Randomised controlled trial of cultural-adapted and programme-adopted cognitive behavioural therapy for children and adolescents' anxiety in Japan: protocol for a Multi-, Inter-, and Cross-cultural Clinical Child Study (MIXCS).

INTRODUCTION: The primary objective of the Multi-, Inter-, and Cross-cultural Clinical Child Study (MIXCS) is to evaluate the hypothesis that the effects of cultural-adapted cognitive behavioural therapy (CA-CBT) and programme-adopted cognitive behavioural therapy (PA-CBT) for children and adolescents' anxiety are both superior to a psychological control (moral education control: MEC) for reducing child and adolescent anxiety disorders and symptoms as well as related constructs. The secondary objective is to explore commonalities and differences in therapy factors between CA-CBT and PA-CBT. METHOD AND ANALYSIS: The study has been designed as a randomised, controlled and assessor masked multicentre superiority trial with three groups: CA-CBT, PA-CBT and MEC. Primary outcome is remission of primary anxiety disorders evaluated by independent evaluators. Secondary outcomes are clinician's severity ratings, child self-reported anxiety symptoms, depressive symptoms, cognitive errors and family accommodation, as well as parent-reported anxiety symptoms, and family accommodation. Competence and adherence of treatment, therapy factors in treatment sessions are also measured based on behavioural observation. Finally, satisfaction and comprehension are collected. We aim to recruit at least 99 families for the analysis. Treatment will be delivered weekly for 10 sessions and assessment will be conducted 2 weeks before the treatment (pre), 3 months after the base date when the treatment starts (post), 6 months (six months follow-up) and 12 months (12 months follow-up) after the postassessment. ETHICS AND DISSEMINATION: The MIXCS study was approved by Doshisha University Research Ethics Review Committee, Kwansei Gakuin University Institutional Review Board for Medical and Biological Research Involving Human Subjects and Shinshu University Certified Review Board of Clinical Research. Regardless of the results, the primary outcome will be published in a journal, and if the efficacy and effectiveness of CA-CBT and/or PA-CBT are empirically supported, the authors will encourage dissemination of the programmes including the assessment system through key stakeholders in education, health, and welfare areas. TRIAL REGISTRATION NUMBER: UMIN000038128.

Association between the Rostral Anterior Cingulate Cortex and Anterior Insula in the Salience Network on Response to Antidepressants in Major Depressive Disorder as Revealed by Isolated Effective Coherence.

INTRODUCTION: Functional connectivity is attracting increasing attention for understanding the pathophysiology of depression and predicting the therapeutic efficacy of antidepressants. In this study, we evaluated effective connectivity using isolated effective coherence (iCoh), an effective functional connectivity analysis method developed from low-resolution brain electromagnetic tomography (LORETA) and estimated its practical usefulness for predicting the reaction to antidepressants in theta and alpha band iCoh values. METHODS: We enrolled 25 participants from a depression treatment randomized study (the GUNDAM study) in which electroencephalography was performed before treatment. We conducted iCoh between the rostral anterior cingulate cortex (rACC) and anterior insula (AI), which are associated with the salience network. The patients were divided into responder and nonresponder groups at 4 weeks after the start of treatment, and iCoh values were compared between the two groups. Additionally, the sensitivity and specificity of iCoh were calculated using the receiver-operating characteristic (ROC) curve. RESULTS: The Mann-Whitney U test showed significantly weaker connectivity flow from the rACC to the left AI in the alpha band in the responder group. The ROC curve for the connectivity flow from the rACC to the left AI in the alpha band showed 82% sensitivity and 86% specificity. DISCUSSION/CONCLUSION: These findings suggest the pathological importance of effective connectivity flow from the rACC to the left AI in the alpha and theta bands and suggest its usefulness as a biomarker to distinguish responders to antidepressants.

Disentangling cognitive inflexibility in major depressive disorder: A transcranial direct current stimulation study.

