Real-world data analysis of perioperative chemotherapy patterns, G-CSF use, and FN status in patients with early breast cancer.

PURPOSE: This study aimed to describe perioperative chemotherapy patterns, granulocyte colony-stimulating factor (G-CSF) use, and febrile neutropenia (FN) status in patients with early breast cancer (EBC) using real-world data in Japan. METHODS: This retrospective observational study used anonymized claims data. The included patients were ≥ 18 years old, were female, and had breast cancer diagnosis and surgery records between January 2010 and April 2020. Measures included perioperative chemotherapy, G-CSF use (daily and primary prophylaxis [PP]), and FN and FN-related hospitalization (FNH), all examined annually. Perioperative chemotherapy was examined separately for human epidermal growth factor receptor 2-positive/negative (HER2±). A multivariate logistic regression was used to explore the factors associated with FNH. RESULTS: Of 32,597 patients, those with HER2 + EBC treated with anthracycline-based regimens followed by taxane + trastuzumab + pertuzumab increased since 2018, and those with HER2 - EBC treated with doxorubicin/epirubicin + cyclophosphamide followed by taxane and dose-dense regimens increased after 2014. The proportion of patients prescribed daily G-CSF declined after 2014, whereas that of pegfilgrastim PP increased. The incidence proportion of FN remained at approximately 24-31% from 2010 to 2020, while that of FNH declined from 14.5 to 4.0%. The odds of FNH were higher in those aged ≥ 65 years and lower with pegfilgrastim PP administration. CONCLUSION: Despite the increasing use of escalated regimens in the last 5-6 years, FNH continuously declined, and the odds of FNH were lower among patients treated with pegfilgrastim PP. These results may suggest the contribution of PP in part to suppressing FNH levels over the last 5-6 years.

Human immune and gut microbial parameters associated with inter-individual variations in COVID-19 mRNA vaccine-induced immunity.

COVID-19 mRNA vaccines induce protective adaptive immunity against SARS-CoV-2 in most individuals, but there is wide variation in levels of vaccine-induced antibody and T-cell responses. However, the mechanisms underlying this inter-individual variation remain unclear. Here, using a systems biology approach based on multi-omics analyses of human blood and stool samples, we identified several factors that are associated with COVID-19 vaccine-induced adaptive immune responses. BNT162b2-induced T cell response is positively associated with late monocyte responses and inversely associated with baseline mRNA expression of activation protein 1 (AP-1) transcription factors. Interestingly, the gut microbial fucose/rhamnose degradation pathway is positively correlated with mRNA expression of AP-1, as well as a gene encoding an enzyme producing prostaglandin E2 (PGE2), which promotes AP-1 expression, and inversely correlated with BNT162b2-induced T-cell responses. These results suggest that baseline AP-1 expression, which is affected by commensal microbial activity, is a negative correlate of BNT162b2-induced T-cell responses.

Characteristics, treatment trends, and long-term outcomes of Japanese patients with pregnancy-associated breast cancer (PABC).

PURPOSE: To clarify the characteristics, treatment trends, and long-term outcomes of patients with pregnancy-associated breast cancer (PABC). METHODS: PABC includes breast cancer diagnosed during pregnancy (PBC) and breast cancer diagnosed within 1 year after childbirth or during lactation (LBC). We compared clinical characteristics of 126 patients with LBC and 49 patients with PBC who underwent surgery at our hospital from 1946 to 2018. Survival was compared between patients with LBC and those with PBC in terms of breast cancer-specific disease-free survival (BC-DFS) and overall survival (OS). RESULTS: Patients with LBC were more likely to have family history, lymph node metastasis, lymphatic invasion, and to receive chemotherapy than patients with PBC. Patients with LBC showed poorer BS-DFS and OS than patients with PBC. Among patients with LBC, those treated after 2005 were older at surgery, had a smaller tumor size, received more systemic therapy, and had a more favorable prognosis than patients treated before 2004. Family history, breast cancer within 1 year after childbirth, and surgery before 2004 as well as cStage, lymph node metastasis, and lymphatic invasion were significantly associated with poor prognosis in patients with LBC. In the multivariate analysis for BC-DFS and OS among patients with PABC, LBC vs PBC did not remain as an independent prognostic factor while cStage remained. CONCLUSION: Patients with LBC had a poorer prognosis than those with PBC, most likely due to disease progression rather than biological characteristics. Early detection and optimization of systemic treatments are critical for improving the outcomes of patients with LBC.

