEGF levels were higher in patients who had smaller tumors (p < or = 0.05). Post-chemotherapy sP-selectin levels were highest in women who had received epirubicin, cytoxan, 5-fluorouracil chemotherapy (p < or = 0.01). These findings indicate that chemotherapy treatment can be associated with elevations in certain markers of inflammation, particularly markers of endothelial and platelet activation. Inflammation in response to chemotherapy is most significantly related to inflammation that existed prior to chemotherapy but also potentially to treatment regimen and to certain disease characteristics.     

Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer

This investigation used a non-randomized controlled design to evaluate the effect and feasibility of a mindfulness based stress reduction (MBSR) program on immune function, quality of life (QOL), and coping in women recently diagnosed with breast cancer. Early stage breast cancer patients, who did not receive chemotherapy, self-selected into an 8-week MBSR program or into an assessment only, control group. Outcomes were evaluated over time. The first assessment was at least 10 days after surgery and prior to adjuvant therapy, as well as before the MBSR start-up. Further assessments were mid-MBSR, at completion of MBSR, and at 4-week post-MBSR completion. Women with breast cancer enrolled in the control group (Non-MBSR) were assessed at similar times. At the first assessment (i.e., before MBSR start), reductions in peripheral blood mononuclear cell NK cell activity (NKCA) and IFN-γ production with increases in IL-4, IL-6, and IL-10 production and plasma cortisol levels were observed for both the MBSR and Non-MBSR groups of breast cancer patients. Over time women in the MBSR group re-established their NKCA and cytokine production levels. In contrast, breast cancer patients in the Non-MBSR group exhibited continued reductions in NKCA and IFN-γ production with increased IL-4, IL-6, and IL-10 production. Moreover, women enrolled in the MBSR program had reduced cortisol levels, improved QOL, and increased coping effectiveness compared to the Non-MBSR group. In summary, MBSR is a program that is feasible for women recently diagnosed with early stage breast cancer and the results provide preliminary evidence for beneficial effects of MBSR; on immune function, QOL, and coping.     

Étude de la participation des patientes au choix thérapeutique en oncologie

The aim of this study is to help patients with breast cancer express their preferences concerning adjuvant chemotherapy and to observe how they perceive and experience the information and the situation of choice. Ten women with breast cancer without axillary extension were observed. We choose to use the decision board method, which consists of both a printed interview guide and a visual aid, designed to inform patients as objectively as possible, to help them choose between two options, chemotherapy or no chemotherapy. Based on interviews with patients we investigated how the patients perceive information given and the situation of choice with which they have been confronted. The results of this study show how patients reached their decision and what factors intervene in the decision process. This study underlies the difficulties of the health care decision process and shows how the patients react when faced with the information and the choice. The most interesting observation is that patients don’t make a rational choice according to the information given by the decision board, but mainly make an irrational choice based on the interpretation of the physician’s intent.     

Monocyte procoagulant activity in breast cancer

Abnormalities of blood coagulation associated with neoplasia may be important in the pathogenesis of tumour spread. Most patients with advanced malignancy have evidence of activated coagulation, but the mechanisms underlying this are unclear. We have examined in vitro monocyte procoagulant activity and compared this to plasma levels of fibrinopeptide A, in 52 patients with clinically localised breast cancer. Patients with localised breast cancer and activated coagulation displayed a strong positive correlation between monocyte procoagulant activity and level of fibrinopeptide A(r = +0.86, p less than 0.001). No such relationship was demonstrated in a smaller number of patients with metastatic breast cancer. It is concluded that monocyte procoagulant activity plays an important role in coagulation activation in patients with localised breast cancer. The implications of this for adjuvant anticoagulant therapy in breast cancer are discussed.     

Psychological intervention and health outcomes among women treated for breast cancer: a review of stress pathways and biological mediators

Breast cancer is a common cancer among American women. The diagnosis, treatment, and the challenges of survivorship all have potential to increase women’s levels of distress to levels that might influence their adaptation and possibly the course of their disease. Psychological distress can influence tumor progression via many different pathways (e.g., genetic changes, immune surveillance, pro-angiogenic processes). Psychological intervention has been shown to facilitate psychological adaptation to breast cancer. But can psychological intervention influence cancer relevant biological outcomes among breast cancer survivors? We review the literature on how psychological intervention can influence cancer relevant biological outcomes among breast cancer patients. We limited the present review to randomized controlled trials reported in the past 6 years that tested the effects of psychological intervention on biological dependent variables among patients with non-metastatic breast cancer. There are data to suggest that psychological intervention can influence neuroendocrine (e.g., cortisol) and immune function indicators, especially lymphocyte proliferation and TH1 cytokine production. Future psychological intervention studies should also focus on more newly discovered stress-tumor pathways (e.g., neuroendocrine processes promoting tumor growth and metastasis) and follow larger cohorts of the more vulnerable patients over longer periods to evaluate the biobehavioral mechanisms and lasting effects of these interventions on health and quality of life.     