BACKGROUND: Cognitive dysfunction is a persistent residual symptom in major depressive disorders (MDDs) that hinders social and occupational recovery. Cognitive inflexibility is a typical cognitive dysfunction in MDD and refers to difficulty in switching tasks, which requires two subcomponents: forgetting an old task and adapting to a new one. Here, we aimed to disentangle the subcomponents of cognitive inflexibility in MDD and investigate whether they can be improved by transcranial direct current stimulation (tDCS) on the prefrontal cortex. METHODS: The current study included 20 patients with MDD (seven females) and 22 age-matched healthy controls (HCs) (seven females). The participants received anodal tDCS on either the dorsomedial prefrontal cortex (DMPFC) or dorsolateral prefrontal cortex (DLPFC) in a crossover design. Before and after the application of tDCS, the participants performed a modified Wisconsin Card Sorting Test, in which the task-switching rules were explicitly described and proactive interference from a previous task rule was occasionally released. RESULTS: We found that the behavioral cost of a task switch was increased in patients with MDD, but that of proactive interference was comparable between patients with MDD and HCs. The response time for anodal DMPFC tDCS was decreased compared with that for anodal tDCS on the DLPFC in MDD. CONCLUSIONS: These findings suggest that cognitive inflexibility in MDD is primarily explained by the difficulty to adapt to a new task and environment, and that tDCS on the DMPFC improves behavioral performance during cognitively demanding tasks that require conflict resolution.

Pre-stimulus Brain Activity Is Associated With State-Anxiety Changes During Single-Session Transcranial Direct Current Stimulation.

Transcranial direct current stimulation is a promising neuromodulation method for treating depression. However, compared with pharmacological treatment, previous studies have reported that a relatively limited proportion of patients respond to tDCS treatment. In addition, the neurophysiological mechanisms underlying tDCS treatment remain unclear, making it difficult to identify response predictors for tDCS treatment based on neurophysiological function. Because treatment effects are achieved by repetitive application of tDCS, studying the immediate effects of tDCS in depressive patients could extend understanding of its treatment mechanisms. However, immediate changes in a single session of tDCS are not well documented. Thus, in the current study, we focused on the immediate impact of tDCS and its association with pre-stimulus brain activity. To address this question, we applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC) or dorsomedial prefrontal cortex (DMPFC) in 14 patients with major depressive disorder (MDD) and 19 healthy controls (HCs), at an intensity of 1.0 mA for 20 min in a single session. To evaluate anxiety, the state trait anxiety inventory was completed before and after tDCS. We recorded resting electroencephalography before tDCS, and calculated electrical neuronal activity in the theta and alpha frequency bands using standardized low-resolution electromagnetic tomography. We found that, during application of left DLPFC tDCS to patients with MDD, the anxiety reduction effect of tDCS was related to higher baseline theta-band activity in the rostral anterior cingulate cortex (rACC) and no medication with benzodiazepine used as hypnotic. For DMPFC stimulation in MDD, the anxiety reduction effect was associated with lower baseline alpha-band activity in the left inferior parietal lobule. In contrast, in HCs, the anxiety reduction effect was associated with higher baseline alpha activity in the precuneus during DMPFC stimulation. The current results suggest that the association between pre-tDCS brain activity and the anxiety reduction effect of tDCS depends on psychopathology (depressed or non-depressed) as well as the site of stimulation (DMPFC or left DLPFC) and insomnia. Furthermore, the results suggest that tDCS response might be associated with baseline resting state electrophysiological neural activity.

Hyperactivation of the Frontal Control Network Revealed by Symptom Provocation in Obsessive-Compulsive Disorder Using EEG Microstate and sLORETA Analyses.

The aim of this study was to investigate the changes of brain electric field induced by symptom provocation in patients with obsessive-compulsive disorder (OCD) in comparison to healthy controls in the resting state. For this purpose, EEG recordings in conditions of initial rest, clean control, symptom provocation by imaginal exposure, and final rest were used for computing spatiotemporal activity characteristics based on microstate segmentation. Within-group comparisons were significant for the symptom provocation condition: OCD showed high global field power (GFP) and transition rates into a medial frontal microstate, whereas healthy controls showed high frequency of occurrence and high percent of dwelling time for a medial occipitoparietal microstate. Between-group comparisons demonstrated significantly lower GFP and dwelling time for the medial occipitoparietal microstate in OCD in several conditions including initial rest and symptom provocation. In addition, OCD compared to healthy controls showed significant instability of the medial occipitoparietal microstate, with high preference for transitions into the medial frontal microstate. In conclusion, during rest and symptom provocation, OCD patients make preferential use of a medial frontal brain network, with concomitant reduction of use of a medial occipitoparietal network, as shown by dwelling times, explained variance, and dynamic transition rates. These findings support the idea of a possible biological marker for OCD, which might correspond to pathological hyperactivation of the frontal control network.

Functional localization and effective connectivity of cortical theta and alpha oscillatory activity during an attention task.

