A randomized trial of the impact of symptom monitoring using an electronic patient-reported outcome app on health-related quality of life in postmenopausal breast cancer patients receiving adjuvant endocrine therapy.

BACKGROUND: Electronic patient-reported outcomes (ePRO) monitoring is a useful communication tool for cancer patients and healthcare providers. In this study, we examined the impact of symptom monitoring using an ePRO app on quality of life (QoL) in postmenopausal breast cancer patients receiving adjuvant endocrine therapy. METHODS: The free app "Welby My Carte ONC" was used in the study. Patients with breast cancer starting adjuvant endocrine therapy were randomly assigned in a 1:1 ratio to ePRO monitoring (ONC) and control groups. The ONC group reported five symptoms extracted from the Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE) (insomnia, joint pain, headache, anxiety, and hot flashes) weekly for 3 months through the app. Reported symptoms were shared with medical personnel. When serious symptoms were reported, these personnel ascertained the patient's health status and provided advice over the phone. The primary endpoint was QoL measured by the Functional Assessment of Cancer Therapy-Breast (FACT-B) at 3 months from enrollment. Differences between groups were tested using analysis of covariance. RESULTS: The study included 125 subjects with mean age of 64 years in the ONC group (n = 61) and 63 years in the control group (n = 64). In the ONC group, the response rate to PRO-CTCAE was about 70% or higher until week 10. The item missing rate was 0. The ONC group reported more symptoms related to joint pain and insomnia. The difference in FACT-B total score between the groups was - 1.55 (95% confidence interval: - 5.91, 2.81), indicating no significant difference. CONCLUSIONS: Symptom monitoring using ePRO early after initiation of adjuvant endocrine therapy after surgery did not improve QoL of breast cancer patients.

Pilot trial of an electronic patient-reported outcome monitoring system in patients with metastatic breast cancer undergoing chemotherapy.

BACKGROUND: Electronic patient-reported outcomes monitoring (ePROM) is a useful communication tool for patients and healthcare providers in cancer chemotherapy. In this study, we examined the feasibility of our newly developed ePROM system, which we refer to as "Hibilog". METHODS: An ePROM app was developed by extracting 18 items from the Patient-Reported Outcome-Common Terminology Criteria for Adverse Events (PRO-CTCAE). Symptom monitoring was conducted every two weeks for patients with metastatic breast cancer undergoing chemotherapy. The primary outcome was the response rate to the ePROM system. The secondary outcomes were response time, item missing rate, and distribution of responses for each symptom. RESULTS: A total of 71 cases (mean age 52.6 years) were analyzed. Performance status was 0 in 76% of the cases and 1 or higher in 24%. First-line treatment was being administered in 30% of cases, second-line treatment in 17%, and third-line or higher treatment in 53%. The response rate to the ePROM system from registration to week 40 remained high at around 80%, indicating good compliance. The average response time was 5.5 min and the missing rate for each item was below 0.4%. Among 1,093 responses, the top 3 symptoms causing interference with daily life were Fatigue (63%), Numbness and tingling (48%), and General pain (46%). CONCLUSION: Our developed ePROM system was able to capture symptoms accurately in patients with metastatic breast cancer undergoing chemotherapy while maintaining a high response compliance.

Application of Personal Health Record in Enhancing the Quality of Life in Patients With Breast Cancer Who Received Adjuvant Hormonal Therapy.

Objective: Recently, personal health records (PHR) have become a communication tool between patients and medical professionals. PHR applications (PHR app) can be installed on smartphones to record patient-reported outcomes (PROs). This study prospectively examined whether patients with breast cancer could record PROs, including subjective and objective symptoms, on PHR app. Materials and Methods: Patients who received adjuvant hormonal therapy were enrolled. The patients were asked to collect PROs related to physical conditions, symptoms, and medications on their PHR app from the beginning of therapy for one month. Quality of life (QoL) was evaluated before treatment initiation and one month after. Patients completed a questionnaire of their opinions concerning the PHR app after use. Results: Fourteen patients were enrolled between October and December 2020. All patients could use the PHR app during the study period without any negative effects on QoL. Eleven (79%) patients fully recorded their PROs on the app. Typical side effects induced by hormonal therapy to reduce the QoL were observed (hot flash in two patients, 14.3%). The questionnaire revealed that approximately 70% wanted to use the PHR app in the future to communicate with medical staff and to report adverse events. Specifically, 90% of patients who experienced difficulty communicating with medical staff wanted to use the PHR app. Some patients wanted to utilize the PHR app to set reminders to take medications. Conclusion: The PHR app can be applied as a communication tool between patients taking adjuvant hormonal therapy and medical professionals.

