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Rechallenge of immune checkpoint inhibitors has been reported for neoplasms other than breast cancer. Reported here is a case of a 55-year old woman diagnosed as having triple-negative right breast cancer with multiple metastases including lung. Atezolizumab and nab-paclitaxel were administered followed by epirubicin–cyclophosphamide. With subsequent eribulin, the overall best response was progressive disease, and curative surgical resection was performed. Three months after surgery (1.5 years after initial response of lung metastasis), right lung metastasis emerged at a site different from baseline. Based on the microsatellite instability-high status, pembrolizumab was administered and showed a good response. The patient has been treated with pembrolizumab, maintaining partial response, for over 9 months, which suggests the benefit of immune checkpoint inhibitors rechallenge in breast cancer.

Purpose Our primary objective was to determine the benefit/risk of anthracycline-free regimens by comparing docetaxel + cyclophosphamide (TC) alone, fluorouracil + epirubicin + cyclophosphamide (FEC) followed by TC, or TC followed by FEC as a primary treatment for patients with HR-positive, HER2-negative BC. Methods We randomized patients with stage I–III HR-positive HER2-negative, operable BC to receive either six cycles of TC (TC6), three cycles of FEC followed by three cycles of TC (FEC-TC), or three cycles of TC followed by three cycles of FEC (TC-FEC). The primary endpoint was the pathological response. Secondary endpoints included clinical response, type of surgical procedure, recurrence, death, and adverse events (by NCI-Common Terminology Criteria for Adverse Events v.3.0). We conducted all statistical analyses using SAS Version 9.2. Results We enrolled 195 patients and analyzed data from 193 as the intention-to-treat population. Pathological complete response rates were numerically higher in the TC6 group than in the other groups (p = 0.321). The breast conservation rate was significantly higher in the TC6 group (73%) than in the other groups (FEC-TC 51%, TC-FEC 45%, p = 0.007). Adverse events with grade > 3 were not common in the treatment groups (p = 0.569). The overall and distant disease-free survivals were similar among the groups with median follow-up of 5.80 years. Conclusions Despite similar long-term efficacy and safety profile, the higher breast conservation rate in the TC6 group suggests that preoperative chemotherapy without an anthracycline may benefit patients with HR-positive HER2-negative BC. Trial registration UMIN000003283 https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000003873.

A liposomal formulation of eribulin, E7389-LF, may provide improved pharmacokinetics and allow increased access to tumour tissues. This expansion of a phase 1 study assessed the safety and efficacy of E7389-LF in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer.Patients received E7389-LF 2.0 mg/mOf 28 patients included, 75.0% had hormone receptor-positive breast cancer (HR+ BC) and 25.0% had triple-negative breast cancer (TNBC). The most common grade ≥3 treatment-related treatment-emergent adverse events included neutropenia (67.9%), leukopenia (42.9%), thrombocytopenia (32.1%), and febrile neutropenia (25.0%). Rates of neutropenia and febrile neutropenia were lower among patients who received prophylactic pegfilgrastim. Objective response rate was 35.7% (95% confidence interval [CI]: 18.6-55.9) for all patients and 42.9% (95% CI: 21.8-66.0) for patients with HR+ BC. Median progression-free survival was 5.7 months (95% CI: 3.9-8.3). The median overall survival was 18.3 months (95% CI: 13.2-not estimable). Among the 54 biomarkers assessed, 27, including 5 of 7 vascular markers, were significantly altered by E7389-LF treatment from baseline to any time point.E7389-LF was tolerable and favourable antitumour activity was observed, particularly in patients with HR+ BC. Prophylactic pegfilgrastim can be considered in patients at high risk for neutropenia and febrile neutropenia.NCT03207672.