Altered pre-existing SARS-CoV-2-specific T cell responses in elderly individuals.

Pre-existing SARS-CoV-2-specific T cells, but not antibodies, have been detected in some unexposed individuals. This may account for some of the diversity in clinical outcomes ranging from asymptomatic infection to severe COVID-19. Although age is a risk factor for COVID-19, how age affects SARS-CoV-2-specific T cell responses remains unknown. We found that pre-existing T cell responses to specific SARS-CoV-2 proteins, Spike (S) and Nucleoprotein (N), were significantly lower in elderly donors (>70 years old) than in young donors. However, substantial pre-existing T cell responses to the viral membrane (M) protein were detected in both young and elderly donors. In contrast, young and elderly donors exhibited comparable T cell responses to S, N, and M proteins after infection with SARS-CoV-2. These data suggest that although SARS-CoV-2 infection can induce T cell responses specific to various viral antigens regardless of age, diversity of target antigen repertoire for long-lived memory T cells specific for SARS-CoV-2 may decline with age; however, memory T cell responses can be maintained by T cells reactive to specific viral proteins such as M. A better understanding of the role of pre-existing SARS-CoV-2-specific T cells that are less susceptible to age-related loss may contribute to development of more effective vaccines for elderly people.

Prevalence and Characteristics of Individuals with Preserved Ratio Impaired Spirometry (PRISm) and/or Impaired Lung Function in Japan: The OCEAN Study.

PURPOSE: Many individuals with obstructive airway disease (OAD), including chronic obstructive pulmonary disease (COPD) and asthma, remain undiagnosed, despite the potential for reducing disease burden through early detection and treatment. OCEAN aimed to determine the prevalence of, and characteristics associated with, impaired lung function in a Japanese population, with the goal of improving strategies for early OAD detection. METHODS: OCEAN was an observational, cross-sectional study in sequentially recruited Japanese individuals ≥40 years of age undergoing routine health examinations. Participants completed screening questionnaires and spirometry testing. Airflow limitation was defined as forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.7 by pre-bronchodilator spirometry. Preserved ratio impaired spirometry (PRISm) was defined as FEV1/FVC ≥0.7 and FEV1 <80% predicted. The primary endpoint was prevalence of spirometry-based airflow limitation and PRISm. The characteristics of study participants were reported as secondary endpoints. RESULTS: Overall, 2518 individuals were included; 79% were <60 years of age (mean 52.0 years). Airflow limitation and PRISm were observed in 52 (2.1%) and 420 (16.7%) participants, respectively. FEV1 in the PRISm group was between that in the no airflow limitation/PRISm and airflow limitation groups, FVC was similar in the PRISm and airflow limitation groups. The PRISm group had higher mean body mass index and a higher proportion of comorbid metabolic disease compared with the airflow limitation group. The prevalence of airflow limitation and PRISm was highest among current smokers (3.9% and 21.3%, respectively) versus former or never smokers. CONCLUSION: A significant proportion of Japanese individuals <60 years of age attending their annual health examination had impaired lung function (airflow limitation and PRISm); prevalence was highest among current smokers. These findings support screening of current or former smokers ≥40 years of age using patient-reported questionnaires to inform the need for spirometry to confirm an OAD diagnosis.

Breast Cancer, Diabetes Mellitus and Glucagon-Like Peptide-1 Receptor Toward Exploring Their Possible Associations.

