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Kanako Azuma,1 Takashi Kawaguchi,2 Takuhiro Yamaguchi,3 Sayuri Motegi,1 Kimito Yamada,4 Kenji Onda,5 Satoru Iwase,6 Sakae Unezaki,2 Hironori Takeuchi1 1Department of Pharmacy, Tokyo Medical University Hospital, Tokyo, Japan; 2Department of Practical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 3Division of Biostatistics, Tohoku University Graduate School of Medicine, Miyagi, Japan; 4Department of Breast Surgery, Tokyo Medical University Hospital, Tokyo, Japan; 5Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; 6Department of Emergency & Palliative Medicine, Faculty of Medicine, Saitama Medical University, Saitama, JapanCorrespondence: Takashi Kawaguchi Email tkawa@toyaku.ac.jpPurpose: The importance of shared decision-making (SDM) between physicians and patients is increasingly recognized. In Japan, patients have shown more willingness to participate in treatment if medical professionals provide sufficient information; however, relationships between physicians and patients have traditionally been asymmetric, with patients accepting information from physicians without discussion. To explore the benefits of SDM in cancer treatment, including confidence in treatment decisions, satisfaction with treatment, and trust in healthcare providers, this study developed Japanese versions of the Control Preference Scale (CPS) and Information Needs Questionnaire (INQ).Patients and Methods: Reliability and validity of the CPS and INQ were tested with 49 breast cancer patients.Results: The CPS showed good test–retest reliability (kappa coefficient: 0.61, weighted kappa coefficient: 0.61, Kendall’s tau coefficient: 0.61) and acceptable criterion validity. The INQ showed adequate consistency; the mean number of circular triads and coefficient of consistency were 3 (range 0– 19) and 0.9 (range 0.37– 1), respectively. Using the CPS and INQ to identify patients’ roles in decision-making and information needs, results further suggested that breast cancer patients in Japan want to participate in SDM. Medical issues, including disease spread and cure, were found to be of high interest, while social and psychological issues, including sexual attractiveness, genetic risk, and family impact, tended to be low.Conclusion: The Japanese CPS and INQ can be used to assess patients’ needs to improve care. Further, as patients’ information needs change along the care trajectory, these tools should be used throughout treatment.Keywords: shared decision-making, breast cancer, treatment option, control preference scale, information needs questionnaire

Background With the introduction of dose-dense therapy, the use of primary pegfilgrastim (PEG-G) has been increasing in breast cancer treatment. A rare side effect of PEG-G is aortitis. We describe a case of PEG-G-induced aortitis. Case presentation The patient was a 43-year-old woman with stage IIA breast cancer. Due to the subtype of triple-negative breast cancer, preoperative dose-dense epirubicin–cyclophosphamide chemotherapy was started. PEG-G was administered on day 3 after the first cycle of epirubicin–cyclophosphamide chemotherapy. On day 11, she had a fever (39.4 °C) and an elevated C-reactive protein level (27.1 mg/dL). Emergency computed tomography revealed diffused wall thickening of the aortic arch without any other signs of infection. Despite administering antibiotics, her general condition and laboratory findings deteriorated until day 18. Based on these observations, she was diagnosed with PEG-G-induced aortitis. Antibiotics were discontinued, and she was treated with prednisolone thereafter. Subsequently, her clinical symptoms and laboratory findings improved around day 39. A second computed tomography scan revealed a decrease in the aortic arch wall thickening, and she was discharged on day 43. Conclusions We successfully treated PEG-G-induced aortitis using prednisolone. Although this side effect is rare, cancer patients receiving PEG-G for chemotherapy should be monitored for aortic inflammation.

Neoadjuvant chemotherapy (NAC) is essential for surgical downstaging of early-stage breast cancer, but taxane administration is associated with neuropathy. We investigated whether eribulin induces less neuropathy than paclitaxel.In this multicentre, randomised study (UMIN000012817), patients diagnosed with invasive breast cancer between December 2013 and April 2016 were randomly assigned to group E (eribulin followed by fluorouracil, epirubicin, and cyclophosphamide; FEC) or group P (paclitaxel followed by FEC). The primary endpoint was incidence of grade 1 or higher peripheral neuropathy according to the Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints were pathological complete response (pCR), clinical response, breast-conserving surgery, adverse events, disease-free survival (DFS), and patient neurotoxicity questionnaire (PNQ) analysis.One hundred and eighteen cases were analyzed for safety and 115 were evaluated for efficacy. Peripheral sensory neuropathy was significantly lower in group E after week 6, while peripheral motor neuropathy in group E was significantly lower at weeks 9, 12, and 15. pCR in groups E and P was 20.7% and 29.8% (P = .289), respectively, and clinical response was 55.2% and 77.2% (P = .017), respectively. Three-year DFS was 89.7% in group E and 86.0% in group P (P = .561). Neutropenia was more frequent and more severe in group E. PNQ was evaluated for 4 years, and item 1 (sensory) was consistently lower in group E.Neuropathy was significantly less frequent and less severe in patients who received eribulin compared with paclitaxel. Thus, eribulin could be a good alternative to paclitaxel in patients suffering severe neuropathy.

