Yuko Yoshida

Low FOXA1 expression predicts good response to neo-adjuvant chemotherapy resulting in good outcomes for luminal HER2-negative breast cancer cases

Background:FOXA1 expression is a good prognostic marker for endocrine therapy in hormone-positive breast cancer. We retrospectively examined breast cancer patients with luminal human epidermal growth factor receptor 2 (HER2)-negative tumours, as defined by immunohistochemistry, who received neo-adjuvant chemotherapy (NAC) and investigated the relationship between treatment effects and FOXA1 expression.Methods:Biopsy specimens from 103 luminal HER2-negative tumours were immunohistochemically examined. FOXA1 effects on chemo-sensitivity were also investigated employing in vitro experiments.Results:FOXA1 and Ki67 expressions independently predicted a pathological complete response (pCR). Knockdown of FOXA1 by siRNA boosted the chemo-effect in oestrogen receptor-positive cells. The Cox hazards model revealed a pCR to be the strongest factor predicting a good patient outcome.Conclusions:Our present study showed low FOXA1 expression to be associated with a good response to NAC in luminal HER2-negative breast cancer. Improved outcomes of these patients suggest that NAC should be recommended to patients with low FOXA1 tumours.

Two cases of mucinous cystadenoma of the appendix successfully treated by laparoscopy.

Two cases of mucinous cystadenoma of the appendix successfully treated by laparoscopy are reported. An 81-year-old woman with lower right back pain was diagnosed with mucinous cystadenoma of the appendix or appendiceal carcinoma and underwent elective laparoscopic surgery. The other case involved a 70-year-old man with hematochezia who was diagnosed with mucinous cystadenoma. He also underwent elective laparoscopic surgery. In these two cases, gauze was folded around the tumors rather than grasping them directly. The postoperative courses were uneventful, and these patients had no recurrent disease at 2-year follow-up. In such cases, surgical excision of the tumor without rupture is of paramount importance because rupture of the lesion can cause pseudomyxoma peritonei. Though appendiceal mucinous cystadenoma has been considered a contraindication of laparoscopic resection, it was possible to achieve this by using a laparoscopic procedure with a gauze technique.

Unroofing technique for endoscopic resection of a large colonic lipoma.

A 77-year-old man presented with repeated episodes of melena. He had a medical history of hypertension, atrial fibrillation and cardiogenic brain infarction and took medications, i.e. an antiplatelet agent. Laboratory data revealed iron deficiency anemia. Colonoscopy revealed a yellowish smooth submucosal tumor, 50 mm in diameter, on the Bauhin valve. The lesion was soft and compressible. The overlying mucosa was erosive. CT scan showed a uniform mass with very low density in the ascending colon, corresponding to the above-detected lesion. The clinical diagnosis of colonic lipoma was established. Using a 25 mm electrocautery snare (Olympus, Tokyo, Japan), we transected the upper portion of the mass to unroof the lesion. The mucosa layer was thick and hard. Fat tissue was observed extruding from the cut surface, consistent with the diagnostic hypothesis. After dissecting the overlying mucosa on the anal side by means of an IT knife (Olympus) in order to completely extrude the mass, the fat tissue was further exposed. It took about 26 min to perform the whole procedure. There were no procedure-related complications. Macroscopically, the resected lesion was a yellow solid tumor, 1.6 × 1.5 × 0.7 cm in diameter. Histopathologic examination of the excised specimen confirmed the diagnosis of a lipoma. The clinical course was uneventful. A follow-up endoscopy 1 month later showed a scarred mucosa at the resection site. Similarly, a follow-up CT scan 2 months later revealed no evidence of residual lipoma. The unroofing technique is safe, easy and suitable for the treatment of large lipomas.

Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients

Background Ki67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity. The Ki67 expression level, which indicates that a cell is undergoing division (cell cycle), rises when proliferation activity increases. Thus, Ki67 expression might be affected by hormonal stimuli. We hypothesised that Ki67 expression level might change during the menstrual cycle. We examined pairs of biopsy and surgical specimens from individual patients to evaluate this hypothesis. Methods First, the effects of estradiol on Ki67 expression in breast cancer cell lines were examined employing immunocytochemistry and Western blotting. Next, differences in Ki67 expression between biopsy and surgical specimens from 131 patients with estrogen receptor-positive tumours were retrospectively examined. Results In vitro experiments showed Ki67 expression in estrogen receptor-positive cancer cells to be dependent on estradiol stimulation. Ki67 expression was higher in biopsy samples collected in the luteal phase than in those from other phases. When biopsy and surgical samples were obtained at different times during the menstrual cycle in the same individual, there were differences in Ki67 expression between these samples. Those collected in the luteal phase showed higher Ki67 expression than samples obtained during other phases (p<0.01). Conclusions Ki67 expression varied in the same patients according to menstrual cycle phase. Our results suggest that Ki67 expression in estrogen receptor-positive breast cancer should be carefully assessed bearing in mind the patients menstrual cycle, since the interpretation of expression could affect treatment decisions.