BRCAness as a prognostic indicator in patients with early breast cancer.

BRCAness is defined as a phenotypic copy of germline BRCA mutations, which describes presence of homologous recombination defects in sporadic cancers. We detected BRCAness by multiplex ligation-dependent probe amplification (MLPA) and explored whether BRCAness can be used as a predictor of prognosis. BRCAness status was classified for total 121 breast cancer patients. Forty-eight patients (39.7%) were identified as BRCAness positive. Tumors of BRCAness were more likely to be hormone receptors negative (95.8% vs. 50.7%, P < 0.001), nuclear grade III (76.1% vs. 48.4%, P = 0.001) and triple-negative breast cancer subtype (91.6% vs. 42.5%, P < 0.001). Five-year disease free survival (DFS) (54.0% vs. 88.0%, P < 0.001) and overall survival (OS) (76.3% vs. 93.1%, P = 0.002) were significantly lower in BRCAness patients. In neoadjuvant chemotherapy subgroup analysis, clinical response rate for taxane-based regimen was significantly lower in BRCAness patients (58.3% vs. 77.8%, P = 0.041). Cox regression multivariate analysis showed that BRCAness was the independent prognostic factor for DFS (HR 2.962, 95%CI 1.184-7.412, P = 0.020), but not for OS (HR 2.681, 95%CI 0.618-11.630, P = 0.188). BRCAness is associated with specific characteristics and may suggest resistance to taxane-based chemotherapy. BRCAness can be used as a negative prognostic indicator for breast cancer.

Effectiveness of a Smartphone Application as a Support Tool for Patients Undergoing Breast Cancer Chemotherapy: A Randomized Controlled Trial.

BACKGROUND: Outpatients undergoing cancer chemotherapy experience anxiety related to adverse drug reactions that they can experience at home. We developed a breast cancer patient support system (BPSS) application (app). The BPSS app chronologically and quantitatively records patients' subjective and objective symptoms during breast cancer chemotherapy, with the goal of providing supportive management for adverse drug reactions. The present study examined whether the BPSS app is an effective tool for supporting patients undergoing chemotherapy. PATIENTS AND METHODS: A total of 102 patients undergoing chemotherapy at the Showa University Hospital (Tokyo, Japan) were enrolled in the present order- and age-controlled clinical trial and randomized into BPSS or no-BPSS app groups. The patients underwent 4 courses of chemotherapy. The primary outcome was the change in the hospital anxiety and depression scale score, which was assessed directly before and after the 4 courses of chemotherapy. Other outcomes included health literacy (measured using the 14-item health literacy scale (HLS-14), side effects, and app adherence. RESULTS: Of the 102 patients, 95 completed the present study. No significant improvement was seen in anxiety, depression, or health literacy at the end of treatment between the BPSS and no-BPSS app groups. Overall, 1868 side effects were reported. When the patients' records were compared with the medical staff records, the analysis revealed that the medical staff had underestimated some grade 3 symptoms. CONCLUSION: The BPSS app is a feasible tool for patients with breast cancer and might be useful as a support tool for information sharing between patients and medical staff in an effort to optimize chemotherapy and deliver suitable patient care and support.

α7 nAChRs expressed on antigen presenting cells are insensitive to the conventional antagonists α-bungarotoxin and methyllycaconitine.