OBJECTIVES: The aim of this paper is to investigate cortical electric neuronal activity as an indicator of brain function, in a mental arithmetic task that requires sustained attention, as compared to the resting state condition. The two questions of interest are the cortical localization of different oscillatory activities, and the directional effective flow of oscillatory activity between regions of interest, in the task condition compared to resting state. In particular, theta and alpha activity are of interest here, due to their important role in attention processing. METHODS: We adapted mental arithmetic as an attention ask in this study. Eyes closed 61-channel EEG was recorded in 14 participants during resting and in a mental arithmetic task ("serial sevens subtraction"). Functional localization and connectivity analyses were based on cortical signals of electric neuronal activity estimated with sLORETA (standardized low resolution electromagnetic tomography). Functional localization was based on the comparison of the cortical distributions of the generators of oscillatory activity between task and resting conditions. Assessment of effective connectivity was based on the iCoh (isolated effective coherence) method, which provides an appropriate frequency decomposition of the directional flow of oscillatory activity between brain regions. Nine regions of interest comprising nodes from the dorsal and ventral attention networks were selected for the connectivity analysis. RESULTS: Cortical spectral density distribution comparing task minus rest showed significant activity increase in medial prefrontal areas and decreased activity in left parietal lobe for the theta band, and decreased activity in parietal-occipital regions for the alpha1 band. At a global level, connections among right hemispheric nodes were predominantly decreased during the task condition, while connections among left hemispheric nodes were predominantly increased. At more detailed level, decreased flow from right inferior frontal gyrus to anterior cingulate cortex for theta, and low and high alpha oscillations, and increased feedback (bidirectional flow) between left superior temporal gyrus and left inferior frontal gyrus, were observed during the arithmetic task. CONCLUSIONS: Task related medial prefrontal increase in theta oscillations possibly corresponds to frontal midline theta, while parietal decreased alpha1 activity indicates the active role of this region in the numerical task. Task related decrease of intracortical right hemispheric connectivity support the notion that these nodes need to disengage from one another in order to not interfere with the ongoing numerical processing. The bidirectional feedback between left frontal-temporal-parietal regions in the arithmetic task is very likely to be related to attention network working memory function. SIGNIFICANCE: The methods of analysis and the results presented here will hopefully contribute to clarify the roles of the different EEG oscillations during sustained attention, both in terms of their functional localization and in terms of how they integrate brain function by supporting information flow between different cortical regions. The methodology presented here might be clinically relevant in evaluating abnormal attention function.

Indication for sentinel lymph node biopsy for breast cancer when core biopsy shows ductal carcinoma in situ.

BACKGROUND: The use of sentinel lymph node biopsy (SLNB) for ductal carcinoma in situ (DCIS) is controversial. METHODS: A total of 103 primary breast cancer patients who were diagnosed with DCIS by needle biopsy preoperatively and underwent initial SLNB were analyzed retrospectively. RESULTS: No sentinel nodal metastasis was detected in 66 patients with the final diagnosis of DCIS. However, 2 (5.4%) of 37 patients with invasive ductal carcinoma at final diagnosis had positive sentinel nodes. Multivariate logistic regression analysis identified 2 independent significant predictors of existence of invasive components: presence of a palpable tumor (odds ratio, 4.091; 95% confidential interval, 1.399-11.959; P = .010) and tumor size of 2.0 cm or larger on magnetic resonance imaging (odds ratio, 4.506; 95% confidence interval, 1.322-15.358; P = .016). CONCLUSIONS: Initial SLNB should be considered for patients diagnosed with DCIS by needle biopsy when they have a high risk for harboring invasive ductal cancer preoperatively.

A clear correlation between WT1-specific Th response and clinical response in WT1 CTL epitope vaccination.

Clinical studies of WT1-targeted cancer vaccine are being performed. However, WT1-specific Th response in cancer patients remains unclear. Using quantitative real-time RT-PCR, we investigated IFN-gamma and IL-10 mRNA expression from Th cells by stimulation with helper peptide WT1(332). Seventeen patients, of whom 10 had achieved stable disease and the remaining 7 had progressive disease, were weekly vaccinated with WT1 CTL epitope (modified WT1(235)) and examined for WT1(332)-specific Th response. A clear correlation between WT1(332)-specific Th response and clinical response was observed at 4 weeks post-vaccination. In patients who responded, a clear inverse correlation between IL-10-type and IFN-gamma-type WT1(332)-specific Th response was detected at pre- and 4 weeks post-vaccination, and the shift of the Th response from IL-10-type dominancy at early phase to IFN-gamma-type dominancy at late phase was observed. From this study we concluded that occurrence of WT1(332)-specific Th response could predict good clinical response of WT1 CTL epitope vaccination.