Background: In the International Consensus Conference Guidelines for Advanced Breast Cancer, most experts agreed that the maintenance endocrine therapy after induction chemotherapy was reasonable. The combination therapy of bevacizumab (B) and paclitaxel (P) has proved to prolong progression free survival (PFS) and improve response rate in E2100 and MERiDiAN study for advanced and metastatic breast cancer (AMBC). Because of its long PFS, developing optimal therapeutic strategy of B+P to improve survival, including management of toxicity is crucial. However, it has not been assessed what therapy is optimal as maintenance therapy or how effective B+P re-challenge after failure of maintenance therapy is. Methods: In this multi-center randomized phase II study (KBCSG-TR1214), we compared endocrine therapy alone (E) and endocrine therapy with capecitabine (E+C) as a maintenance therapy after the induction chemotherapy with B+P. .Hormone receptor (HR)-positive and HER2-nagative patients who have experienced none or one prior chemotherapy for AMBC were enrolled. Patients without progression in 4-6 cycles of B+P were randomized to arm E (with E) or arm E+C (with E+C). In both arms, endocrine agents were decided by physician’s choice and in arm E+C, capecitabine (1657mg/m2 on day1 to 21 q4w) was added to E. After progression of either maintenance therapies, B+P started again as a re-challenge therapy. Primary end point was progression free survival (PFS) of maintenance therapy. Secondary end points include time to failure of strategy from randomization (TFS), efficacy of re-challenge therapy, overall survival (OS) and safety of induction therapy. Results:116 patients were enrolled until April 2016. 90 patients had been successful to shift to randomization. Median age was 59.8 years-old (34-81). 28 (60.9%) of 46 patients in arm E and 27 (61.4%) of 44 patients in arm E+C were administrated by aromatase inhibitor (AI) or AI+LH-RH analog. Median PFS of maintenance therapy was significantly longer in arm E+C (11.3month, 95%CI; 8.0-11.8) than in arm E (4.3months, 95%CI; 3.6-6.0) (HR:0.53, p=0.0054). Clinical benefit rate was 50.0% in arm E and 72.7% in arm E+C (p=0.0320). Median PFS, objective response rate and clinical benefit rate of P+B as re-challenge therapy following either E or E+C were 7.8months (95%CI; 6.7-9.5), 20.4% and 63.0%, respectively. There was a strong trend of improvement in OS at 24 months from randomization in arm E+C (73.0%) compared with in arm E (53.1%) (p=0.0524). We have not observed any new adverse toxicity profile regarding to E or E+C. Conclusions: Adding capecitabine to maintenance endocrine therapy was demonstrated to improve PFS and OS. To our knowledge, this is the first clinical trial to show the efficacy of endocrine therapy combined with metronomic chemotherapy as maintenance therapy after induction chemotherapy in HR-positive and HER2-negative AMBC patients. The concept of induction-maintenance could be a new therapeutic strategy for ABMC. (UMIN000008662). Citation Format: Tetsuhiro Yoshinami, Takahiro Nakayama, Masahiko Ikeda, Makiko Mizutani, Miki Yamaguchi, Yoshifumi Komoike, Tsutomu Takashima, Katsuhide Yoshidome, Junji Tsurutani, Mitsuhiko Iwamoto, Fumie Fujisawa, Hiroyuki Yasojima, Jun Yamamura, Hirotaka Morishima, Fuminori Aki, Tomomi Yamada, Satoshi Morita, Norikazu Masuda. Addition of capecitabine to maintenance endocrine therapy after induction therapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-12-01.

Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab–paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m2/day on days 1–21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab–paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0–11.8} months) than in group E (4.3 {3.6–6.0} months) (hazard ratio, 0.53, p &lt, 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41, p = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.

Background This study aimed to investigate whether schedule modification is safe and effective in patients intolerant to the standard eribulin dose and schedule. Methods Patients with metastatic breast cancer (MBC) treated with both anthracycline and taxane and ≤ 3 prior regimens of chemotherapy for MBC received eribulin at the standard dose and schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) in the first cycle; change of dosing schedule (1.4 mg/m2 on days 1 and 15 of a 28-day cycle) was determined by change in neutrophil count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, serum creatinine, and non-hematological toxicity on day 8 of the first cycle or day 1 of the second cycle. Clinical benefit rate (CBR; primary endpoint), time to treatment failure (TTF), overall survival (OS), and safety were evaluated. Results Of the 88 patients who were enrolled and received standard eribulin therapy in the first cycle, 42 patients were moved to the bi-weekly therapy group and 40 continued standard therapy. In the bi-weekly and standard therapy groups, mean relative dose intensity was 62.7 and 90.9%, CBR was 31.0 and 25.0%, median TTF was 81.5 and 75 days, and OS was 523 and 412 days, respectively. Neither group reported severe adverse events. Conclusion This is the first study to show that a bi-weekly eribulin schedule is tolerable and has comparable efficacy in patients intolerant to the standard eribulin schedule. Clinical trial registration University Hospital Medical Information Network (UMIN) Center (ID: UMIN 000008491). Electronic supplementary material The online version of this article (10.1007/s12282-018-0843-y) contains supplementary material, which is available to authorized users.