Expression of α7 nicotinic acetylcholine receptors (nAChRs) on antigen presenting cells (APCs), such as macrophages and dendritic cells, is now well established. We have shown that GTS-21, a selective α7 nAChR agonist, downregulates APC-dependent CD4+ T cell differentiation into regulatory T cells (Tregs) and effector Th1, Th2 and Th17 cells by inhibiting antigen processing, thereby interfering with antigen presentation. α7 nAChRs on Jurkat human leukemic T cells require functional T cell receptors (TCRs)/CD3 and leukocyte-specific tyrosine kinase to mediate nicotine-induced Ca2+-signaling via Ca2+ release from intracellular stores, and are insensitive to two conventional α7 nAChR antagonists, α-bungarotoxin (α-BTX) and methyllycaconitine (MLA). We investigated the effects of GTS-21, α-BTX and MLA on ovalbumin (OVA)-induced Th cytokine release from spleen cells isolated from OVA-specific TCR transgenic DO11.10 mice. We found that: (1) GTS-21 dose-dependently suppresses OVA-induced IFN-γ, IL-4 and IL-17 release, but neither α-BTX nor MLA alone affected the OVA-induced cytokine release. (2) Neither α-BTX nor MLA abolished the suppressive effects of GTS-21 on IFN-γ and IL-17 release from OVA-activated DO11.10 spleen cells. (3) GTS-21 significantly suppressed OVA-induced APC-dependent CD4+ T cell differentiation into Tregs. Neither MLA nor mecamylamine, a non-specific nAChR antagonist, abolished the suppressive effect of GTS-21 on Treg differentiation. These results suggest that α7 nAChRs on APCs involved in cytokine synthesis and T cell differentiation are insensitive to the conventional α7 nAChR antagonists, α-BTX and MLA, and that α7 nAChRs on APCs differ pharmacologically from those in neurons.

Differences in perception of breast cancer treatment between patients, physicians, and nurses and unmet information needs in Japan.

PURPOSE: Discrepancies exist between healthcare provider and patient perceptions surrounding breast cancer treatment. Significant treatment changes in the last 10 years have made re-evaluation of these perceptions necessary. METHODS: Physicians and nurses involved in breast cancer treatment, and patients who had received breast cancer chemotherapy (past 5 years), were questioned using an Internet survey. Participants ranked physical concerns (treatment side effects), psychological concerns, priorities for treatment selection, and side effects to be avoided during treatment. Patients were asked about desired treatment information/information sources. Rankings were calculated using the mean value of scores. Spearman's rank correlation was used to determine the concordance of rankings among groups. RESULTS: Survey respondents included 207 patients, 185 physicians, and 150 nurses. Patients and nurses similarly ranked distressing physical concerns; physician rankings differed. Quality of life (QoL) and treatment response ranked high with physicians and patients when considering future treatment; nurses prioritized QoL. All three groups generally agreed on ranking of psychological concerns experienced during chemotherapy, explanation of treatment options, and how treatment decisions were made, although more patients thought treatment decisions should be made independently. Healthcare providers reported providing explanations of treatment side effects and information on physical/psychological support options while patients felt both were lacking. Concordance was calculated as 0.47 (patient-physician), 0.83 (patient-nurse), and 0.76 (physician-nurse). Patients desired additional information, preferring healthcare providers as the source. CONCLUSIONS: Specific areas for improvement in breast cancer patient care were identified; programs should be implemented to address unmet needs and improve treatment in these areas.

Functional Phenotypic Diversity of Regulatory T Cells Remaining in Inflamed Skin.

Regulatory T cells (Tregs) migrate between lymphoid and peripheral tissues for maintaining immune homeostasis. Tissue-specific function and functional heterogeneity of Tregs have been suggested, however, correlation between them and inter-tissue movement remain unknown. We used a contact hypersensitivity model of mice expressing a photoconvertible protein for tracking migratory cells. After marking cells in skin, we purified Tregs exhibiting a different migration pattern [Tregs recruiting to or remaining in the skin and emigrating from the skin to draining lymph nodes (dLNs) within half a day] and examined single-cell gene and protein expression profiles. Correlation and unsupervised clustering analyses revealed that Tregs in both skin and dLNs comprised two subpopulations, one highly expressing Nrp1 with variable CD25, Granzyme B, and/or CTLA-4 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Characteristic subsets of Tregs remaining in the skin displayed higher CD25 and CD39 expression and lower Granzyme B and CTLA-4 expression compared with Tregs migrating to the skin. In addition, CCR5 expression in Tregs in skin was positively and negatively correlated with CD39 and Nrp-1 expression, respectively. To assess the predictive value of these data for immunotherapy, we blocked CCR5 signaling and found modest downregulation of CD39 and modest upregulation of Nrp1 expression in skin Tregs. Our data reveal a high functional diversity of Tregs in skin that is strongly related to trafficking behavior, particularly skin retention. Modulation of tissue-specific trafficking and function is a promising clinical strategy against autoimmune, infectious, and neoplastic diseases. Significance Statement: Regulatory T cells (Tregs) are essential for maintaining immune homeostasis. To reveal tissue-specific immunoinhibitory functions and inter-tissue movement correlation based on Treg functional heterogeneity, we examined single-cell gene and protein expression profiles of Tregs recruited to, remaining in, or emigrating from the contact hypersensitivity-induced inflamed skin. Tregs in skin were composed of several subpopulations; one with high Nrp1 expression and another with 3 subsets strongly expressing CD25, Granzyme B, or CTLA-4 together with CD39. Tregs remaining in skin displayed highCD25, CD39, and CCR5 expression, and CCR5 signaling blockade downregulated CD39. A high Treg functional diversity in skin is strongly related to trafficking behavior. Tissue-specific trafficking and functional modulation are a promising clinical strategy against autoimmune, infectious, and neoplastic diseases.

