Cytomorphological disparities in invasive breast cancer cells following neoadjuvant endocrine therapy and chemotherapy.

INTRODUCTION: Neoadjuvant endocrine therapy (NAE) offers a breast-conserving surgery rate and clinical response rate similar to those of neoadjuvant chemotherapy (NAC), while presenting fewer adverse events and lower pathological complete response rates. The assessment of pathological response determines degenerative changes and predicts the prognosis of breast cancer treated with NAC. This study clarified the degenerative changes occurring in breast cancer following NAE. METHODS: Our study encompassed two groups: NAE, consisting of 15 patients, and NAC, comprising 18 patients. Tissue samples were obtained from core needle biopsies and surgeries. Nuclear and cell areas were calculated using Autocell analysis. Furthermore, we assessed markers associated with microtubule depolymerization (KIF2A) and initiators of apoptosis (caspase-9). RESULTS: In the NAC group, we observed significant increases in both cytoplasmic and cell areas. These changes in cytoplasm and cells were notably more pronounced in the NAC group compared to the NAE group. Post-treatment, KIF2A exhibited a decrease, with the magnitude of change being greater in the NAE group than in the NAC group. However, no discernible differences were found in caspase-9 expression between the two groups. CONCLUSION: Our findings indicate that NAE induces condensation in cancer cells via cell cycle arrest or apoptosis. Conversely, NAC leads to cell enlargement due to the absence of microtubule depolymerization. These discrepancies underscore the importance of accounting for these distinctions when establishing criteria for evaluating pathological responses.

Hippocampal-prefrontal long-term potentiation-like plasticity with transcranial direct current stimulation in rats.

Transcranial direct current stimulation (tDCS) has been explored as a new treatment method for improving cognitive and motor functions. However, the neuronal mechanisms of tDCS in modulating brain functions, especially cognitive and memory functions, are not well understood. In the present study, we assessed whether tDCS could promote neuronal plasticity between the hippocampus and prefrontal cortex in rats. This is important because the hippocampus-prefrontal pathway is a key pathway in cognitive and memory functions and is involved in various psychiatric and neurodegenerative disorders. Specifically, the effect of anodal or cathodal tDCS on the medial prefrontal cortex was investigated in rats by measuring the medial prefrontal cortex response to electrical stimulation applied to the CA1 region of the hippocampus. Following anodal tDCS, the evoked prefrontal response was potentiated compared to that in the pre-tDCS condition. However, the evoked prefrontal response did not show any significant changes following cathodal tDCS. Furthermore, the plastic change of the prefrontal response following anodal tDCS was only induced when hippocampal stimulation was continuously applied during tDCS. Anodal tDCS without hippocampal activation showed little or no changes. These results indicate that combining anodal tDCS of the prefrontal cortex with hippocampal activation induces long-term potentiation (LTP)-like plasticity in the hippocampus-prefrontal pathway. This LTP-like plasticity can facilitate smooth information transmission between the hippocampus and the prefrontal cortex and may lead to improvements in cognitive and memory function.

Postmortem genetic analysis of 17 sudden cardiac deaths identified nonsense and frameshift variants in two cases of arrhythmogenic cardiomyopathy.

Sudden death, or unexpected natural death of a healthy individual, is a serious problem in all nations. Sudden cardiac death (SCD) mainly due to ischemic heart diseases is the top cause of sudden death. However, there are pathophysiological conditions, referred to as sudden arrhythmic death syndrome, in which no apparent lesion can be identified even after complete conventional or ordinary autopsy. While postmortem genetic analyses have accumulated evidence about underlying genetic abnormality in such cases, the precise relationships between genetic background and the phenotype have been largely elusive. In this study, a retrospective investigation of 17 autopsy cases in which lethal arrhythmia was suspected to be the cause of death was carried out. Genetic analysis focusing on 72 genes reported to be associated with cardiac dysfunctions was performed, in combination with detailed histopathological and postmortem imaging examination, and a family study. As a result, in two cases of suspected arrhythmogenic cardiomyopathy (ACM), we found a nonsense variant in PKP2 and frameshift variant in TRPM4 gene. In contrast, the other 15 cases showed no morphological changes in the heart despite the presence of a frameshift variant and several missense variants, leaving the clinical significance of these variants obscure. The findings of the present study suggest that nonsense and frameshift variants could be involved in the morphological abnormality in cases of SCD due to ACM, while missense variants alone rarely contribute to massive structural changes in the heart.