Indication of a role of plasminogen activator inhibitor type I in protecting murine fibrosarcoma cells against apoptosis

In a number of cancer types high tumor tissue levels of plasminogen activator inhibitor type 1 (PAI-1) protein are strongly associated with shorter cancer patient survival. This association has been intriguing since PAI-1 is known to inhibit urokinase plasminogen activator (uPA) that converts plasminogen to plasmin, which is actively involved in tumor progression and invasion. In order to further explore the biological role of PAI-1 in cancer, we have prepared fibroblasts from PAI-1 gene deficient mice and from their wild type littermates. From these fibroblasts fibrosarcoma cell lines were established and characterized. Both types of fibroblasts underwent spontaneous transformation as indicated by aneuploidy, immortalization, clonogenicity in soft agar and tumor formation in vivo. While both PAI-1 deficient and PAI-1 expressing cell lines showed similar proliferation rates in vitro, cells devoid of PAI-1 were significantly more sensitive to apoptotic stimuli. When inoculated subcutaneously into nude mice PAI-1 expressing cells rapidly established tumors, while PAI-1 deficient cells had a significantly longer lag-phase before they started to grow (p<0.0001). The present study suggests that PAI-1, besides its uPA inhibiting function, has a role in cancer progression by protecting tumor cells from undergoing apoptosis.     

Emotional reactions to the diagnosis and treatment of early breast cancer

Forty-four patients with early breast cancer were interviewed before mastectomy and on three occasions during the following year about psychiatric symptomatology, and their emotional reactions to various aspects of the illness and its treatment. Eight patients developed symptoms of depressive illness. Thirty-five patients expressed emotional distress related to the diagnosis or the loss of the breast or both. All ten who had adjuvant chemotherapy considered this the most unpleasant aspect of treatment. Post-operative distress could often be predicted by a high score on the General Health Questionnaire, or a high level of expressed concern before the operation.     

PAI-I 4G/5G polymorphism and sudden cardiac death in patients with coronary artery disease.

The 4G/5G polymorphism of the plasminogen activator inhibitor type I (PAI-I) gene is involved in coronary artery disease (CAD), with the highest risk in 4G/4G homozygotes. The role of PAI-I polymorphism in patients suffering from CAD and history of sudden cardiac death (SCD) has not been addressed yet. We studied the frequency distribution of the PAI-I gene to test the hypothesis that the 4G/4G genotype favors myocardial ischemia and, even in the absence of acute infarction, promotes SCD in patients with CAD. Methods: The PAI-I 4G/5G genotypes and PAI-I antigen plasma levels were determined in 97 patients with CAD and a history of SCD treated with an implantable cardioverter defibrillator (ICD) (defibrillator group) comparing to 113 patients with CAD but no history of SCD (control group). Results: The defibrillator group consisted of significantly more 4G/4G homozygotes and higher PAI-I levels than the control group (44% vs. 24%, 173+/-41 vs. 144+/-49 ng/ml; P<.01). The carriers of 4G allele had a significantly higher risk for SCD (odds ratio (OR) 1.9) with the highest risk in the 4G/4G genotype (OR 3.6, P<.01). Conclusion: These results suggest that the PAI-I 4G/4G genotype is associated with SCD in patients suffering from CAD.     

A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer

Given the improvement in mortality rates associated with breast cancer, the importance of understanding the long-term neuropsychological consequences of chemotherapy is becoming increasingly vital. This study applies meta-analytic techniques to the scant literature on the relationship between contemporary adjuvant chemotherapy treatment for breast cancer and cognitive dysfunction as examined through neuropsychological indices. Seven studies (involving more than 300 participants) were selected from over 200 potential articles, based on three inclusion criteria: presence of breast cancer, administration of chemotherapy treatment, and use of neuropsychological tests. From these, nine treatment-control comparisons were used to generate 129 Hedge's d effect sizes across the cognitive domains of simple attention, working memory short- and long-term memory, speed of processing, language, spatial abilities, and motor function. Small to medium cumulative effect sizes, showing diminished cognitive function for chemotherapy treatment groups compared to control groups, were obtained for each of the eight cognitive domains. Overall, these results suggest that women who undergo adjuvant chemotherapy as treatment for breast cancer may experience subtle yet consequential cognitive decline.     

VEGF、uPA在侵袭性垂体腺瘤中的表达及意义

目的探讨血管内皮生长因子（VEGF）、尿激酶型血纤溶酶原激活剂（uPA）在侵袭性垂体腺瘤和非侵袭性垂体腺瘤中的表达及其临床意义。方法应用免疫组化法检测26例侵袭性垂体腺瘤和20例非侵袭性垂体腺瘤中VEGF、uPA的表达，并结合临床资料分析。结果VEGF和uPA在侵袭性垂体腺瘤的表达明显高于在非侵袭性垂体腺瘤中的表达，VEGF和uPA的表达水平与垂体腺瘤的侵袭性正相关。其中uPA在垂体腺瘤中的表达强度高于VEGF。结论VEGF和uPA与垂体腺瘤侵袭性生长及复发相关。