Circulating plasma microRNA profiling in patients with polymyositis/dermatomyositis before and after treatment: miRNA may be associated with polymyositis/dermatomyositis

BackgroundMicroRNAs (miRNAs) are involved in the regulation of key biological processes and have been implicated in various diseases, including autoimmune disorders. The pathogenesis of polymyositis (PM) and dermatomyositis (DM) is considered to be mediated by autoimmune reactions. To determine miRNA role in the development and progression of PM and DM, we performed plasma miRNA profiling in PM/DM patients before and after treatment.MethodsTotal RNA was isolated from plasma of 10 patients before and after treatment with prednisolone, or, in case of prednisolone resistance or complications, with the combination of calcineurin inhibitors (cyclosporine or tacrolims) and/or pulse intravenous cyclophosphamide. The expression of miRNAs was determined using miRNA microarray and validated by qRT-PCR.ResultsMore differentially expressed miRNAs were found in plasma of DM patients compared to PM patients before and after treatment, and their profiles were different. Among the differentially expressed plasma miRNA identified by microarray, the levels of hsa-miR-4442 were confirmed by qRT-PCR to be significantly decreased by treatment. In addition, plasma hsa-miR-4442 content in active PM/DM significantly exceeded that in other active autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as in healthy individuals. The level of plasma hsa-miR-4442 was positively correlated with Skeletal Disease Activity in MITAX (Myositis Intention to Treat Activity Index).ConclusionThis is the first report describing plasma miRNA expression profiles in PM/DM patients. The present data suggest that plasma levels of miRNAs may be associated with polymyositis/dermatomyositis and hsa-miR-4442 could be used as a biomarker for PM/DM diagnosis and/or disease activity.

Kinase inhibitors of the IGF-1R as a potential therapeutic agent for rheumatoid arthritis

Abstract We have previously shown that the inhibition of connective tissue growth factor (CTGF) is a potential therapeutic strategy against rheumatoid arthritis (RA). CTGF consists of four distinct modules, including the insulin-like growth factor binding protein (IGFBP). In serum, insulin-like growth factors (IGFs) bind IGFBPs, interact with the IGF-1 receptor (IGF-1 R), and regulate anabolic effects and bone metabolism. We investigated the correlation between IGF-1 and the pathogenesis of RA, and the inhibitory effect on osteoclastogenesis and angiogenesis of the small molecular weight kinase inhibitor of the IGF-1 R, NVP-AEW541, against pathogenesis of RA in vitro. Cell proliferation was evaluated by cell count and immunoblotting. The expression of IGF-1 and IGF-1 R was evaluated by RT-PCR. Osteoclastogenesis was evaluated using tartrate-resistant acid phosphatase staining, a bone resorption assay, and osteoclast-specific enzyme production. Angiogenesis was evaluated by a tube formation assay using human umbilical vein endothelial cells (HUVECs). The proliferation of MH7A cells was found to be inhibited in the presence of NVP-AEW541, and the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt was downregulated in MH7A cells. IGF-1 and IGF-1 R mRNA expression levels were upregulated during formation of M-colony stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL)-mediated osteoclast formation. Moreover, osteoclastogenesis was suppressed in the presence of NVP-AEW541. The formation of the tubular network was enhanced by IGF-1, and this effect was neutralized by NVP-ARE541. Our findings suggest that NVP-AEW541 may be utilized as a potential therapeutic agent in the treatment of RA.

Connective Tissue Growth Factor Neutralization Aggravates the Psoriasis Skin Lesion: The Analysis of Psoriasis Model Mice and Patients

Background Connective tissue growth factor (CTGF) is a multifunctional cellular protein and playing a role as a central mediator in tissue remodeling and fibrosis. The physiological function of CTGF in psoriasis is unknown. Objective The purpose of this study was to investigate the function of CTGF in psoriasis using the established imiquimod (IMQ)-induced psoriasis murine model and psoriasis patients. Methods Anti-CTGF monoclonal antibody was applied to IMQ induced psoriasis mice and those skin were clinically, pathologically and immunologically analyzed. Additionally, CTGF expression was analyzes using skin samples and plasma from psoriasis patients. Results CTGF expression was observed in the dermis from both IMQ-induced psoriatic mice and psoriasis patients. CTGF inhibition using an anti-CTGF antibody slightly worsened IMQ-induced dermatitis. In addition, the increase of CTGF showed tendency to suppress the psoriatic dermatitis through inhibition of suprabasal cells proliferation and macrophage infiltration in the skin. CTGF was also detected significantly higher in plasma from psoriasis patients comparing with healthy control. Conclusion Our findings suggest that CTGF could contribute to the healing rather than the worsening of psoriasis skin lesions.