Summary Small invasion into ductal carcinoma in situ (DCIS) can easily be overlooked in resected breast specimens. To disclose useful markers predictive of invasive foci within preoperatively diagnosed DCIS lesions, a retrospective histopathological comparison was made between postoperatively diagnosed invasive ductal carcinoma with a predominant intraductal component (IDCPIC) (n = 43) and pure DCIS (n = 82). Through a multivariate logistic regression analysis model, 5 variables (DCIS grade, “tumor thickness,” extent of retraction cleft, presence of lymph node metastasis, and HER2 score) were found to be significantly associated with the presence of invasive foci within DCIS; with a cutoff point of 0.315, sensitivity, specificity, positive predictive value, and negative predictive value were 0.93, 0.77, 0.68, and 0.95, respectively. No statistically significant difference was observed in recurrence-free survival between IDCPIC and pure DCIS, whereas the IDCPIC curve showed a slightly earlier decline than the DCIS one. In general, preoperative detection of lymph node metastasis in DCIS patients is elusive because of the extremely tiny metastatic size in most cases; thus, a 4-variable model, without lymph node metastasis, would be the actual working model. Furthermore, tumor “thickness” was found to be the most significant parameter predictive of invasive foci within DCIS. Although IDCPIC and pure DCIS showed similar recurrence-free survival curves, prediction of invasive foci within DCIS necessitates postoperative pathological analysis of surgically resected lesions.

We herein present the case of a 49-year-old female patient presenting with nausea and headache. The patient's medical history included breast cancer with bone and lymph node metastasis. Computed tomography (CT) examination revealed a high-density lesion in the right subdural space, suggesting hematoma. During surgery planned for subdural hematoma drainage, an en plaque subdural yellowish-white tumor was identified, without hematoma. Histopathological examination revealed metastatic breast cancer. The patient was administered predonisolone and her neurological symptoms gradually recovered. However, 12 days after the first operation, the clinical course was complicated by vomiting and rapid loss of consciousness. Emergency CT revealed that the subdural tumor had enlarged and decompression was performed as life-saving surgery. However, the patient's condition progressively deteriorated and she finally succumbed to the disease 2 months after the second operation. The aim of this study was to present the case of a patient with a large en plaque subdural tumor mimicking subdural hematoma and causing rapid loss of consciousness and cerebral herniation.

Introduction Chemotherapy induced peripheral neuropathy (CIPN) is a major problem for patients who receive chemotherapy, and it sometimes deteriorate patients' QOL. Many CIPN prevention trials have been conducted, but no one succeeded to date. Objectives To investigate if frozen glove (FG) prevents peripheral neuropathy induced by nanoparticle albumin-bound paclitaxel (nab-PTX). Methods We conducted CIPN prevention study using FG, as part of multi-institutional phase II study which analyze efficacy and safety of nab-PTX (260mg/m2 q3w) followed by FEC (500/100/500 mg/m2, q3w) in pre-operative setting (KBCSG-TR 1213 trial). Each patient wore an FGs for a total of 60 minutes (15mins before and after nab-PTX treatment) on both hands. CIPN were assessed during treatment period with nab-PTX by the Patient Neurotoxicity Questionnaire (PNQ) and the FACT/GOG (Gynecologic Oncology Group) Neurotoxicity (Ntx) subscale. Patients were asked to access PNQ and FACT/GOG Ntx on a daily basis and recorded in the CIPN diary. Results Sixty two patients were registered for KBCSG-TR 1213 trial. And forty two pts (68%) who turned in the diary were analyzed. Median age and median body mass index (BMI) was 48 years old and 21.6 kg/m2, respectively. We analyzed following 6 categories, 1) symptoms of hands and arms, 2) symptoms of foots, 3) symptoms of general, 4) symptoms of ears 5) muscle weakness of hands and arms and 6) muscle weakness of foots. Median time to each event was 1) 25.5 days, 2) 5days, 3) 3days, 4) not available, 5) 46.5days, 6)4 days. By using FG, time to event of hands and arms was much longer compared with that of foots. Conclusions CIPN could be prevented or lessened by FG. Randomized phase II CIPN prevention study has been just launched. Citation Format: Nakayama T, Yasojima H, Morimoto T, Yoshidome K, Mizutani M, Takashima T, Matsunami N, Enami A, Kagawa M, Nomura T, Shiba E, Nishi T, Kamigaki S, Kozuma Y, Yoshinami T, Masuda N. Frozen glove could be a new hope for prevention of chemotherapy induced peripheral neuropathy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-26.