Background A subgroup of triple-negative breast cancer (TNBC) shows impaired BRCA1 function owing to causes other than mutation, which is called “BRCAness.” DNA-damaging agents are known to have more efficacy in BRCA1-mutant tumors than mitotic poisons. We conducted a prospective single-arm clinical trial of neoadjuvant chemotherapy (NAC) using an anthracycline-based regimen without taxanes for BRCAness TNBCs. Materials and methods BRCAness was examined using the multiplex ligation-dependent probe amplification (MLPA) method in TNBC cases. For BRCAness cases, NAC was performed with anthracycline-based regimens without additional taxanes. Results A total of 30 patients with TNBC were enrolled. MLPA was successfully performed in 25 patients. Eighteen patients (72%) showed BRCAness. Twenty-three patients received NAC as per the protocol. On analysis, the clinical response rate (complete response plus partial response) was 76.4%, and the pathological complete response rate was 35.3%. Conclusions The interim analysis revealed that the pathological complete response rate was lower than estimated. Therefore, BRCAness by MLPA was not sufficient to predict the therapeutic response to anthracycline-based regimens in TNBC.

β-ray strontium-89 (Sr-89) intra-irradiation therapy has been approved and clinically used to reduce bone metastasis pain not alleviated by bone-modifying agents, external radiation, and analgesic agents. We examined the efficacy of zoledronic acid (ZOL) and Sr-89 combination therapy compared with ZOL alone in breast cancer patients with bone metastases.A randomized controlled trial was conducted on breast cancer patients with bone metastasis to compare the efficacy between ZOL monotherapy and ZOL plus Sr-89 combination therapy. The primary endpoints were changes in urinary NTX levels at 13 weeks and brief pain inventory scores. The secondary endpoints were analgesic drug usages, response rates, changes in bone metabolism markers, quality of life, and adverse event rates.Thirty of the planned 60 cases were randomly assigned to ZOL alone or ZOL + Sr-89. There were no significant differences in the changes in urinary NTX levels between the 2 groups (P = 0.365). There was no consistent difference in the pain score changes between the 2 groups. Sr-89 addition to ZOL slightly reduced the white blood cell and platelet counts. However, all adverse events were Grade 1. Safety and analgesic drug dose reduction were more evident in ZOL + Sr-89.This trial showed the lack of benefits from Sr-89 addition to ZOL for breast cancer patients with painful bone metastases. However, safety and analgesic drug dose reduction were more evident in ZOL + Sr-89, indicating its potential for pain control. Sr-89 therapy is safe, thus more effective radiopharmaceuticals are anticipated.

Background/Aim: To investigate the utility of peripheral blood biomarkers – absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) – for predicting outcomes in eribulin-treated patients with metastatic human epidermal growth factor receptor type 2 (HER2)-negative breast cancer. Patients and Methods: ALC, NLR, and PLR were retrospectively obtained from pre-treatment blood sampling results of 120 patients and stratified according to means. Univariate and multivariate analyses were performed to investigate the association of clinicopathological factors, including these values, with overall survival (OS) and progression-free survival (PFS). Results: The ALC, NLR, and PLR cut-off points were 1,285/μl, 3.3, and 235, respectively. No biomarkers were associated with PFS. However, univariate analysis showed ALC (p=0.044) and PLR (p=0.044) to be significantly associated with OS. Conclusion: ALC and PLR can predict eribulin efficacy in terms of OS, reflecting the antitumour immune response in the microenvironment and indicating eribulin’s effectiveness.

BACKGROUND/AIM Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated. PATIENTS AND METHODS Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses. RESULTS In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant. CONCLUSION BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

BACKGROUND: Anthracycline-containing regimens are standard treatment options in adjuvant and neoadjuvant chemotherapy in breast cancer. Chemotherapy-induced nausea and vomiting (CINV) is experienced frequently in patients receiving these regimens, but the risk factors for CINV are unknown. OBJECTIVE: The aim of this study was to investigate risk factors for CINV in anthracycline-containing regimens retrospectively. METHODS: Data were collected from the JONIE study, which was conducted in order to estimate the efficacy of zoledronic acid in a neoadjuvant setting from March 2010 to June 2012 (UMIN000003261). A total of 180 patients were recruited, and we used CINV data from the first cycle of FEC100 treatment and patient backgrounds. As the protocol regulation allowed the use of antiemetic drugs,in the first cycle of the FEC100 regimen, patients received various types of antiemetic agents, which we classified into four groups: Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3)+neurokinin-1 receptor antagonist (NK1) (DEX+5-HT3+NK1) group; Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3) (DEX+5HT3) group; Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3)+dopamine receptor antagonist (DRA) (DEX+5HT3+DRA) group; and Dexamethasone (DEX)+5-HT3 receptor antagonist (5-HT3)+neurokinin-1 receptor antagonist (NK1)+ dopamine receptor antagonist (DRA) (DEX+5-HT3+NK1+DRA) group. Risk factors were selected from patient backgrounds and the combinations of antiemetic drugs. In patient backgrounds, the body mass index (BMI) was stratified into 3 categories: Less than 18.5 (underweight group); equal to or more than 18.5 but less than 25 (standard BMI group); and equal to or more than 25 (overweight group). The risks for CINV were analyzed by univariate and multivariate analyses. P values of less than 0.05 were defined as significant. RESULTS: In a univariate analysis of nausea, the body mass index (BMI) was the only significant factor (P CONCLUSIONS: This study revealed that BMI was the most important risk factor for nausea, and that BMI and the combination of antiemetic drugs were risk factors for vomiting. Underweight-patients tend to have CINV in anthracycline-containing regimen. The DEX+5-HT3+NK1 group was the best antiemetic drug combination. These result show that following the CINV guideline treatment is mandatory in order to prevent CINV. Citation Format: Hayashi M, Nakazawa K, Hasegawa Y, Horiguchi J, Miura D, Ishikawa T, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Tanino Y, Yamada K, Kimura K, Akazawa K, Kohno N. Risk analysis for chemotherapy induced nausea and vomiting (CINV) in patients receiving FEC100 treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-07.