[A Case of Bilateral HER2-Positive Invasive Ductal Carcinoma with Complete Response on One Side with Trastuzumab Deruxtecan].

A 52-year-old female with stage Ⅳ, bilateral, HER2-positive, breast cancer as well as bilateral axillary lymph node(LN) metastasis and bilateral pulmonary metastasis was administered trastuzumab plus pertuzumab plus docetaxel as a standard chemotherapy. After this treatment the right breast cancer, right axillary LN metastasis, and bilateral pulmonary metastases contracted, while the left breast cancer and left axillary LN metastasis expanded. Trastuzumab emtansine was then administered, and the left axillary LN metastasis contracted, however, the left breast cancer expanded, resulting in marked breast engorgement. When trastuzumab deruxtecan(T-DXd)was administered, the left breast cancer contracted for the first time during the overall treatment process, and the signs of breast inflammation disappeared. Other lesions showed no recrudescence. T-DXd was administered seven times, and, at the stage of maximum contraction during the treatment period, a total left mastectomy and left axillary LN dissection were performed. Pathological examination then confirmed that tumor cells were no longer present in the left breast and left axillary LN. In this case T-DXd was highly effective for the local treatment of intractable, HER2-positive, breast cancer.

Moving a neodymium magnet promotes the migration of a magnetic tracer and increases the monitoring counts on the skin surface of sentinel lymph nodes in breast cancer.

BACKGROUND: We suspected that moving a small neodymium magnet would promote migration of the magnetic tracer to the sentinel lymph node (SLN). Higher monitoring counts on the skin surface before making an incision help us detect SLNs easily and successfully. The present study evaluated the enhancement of the monitoring count on the skin surface in SLN detection based on the magnet movement in a sentinel lymph node biopsy (SNB) using superparamagnetic iron oxide (SPIO) nanoparticles. METHODS: After induction of general anesthesia, superparamagnetic iron oxide nanoparticles were injected sub-dermally into the subareolar area or peritumorally. The neodymium magnet was moved over the skin from the injection site to the axilla to promote migration of the magnetic tracer without massage. A total of 62 patients were enrolled from February 2018 to November 2018: 13 cases were subjected to magnet movement 20 times (Group A), 8 were subjected to 1-min magnet movement (Group B), 26 were given a short (about 5 min) interval from injection to 1-min magnet movement (Group C), and 15 were given a long (about 25 min) interval before 1-min magnet movement using the magnetometer's head (Group D). In all cases, an SNB was conducted using both the radioisotope (RI) and SPIO methods. The monitoring counts on the skin surface were measured by a handheld magnetometer and compared among the four groups. Changes in the monitoring count by the interval and magnet movement were evaluated. RESULTS: The identification rates of the SPIO and RI methods were 100 and 95.2%, respectively. The mean monitoring counts of Group A, B, C, and D were 2.39 µT, 2.73 µT, 3.15 µT, and 3.92 µT, respectively (p < 0.0001; Kruskal-Wallis test). The monitoring counts were higher with longer magnet movement and with the insertion of an interval. Although there were no relationships between the monitoring count on the skin surface and clinicopathologic factors, magnet movement strongly influenced the monitoring count on the skin surface. CONCLUSION: Moving a small neodymium magnet is effective for promoting migration of a magnetic tracer and increasing monitoring counts on the skin surface. TRIAL REGISTRATION: UMIN, UMIN000029475. Registered 9 October 2017.

Patterned Superhydrophobic SERS Substrates for Sample Pre-Concentration and Demonstration of Its Utility through Monitoring of Inhibitory Effects of Paraoxon and Carbaryl on AChE.