Background: The prognosis of breast cancer patients with brain metastasis (BM) is extremely poor, and the survival after development of BM is very short. We aimed to investigate clinicopathological factors related to significant effects on the prognosis after BM development. Patients and Methods: This is a retrospective study of 75 early breast cancer patients who received the standard of care and subsequently developed BM. Results: Breast cancer subtype was one of the significant predictors for prognosis after BM diagnosis. Luminal HER2 patients had the most favorable prognosis after BM diagnosis (p = 0.011). Favorable performance status (PS) at BM diagnosis (p < 0.001) and a single metastatic brain tumor (p = 0.032) were significantly associated with good prognosis after BM diagnosis. Metastatic time courses of the patients was found not to be significantly associated with survival after BM diagnosis. Univariate and multivariate analysis indicated that luminal HER2 cancer, favorable PS at BM diagnosis, and a single metastatic brain tumor were the independent prognostic factors for survival after BM development, making a decisive influence on local or systemic control. Conclusion: Appropriate treatments for tumor subtypes and to improve the general condition of patients would result in improved outcomes for the patients with BM.

A 41-year-old female presented with a walnut-sized lump in her right breast. Half a year ago, she underwent a curative resection of low grade endometrial stromal sarcoma (LGESS/StageIA, total hysterectomy+bilateral salpingo-oophorectomy). Ultrasound(US) revealed a localized breast tumor (2.7cm). The Result of her breast biopsy showed invasive ductal carcinoma (solid tub.ca. ER+/PgR-/HER2-/grade3/Ki67 90%)/cT2N0M0, StageIIA. Neoadjuvant chemotherapy: paclitaxel monotherapy (80mg/m2 once weekly for 12 weeks) was performed with response-guided imaging scan(MRI/US) to avoid the anthracycline toxicity due to pretreatment of leukemia in her teens. Tumor shrinkage shown after 4 times and further therapeutic response indicated high sensitivity to taxane. Minimal hypoechoic area suspected residual lesions or scar tissue after 9 times. Late in the course of therapy, dose reduction (80mg/m2x10 times, 70 mg/m2x2) was required for peripheral neuropathy(G2). The promising antitumor activity and acceptable adverse drug reactions let her achieve whole cycle chemotherapy and maintain QOL. Imaging scan showed no residual tumor. Partial mastectomy was performed and the pathologic complete response was confirmed. Aromatase inhibitor is being considered as adjuvant endocrine therapy. Genetic counseling will be helpful and we are looking into genetic testing. The risk of developing a secondary cancer from previous cytotoxic treatments, and the certain predispositions like hereditary factor should be taken into account. Past history 15y. acute lymphoblastic leukemia BCP-ALL/chemo-1st CR (toxic drug DNR/ADM/CPM)+prophylactic cranial irradiation(18Gy). 28y. tongue cancer -non relapse/partial glossectomy+defect repair (left forearm flap). Hepatitis B/C carrier. Gynecologic 10y. menarche, teenage. menses resumption after chemo, 36y. myomectomy, 37y. delivery (daughter). Family history two females/breast cancer (fourth-degree relative/onset age, unconfirmed).