A 52-year-old woman with a strong family history of breast cancer was diagnosed as having triple-negative breast cancer (TNBC) in her right breast. Neoadjuvant chemotherapy (NAC; four cycles of epirubicin/cyclophosphamide/5-fluorouracil) was performed, followed by breast-conserving surgery and axillary lymph node dissection. Histopathological analysis of the surgical specimens demonstrated a few focal tumor cells remaining in the stroma, but not a pathological complete response (pCR). Weekly paclitaxel was subsequently added to the treatment regimen. A total of 17 months after the adjuvant treatments, TNBC recurred in her left breast with massive lymph node metastasis. Because of the early recurrence after standard treatment, NAC was administered together with carboplatin and paclitaxel. Histopathological analysis of the partially resected breast and axillary lymph nodes demonstrated a pCR. No recurrent disease was found 2 years after the second TNBC treatment. This case underlines the importance of platinum-based chemotherapy and prophylactic mastectomy for patients with BRCA dysfunction.

Background Pathological complete response (pCR) is often achieved by neoadjuvant chemotherapy (NAC), particularly in hormone receptor-negative breast cancer. Contrast-enhanced magnetic resonance imaging (cMRI) is the most reliable imaging modality to evaluate the pathological effect of NAC. Ultrasonography is indispensable to collect representative specimens from the target lesion by core needle biopsy (CNB). This study aimed to evaluate the accuracy of predicting pCR by adding CNB after NAC, in cases with complete clinical response (cCR) diagnosed by cMRI. Methods In this prospective multicentre study, we evaluated patients diagnosed with cCR by cMRI after NAC. Ultrasound-guided CNB (uCNB) using a 14G needle was performed without clip markers under general anaesthesia as planned surgery. Specimens collected by uCNB were compared to those resected surgically and were categorized as (i) no carcinoma (ypT0), (ii) no invasive carcinoma and only residual carcinoma in situ (ypTis) and (iii) residual invasive carcinoma. The concordance of pathological results between the uCNB and surgical specimens was evaluated. Results Of the 83 patients evaluated, 41 (49.4%) and 17 (20.5%) of them had ypT0 and ypTis, respectively. The false negative rates (FNR), sensitivity and specificity for predicting ypT0 by uCNB were 50.0%, 50.0%, 100%, respectively, and those for predicting ypT0+ypTis were 28.0%, 72.0% and 98.3%, respectively. The concordance rates were 74.7% (62/83) for ypT0 and 90.4% (75/83) for ypT0+ypTis. Conclusion In cCR cases diagnosed by cMRI, uCNB was not accurate enough to predict pCR. Additional modalities like clip placements and/or thicker core needles may be required for better prediction.

Background: Neoadjuvant chemotherapy (NAC) for breast cancer has been improved and pathological complete response (pCR) achieved in about 50% of Her2 positive tumor and over 30% of triple negative tumor. It is possible that not to perform surgery if pCR is diagnosed accurately. This study was performed to examine diagnostic ability of core needle biopsy (CNB) to detect pCR by NAC. (Study registry number: UMIN000012035) Methods: In this multicenter study, we registered histologically proved breast cancer patients who were diagnosed as clinical complete response (cCR) after NAC. The cCR was diagnosed by contrast-enhanced magnetic resonance imaging (MRI) after NAC by radiologists in each facility. Regimens of NAC were not specified by study protocol. A clip marker was not placed in the tumor before NAC. At the operating table, ultrasound-guided CNB is performed before starting the surgery. The CNB was performed with 14 gauge needle without vacuum assistance and requiring three biopsy specimens. The concordance of pathological results between a core needle biopsy and a surgical specimen is examined by pathologists at each facility. The pathological diagnosis was categorized as i) no carcinoma (pCR), ii) carcinoma in situ (CIS) and iii) invasive carcinoma. Results: The study included 86 women from 10 facilities, accrued from December 2013 to March 2017. Median age was 53.5 (31-75) years and median tumor size before NAC was 2.3 (0.9-7.3) cm. Estrogen receptor was positive in 32 (37%). HER2 was positive in 40 (47%). The clinical stage before NAC was stage I 19 (22%), II 48 (56%), III 16 (19%) and IV 3 (3%). All cases were administered cytotoxic agents. Both anthracycline and taxane were given in 70 cases (81%), and trastuzumab was administered in 35 (41%) cases. As for breast surgery, partial resection was performed in 53 cases (62%), whereas 33 cases (38%) underwent mastectomy. Pathological examination on surgical specimen revealed pCR (i) in 41 cases (48%), CIS (ii) in 17 cases (20%) and invasive carcinoma (iii) in 28 cases (32%). Results of pathology of CNB and surgical specimens are shown in table 1. Table 1. Pathological diagnosis of CNB and surgical specimens Surgical specimen No carcinoma (pCR)Residual carcinomaTotalCNBNo carcinoma (pCR)41 (NPV=63%, spec.=100%)24 (FNR=53%, 14 were CIS)65 (76%) Residual carcinoma021 (PPV=100%, sens.=47%)21 (24%)Total41 (48%)45 (52%)86 (100%)CNB: core needle biopsy, FNR: false-negative rate, CIS: carcinoma in situ, NPV: negative predictive value, PPV: positive predictive value, sens.: sensitivity, spec.: specificity. The kappa value was 0.455 which was not enough for accurate diagnosis. In 24 discordant cases, residual tumor was found in surgical specimen but not in CNB, residual disease was CIS in 14 cases. Conclusions: Up to 10% false negative rate of pCR may allow us to proceed to an observational study without performing surgery.This study revealed that the ultrasound-guided CNB for cCR cases by MRI was not accurate enough to omit surgery. Thus, imaging diagnosis and biopsy methods need to be improved. However, it is still possible to consider because the post-operative radiotherapy may compensate for surgery in cases with CIS after NAC. Citation Format: Narui K, Ishikawa T, Hasegawa Y, Kaise H, Kawate T, Yamada K, Suzuki Y, Niikura N, Kohno N, Kimoto T, Sugae S, Yamada A, Kosaka Y, Miyashita M, Okamura T, Shimizu D, Tanino H, Sakamaki K, Tokuda Y. Feasibility study to diagnose pathological complete response by neoadjuvant chemotherapy in breast cancer adding core needle biopsy (KBOG1301 supported by JONIE) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-22-09.