We describe a patterned surface-enhanced Raman spectroscopy (SERS) substrate with the ability to pre-concentrate target molecules. A surface-adsorbed nanosphere monolayer can serve two different functions. First, it can be made into a SERS platform when covered by silver. Alternatively, it can be fashioned into a superhydrophobic surface when coated with a hydrophobic molecular species such as decyltrimethoxy silane (DCTMS). Thus, if silver is patterned onto a latter type of substrate, a SERS spot surrounded by a superhydrophobic surface can be prepared. When an aqueous sample is placed on it and allowed to dry, target molecules in the sample become pre-concentrated. We demonstrate the utility of the patterned SERS substrate by evaluating the effects of inhibitors to acetylcholinesterase (AChE). AChE is a popular target for drugs and pesticides because it plays a critical role in nerve signal transduction. We monitored the enzymatic activity of AChE through the SERS spectrum of thiocholine (TC), the end product from acetylthiocholine (ATC). Inhibitory effects of paraoxon and carbaryl on AChE were evaluated from the TC peak intensity. We show that the patterned SERS substrate can reduce both the necessary volumes and concentrations of the enzyme and substrate by a few orders of magnitude in comparison to a non-patterned SERS substrate and the conventional colorimetric method.

Harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters for stage IV breast cancer prognosis. Multicenter study in Japan.

OBJECTIVE: The prognostic value of harmonized pretreatment volume-based quantitative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters in metastatic breast cancer patients was investigated. SUBJECTS AND METHODS: Records of 65 stage IV breast cancer patients, including 29 estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 23 HER2-positive, and 13 triple-negative cases, from four different institutions were retrospectively reviewed. Harmonized standardized uptake value (SUVmax) of the primary tumor (pSUVmax), highest SUVmax of all malignant lesions (wSUVmax), whole-body metabolic tumor volume (WB MTV), and whole-body total lesion glycolysis (WB TLG) shown by pretreatment 18F-FDG PET/CT imaging were calculated. Cox proportional hazards model and log-rank test results were used to evaluate relationships among clinicopathological factors, volume-based quantitative 18F-FDG PET/CT parameters, progression-free survival, and overall survival (OS). RESULTS: Disease progression occurred in 54 patients and 28 died during a median follow-up period of 52.5 months (range 2.6-133.6 months). Univariate analysis of all cases showed associations of negative ER and progesterone receptor (PR) status (P=0.0025), and high T/N stage (P=0.037/P=0.019), pSUVmax (P=0.049), WB MTV (P=0.021), and WB TLG (P=0.0010) with significantly shorter OS. Multivariate analysis confirmed negative ER and PR status (hazard ratio [HR]: 6.42, 95% confidence interval [CI]: 2.27-19.38; P=0.0054), high T stage (HR: 5.10, 95% CI:1.96-18.61, P=0.0064) and WB TLG (HR: 4.69, 95% CI:1.67-12.79, P=0.049) as independent negative OS predictors. In two groups of ER-positive/HER2-negative and triple-negative, WB TLG had a significant association with death (P=0.021 and P=0.037, respectively) on univariate analysis. In a HER2-positive group, no independent negative OS predictors were observed. CONCLUSION: In metastatic breast cancer patients, harmonized pretreatment quantitative volume-based 18F-FDG PET/CT parameters, especially whole-body TLG, are potential surrogate markers for prognosis.