Background: We compared and evaluated three 6-cycle, docetaxel and cyclophosphamide (TC)-containing chemotherapy regimens in a multicenter randomized phase II study. The main aim was to investigate whether anthracyclines are needed or can be omitted, and whether the order of chemotherapy is important, for treating luminal-type breast cancer. Methods: We recruited patients (pts) with ER-positive, HER2-negative breast cancer aged 20–70 years, and histo-pathologically invasive breast cancer (T1c-3, N0-1, M0), T≤7cm. Pts were randomized to 3 groups for the following treatments: 6 cycles of TC; 3 cycles of 5-FU/epirubicin/cyclophosphamide (FEC) followed by 3 cycles of TC (FEC-TC); and 3 cycles of TC followed by 3 cycles of FEC (TC-FEC). TC treatment consisted of administration of docetaxel at 75 mg/m2 and cyclophosphamide at 600 mg/m2 once every 3 weeks. FEC treatment consisted of administration of 5-FU at 500 mg/m2, epirubicin at 100 mg/m2, and cyclophosphamide at 500 mg/m2 once every 3 weeks. We aimed to enroll 65 pts per group based on an expected pCR rate among regimens of adding 10% at a threshold of 9%. The primary endpoint was pathological complete response (pCR) rate. Secondary endpoints were overall response rate (ORR), breast conservation rate and safety. Results: A total of 195 pts (median age, 49.5 years (range, 26–69); median tumor size, 32.8 mm (range, 9–82); 91 pts with N(+) (51%)) were enrolled and randomized as follows: FEC-TC (n = 65), TC-FEC (n = 63), and TC group (n = 67). There were no differences in backgrounds among groups. Both the intention-to-treat population and the safety analysis set included 65, 63 and 65 pts in these groups, respectively. The 6-cycle treatment completion rates were 96.9%, 96.8% and 84.6%, respectively. pCR, defined as yT0/isyN0, was achieved by 9.2% of pts in the FEC-TC group, 8.1% in the TC-FEC group, and 15.9% in the TC group (p = 0.321). A quasi pCR in breast (yT0/is and near pCR) was achieved by 13.9%, 14.5%, and 17.5%, respectively. These responses did not differ among the 3 groups. ORRs, assessed by MRI or CT, were 75.8% (CR: 12.9%), 75% (CR: 5%), and 82.2% (CR: 17.9%) in the FEC-TC, TC-FEC and TC groups, respectively. Breast conservation rates were 50.8%, 45.2%, and 73.0%, respectively.Adverse events of Grade≥3 were observed in 20.0%, 27.0%, and 20.3% of pts in the FEC-TC, TC-FEC, and TC groups, respectively, with no significant differences. Febrile neutropenia was observed in 17.2%, 21.0%, and 11.3%, respectively, but in most cases it was managed sufficiently on an outpatient basis. Of 28, 27 and 23 pts in these groups in whom mastectomy was planned, 9 (32%), 5 (19%), and 10 (44%) were successfully converted to undergo breast-conserving surgery. Of 37, 35 and 40 pts in the FEC-TC, TC-FEC and TC groups in whom breast-conserving surgery was planned, 13 (35%), 12 (34%), and 4 (10%) underwent mastectomy. Conclusion: Six cycles of TC had therapeutic effects and safety equivalent to FEC-TC and TC-FEC. The 3 treatment groups showed similar pCR rates, although the breast conservation rate was significantly higher in the TC group than in the other 2 groups. It may be possible to conduct preoperative chemotherapy for pts with ER-positive breast cancer without using an anthracycline. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-14-05.