PURPOSE: Diabetes Mellitus (DM) has been one of the well known risk factors of breast cancer (BC) development and also associated with adverse clinical outcomes of BC patients. Glucagon-like peptide-1 (GLP-1) receptor agonists have been used as antidiabetic therapeutic agents and recent epidemiological studies have reported their use to be correlated with increased BC risks. However, biological or pathological details have remained unknown. Therefore, in this study, we examined the status of GLP-1 receptor (GLP-1R) in BC with and without DM and correlated the findings with the clinicopathological factors of the patients to explore the possible involvement of GLP-1 in BC pathology. METHODS: We immunolocalized GLP-1R in cancer and adjacent non-pathological breast tissues in BC patients with DM (125 cases) and without DM (58 cases). We then compared the status of GLP-1R with that of fibroblast growth factor 7 (FGF7) and fibroblast growth factor receptor 2 (FGFR2), Ki-67 labeling index (Ki-67 LI) and disease free survival (DFS) of the patients and also between cancerous and non-pathological breast tissues. RESULTS: GLP-1R immunoreactivity was significantly higher (p = 0.044) in the patients with DM than without in carcinoma tissues. However, this was detected only in invasive carcinoma (p < 0.01) and not in non-invasive carcinoma nor non-pathological mammary glands. FGF7 was significantly correlated with the status of GLP-1R in BC (p = 0.045). In addition, in ER positive BC cases, those with GLP-1R positive status tended to have higher Ki-67 LI of more than 14% (p = 0.070). CONCLUSION: These findings all demonstrated the possible association between GLP-1R status and biological features of BC, especially of invasive BC in DM patients.

Utility of Self-Administered Questionnaires for Identifying Individuals at Risk of COPD in Japan: The OCEAN (Okinawa COPD casE finding AssessmeNt) Study.

Purpose: A considerable proportion of patients with chronic obstructive pulmonary disease (COPD) remain undiagnosed and untreated even though they may have a burden of respiratory symptoms that impact quality of life. The OCEAN study assessed the ability of screening questionnaires to identify individuals with, or at risk of, COPD by comparing questionnaire outcomes with spirometric measures of lung function. Methods: This observational study included participants ≥40 years of age presenting for their annual health examination at a single medical center in Okinawa, Japan. Participants completed COPD screening questionnaires (CAPTURE and COPD-Q), the Chronic Airways Assessment Test (CAAT), and general demographic and health-related questionnaires. The performance characteristics of CAPTURE and COPD-Q were compared with spirometry-based airflow limitation by calculating the area under the receiver operating characteristic (ROC-AUC) curve. Results: A total of 2518 participants were included in the study; 79% of whom were <60 years of age (mean 52.0 years). A total of 52 (2.1%) participants had airflow limitation defined as forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) <0.7, and 420 (16.7%) participants were classified as Preserved Ratio Impaired Spirometry (PRISm). Among participants with PRISm, 75 (17.9%) had a CAAT total score ≥10. Airflow limitation and PRISm were more prevalent in current smokers versus past smokers. For the CAPTURE questionnaire, ROC-AUC for screening airflow limitation, PRISm, and PRISm with a CAAT total score ≥10 were 0.59, 0.55, and 0.69, respectively; for COPD-Q, these three clinical features were 0.67, 0.58 and 0.68, respectively. Conclusion: This study demonstrated that CAPTURE and COPD-Q appear to be effective screening tools for identifying symptomatic individuals with undiagnosed, or at risk of developing COPD in adults ≥40 years of age in Okinawa. Furthermore, early diagnosis and management of PRISm is important to improve future outcomes and the societal burden of disease.

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

BACKGROUND: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G). PATIENTS AND METHODS: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors. RESULTS: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 µl (0.8) remained significant. CONCLUSIONS: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC.

Physician's knowledge, attitudes and practice pattern for breast cancer diagnosed during pregnancy: a survey among breast care specialists in Japan.