We experienced a case of meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) with symptomatic intratumoral hemorrhage in a 67-year-old Japanese woman. Her chief complaints were sudden onset of motor aphasia and right hemiparesis. Brain computed tomography showed the hemorrhagic mass adjacent to the superior sagittal sinus. The mass was resected and pathological examination of the specimen revealed a tumor that is rich in vessels and accompanied with intratumoral hemorrhage. Short spindle tumor cells were proliferating with myxoid stroma. Tumor cells appeared to be arranged around the vessels and sometimes attached to the vessel wall directly. Although hyalinization of the vessel wall was observed, neither patternless pattern nor staghorn vessels were seen. Immunohistochemistry revealed that the tumor cells were positive for both CD34 and nuclear STAT6. Moreover, gene analyses revealed unique NAB2-STAT6 fusion. Immunohistochemical findings and fusion-gene analyses enabled us to make the definite diagnosis of meningeal myxoid SFT/HPC. The present case showed the three unique features such as clinically symptomatic intratumoral hemorrhage at the onset, rare variant of myxoid SFT/HPC, and unique NAB2-STAT6 fusion. Keyword: Meninx, Myxoid solitary fibrous tumor/hemangiopericytoma, Cerebral hemorrhage, NAB2-STAT6 fusion

Background Cowden syndrome is characterized by multiple hamartomas in various tissues, including the skin, brain, breast, thyroid, mucous membrane, and gastrointestinal tract, and is reported to increase the risk of malignant disease. Case presentation We describe the case of a 52-year-old woman in whom a tumor was diagnosed in the left cerebellar hemisphere and treated by surgical resection. Phosphatase and tensin homolog (PTEN) mutation in exon 8 insertion was found in the brain tumor tissue and leukocytes. This finding supported the diagnosis of Cowden syndrome. She consequently developed endometrial cancer and underwent abdominal total hysterectomy with bilateral salpingo-oophorectomy. Four years later, hormone receptor-positive breast cancer was found in the right breast, and breast-conserving surgery with radiation therapy and sentinel lymph node biopsy was performed. Conclusions Herein, we describe a patient who was diagnosed as having familial breast cancer associated with PTEN mutation-related Cowden syndrome. We also reviewed reports of this syndrome in the literature for disease appraisal.

Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel.

My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists' Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

Background Many triple-negative breast cancers (TNBCs) show impaired breast cancer susceptibility gene I (BRCA1) function, called BRCAness. BRCAness tumors may show similar sensitivities to anticancer drugs as tumors with BRCA1 mutations. In this study, we investigated the association of BRCA mutations or BRCAness with drug sensitivities in TNBC. Methods BRCAness was evaluated as BRCA1-like scores, using multiplex ligation-dependent probe amplification in 12 TNBC cell lines, including four with mutations. Sensitivities to docetaxel, cisplatin, and epirubicin were compared with BRCA mutations and BRCA1-like scores. Cisplatin sensitivity was examined in BRCA1 knockdown Michigan Cancer Foundation-7 cell lines. Results Eight and four cell lines had characteristics of BRCAness and non-BRCAness, respectively. The 50% inhibitory concentration of docetaxel was higher in BRCA mutant and BRCAness cell lines than their counterparts. BRCA1-like scores showed a weak positive correlation with docetaxel sensitivity (r = 0.377; P = 0.039). Regarding cisplatin, scores were lower in BRCA mutants and BRCAness tumors than their counterparts. A negative correlation was found between BRCA1-like scores and cisplatin sensitivity (r = −0.407; P = 0.013). No differences were found for epirubicin. BRCA1 gene knockdown increased the cisplatin sensitivity of Michigan Cancer Foundation-7 cells. Conclusions BRCA1-like scores were associated with cisplatin sensitivity and docetaxel resistance. BRCA1-like score is hence a promising indicator for estimating drug sensitivities in TNBC.