Abstract P5-15-09: National survey of chemotherapy-induced appearance issues in breast cancer patients

Background: Many breast cancer patients suffer hair loss due to chemotherapy, and not only scalp hair loss, but also eyebrow loss, eyelash loss and nail changes induced by chemotherapy are traumatic for patients. These side effects diminish self-esteem and greatly reduce quality of life. However, there has been little research in this field until now. To clarify the actual situation concerning appearance issues in breast cancer patients who received adjuvant chemotherapy, and to consider a support system for these patients, we conducted a questionnaire survey. Methods: Disease-free breast cancer patients who have received adjuvant chemotherapy containing anthracycline and/or taxane within 5 years were recruited from 47 hospitals or clinics in Japan from April to October 2013. The patients participating in this survey completed a 65-question questionnaire concerning appearance issues (48) and their perception of physical and non-physical side effects (17). The drugs administered and treatment period were filled out by their doctors beforehand. The completed questionnaires were mailed directly to the data center by the patients. Results: A total of 1511 patients returned the questionnaire to the data center with a response rate of 82% (1511/1853). Since 33 patients did not meet the entry criteria, the questionnaires returned by 1478 patients were analyzed in this survey. The mean age was 54.7 years (+-10.4, range 17-79). The distribution of the patients by time from the end of chemotherapy to this survey was as follows: Conclusions: Our survey demonstrated the outline of hair loss and appearance issues in breast cancer patients who received chemotherapy. Hair loss is the most distressing and occasionally long-lasting side effect. Lack of information is a serious problem. These facts suggested a need for long-time and careful support of these patients. Citation Format: Takanori Watanabe, Hiroshi Yagata, Mitsue Saito, Hiroko Okada, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of chemotherapy-induced appearance issues in breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-09.

Abstract P5-15-17: National survey of long-term recovery from chemotherapy-induced hair loss in patients with breast cancer

Background: Altered appearance due to chemotherapy is a very distressing adverse event and can remain unrecovered for a long time after chemotherapy. To clarify the current status of appearance change and its support systems, we conducted a national questionnaire survey of patients with breast cancer who had received chemotherapy in Japan. Here, we report on the long-term recovery of scalp hair loss during and after chemotherapy. Patients and methods: A questionnaire was distributed to patients in hospitals throughout Japan between April and October 2013. The questionnaire was regarding the current status of the patients’ appearance issues (scalp hair, eyebrows, eyelashes, nails, skin) related to chemotherapy and its support systems, including chemotherapy regimens received, endocrine therapy received, and duration after chemotherapy. Eligible patients were women with breast cancer without any recurrence who had received adjuvant or neoadjuvant chemotherapy containing anthracycline (A) and/or taxanes (paclitaxel, P; docetaxel, D) and who were within 5 years from the last chemotherapy treatment. The physicians of each hospital asked their patients to fill out the questionnaire and mail it directly to the data center. The scalp hair status was analyzed in a cross-sectional manner according to the duration from chemotherapy. Results: The questionnaires were returned from 1511 patients in 47 hospitals (response rate, 82%; 1511/1853). Thirty-three patients were excluded, mainly because >5 years had passed since chemotherapy. In total, 1478 questionnaires were ultimately analyzed. The median age was 50 (range, 17–79) years. The distribution of patients according to time from the last chemotherapy treatment was as follows: 80% hair loss. Hair growth began during chemotherapy in 13.1% of patients and after chemotherapy in 80.3% (6.6% left the question unanswered). Within 6 months from the start of hair growth, 65% of patients felt a change in hair thickness, while 82% felt it was becoming thin. Of the patients, 70% felt a change in quality, while 48% felt that it had become unruly; 44% felt a color change, while 80% felt that they were growing more gray hair. Of the patients who answered the questions, >80% hair volume recovery was seen in 52.7% of patients within 1 year; in 63.5%, in 1–3 years; and in 61.7%, even after 3 years. After 3 years, volume recovery was seen in 67.8% of patients after an A+P–containing regimen; in 43.4%, after A+D; in 63.5%, after D; and in 88.9%, after A. Patients who had received A+P, D, and A+D had significantly less volume recovery than patients who had received A (P Conclusions: Almost all patients with breast cancer experienced severe hair loss during standard chemotherapy, but a recovery trend was noted after chemotherapy. However, hair remained unrecovered to various degrees in a significant number of patients even 3–5 years after chemotherapy, especially in those who had received taxane-containing regimens. We should consider the support needs of patients who experience chemotherapy-induced hair loss. Citation Format: Hiroshi Yagata, Takanori Watanabe, Hiroko Okada, Mitsue Saito, Tomoko Takayama, Hirohisa Imai, Yuko Yoshida, Nao Tamai, Keiko Nozawa, Tamiko Yajima, Kojiro Shimozuma. National survey of long-term recovery from chemotherapy-induced hair loss in patients with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-17.