BACKGROUND: Breast cancer diagnosed during pregnancy (BCP) is uncommon, and thus there is limited evidence on its treatment. However, the incidence of BCP is increasing probably due to women having children at an older age. We aimed to clarify the practice patterns and limitations in treatment for BCP in Japan. METHODS: A cross-sectional survey was developed for board-certified Japanese breast cancer specialists (n = 1583) to evaluate their knowledge, attitude, experience, and practice patterns regarding BCP. Survey items also included questions regarding potential barriers of practice toward patients diagnosed during pregnancy and respondents' background. RESULTS: In March 2018, 492 (31.1%) breast oncologists responded to the survey. Among them, 234 (48%) respondents had the experience of treating at least one case of BCP. The accuracy of knowledge about BCP was evaluated by three items regarding BCP treatment from the latest Japanese Breast Cancer Society treatment guideline, and 265 (54%) were categorized to have "appropriate knowledge". Majority of the physicians (89%) have responded that patients should be treated in a center where both a cancer-treating team and obstetrician exist, and 48% responded that treating patients by the collaboration of cancer-treating team and obstetric team in different institutes is an alternative reasonable option. CONCLUSIONS: Interest, knowledge, and awareness of the guidelines appear to influence physician attitude, and thus it is urgently important to lay out educational materials and learning opportunities regarding BCP for breast specialists. A regional network of oncologists, obstetricians, and pediatricians to support the BCP patients should be developed.

Quantitative digital image analysis of tumor-infiltrating lymphocytes in HER2-positive breast cancer.

As visual quantification of the density of tumor-infiltrating lymphocytes (TILs) lacks in precision, digital image analysis (DIA) approach has been applied in order to improve. In several studies, TIL density has been examined on hematoxylin and eosin (HE)-stained sections using DIA. The aim of the present study was to quantify TIL density on HE sections of core needle biopsies using DIA and investigate its association with clinicopathological parameters and pathological response to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The study cohort comprised of patients with HER2-positive breast cancer, all treated with neoadjuvant anti-HER2 therapy. DIA software applying machine learning-based classification of epithelial and stromal elements was used to count TILs. TIL density was determined as the number of TILs per square millimeter of stromal tissue. Median TIL density was 1287/mm2 (range, 123-8101/mm2). A high TIL density was associated with higher histological grade (P = 0.02), estrogen receptor negativity (P = 0.036), and pathological complete response (pCR) (P < 0.0001). In analyses using receiver operating characteristic curves, a threshold TIL density of 2420/mm2 best discriminated pCR from non-pCR. In multivariate analysis, high TIL density (> 2420/mm2) was significantly associated with pCR (P < 0.0001). Our results indicate that DIA can assess TIL density quantitatively, machine learning-based classification algorithm allowing determination of TIL density as the number of TILs per unit area, and TIL density established by this method appears to be an independent predictor of pCR in HER2-positive breast cancer.

Impact of Topoisomerase IIα, PTEN, ABCC1/MRP1, and KI67 on triple-negative breast cancer patients treated with neoadjuvant chemotherapy.

PURPOSE: Triple-negative breast cancer (TNBC) patients with residual disease following neoadjuvant chemotherapy (NAC) harbor higher risk of relapse, and eventual demise compared to those who achieve pathologic complete response. Therefore, in this study, we assessed a panel of molecules involved in key pathways of drug resistance and tumor progression before and after NAC in TNBC patients, in order to clarify the underlying mechanisms. METHODS: We studied 148 TNBC Japanese patients treated with anthracycline/taxane-based NAC. KI67, Topoisomerase IIα (TopoIIα), PTEN, p53, Bcl2, vimentin, ABCG2/BCRP1, ABCB1/MDR1, and ABCC1/MRP1 were immunolocalized in surgical pathology materials before and after NAC. RESULTS: The status of vimentin and increasing labeling index (LI) of TopoIIα and KI67 in biopsy specimens were significantly associated with those who responded to NAC treatment. The abundance of p53 (p = 0.003), ABCC1/MRP1 (p = 0.033), ABCB1/MDR1 (p = 0.022), and a loss of PTEN (p < 0.0001) in surgery specimens following treatment were associated with pathologic parameters. TopoIIα, PTEN, and ABCC1/MRP1 status predicted pathologic response. In addition, the status of PTEN, ABCC1/MRP1, ABCB1/MDR1, Bcl2, and vimentin in surgical specimens was also significantly associated with adverse clinicopathological factors in surgery specimens, suggesting that these alterations could be responsible for tumor relapse in TNBC patients. CONCLUSION: KI67, TopoIIα, PTEN, and ABCC1/MRP1 status could predict treatment response and/or eventual clinical outcomes. These results could also provide an insight into the mechanisms of drug resistance and relapse of TNBC patients receiving NAC.