Background: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. Patients and methods: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I–IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1–L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were (1) rate of change in the lumbar spine (L1–L4) BMD after 2, 3, 4, and 5 years; (2) rate of change in the femoral neck BMD; (3) rate of change in radius BMD (determined using an ultrasonic bone densitometer); (4) changes in calcium and bone metabolism markers (TRAP 5b, bone alkaline phosphatase, and pentosidine); (5) development of pathological fracture within 3 years; (6) disease-free survival; (7) overall survival (OS); (8) adverse events; and (9) quality of life. Ethics and dissemination: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. Trial registration: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.

Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.

The clinical features of the early stages of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in patients with breast cancer remain unclear. A retrospective cohort study was conducted of patients with breast cancer who received intravenous bisphosphonate (BP) treatment in a single center in order to clarify the status of the early stages of BRONJ.A BRONJ oral monitoring program was established in 247 breast cancer patients given intravenous BP treatment at the institution. The differences in age, BP treatment period, number of remaining teeth, oral hygiene status, presence of regular oral monitoring and the existence of suspected BRONJ (stage 0) among eight BRONJ and 36 non-BRONJ subjects who completed oral examinations were then compared.BRONJ was observed in 0.4% of subjects on the first visit to the oral surgery clinic and in 3.2% of subjects during the follow-up period. Logistic regression analysis revealed that the odds ratio for identifying patients with BRONJ during follow-up by the presence of stage 0 at first visit was 24.0 (95% confidence interval [CI] = 3.6-161.7). The area under the receiver operating characteristic curve for identifying subjects with BRONJ by the presence of stage 0 was 0.82 (95% CI = 0.63-1.00).The results suggest that patients with stage 0 BRONJ on the first visit may progress to advanced BRONJ during the follow-up period. The oral monitoring program may contribute to the early detection of BRONJ.

The radionuclide (RN) method employed for sentinel lymph node biopsy is generally safe for adult medical care workers. However, the number of pregnant medical care workers who attend surgery has recently been increasing, along with the increasing number of female surgeons. In particular, female surgeons are concerned about the position of a surgeon's lower abdominal region being close to the RN injection site. We measured the exposure dose of the lower abdominal region in medical care workers and investigated the possible exposure effect on fetuses.A dose of (99m)Tc-phytic acid (37 MBq) was subcutaneously injected into the areola of the nipple of patients. Scintigraphy and surgery were performed after 1 and 4 h, respectively. At the time of the local injection, a personal dosimeter measured the exposure dose in the surgeon, first and second assistants, anesthesiologist, and scrub nurse.The median exposure doses were 3, 1, 1, 0, and 0 μSv in the surgeon, first and second assistants, anesthesiologist, and scrub nurse, respectively. Protective clothing reduced the mean exposure dose by 66 %.In surgeons, the exposure dose from daily life activities (1 mSv/year) corresponds to the dose received after performing 333 surgeries (using 3 μSv as the median). However, the maximum value measured was 24 μSv; at this value, the total exposure dose exceeds 1 mSV in the 42nd surgery. Medical care workers can further reduce their exposure dose by paying attention to the surgical procedure and to their posture and position.

Background and Objective We evaluated an alternative procedure for sentinel lymph node biopsy (SLNB) for breast cancer after approval of the study by the Ethics Committee of Tokyo Medical University Hospital in 2004. We examined the efficacy and safety of SLNB using the photosensitizer talaporfin sodium (Laserphyrin®, Meiji Seika Pharma, Tokoyo, Japan), compared with current methods. Study Design/Patients and Methods The study included 21 breast cancer patients (Japanese women; median age, 54 years; range, 35–75). All patients received a breast cancer operation combined with SLNB between June 2004 and May 2005. Three milliliters of talaporfin solution was locally injected into the subareolar region just before the operation. We attempted to identify a sentinel lymph node (SLN) that exhibited fluorescence and was consistent with a radioisotope (RI) localization technique. Our purpose was to verify the accuracy and validity of the talaporfin fluorescence imaging method after 8 years of application. Results There was no consistent correlation between fluorescence and pathological SLN metastasis, although all four cases of pathological SLN metastasis revealed positive fluorescence. In some cases in which we could not identify SLNs by the RI technique, we could identify SLNs using talaporfin. The method using talaporfin did not adversely affect the patients after the operation, even the chronic renal failure patient. After 8 years, all patients are alive, and none had lymph node recurrence. Side effects were not observed. Conclusion SLNB using the photosensitizer talaporfin sodium in breast cancer patients is considered to be useful as complementary to other current methods. We could evaluate the accuracy and validity of this method 8 years after all of the procedures were performed. In the future, a large-scale clinical study with statistical analyses should be conducted. Lasers Surg. Med. 45:558–563, 2013. © 2013 Wiley Periodicals, Inc.