Distinct Roles of α7 nAChRs in Antigen-Presenting Cells and CD4+ T Cells in the Regulation of T Cell Differentiation.

It is now apparent that immune cells express a functional cholinergic system and that α7 nicotinic acetylcholine receptors (α7 nAChRs) are involved in regulating T cell differentiation and the synthesis of antigen-specific antibodies and proinflammatory cytokines. Here, we investigated the specific function α7 nAChRs on T cells and antigen presenting cells (APCs) by testing the effect of GTS-21, a selective α7 nAChR agonist, on differentiation of CD4+ T cells from ovalbumin (OVA)-specific TCR transgenic DO11.10 mice activated with OVA or OVA peptide323-339 (OVAp). GTS-21 suppressed OVA-induced antigen processing-dependent development of CD4+ regulatory T cells (Tregs) and effector T cells (Th1, Th2, and Th17). By contrast, GTS-21 up-regulated OVAp-induced antigen processing-independent development of CD4+ Tregs and effector T cells. GTS-21 also suppressed production of IL-2, IFN-γ, IL-4, IL-17, and IL-6 during OVA-induced activation but, with the exception IL-2, enhanced their production during OVAp-induced activation. In addition, during antigen-nonspecific, APC-independent anti-CD3/CD28 antibody-induced CD4+ polyclonal T cell activation in the presence of respective polarizing cytokines, GTS-21 promoted development of all lineages, which indicates that GTS-21 also acts via α7 nAChRs on T cells. These results suggest 1) that α7 nAChRs on APCs suppress CD4+ T cell activation by interfering with antigen presentation through inhibition of antigen processing; 2) that α7 nAChRs on CD4+ T cells up-regulate development of Tregs and effector T cells; and that α7 nAChR agonists and antagonists could be potentially useful agents for immune response modulation and enhancement.

QOL Evaluation of Nab-Paclitaxel and Docetaxel for Early Breast Cancer.

OBJECTIVE: A previous randomized phase II study showed that neoadjuvant nab-paclitaxel (nab-PTX) 100 mg/m2) was effective and well-tolerated in patients with HER2-negative early-stage breast cancer, compared with docetaxel (DTX). We evaluated patient outcomes in terms of the Functional Assessment of Cancer Therapy-Breast (FACT-B), as a measure of health-related quality of life (HRQoL). MATERIALS AND METHODS: Stage I-III HER2-negative breast cancer patients from the previous study were included. They received either four cycles of nab-PTX (100 mg/m2 days 1/8/15) every 4 weeks, or DTX (75 mg/m2 day 1) every 3 weeks, both followed by four cycles of 5-fluorouracil/epirubicin/cyclophosphamide (FEC). Patients completed a health-related quality-of-life questionnaire at baseline, after one and four cycles of taxanes, before administration of FEC, and after administration of one and four cycles of FEC. RESULTS: Thirty-six eligible patients were enrolled. The baseline characteristics of the two groups were well balanced. FACT-B scores at baseline and after four cycles of taxanes were 115/108 (DTX/nab-PTX) and 99/92, respectively. There were no significant differences between DTX and nab-PTX for FACT-B, FACT-B-Trial Outcome Index (FACT-B-TOI) and FACT-General. FACT-B and FACT-B TOI scores tended to decrease after one cycle and after four cycles of chemotherapy which did not recover to the baseline scores through the end of chemotherapy in each group. CONCLUSION: There were no significant safety differences between nab-PTX and DTX. HRQoL tended to decrease during taxane-based anticancer treatment, with no significant differences between the treatments. We suggest that the HRQoL questionnaire has limited ability to evaluate different chemotherapy schedules. Trial registration UMIN000009855. Nov 20, 2012 registered.

Randomized Multicenter Phase II Trial of Neoadjuvant Therapy Comparing Weekly Nab-paclitaxel Followed by FEC With Docetaxel Followed by FEC in HER2- Early-stage Breast Cancer.