Granulocyte-colony stimulating factor-associated aortitis in a woman with advanced breast cancer: a case report and review of the literature.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is increasingly been used to prevent febrile neutropenia (FN) associated with the administration of chemotherapy for various cancers. The most common adverse effects of G-CSF are bone pain and injection-site reactions and aortitis has rarely been reported. We report herein a rare case of G-CSF associated with aortitis in a woman with advanced breast cancer. CASE PRESENTATION: A 72-year-old woman with estrogen receptor-negative human epidermal growth factor 2-positive breast cancer with distant metastases in the lung was admitted. Her treatment was initiated with docetaxel in combination with trastuzumab and pertuzumab followed by the supportive use of a long-acting G-CSF, pegfilgrastim. After administration of pegfilgrastim on day 5, the patient had an intermittent fever (body temperature up to 39.6 °C) on day 9 which continued irrespective of taking levofloxacin. She visited our outpatient clinic on day 13 with no objective symptoms other than fever. Laboratory tests revealed a high neutrophil count (15,000/µl) and a high C-reactive protein (CRP) level (46.35 mg/dl) without any other abnormalities. There was no response upon administration of antimicrobial agents. An 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed thickening of the wall of the descending thoracic aorta and left pleural effusion. Therefore, thoracic aortitis induced by pegfilgrastim was suspected. On day 19, the fever resolved spontaneously followed by a gradual reduction in the neutrophil count and CRP level. In the follow-up CT, the aortic wall thickness and pleural effusion had disappeared. CONCLUSIONS: G-CSF may cause aortitis due to stimulation of the production of inflammatory cytokines. In case of high continuous fever after administration of pegfilgrastim, aortitis should be suspected unless there are other infectious findings.

Multicenter clinical trial on sentinel lymph node biopsy using superparamagnetic iron oxide nanoparticles and a novel handheld magnetic probe.

BACKGROUND: Sentinel lymph node biopsy is a standard staging procedure for early axillary lymph node-negative breast cancer. As an alternative to the currently used radioactive tracers for sentinel lymph node (SLN) detection during the surgical procedure, a number of studies have shown promising results using superparamagnetic iron oxide (SPIO) nanoparticles. Here, we developed a new handheld, cordless, and lightweight magnetic probe for SPIO detection. METHODS: Resovist (SPIO nanoparticles) were detected by the newly developed handheld probe, and the SLN detection rate was compared to that of the standard radioisotope (RI) method using radioactive colloids (99m Tc) and a blue dye (indigo carmine). This was a multicenter prospective clinical trial that included 220 patients with breast cancer scheduled for sentinel node biopsy after a clinical diagnosis of negative axillary lymph node from three facilities in Japan. RESULTS: Of the 210 patients analyzed, SLN was detected in 94.8% (199/210 cases, 90% confidence interval [CI]) with our magnetic method and in 98.1% (206/210 cases, 90% CI) with the RI method. The magnetic method exceeded the threshold identification rate of 90%. CONCLUSION: This was the first clinical study to use a novel handheld magnetometer to detect SLN, which we demonstrate to be not inferior to the RI method.

Quality of care in hospitalized cancer patients before and after implementation of a systematic prevention program for delirium: the DELTA exploratory trial.

BACKGROUND: We evaluated whether the DELirium Team Approach (DELTA) program-a systematic management program aimed at screening high-risk groups and preventing delirium-would improve quality of care in patients hospitalized with cancer. METHODS: A retrospective before-after study was conducted during a pre-intervention period (between October 2012 and March 2013) and a post-intervention period (between October 2013 and March 2014) at a Japanese hospital providing specialized treatments for cancer. A total of 4180 inpatients were evaluated before the implementation of the DELTA program and 3797 inpatients were evaluated after implementation. RESULTS: After program implementation, the incidence of delirium decreased from 7.1 to 4.3% (odds ratio [OR], 0.52; 95% CI, 0.42-0.64). The incidence of adverse events, including falls or self-extubation, also decreased, from 3.5 to 2.6% (OR, 0.71; 95% CI, 0.54-0.92). There was a significant decrease in the prescription of benzodiazepines (OR, 0.79; 95% CI, 0.71-0.87), increase in the level of independence in activities of daily living at discharge (OR, 1.94; 95% CI, 1.11-3.38), and decrease in the length of stay (risk ratio 0.90; 95% CI, 0.90-0.90). CONCLUSIONS: The systematic management program for delirium decreased the incidence of delirium and improved several clinical outcomes. These data suggest that this simple cost-effective program is feasible and implementable as routine care in busy wards.

Decision-Making Capacity for Chemotherapy and Associated Factors in Newly Diagnosed Patients with Lung Cancer.