Background: Zoledronic acid (Zol) is the most potent inhibitor of bone resorption in bisphosphonates. In order to examine whether the inhibitory effect is involved in the mechanism of bone metastasis in breast cancer, a bone-seeking clone was examined. It was established by repeated sequential passages of metastatic cells from bone in nude mice and in vitro, and it exclusively metastasizes to bone with larger osteolytic lesions than MDA-MB-231 parental cells. Recent findings indicate that epidermal growth factor (EGF) signaling is also an important mediator of bone metastasis. We examined the synergistic effects of gefitinib on the proliferation and invasion of a bone-seeking clone compared with MDA-MB-231. Materials and Methods: The cellular proliferation was estimated using WST-1. Migration in the matrigel in a Boyden chamber was applied to the invasion assay. Results: Treatment with 1 µM of Zol reduced 51% of cell proliferation in the bone-seeking clone; however, the inhibited rate was 37% in MDA-MB-231. The migration was also inhibited with 10 µM of Zol (bone-seeking clone: 69% reduction, MDA-MB-231: 54% reduction). The reduction rates of both assays by Zol treatment were significantly higher in the bone-seeking clone than in MDA-MB-231. Treatment with 10 µM of Zol plus 1 µM of gefitinib resulted in a proliferation reduction rate of 27% compared to that with 10 µM Zol treatment in the bone-seeking clone and no reduction in MDA-MB-231. The migration reduction rate was 88% in the bone-seeking clone and no reduction in MDA-MB-231. There was a significant difference between the bone-seeking clone and MDA-MB-231 in the reduction rates of both cellular proliferation and migration. Although the effect of gefitinib was synergistic with that of Zol in the bone-seeking clone, it was not clear in MDA-MB-231. Conclusion: There appear to be at least two independent signaling pathways that occur in osteolytic bone metastasis. One is involved in the bone resorption of bisphosphonates, and the other is an EGFR signaling pathway. Clinically, the combination of Zol and gefitinib is suggested to be a strong therapy specific to bone metastasis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-09.

Background and Objectives We have been engaged in basic and clinical research on photodynamic therapy (PDT) and photodynamic diagnosis (PDD) for more than 25 years. Study Design/Materials and Methods PDT for 264 centrally located early-stage lung cancer lesions yielded an initial complete response (CR) rate of 84.8%. PDT is now becoming a standard option for centrally located stage 0 (TisN0M0) and stage I (T1N0M0) lung cancer. It is an attractive option for elderly patients in poor physical condition. Results Recent results of interstitial PDT for peripheral-type lung cancers suggest that it may be a promising local curative treatment modality for lesions less than 1.0 cm in diameter. Conclusions In this article, we introduce our recent clinical trials of PDT for lung cancers (both central and peripheral), and new techniques of PDD in sentinel node navigation biopsy for breast cancers. Moreover, we introduce basic research on cancers and infectious diseases in order to expand the clinical applications of PDT. Lasers Surg. Med. 38:371–375, 2006. © 2006 Wiley-Liss, Inc.

My arguments regarding postmastectomy radiotherapy (PMRT) for this case are based on the following 4 reasons: (1) high rate of local recurrence in the no PMRT group in the Early Breast Cancer Trialists’ Collaborative Group meta-analysis on which the present guideline is based, (2) stage migration by sentinel node biopsy, (3) possible adverse events of radiotherapy, and (4) problems on extrapolation of data from western countries.

We evaluated an alternative procedure for sentinel lymph node biopsy (SLNB) for breast cancer after approval of the study by the Ethics Committee of Tokyo Medical University Hospital in 2004. We examined the efficacy and safety of SLNB using the photosensitizer talaporfin sodium (Laserphyrin®, Meiji Seika Pharma, Tokoyo, Japan), compared with current methods.The study included 21 breast cancer patients (Japanese women; median age, 54 years; range, 35-75). All patients received a breast cancer operation combined with SLNB between June 2004 and May 2005. Three milliliters of talaporfin solution was locally injected into the subareolar region just before the operation. We attempted to identify a sentinel lymph node (SLN) that exhibited fluorescence and was consistent with a radioisotope (RI) localization technique. Our purpose was to verify the accuracy and validity of the talaporfin fluorescence imaging method after 8 years of application.There was no consistent correlation between fluorescence and pathological SLN metastasis, although all four cases of pathological SLN metastasis revealed positive fluorescence. In some cases in which we could not identify SLNs by the RI technique, we could identify SLNs using talaporfin. The method using talaporfin did not adversely affect the patients after the operation, even the chronic renal failure patient. After 8 years, all patients are alive, and none had lymph node recurrence. Side effects were not observed.SLNB using the photosensitizer talaporfin sodium in breast cancer patients is considered to be useful as complementary to other current methods. We could evaluate the accuracy and validity of this method 8 years after all of the procedures were performed. In the future, a large-scale clinical study with statistical analyses should be conducted.

Aminolevulinic acid (5-ALA) has been used successfully to resect meningioma without leaving a residual mass. The authors report their experience resecting meningiomas in 17 patients using 5-ALA. Except for one case, all meningiomas fluoresced intra-operatively under the microscope. Invasion to the dura mater, brain parenchyma, or skull showed fluorescence, allowing for confirmation of residual tumor; total removal of the meningioma could be performed more easily, and unexpected neurological deficits could be prevented by precise removal of the tumor under the microscope. With invasion to the dura mater or skull in one case, the extent of dural removal was decided by 5-ALA fluorescence with 1- to 2-cm safety margins. In another case with parenchymal invasion, close removal of the tumor without leaving residual tumor could be performed with 5-ALA fluorescence. With the above methods, no serious side effects or complications occurred in this study. Not all meningiomas fluoresced with 5-ALA, and 5-ALA is available for about 95% of meningiomas. 5-ALA appears easy to use and helpful for finding residual tumor and preventing recurrences by total removal of meningiomas.