BACKGROUND: Weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) demonstrated greater efficacy with less toxicity than docetaxel in metastatic breast cancer. We conducted a randomized phase II to compare these regimens as neoadjuvant chemotherapy for HER2- early-stage breast cancer. PATIENTS AND METHODS: Stage I-III human epidermal growth factor receptor-negative (HER2-) breast cancer patients were included in the present trial and received either docetaxel every 3 weeks or nab-paclitaxel on days 1, 8, and 15 every 28 days for 4 cycles, followed by FEC (5-fluorouracil, epirubicin, cyclophosphamide) every 3 weeks for 4 cycles. The primary endpoint was the pathologic complete response (pCR) rate, defined as ypT0 and ypN0. The secondary endpoints were pCR (ypT0/ypTis and ypN0), the clinical response rate (using the Response Evaluation Criteria In Solid Tumors criteria), histologic effect of treatment (using the Japanese Breast Cancer Society classification), breast conservation rate, and adverse events. RESULTS: A total of 152 eligible patients were enrolled at 6 centers. The baseline characteristics were well balanced. In comparing the 2 regimens (docetaxel/nab-paclitaxel), the pCR rate was 12% and 17% (P = .323). In the Ki67 > 20% group, the pCR rate was greater (24%) for the nab-paclitaxel arm than for the docetaxel arm (16%; P = .432). The most common grade 3/4 adverse event was neutropenia, observed in 40% and 36% of cases in the nab-paclitaxel and docetaxel arms, respectively. The nonhematologic adverse events of any grade were myalgia (34% and 32%), arthralgia (42% and 35%), and peripheral sensory neuropathy (55% and 65%) for the 2 treatment arms. No grade 3/4 peripheral sensory neuropathy was observed in the nab-paclitaxel arm. CONCLUSION: Weekly nab-paclitaxel administered at a dose of 100 mg/m2 showed equivalent efficacy and was well tolerated compared with docetaxel as neoadjuvant therapy. Nab-paclitaxel might be more effective in patients with highly proliferative cancer.

Epithelial membrane protein 3 (Emp3) downregulates induction and function of cytotoxic T lymphocytes by macrophages via TNF-α production.

Tetraspanin membrane protein, epithelial membrane protein 3 (Emp3), is expressed in lymphoid tissues. Herein, we have examined the Emp3 in antigen presenting cell (APC) function in the CD8+ cytotoxic T lymphocytes (CTLs) induction. Emp3-overexpressing RAW264.7 macrophage cell line derived from BALB/c mice reduced anti-C57BL/6 alloreactive CTL induction, while Emp3-knockdown RAW264.7 enhanced it compared with parent RAW267.4. Emp3-overexpressing RAW264.7 inhibited, but Emp3-knockdown RAW264.7 augmented, CD8+ T cell proliferation, interferon-γ secretion, IL-2 consumption, and IL-2Rα expression on CD8+ T cells. The supernatant from co-culture with Emp3-overexpressing RAW264.7 contained higher amount of TNF-α, and TNF- α neutralization significantly restored all these inhibitions and the alloreactive CTL induction. These results suggest that Emp3 in allogeneic APCs possesses the inhibitory function of alloreactive CTL induction by downregulation of IL-2Rα expression CD8+ T cells via an increase in TNF-α production. This demonstrates a novel mechanism for regulating CTL induction by Emp3 in APCs through TNF-α production.

Comparison of adverse events following injection of original or generic docetaxel for the treatment of breast cancer.

PURPOSE: The approval of injectable generic drugs does not require bioequivalence testing. However, although generic products contain the same level of the active compound, the levels and types of additives present can differ from those used in the original product. Since docetaxel is highly lipophilic, polysorbate 80 (PS80), polyethylene glycol (PEG), and ethyl alcohol are employed to solubilize this anticancer agent. This retrospective study compared the safety of five docetaxel products (Taxotere®, Docetaxel Hospira, Docetaxel Sandoz, Docetaxel Sawai, and Docetaxel EE). METHODS: The incidence and severity of adverse events were analyzed using the medical records of operable breast cancer patients (n = 363) treated with docetaxel (75 mg/m2) in Showa University Hospital, Japan, from Jan 2013 to Mar 2016. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: Significant product-related differences were observed in the following non-hematological adverse events: injection site reaction (P = 0.0012), hand-foot syndrome (≥grade 3) (P = 0.0003), and oral mucositis (≥grade 3) (P = 0.0080). Multivariate logistic regression analyses of the associations between these adverse events and the total additive administered (g/m2) identified significant negative effects of PS80 and ethyl alcohol. CONCLUSIONS: Injectable docetaxel products had different adverse event profiles, which showed negative associations with the amounts of PS80 and ethyl alcohol present. This finding indicated that there might be additive-related pharmacokinetic and physiochemical differences among these products, suggesting a need for further pre- or post-approval testing of injectable generic products containing noticeable different levels of additives.