BACKGROUND: The objective of this study was to assess decision-making capacity in patients newly diagnosed with lung cancer, clinical factors associated with impaired capacity, and physicians' perceptions of patients' decision-making capacity. MATERIALS AND METHODS: We recruited 122 patients newly diagnosed with lung cancer. One hundred fourteen completed the assessment. All patients were receiving a combination of treatments (e.g., chemotherapy, chemo-radiotherapy, or targeted therapy). Decision-making capacity was assessed using the MacArthur Competence Tool for Treatment. Cognitive impairment, depressive symptoms, and frailty were also evaluated. Physicians' perceptions were compared with the ascertainments. RESULTS: Twenty-seven (24%, 95% confidence interval [CI], 16-31) patients were judged to have incapacity. Clinical teams had difficulty in judging six (22.2%) patients for incapacity. Logistic regression identified frailty (odds ratio, 3.51; 95% CI, 1.13-10.8) and cognitive impairment (odds ratio, 5.45; 95% CI, 1.26-23.6) as the factors associated with decision-making incapacity. Brain metastasis, emphysema, and depression were not associated with decision-making incapacity. CONCLUSION: A substantial proportion of patients diagnosed with lung cancer show impairments in their capacity to make a medical decision. Assessment of cognitive impairment and frailty may provide appropriate decision-making frameworks to act in the best interest of patients. IMPLICATIONS FOR PRACTICE: Decision-making capacity is the cornerstone of clinical practice. A substantial proportion of patients with cancer show impairments in their capacity to make a medical decision. Assessment of cognitive impairment and frailty may provide appropriate decision-making frameworks to act in the best interest of patients.

Prognostic utility of atypical mitoses in patients with breast cancer: A comparative study with Ki67 and phosphohistone H3.

BACKGROUND AND OBJECTIVES: Emerging evidence suggests that the presence of atypical mitoses is associated with poor prognosis in some types of cancer, but its clinical significance remains uncertain. Here, we investigated the occurrence of atypical mitoses in breast cancers. METHODS: Mitotic figures, including normal and atypical mitoses, were assessed in resected histological sections from 109 patients with invasive carcinoma of no special type (ICNST). Comparisons with clinicopathological features and biomarkers such as Ki67 and phosphohistone H3 (PHH3) were performed. RESULTS: The total number of mitotic figures, including atypical mitoses, was higher in situ and invasive ductal carcinoma components than in normal ducts. Morphological characteristics of atypical mitoses included multipolar, lagged, ring, asymmetrical mitoses, and anaphase bridge. Patients with higher total mitoses and PHH3, and the presence of atypical mitoses showed reduced overall survival (OS), compared to those with lower total mitoses and PHH3, and without atypical mitoses (P = 0.03, 0.02, and <0.001, respectively). In multivariate analysis, the presence of atypical mitoses alone attained significant correlation with shorter OS (P < 0.001). CONCLUSIONS: Atypical mitoses in routinely resected specimens have a robust prognostic value for ICNST of the breast, but its clinical utility remains to be validated in a multicenter large material.

Complication analysis of complete versus partial coverage of tissue expanders using serratus anterior musculofascial flaps in immediate breast reconstruction.

PURPOSE: To prevent tissue expander (TE) exposure following mastectomy flap necrosis in immediate breast reconstruction, the TE is usually covered completely or partially with a musculofascial (MF) flap. This study compares the complications of the two coverage methods. METHODS: We reviewed, retrospectively, 106 cases of immediate TE-based breast reconstruction. The patients were divided into two groups according to whether complete or partial TE coverage was done. In the complete coverage group, the serratus anterior MF flap was dissected and sutured to the pectoralis major muscle to cover the TE completely. In the partial coverage group, the serratus anterior MF flap was not dissected, and the lateral border of the pectoralis major muscle was sutured to the mastectomy skin flaps. RESULTS: The TEs were covered completely in 60 breasts and partially in 46 breasts. The mastectomy flap necrosis rate was significantly higher in the complete coverage group (p < 0.01), but there was no incidence of TE exposure in either groups. The lateral migration rate was significantly higher in the partial coverage group (p = 0.033). There were no significant differences in the cranial migration rate (p = 0.133). CONCLUSIONS: The complete coverage method is a better option if there is a high risk of mastectomy flap necrosis; however, surgeons should monitor carefully for cranial migration.