BACKGROUND: BRCA1 impaired cancers are sensitive to DNA damage. This is associated with the defective homologous recombination (HR) pathway in these tumors. In contrast, these tumors are resistant to mitotic poisons, because BRCA1 protein activates the mitotic spindle checkpoint and triggers apoptosis in microtubule damage. Both preclinical evidence and clinical evidence have shown that the single-agent taxane is not active for BRCA1 mutated breast cancers. It is reported that BRCA1 function may be impaired in approximately 60% of triple negative breast cancer (TNBC) without mutation. This is called ‘BRCAness’. Previous studies have demonstrated that BRCAness identified tumors with HR deficiency. Thus, taxane may not be necessary for all TNBC cases, although combined treatments of anthracycline and taxane are standard at present. STUDY PROTOCOL: We have launched a single arm study of neoadjuvant chemotherapy (NAC) for TNBC to confirm that taxane is unnecessary in BRCAness cases. For the study protocol, TNBC cases requiring NAC are enrolled. Four cycles of an anthracycline-based regimen (FEC 100 or dose-dense EC) are started and BRCAness is examined simultaneously in core-needle specimens. BRCAness is determined by Multiple Ligation-dependent Probe Amplification (MLPA) methods (FALCO Biosystems), which consist of 2 steps. These include copy number analysis in 34 loci specific to BRCA1 mutant and scoring with prediction analysis for microarray. If BRCAness is determined by MLPA, surgery is performed without proceeding to taxane. The primary endpoint is a pathological complete response (pCR) in surgical specimens. The expected pCR and threshold pCR are estimated at 55% and 40%, respectively, based on our previous randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel for hormone receptor-negative breast cancer (Ishikawa T. ASCO 2013). With a one-sided significance of 5%, 70 BRCA cases are required. This study was approved in September 2015 and has been started. Interim analysis is planned when 30 cases are completed. Citation Format: Takashi Ishikawa, Saeko Teraoka, Hiroshi Kaise, Kimito Yamada, Mari Hosonaga, Ai Ueda, Yoko Kawai, Miki Okazaki, Mari S. Oba, Eiichi Sato. Single arm study of neoadjuvant chemotherapy without taxane for BRCAness cases in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT126.

e12520Background: It is not clear which anthracycline regimen for breast cancer is most effective in the neoadjuvant chemotherapy. We compared CEF therapy with EC therapy in neoadjuvant setting for axillary lymph nodes metastasis-positive breast cancer in our hospital in order to examine which anthracycline regimen is more effective. Methods: We treated 221 cases (cT1-4 N1-3 M0) of breast cancers, performed operation after neoadjuvant chemotherapy (anthracycline and taxanes) in May 2003 to July 2014. The average observation period was 5.5 years. We separated 2 groups, CEF and EC. CEF group were patients performed CEF therapy (C: 500mg/m², E: 100mg/m², 5FU: 500mg/m² every 3 weeks intravenous drip) followed by taxanes. EC group were patients performed EC therapy (E: epirubicin 90mg/m², C: cyclophosphamide 600mg/m² every 3 weeks intravenous drip) followed by taxanes. Some patients received zoledronic acid or denosumab in clinical trials. We examined the percentage of pCR (pathological complete response), the...

Few studies have been conducted to elucidate the psychological distress of cancer outpatients being treated with chemotherapy. In this study, we attempted to determine the types of psychological distress endured by cancer outpatients being treated with chemotherapy.We investigated 194 outpatients with various malignancies, including hematological, esophageal, gastric, pancreatic, colon, lung, breast, ovarian, uterine and skin cancers, using the Japanese version of the Self-Rating Depression Scale, from June through December 2010, in our hospital.The results of the survey questionnaire indicated suspected adjustment disorders in 84 patients(43. 3%)and major depression in 14 patients(7. 2%). Medications prescribed for psychological distress were antianxiety drugs(18 patients: 9. 3%), antidepressant drugs(2 patients: 1. 0%), and sleeping pills(50 patients: 25. 8%).Our findings may be useful for the development of management strategies for psychological distress, and we suggest that there is a need for improvement in the quality of life of cancer outpatients being treated with chemotherapy.