Spirulina lipopolysaccharides inhibit tumor growth in a Toll-like receptor 4-dependent manner by altering the cytokine milieu from interleukin-17/interleukin-23 to interferon-γ.

Th17 cells and the cytokine they produce, interleukin (IL)-17, play an important role in tumor progression in humans and in mice. IL-6 and IL-23 are critical cytokines for the differentiation and propagation of Th17 cells, respectively. Bacterial lipopolysaccharides (LPS) are known to stimulate immune cells to produce such inflammatory cytokines. Contrary to Escherichia coli (E. coli) LPS, LPS from Spirulina has low toxicity and barely induces in vivo production of IL-6 and IL-23 in mice. We examined the antitumor effects of Spirulina LPS compared to E. coli LPS in an MH134 hepatoma model. Administration of Spirulina LPS suppressed tumor growth in C3H/HeN mice, but not in Toll-like receptor 4 (TLR4)-mutant C3H/HeJ mice, by reducing serum levels of IL-17 and IL-23, while increasing interferon (IFN)-γ levels. The antitumor activity and IFN-γ production were mediated by T cells. Moreover, in vitro experiments showed that Spirulina LPS impaired the antigen-presenting function that supports the generation of IL-17-producing cells in a toll-like receptor (TLR)4-dependent manner. Of note, injection of anti-IL-17 antibody in tumor-bearing C3H/HeN mice in the absence of Spirulina LPS markedly suppressed tumor growth and augmented IFN-γ responses. Thus, our results support the notion that IFN-γ and IL-17/IL-23 mutually regulate Th17 and Th1 responses in tumor-bearing hosts, and Spirulina LPS modulates the balance of the IFN-γ-IL-17/IL-23 axis towards IFN-γ production, which leads to tumor inhibition. Furthermore, Spirulina LPS effectively inhibited the spontaneous development of mammary tumors. This study has important implications for the exploitation of TLR-based immunomodulators for cancer immunotherapy.

Development of Support System for Breast Cancer Patients--Managing Side Effects through an Internet-Based System.

Chemotherapy in the outpatient setting is effective in improving patients' quality of life (QOL). However, the increasing availability of targeted molecular agents in addition to conventional anti-cancer medications has placed increased importance on managing adverse events and educating patients about side effects that can affect their QOL. We developed an Internet-based "Patient Support System"to enable patients at home to communicate symptoms of side effects and administration status to a hospital interface that documents and monitors the ongoing side-effect profile. In a trial of 8 patients scheduled to receive chemotherapy before or after surgery, our system enabled medical staff to quantitatively confirm data on side effects recorded daily by the outpatients, demonstrating that it functions effectively in maintaining the patient's QOL. Moreover, it clearly identified significant differences in the occurrence and status of side effects between patients receiving the same anticancer medication. Patients reported that the onset of side effects and recovery status could be confirmed objectively, thus enabling self-management of the disease, which helped greatly in managing side effects and schedules throughout the treatment period. This system has potential as a supportive tool for activities of daily living while maintaining QOL and improving the overall therapeutic effect.

BRCAness predicts resistance to taxane-containing regimens in triple negative breast cancer during neoadjuvant chemotherapy.

BACKGROUND: To provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response. PATIENTS AND METHODS: We retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information. RESULTS: We obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients-all with BRCAness-had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049). CONCLUSION: Identifying BRCAness can help predict the response to taxane, and changing regimens for BRCAness TNBC might improve patient survival. A larger prospective study is needed to further clarify this issue.

Regulatory effects of Spirulina complex polysaccharides on growth of murine RSV-M glioma cells through Toll-like receptor 4.