BRCA1 alterations with additional defects in DNA damage response genes may confer chemoresistance to BRCA-like breast cancers treated with neoadjuvant chemotherapy.

The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR. The methylation and/or loss or uniparental disomy (UPD) of BRCA1 (BRCA1 alterations) and the loss or UPD of BRCA2 (BRCA2 alterations) were detected in 27 (37%) and 21 (29%), respectively, of the 73 tumors. Tumors with BRCA1 or BRCA2 alterations were associated with a higher number of genomic aberrations (P < 0.001 and P < 0.001) and higher percentage of TP53 alterations (P < 0.001 and P < 0.001) than those without. Overall survival (OS) rates were similar between patients with or without BRCA1 or BRCA2 alterations. However, when 27 patients with BRCA1-altered tumors were classified into those with or without the loss or UPD of PALB2, PAGR1, RAD51B, FANCM, MLL4, or ERCC1/2 in tumors, patients with additional defects in DNA damage response genes had worse OS (P = 0.037, 0.045, 0.038, 0.044, 0.041, or 0.019) than those without. These defects may confer chemoresistance and predict poor outcomes in patients with BRCA1-altered breast cancer.

IMP3 contributes to poor prognosis of patients with metaplastic breast carcinoma: A clinicopathological study.

Metaplastic breast carcinoma (MBC) is a rare type of tumor with heterogenous histological patterns. We investigated the immunohistochemical expression of IMP3, an oncofetal protein, in 31 MBC patients in association with histological subtypes and clinical outcomes. The cohort consisted of spindle cell carcinoma (SPC) (n=11), squamous cell carcinoma (SCC) (n=14), matrix-producing carcinoma (MPC) (n=4), carcinoma with osteocartilaginous elements (COC) (n=1), and low grade adenosquamous cell carcinoma (ASC) (n=1). IMP3 expression was identified in 7 cases of SPC (64%) and 6 patients of all the other subtypes (p=0.051). In comparison between IMP3 high (n=13) and low (n=18) groups, a large-sized tumor (≥4.0cm) was identified in 9 IMP3 high patients, and 14 IMP3 low patients had a small-sized tumor (p=0.01). High Ki67 positivity was detected in all of the IMP3 high patients and in 7 of the IMP3 low patients (p=0.002). During the follow-up period, 9 IMP3 high patients died, whereas 15 of the 18 IMP3 low patients remained alive (p=0.004). A univariate analysis revealed that IMP3 expression and tumor size were significantly associated with poor clinical outcomes (p=0.03 and <0.001, respectively). The IMP3 high group was likely to be associated with reduced overall survival compared to the IMP3 low group (p=0.06). These findings indicate that IMP3 may contribute to the aggressive behavior of MBC, and that this expression could potentially be a prognostic marker of MBC.

Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy.

BACKGROUND: Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment. METHODS: In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601). RESULTS: Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14% and 52% of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25% vs 67% for clinical response, p = 0.011, N = 51; 0% vs 41% for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not. CONCLUSIONS: Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE. TRIAL REGISTRATION: UMIN C000000345 (2006/03/06).

Joint symptoms and health-related quality of life in postmenopausal women with breast cancer who completed 5 years of anastrozole.