Predictive factors for anthracycline-based chemotherapy for human breast cancer.

Predictive factors for anthracycline-based chemotherapy have yet to be incorporated into daily practice. Meta-analyses of studies using anthracycline-based treatment regimens have shown an improved prognosis for human epidermal growth factor receptor type 2 (HER2)-positive tumors, but not for HER2-negative tumors compared with results of non-anthracycline regimens. Currently it is believed that the positive association between HER2 status and anthracycline sensitivity is indirect, that is, their association may be mediated through topoisomerase II alpha (TOP2A), a target molecule of anthracyclines, since TOP2A is near HER-2 and co-amplification of the TOP2A gene frequently occurs in HER2-amplified tumors. This strongly suggests that TOP2A gene amplification is a predictive factor for anthracyline-based regimens. The Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society has demonstrated that TOP2A-positive and BRCA1-negative subsets evaluated by immunohistochemical staining show a significantly higher pathological complete response when treated with preoperative epirubicin-containing regimens. Combining these findings with the observation that triple-negative tumors and basal-like tumors respond to anthracycline treatment suggests that not only HER2-positive tumors but also a distinct subset of HER2-negative tumors may be sensitive to anthracycline-based regimens.

Potential of reduction in total tumor volume measured with 3D-MRI as a prognostic factor for locally-advanced breast cancer patients treated with primary chemotherapy.

For accurate assessment of the response to primary chemotherapy (PCT) for locally advanced breast cancer, we measured reduction in total tumor volume (TTV) by using three-dimensional magnetic resonance imaging (3D MRI), and examined the relationship between this reduction and patient prognosis. Fifty-one patients with locally advanced breast cancer were treated with four cycles of docetaxel (60 mg/m(2)) before surgery. Tumor size was measured with calipers, ultrasonography (US) and conventional two-dimensional (2D) MRI before and after chemotherapy. TTV was measured with 3D MRI. These and other clinicopathological parameters were statistically analyzed to determine the prognosis for the patients. Median follow-up time was 46 months (1-64 months). Of the 51 patients, 25 developed distant recurrences. Patients whose TTV decreased by 75% or more after PCT showed significantly better prognosis than others, while tumor size measured with calipers, US and 2D MRI showed no significant relationship with patient prognosis. Of the clinicopathological parameters, only reduction in TTV and histological grade showed a significant association with distant recurrence-free survival (p = 0.03 and 0.02, log-rank test), while stepwise multivariate Cox's proportional hazards analysis identified TTV as the strongest independent prognostic factor. Reduction in TTV measured with 3D MRI can be a useful prognostic factor for patients with locally advanced breast cancer treated with PCT.

Cosmetic outcome and patient satisfaction after skin-sparing mastectomy for breast cancer with immediate reconstruction of the breast.

PURPOSE: We conducted a retrospective study to assess the safety, cosmetic outcome, and patients' satisfaction after skin-sparing (SSM) and nipple-sparing mastectomy (NSM) for breast cancer with immediate reconstruction of the breast (SMIBR). METHODS: The subjects were patients, who underwent SMIBR, breast-conserving surgery (BCS), and total mastectomy (MST) between 2000 and 2004 at Osaka University Hospital. Cosmetic outcome was estimated by 4 reviewers by scoring postoperative photographs of the patients. Patient satisfaction was evaluated with a questionnaire for assessment of quality of life for Japanese breast cancer patients. RESULTS: Of the 74 patients who had undergone SMIBR, 4 developed local recurrences (5%). The local recurrence rate for SMIBR patients was greater than that for BCS (4/178) and MST (3/178, P = .10). The distant recurrence rate was similar for all three types of patients (5% for SMIBR, 5% for BCS, and 9% for MST). The median averaged score by 4 reviewers for the estimated cosmetic outcomes was 7.8 for the SMIBR and 7.5 for the BCS group (P = .20), and for age-adjusted patients, the corresponding scores were 8.2 and 8.0 (P = .70). There was no difference in cosmetic outcome between the SSM and NSM subgroups (P = .09). Average scores for patient satisfaction (social activity, physical aspects, and general condition) were the same for the 3 groups. For body image, the BCS and SMIBR groups had higher scores than the MST group (p < 0.05). Average scores for questions relating to bodily pain and sexual aspects were higher for the BCS than the MST group, but were not different between SMIBR and BCS groups. Similar trends for the 3 groups were observed when patients were divided into subgroups by tumor size or axillary dissection. CONCLUSIONS: SMIBR is safe with a comparatively low local recurrence rate and the same distant recurrence rate as for BCS and MST. Moreover, it results in objective cosmetic outcome and patient satisfaction as good as those for BCS, and greater patient satisfaction with body image than that for MST.