This study is the first to report that Spirulina complex polysaccharides (CPS) suppress glioma growth by down-regulating angiogenesis via a Toll-like receptor 4 signal. Murine RSV-M glioma cells were implanted s.c. into C3H/HeN mice and TLR4 mutant C3H/HeJ mice. Treatment with either Spirulina CPS or Escherichia coli (E. coli) lipopolysaccharides (LPS) strongly suppressed RSV-M glioma cell growth in C3H/HeN, but not C3H/HeJ, mice. Glioma cells stimulated production of interleukin (IL)-17 in both C3H/HeN and C3H/HeJ tumor-bearing mice. Treatment with E. coli LPS induced much greater IL-17 production in tumor-bearing C3H/HeN mice than in tumor-bearing C3H/HeJ mice. In C3H/HeN mice, treatment with Spirulina CPS suppressed growth of re-transplanted glioma; however, treatment with E. coli LPS did not, suggesting that Spirulina CPS enhance the immune response. Administration of anti-cluster of differentiation (CD)8, anti-CD4, anti-CD8 antibodies, and anti-asialo GM1 antibodies enhanced tumor growth, suggesting that T cells and natural killer cells or macrophages are involved in suppression of tumor growth by Spirulina CPS. Although anti-interferon-γ antibodies had no effect on glioma cell growth, anti-IL-17 antibodies administered four days after tumor transplantation suppressed growth similarly to treatment with Spirulina CPS. Less angiogenesis was observed in gliomas from Spirulina CPS-treated mice than in those from saline- or E. coli LPS-treated mice. These findings suggest that, in C3H/HeN mice, Spirulina CPS antagonize glioma cell growth by down-regulating angiogenesis, and that this down-regulation is mediated in part by regulating IL-17 production.

Effect of spherical aberration on visual function under photopic and mesopic conditions after cataract surgery.

PURPOSE: To evaluate the effect of spherical aberration on visual function under natural pupil conditions after cataract surgery. SETTING: Keio University Hospital, Tokyo, Japan. METHODS: This study comprised cataract patients who had cataract extraction with implantation of an acrylic intraocular lens. Preoperative and postoperative visual acuity, higher-order aberration in the whole eye, contrast sensitivity function, and pupil diameter under photopic and mesopic conditions 1 month after surgery were measured. The area under log contrast sensitivity function (AULCSF) and spherical aberration corresponding to the individual pupil diameter under photopic and mesopic conditions were evaluated. RESULTS: One hundred seven eyes of 79 patients (30 men, 49 women; mean age 68.0 years +/- 9.6 [SD]) were evaluated. The mean pupil diameter was 2.9 +/- 0.50 mm under photopic conditions and 3.6 +/- 0.57 mm under mesopic conditions. The mean spherical aberration was 0.03 +/- 0.04 mum (range -0.12 to 0.34 mum) under photopic conditions and 0.05 +/- 0.10 mum (range -0.14 to 0.55 mum) under mesopic conditions. The postoperative AULCSF without glare under photopic conditions was significantly negatively correlated with spherical aberration (P = .014). The postoperative AULCSF with and without glare under mesopic conditions was significantly negatively correlated with spherical aberration (P<.001 and P = .01, respectively). CONCLUSIONS: Postoperative spherical aberration had a significant effect on visual function under photopic and mesopic conditions. This result indicates that reduced postoperative spherical aberration improves postoperative visual function under photopic and mesopic conditions.

Discrete types of osteoclast precursors can be generated from embryonic stem cells.

Osteoclast precursors (OCPs) share some characteristics with the monocyte/macrophage lineages, but the early events of OCP development are not yet clear. To investigate osteoclastogenesis from the earliest stage, we used step-wise cultures of embryonic stem (ES) cells to induce mature osteoclasts and assessed the effect of vascular endothelial growth factor receptor (VEGFR)-1/Fc chimeric protein on osteoclast development. Addition of VEGFR-1/Fc for the first 5 days of culture (phase I) severely inhibited the development of OCPs. Although OCPs were detected after culturing for a further 5 days (phase II), the reduction of OCPs in phase I was maintained in phase II. The generation of OCPs in phase I was resistant to signal blocking mediated by Kit receptors, but that in phase II was partially inhibited by either an anti-Kit antagonistic antibody or VEGFR-1/Fc and was severely inhibited by the combination of both reagents. Moreover, the OCPs in phase I gave rise to larger numbers of osteoclasts but required a longer period for maturation than the OCPs in phase II. We thus showed that OCPs expanded in phase II, but the majority of OCPs arose from ES cells in a manner dependent on VEGFR-1 binding factor(s) in phase I.