PURPOSE: To assess the joint symptoms and the impact on patients' health-related quality of life (HRQOL) due to 5 years of anastrozole from the baseline data in the N-SAS BC 05 trial, a randomized clinical trial was designed to assess the efficacy of 5 additional years of anastrozole among women with breast cancer. METHODS: Joint symptoms and HRQOL were evaluated using an original questionnaire for joint symptoms, the Short Form 36-item Health Survey (SF-36), the EuroQol EQ-5D-3L, and a subscale of the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES). RESULTS: Baseline joint symptom and HRQOL data were collected from 330 patients between November 2007 and March 2010. Joint pain and joint stiffness were reported by 61.6 and 59.1 % of patients, respectively, although these symptoms did not affect the activities of daily living in 96.0 and 97.9 % of patients, respectively. Joint pain was reported in the knee by 61.0 % of patients and in the hand by 36.0 % of patients. Joint stiffness mainly affected the hand (67.9 %), especially the proximal interphalangeal joint, and typically occurred upon waking up or in the morning. Most SF-36 domains had good average scores, although slight decreases in physical functioning and role-physical were observed (compared to the national standard scores). The mean EQ-5D utility score was 0.86, and the total FACT-ES subscale score was 62.2/76. CONCLUSIONS: After 5 years of anastrozole, many of the patients reported joint pain and stiffness in mainly the hand and knee with mild symptoms and good HRQOL.

Higher expression of EpCAM is associated with poor clinical and pathological responses in breast cancer patients undergoing neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is a standard regimen in treatment of breast cancer patients, but some are resistant to NAC. We hypothesized that breast cancer cells overexpressing epithelial cell adhesion molecule (EpCAM) could be resistant to NAC, contributing to a poor prognosis. Seventy patients with breast cancer were treated with NAC. Core needle biopsy (CNB) specimens and resected tumors before and after NAC, respectively, were examined for expression of EpCAM. In resected tumors, high EpCAM expression correlated with lymphovascular invasion status and nuclear grade (P = 0.01 and 0.008, respectively), and was associated with poor pathological and clinical responses (P < 0.001). High tumoral EpCAM expression in resected tumor was independently related to a poor pathological response. Patients with high EpCAM expression before and after NAC (high-to-high group) showed worse pathological and clinical responses (P = 0.008 and <0.001, respectively) than the patients with high and low EpCAM expression before and after NAC, respectively (high-to-low group). The overall survival rate of the high-to-high group appeared shorter compared with the high-to low-group (P = 0.049). Our findings imply that higher levels of EpCAM in breast cancer may be associated with poor response to NAC via a potential chemoresistant effect.

ER, PgR, Ki67, p27(Kip1), and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab.

BACKGROUND: Neoadjuvant chemotherapy (NAC) with taxanes followed by fluorouracil, epirubicin, and cyclophosphamide (FEC), and concurrent trastuzumab is a potent regimen for HER2 over-expressing breast cancer. A high pathological complete response (pCR) rate has been achieved using this regimen; however, the predictive factors and prognostic effects of pCR currently remain unclear. In the present study, we determined whether pCR was related to histological grade (HG) and several biological factors including p27(Kip1). We also assessed the prognosis of the pCR and non-pCR groups, and expected differences between those positive and negative for lymph node metastasis after chemotherapy. METHODS: A total of 129 Japanese women with HER2-positive invasive breast cancer received either paclitaxel or docetaxel followed by FEC, with the concomitant administration of trastuzumab. The statuses of HG, ER, PgR, Ki67, and p27(Kip1) were evaluated to determine their relationship with pCR. Relapse-free survival (RFS) and overall survival (OS) were also analyzed for their relationship with pCR and pathological nodal involvement. RESULTS: pCR was obtained in 84 out of 129 patients and the pCR rate was 65.1%. The pCR rates related to 5 factors were as follows: HG (grade 3, 70.0% vs. grades 1-2, 36.8%), ER (negative, 78.6% vs. positive, 40.0%), PgR (negative, 75.3% vs. positive, 38.9%), Ki67 (high, 72.0% vs. low, 47.2%), and p27(Kip1) (low, 71.0% vs. high, 50.0%). RFS was significantly better in the pCR group than in the non-pCR group (p = 0.018). Patients with remaining nodal disease in the pCR group had worse OS (p = 0.0002). CONCLUSIONS: High-HG, low-ER, low-PgR, high-Ki67, and low-p27(Kip1) were identified as predictive factors of pCR in NAC with trastuzumab, while pCR and negative nodes were predictive of better survivals.