Topoisomerase IIalpha-positive and BRCA1-negative phenotype: association with favorable response to epirubicin-based regimens for human breast cancers.

Epirubicin exerts its anti-tumor effect through binding to topoisomerase IIalpha (TOP2A) and inducing DNA double-strand breaks. BRCA1 is involved in the repair of these breaks. We investigated the relationship between TOP2A or BRCA1 immunohistochemical expression and pathological response in 108 primary breast cancers treated with epirubicin-based regimens. The pCR (pathological complete response) rate for TOP2A-positive (17%) was significantly (P < 0.005) higher than for TOP2A-negative (2%), while the pCR rate for BRCA1-negative (11%) was non-significantly higher than for BRCA1-positive (5%). The pCR rate of TOP2A-positive and BRCA1-negative (30%) was significantly higher than for TOP2A-negative and BRCA1-positive (3%; P < 0.05), or TOP2A-negative and BRCA1-negative (0%; P < 0.005). The TOP2A-positive and BRCA1-negative phenotype associates with a favorable response to epirubicin-based regimens.

Low nuclear grade but not cell proliferation predictive of pathological complete response to docetaxel in human breast cancers.

PURPOSE: Predictive factors for response to docetaxel in human breast cancers have yet to be identified. The aim of the present study was to investigate the relationship of various clinicopathological and biological parameters with pathological response to docetaxel in the neoadjuvant setting. METHODS: The study population comprised 78 patients with primary breast cancers who were treated with docetaxel [60 mg/m(2); four (median) cycles, range 3-6; q3w] as neoadjuvant therapy and subsequently treated with mastectomy or breast conserving surgery. Tumor samples obtained before chemotherapy were subjected to histological examination and immunohistochemistry of HER-2 and Ki-67. RESULTS: The pathological complete response (pCR) rate was significantly (P=0.04) higher for tumors with low nuclear grade (NG-I or -II) (21%) than for tumors with high NG (NG-III) (5%). The pCR rate (20%) of small (5 cm) tumors (5%). Combined analysis of NG and tumor size showed that low-NG small tumors have a higher response rate (30%) than high-NG small tumors (11%; P=0.13), low-NG large tumors (11%; P=0.15), and high-NG large tumors (0%; P=0.009). No statistically significant association was observed between pCR rate and menopausal status, lymph node status, ER, PR, HER-2, or Ki-67. CONCLUSIONS: Low nuclear grade, but not cell proliferation determined by Ki-67, is associated with a good pathological response to docetaxel. Combination of low nuclear grade and small tumor size may be useful for the selection of breast tumors with a high pCR rate (30%).

Quantitative assessment of mammographic density and breast cancer risk for Japanese women.

We conducted a case-control study to examine the relationship between breast density (BD) on mammography and breast cancer risk for postmenopausal Japanese women. The mammograms (205 cases and 223 controls) were classified by two doctors employing Wolfe's classification and used to measure BD with original computer software. A weak relationship between breast cancer risk and the parenchymal pattern of Wolfe's classification was found. The BD measured with the computer software, however, showed a significant relationship with breast cancer risk. Analysis after adjustment for epidemiologic factors showed that women in the quintile with the highest BD had a 3.02 times higher risk of breast cancer than those in the quintile with the lowest density. Since mammographic BD is clearly associated with breast cancer risk for postmenopausal Japanese women, our software can be expected to become a useful tool for objective risk assessment of breast cancer.

Preoperative evaluation of residual tumor extent by three-dimensional magnetic resonance imaging in breast cancer patients treated with neoadjuvant chemotherapy.