Randomized trial of aromatherapy versus conventional care for breast cancer patients during perioperative periods.

PURPOSE: Several studies focused on the effect of aromatherapy on mood, quality of life (QOL), and physical symptoms in patients with cancer. We compared the effects on QOL, vital signs, and sleep quality between aromatherapy and conventional therapy during perioperative periods of the breast cancer patients in this study. METHODS: Patients were randomly assigned in a 2:1 ratio to receive aromatherapy or usual care. The primary endpoint was QOL, which was assessed using the quality of life questionnaire QLQ-C30, Version 3.0 of the European Organization for Research and Treatment of Cancer (EORTC) Study Group on quality of life. Secondary endpoints included the necessity of hypnotics, vital signs including blood pressure and heart rate and adverse events. In addition, we also summarized the patients' perception of the experience from a free description-type questionnaire. RESULTS: A total of 249 patients had breast cancer surgery and 162 patients gave physician consent and were recruited; 110 were randomly assigned to aromatherapy group (eight patients showed incomplete EORTC QLQ-C30) and 52 to control group (one patient showed incomplete EORTC QLQ-C30). There were no statistically significant differences between the aromatherapy group and control group in the EORTC QLQ-C30 at the surgery day. As for the results of the post-operation day 1, trends for differentiations of physical functioning and role functioning were detected between aromatherapy group and control group, but the differences did not reach statistical significance (p = 0.08 and 0.09). There were no significant differences of systolic and diastolic blood pressures between aromatherapy group and control group (p = 0.82 and 0.68). There was no statistically significant difference in heart rates between aromatherapy group (70.6 ± 11.0 bpm) and control group (71.2 ± 9.8 bpm) (p = 0.73). Likewise, the rate of hypnotic use was not statistically significant (p = 0.10). No adverse events were reported after aromatherapy and all impressions from aromatherapy group were positive with descriptors such as relaxed, comfortable, and enjoyable being common. CONCLUSION: The results showed no effects of aromatherapy on QOL, sleep quality, and vital sign. However, there was not any harm or adverse event for using aromatherapy. All impressions from self-reporting were positive such as relaxed, comfortable, and enjoyable by the aromatherapy group. Therefore, we can use aromatherapy during perioperative periods in order to meet the expectations of the patients.

[Selection of goal-directed information triggers removal of irrelevant information from working memory].

This study investigated the triggers for removing irrelevant information from working memory. Based on the perspective that removal is a unique process of updating working memory (Ecker et al., 2010), we hypothesized that the removal process begins after selection of task-relevant information. To test this hypothesis, we employed a modified Sternberg task that reflects the time-course for the removal of information. In a standard procedure of this task, the removal process is thought to be completed in approximately 1,500 ms after directing relevant information. If selection induces removal, removal might not end within 1,500 ms when selection requires more time. To increase the time for selection, we created a circumstance with high interference. Experiment 1 showed that removal was incomplete within 2,000 ms after directing relevant information. Experiment 2 showed that removal could be completed given more time. These results support the hypothesis that the trigger for the removal process is the completion of selection. This is in consistent with recent frameworks concerning executive functions.

Intratumoral estrogen production and actions in luminal A type invasive lobular and ductal carcinomas.