Our aim in this study was to examine the safety and efficacy of the concurrent use of the radiopharmaceutical strontium-89 (Sr-89) chloride with zoledronic acid in standard anticancer therapy for breast cancer patients with painful multifocal bone metastases. The study comprised 16 breast cancer patients with painful multifocal bone metastases detected by bone scintigraphy, computed tomography or magnetic resonance imaging. All patients were treated with Sr-89 and zoledronic acid concurrently between March 2007 and February 2011 as part of a standard therapeutic regimen comprising chemotherapy, endocrine therapy, molecular targeting therapy and targeted radiotherapy. Sr-89 was administered intravenously at 2 MBq/kg to a maximum of 141 MBq per person. Safety was evaluated according to myelotoxicity as measured by the Common Terminology Criteria for Adverse Events (v3.0). To assess treatment efficacy, we monitored changes in analgesic drug dosages. Furthermore, bremsstrahlung imaging after the administration of Sr-89 was utilized to examine the relationship between the accumulation of Sr-89 in metastatic sites and treatment efficacy. Based on the results, a total of 14 out of 16 patients (88%) reported bone pain relief, indicating a high efficacy of Sr-89 combined with zoledronic acid. In responsive cases, a strong uptake of Sr-89 was observed on bremsstrahlung imaging at the same sites indicated by 99mTc bone scintigraphy. Moreover, severe myelosuppression (> grade 3) was not observed, and adverse events were tolerable. In conclusion, the use of Sr-89 with zoledronic acid in breast cancer patients with painful bone metastases was safe and effective when administered concurrently with other standard therapies. In the future, the treatment with Sr-89 at the early stage should be considered, and a large-scale clinical study should be conducted.

A 35-year-old woman was admitted to our hospital with acute onset paraparesis, sensory disturbance in her lower body, and urinary disturbance. She had given birth by normal vaginal delivery 6 days before the onset of these symptoms. On admission, paresis of her left leg was more severe than that of her right leg. Deep tendon reflexes of her lower limbs were hyperactive, and bilateral Babinski reflexes were observed. The patient's thermal and pain sensations below the lumbus were impaired. She lost bladder-filling sensation and bladder control. She showed an anterior spinal artery syndrome. Blood analysis revealed thrombocytosis and high fibrolytic activity. MRI of the brain and spinal cord did not show any lesions. Cerebrospinal fluid measurements showed that parameters were within the normal range and that the protein levels were not increased. We considered that a spinal cord infarction had occurred. After administration of antithrombotic agents and methylpredonisolone, her symptoms gradually improved. The coagulation disorders during the peripartum period were assumed to be a cause of anterior spinal artery syndrome in this case. It is very rare for perinatal women to have a spinal cord infarction. Only 3 cases of spinal cord infarction during the perinatal period have been reported thus far.

5-Aminolevulinic acid (ALA) has been successfully used to confirm the target tumor tissues obtained during stereotactic biopsy. The authors report their experience with 2 patients who underwent stereotactic biopsies of thalamic malignant lymphoma and pontine glioma utilizing 5-ALA. Intraoperatively, the tumor specimens fluoresced, allowing for confirmation that the obtained target specimen contained tumor tissues. No serious side effects or complications occurred.

Subarachnoid blood has been reported as a cause of chronic spinal arachnoiditis. Although syringomyelia has been thought to be caused by spinal arachnoiditis, reports of syringomyelia following aneurysmal subarachnoid hemorrhage (SAH) are very rare. We describe two patients with syringomyelia associated with chronic spinal arachnoiditis following SAH. From January 2001 to December 2010, 198 patients with aneurysmal SAH were treated at Kinki University School of Medicine. Two of the 198 patients had syringomyelia following aneurysmal SAH; thus the rate of syringomyelia associated with aneurysmal SAH was 1.0%. Patient 1 was a 54-year-old woman who presented with back pain, back numbness and gait disturbance 20 months after SAH. Her MRI revealed syringomyelia of the spinal cord from C2 to T10. She underwent shunting of the syrinx to the subarachnoid space. Patient 2 was a 49-year-old man, who was admitted to the hospital with headache, diplopia, hoarseness, dysphagia and ataxia five months after SAH. MRI revealed syringomyelia from the medulla oblongata to C6, and an enlargement of the lateral and fourth ventricles. After foramen magnum decompression and C1 laminectomy, a fourth ventricle-subarachnoid shunt was placed by insertion of a catheter. Spinal arachnoiditis and spinal syringomyelia are rare but important chronic complications after SAH.

Factors that promote the aggressiveness of squamous cell carcinoma of the breast are not well understood. To examine the involvement of cell motility and the mechanism of this behavior, a squamous cell carcinoma cell line of the breast (HBC9) was established from a metastatic lymph node of a Japanese woman. HBC9 expressed epidermal growth factor receptor (EGFR), but was negative for Her2 or Her3.The invasive ability of HBC9 was compared with that of four breast ductal carcinoma cell lines by Matrigel invasion assay. EGF stimulation induced the formation of surface protrusions and cell migration in HBC9 cells, and significantly increased the number of cells migrating through the Matrigel. The invasive ability of HBC9 was compared with other cell lines of breast carcinoma; it was much greater than that of MCF-7, BT474, or HBC5, but did not differ significantly from that of MDA-MB-231. Observation of the surface protrusions of HBC9 by confocal laser microscopy revealed co-localization of Arp2 and N-WASP with actin polymerization, detected by visualization with phalloidin, indicating that the protrusions induced by EGF were invadopodia. In HBC9 cells, cortactin also co-localized with the N-WASP/Arp2/3 complex in the protrusions. Immunohistochemistry of 12 cases of squamous cell carcinoma of the breast revealed expression of cortactin and EGFR in all of them, and this was confirmed by western blotting in two cases. These results suggest that EGF-dependent enhancement of cell motility by formation of invadopodia associated with cortactin is a cause of the clinical aggressiveness of squamous cell carcinoma of the breast.