The purpose of this study was to evaluate the usefulness of three-dimensional magnetic resonance imaging (3D MRI) for the preoperative assessment of residual tumor extent in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Thirty-eight breast cancer patients treated with NAC containing taxane and/or anthracycline for 3-6 months were enrolled in this study. Tumor size was measured by means of calipers, ultrasonography, and dynamic MRI before and after NAC. Three-dimensional maximum intensity projection MRIs to measure the tumor size were created for every case. The tumor size determined by calipers, ultrasonography, and 3D MRI after NAC was compared with that determined by pathologic examination. The tumor size determined by 3D MRI showed a strong correlation with that determined by pathologic examination (r = 0.896). Moderate, but significant correlations were found between measurements obtained with calipers and pathology (r = 0.554), and between ultrasonography and pathology (r = 0.484). The response rates to NAC were estimated at 84.2% with calipers, 58.0% with ultrasonography, and 44.7% with 3D MRI. Calipers and ultrasonography thus tended to overestimate the response to NAC compared to 3D MRI (p < 0.001 and 0.240, respectively). Three-dimensional MRI can visualize residual tumor extent after NAC more accurately than calipers and ultrasonography, and seems to be more reliable than other modalities for estimating response to NAC. It should also help surgeons with decision making for breast-conserving surgery after NAC.

Down-regulation of intratumoral aromatase messenger RNA levels by docetaxel in human breast cancers.

PURPOSE: The reason why chemotherapy induces resistance to subsequent hormonal therapy remains to be clarified in postmenopausal breast cancers. We hypothesized that chemotherapy might down-regulate the intratumoral biosynthesis of estrogens. Thus, we have studied the influence of chemotherapy (docetaxel) on intratumoral aromatase mRNA expression because aromatase is a key enzyme for intratumoral biosynthesis of estrogens. EXPERIMENTAL DESIGN: The mRNA levels of aromatase and its inducers [tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and cyclooxygenase 2 (COX-2)] were determined by a real-time polymerase chain reaction assay in breast cancer tissues obtained before and after neoadjuvant chemotherapy with docetaxel (four cycles of 60 mg/m2 every 3 weeks) in 16 postmenopausal patients with estrogen receptor (ER)- and/or progesterone receptor (PR)-positive breast cancers. ER and PR levels in tumor tissues were also determined by enzyme immunoassay before and after chemotherapy. RESULTS: The intratumoral aromatase mRNA levels decreased significantly (P < 0.05) after chemotherapy from 0.84 +/- 0.28 (mean +/- SE) to 0.47 +/- 0.28. The intratumoral TNF-alpha mRNA levels also decreased significantly (P < 0.05) after chemotherapy from 2.40 +/- 0.52 to 0.95 +/- 0.25. On the contrary, the intratumoral IL-6 and COX-2 mRNA levels showed a marginally significant increase (P = 0.07) and a significant increase (P < 0.05), respectively, after chemotherapy. PR levels showed a marginally significant decrease (P = 0.08) after chemotherapy, whereas ER levels were almost constant before and after chemotherapy. CONCLUSIONS: Antitumor activity of docetaxel is mediated, at least in part, through a down-regulation of aromatase expression in tumor tissues, resulting in the suppression of intratumoral estradiol synthesis. Aromatase expression seems to be regulated mostly by TNF-alpha, but not IL-6 and COX-2.

Prognostic significance of intra-tumoral estradiol level in breast cancer patients.

Although the intra-tumoral estradiol (E2) level is thought to be more closely related to the E2-inducible events such as progesterone receptor (PR) induction and tumor growth than the serum E2 level, prognostic significance of the intra-tumoral E2 level in breast cancer patients has yet to be studied. E2 level in tumor tissues obtained from 90 primary breast cancer patients were measured by the high-pressure liquid chromatography-radioimmunoassay method. Relationship between the intra-tumoral E2 level and the various clinicopathological factors including the prognosis was investigated. E2-high tumors (n=45) were significantly more likely to be estrogen receptor (ER)-positive tumors and PR-positive tumors than E2-low tumors (n=45). A significant correlation was observed between the intra-tumoral E2 level and PR level by a simple curve fit test (r=0.39, P<0.01) in the ER-positive tumors. Univariate analysis showed that lymph node status, intra-tumoral E2 level, ER, and PR were significant prognostic factors, and multivariate analysis showed that only lymph node status and PR status were significant independent prognostic factors. PR is induced by E2 through ER in human breast cancers. PR, which warrants both the presence of functional ER and the enough level of intra-tumoral E2, can serve as a better prognostic factor than intra-tumoral E2 level or ER in primary breast cancer patients probably because PR is a better marker of estrogen-dependency of tumor growth than intra-tumoral E2 level or ER.