The great majority of invasive lobular carcinoma (ILC) is estrogen-dependent luminal A type carcinoma but the details of estrogen actions and its intratumoral metabolism have not been well studied compared to invasive ductal carcinoma (IDC). We first immunolocalized estrogen-related enzymes including estrogen sulfotransferase (EST), estrogen sulfatase (STS), 17ß-hydroxysteroid dehydrogenase (HSD) 1/2, and aromatase. We then evaluated the tissue concentrations of estrogens in ILC and IDC and subsequently estrogen-responsive gene profiles in these tumors in order to explore the possible differences and/or similarity of intratumoral estrogen environment of these two breast cancer subtypes. The status of STS and 17ßHSD1 was significantly lower in ILCs than IDCs (p = 0.022 and p < 0.0001), but that of EST and 17ßHSD2 vice versa (p < 0.0001 and p = 0.0106). In ILCs, tissue concentrations of estrone and estradiol were lower than those in IDCs (p = 0.0709 and 0.069). In addition, the great majority of estrogen response genes tended to be lower in ILCs. Among those genes above, FOXP1 was significantly higher in ILCs than in IDCs (p = 0.002). FOXP1 expression was reported to be significantly higher in relapse-free IDC patients treated with tamoxifen. Therefore, tamoxifen may be considered an option of endocrine therapy for luminal A type ILC patients. This is the first study to demonstrate the detailed and comprehensive status of intratumoral production and metabolism of estrogens and the status of estrogen response genes in luminal A-like ILC with comparison to those in luminal A-like IDCs.

Tumor microenvironment in invasive lobular carcinoma: possible therapeutic targets.

Invasive ductal and lobular carcinomas (IDC and ILC) are the two most common histological types of breast cancer, and have been considered to develop from terminal duct lobular unit but their molecular, pathological, and clinical features are markedly different between them. These differences could be due to different mechanisms of carcinogenesis and tumor microenvironment, especially cancer-associated fibroblasts (CAFs) but little has been explored in this aspect. Therefore, in this study, we evaluated the status of angiogenesis, maturation of intratumoral microvessels, and proliferation of CAFs using immunohistochemistry and PCR array analysis to explore the differences of tumor microenvironment between ILC and IDC. We studied grade- and age-matched, luminal-like ILC and IDC. We immunolocalized CD34 and αSMA for an evaluation of CAFs and CD31, Vasohibin-1, a specific marker of proliferative endothelial cells and nestin, a marker of pericytes for studying the status of proliferation and maturation of intratumoral microvessel. We also performed PCR array analysis to evaluate angiogenic factors in tumor stromal components. The number of CAFs, microvessel density, and vasohibin-1/CD31 positive ratio were all significantly higher in ILC than IDC but nestin immunoreactivity in intratumoral microvessel was significantly lower in ILC. These results did indicate that proliferation of CAFs and endothelial cells was more pronounced in ILC than IDC but newly formed microvessels were less mature than those in IDC. PCR array analysis also revealed that IGF-1 expression was higher in ILC than IDC. This is the first study to demonstrate the differences of tumor microenvironment including CAFs and proliferation and maturation of intratumoral vessels between ILC and IDC.

Assessment of the Ki67 labeling index: a Japanese validation ring study.

BACKGROUND: A lack of consistent methods to evaluate Ki67 expression is problematic in terms of accurately predicting prognosis in breast cancer. Accordingly, this study aimed to identify the causes of discrepancies in Ki67 labeling index measurements by different observers under different conditions using breast cancer samples. PATIENTS AND METHODS: This Japanese study group compared and assessed immunohistochemical (IHC) analysis of the Ki67 labeling index when measured by different pathologists. Six pathologists (pathologists A-F) in Japan participated in this ring study. One hundred and ten surgical cases of estrogen receptor-positive and human epidermal growth factor receptor 2-negative invasive breast cancer treated in 2007 were identified from the breast cancer database of Tokai University Hospital and were included in this study. RESULTS: For all 6 pathologists, the Ki67 labeling index were significantly different between grade 3 and grade 1 cases and between grade 3 and grade 2 cases, whereas the index tended to be different between grade 1 and grade 2 cases. Further, the Ki67 labeling indexes measured by the 6 pathologists were strongly correlated (ρ: 0.73-0.88). The IHC scores recorded by pathologist A were in moderate to good agreement with those recorded by the others in patients with a Ki67 labeling index of <13.25 % and in those with a Ki67 labeling index of >13.25 % (κ = 0.429-0.660). The Ki67 low and high concordance rates between pathologist A and the others were 0.452-0.778 and 0.862-0.979, respectively. The most pertinent reason for discrepancy in scores seemed to be the selection of the area for counting and the quality of nuclear staining. CONCLUSION: The Ki67 labeling index measured by 6 pathologists without method standardization was in fair to good agreement. We plan to undertake a second ring study, pending recommendations by the international Ki67 panel.

Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study.

INTRODUCTION: The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8(+) TILs and FOXP3(+) TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC). METHODS: One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8(+) TIL and FOXP3(+) TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8(+) TIL and FOXP3(+) TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated. RESULTS: TNBC patients with high CD8(+) TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8(+) TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537-6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029-4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS (P=0.0064 and P=0.0015, respectively). High CD8(+) TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499-9.581, P=0.0036). Nodal status was also associated with BCSS (P=0.0024). TNBC with a high rate of CD8(+) TIL changes was associated with significantly better RFS compared with the low group (P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates (P=0.011 and P=0.023, respectively). CONCLUSIONS: This is the first study to demonstrate that high CD8(+) TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.

Can we improve breast cancer mortality in Okinawa? Consensus of the 7th Okinawa Breast Oncology Meeting.

The rate of breast cancer mortality in Okinawa has gradually been increasing up to 2010. Now Okinawa has the second worst mortality rate in Japan, in part due to the enormous dietary changes resulting from the post-World War II US military occupation, high incidence of obesity, high non-optimal treatment rate, and low breast-cancer screening rate. To reduce breast cancer mortality in Okinawa, we established the Okinawa Breast Oncology Meeting (OBOM) in 2012. At the 7th OBOM held on January 10th, 2014, we discussed the breast cancer mortality in Okinawa focusing on lifestyle, breast cancer screening and optimal treatments. The Okinawan women who were overweight and/or obese during premenopausal and postmenopausal ages had a statistically significant higher risk of breast cancer development compared to those with non-overweight and/or obese women. The traditional diet of Okinawa consists of foods low in calories but rich in nutritional value. Therefore, we recommend Okinawan people not to forget the Okinawan traditional lifestyle, and to reduce their bodyweight to prevent breast cancer. One of the main goals of the OBOM is to raise breast cancer screening attendance rates to 50% (29.2% in 2010). We should standardize the quality control for breast cancer screening in Okinawa. It is important to continue enlightening the Okinawan population to receive optimal treatment. In addition, we are striving to establish systematic medical cooperation between the hospitals specializing in breast cancer treatment with rural hospitals. The OBOM group endeavors to contribute to the improvement of breast cancer mortality in Okinawa.

Clinical significance of subtype classification in metastatic lymph nodes of breast cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy has been increasingly utilized in the treatment of breast cancer patients. However, there are no established surrogate markers predicting the response to subsequent adjuvant therapy and clinical outcome of patients. In particular, whether primary or lymph nodes metastasis should be evaluated for these analyses has remained unknown. Therefore, in this study, we first evaluated the differences in biomarkers between primary and metastatic cancer tissues in the patients undergoing neoadjuvant chemotherapy. We then correlated the findings with the clinical outcomes of these patients. METHODS: We examined 49 patients receiving neoadjuvant chemotherapy and subsequent surgery with lymph node metastasis. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki-67 were all immunohistochemically evaluated in core needle biopsy samples from primary and metastatic tumors following chemotherapy. RESULTS: No statistically significant differences in these markers were detected between the primary tumor and metastatic lymph nodes following therapy, but the Ki-67 labeling index was significantly higher in metastatic lymph nodes than in primary tumor (p = 0.017). The patients associated with luminal A type carcinoma in their lymph nodes following chemotherapy demonstrated significantly better clinical outcomes (disease-free survival: p = 0.0045, overall survival: p = 0.0006) than those who were not. CONCLUSION: These data indicate that subtype classification following chemotherapy, in the metastatic lymph nodes rather than primary tumor could predict long-term outcomes of patients undergoing neoadjuvant chemotherapy.