Fractalkine, a chemokine anchored to neurons or peripheral endothelial cells, serves as an adhesion molecule or as a soluble chemoattractant. Fractalkine binds CX3CR1 on microglia and circulating monocytes, dendritic cells, and NK cells. The aim of this study is to determine the role of CX3CR1 in the trafficking and function of myeloid cells to the CNS during experimental autoimmune encephalomyelitis (EAE). Our results show that, in models of active EAE, Cx3cr1−/− mice exhibited more severe neurologic deficiencies. Bone marrow chimeric mice confirmed that CX3CR1 deficiency in bone marrow enhanced EAE severity. Notably, CX3CR1 deficiency was associated with an increased accumulation of CD115+Ly6C−CD11c+ dendritic cells into EAE-affected brains that correlated with enhanced demyelination and neuronal damage. Furthermore, higher IFN-γ and IL-17 levels were detected in cerebellar and spinal cord tissues of CX3CR1-deficient mice. Analyses of peripheral responses during disease initiation revealed a higher frequency of IFN-γ– and IL-17–producing T cells in lymphoid tissues of CX3CR1-deficient as well as enhanced T cell proliferation induced by CX3CR1-deficient dendritic cells. In addition, adoptive transfer of myelin oligodendrocyte glycoprotein35–55-reactive wild-type T cells induced substantially more severe EAE in CX3CR1-deficient recipients when compared with wild-type recipients. Collectively, the data demonstrate that besides its role in chemoattraction, CX3CR1 is a key regulator of myeloid cell activation contributing to the establishment of adaptive immune responses.

We report a case of recurrent breast cancer with involvement of the right adrenal grand, which was resected using laparoscopic surgery. The patient was a 41-year-old woman who underwent duct-lobular segmentectomy for ductal carcinoma in situ. Histopathology showed microinvasion, and tested positive for ER and PR, but negative for HER2, so we applied radiation to the remaining breast and administered tamoxifen. After 9 months, local recurrence was detected and quadrantectomy with axillary lymph node dissection was performed. One year and 10 months later, local recurrence was again detected and a tumorectomy was performed. The adjuvant therapy was changed to an LH-RH analog plus anastrozole and it was administered effectively for 5 years. Left ileal metastasis appeared in the 2nd month after completion of the adjuvant chemotherapy, so radiation was applied and an LH-RH analog plus exemestane administration was started. Three years passed without recurrence, but a right adrenal tumor appeared on computed tomography. The tumor grew over 6 months, so laparoscopic right adrenalectomy was performed. Histopathologically, the tumor tested positive for ER and PR, and negative for HER2 so we diagnosed metastasis of breast cancer, and administered an LH-RH analog plus exemestane. The patient's disease has not progressed in the 3 months since surgery.

Background: This phase II study was conducted to evaluate the efficacy and safety of the chemotherapy combination of gemcitabine and vinorelbine in taxane-pretreated Japanese metastatic breast cancer patients. Methods: In this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2-negative breast cancer were administered gemcitabine (1,200 mg/m2) and vinorelbine (25 mg/m2) intravenously on days 1 and 8 every 3 weeks. The primary endpoint was the objective response rate, and other endpoints included progression-free survival, overall survival, and safety. Results: A total of 42 patients were enrolled in this study. The objective response rate and clinical benefit rate were 24 and 43%, respectively. The median progression-free survival was 4.0 months. The median overall survival was 11.1 months. Grade 3/4 neutropenia was the most common hematologic toxicity, occurring in 22 patients (54%). Nonhematologic toxicity was moderate and transient, with fatigue (48%) being the most common condition and no severe adverse event reported. Conclusion: The combination of gemcitabine and vinorelbine is an effective and tolerable regimen for HER2-negative, taxane-pretreated, metastatic breast cancer patients in Japan.

In vitro studies have implicated chemokine receptors in consumption and clearance of specific ligands. We studied the role that various signaling chemokine receptors play during ligand homeostasis in vivo. We examined the levels of ligands in serum and CNS tissue in mice lacking chemokine receptors. Compared with receptor-sufficient controls, Cx3cr1−/− mice exhibited augmented levels of CX3CL1 both in serum and brain, and circulating levels of CXCL1 and CXCL2 were increased in Cxcr2−/− mice. CCR2-deficient mice showed significantly increased amounts of circulating CCL2 compared with wild-type mice. Cxcr3−/− mice revealed increased levels of circulating and brain CXCL10 after experimental autoimmune encephalomyelitis (EAE) induction. CCR2-deficient peripheral blood and resident peritoneal cells exhibited reduced binding capacity and biologic responses to the CCR1 ligand CCL3, suggesting that elevated levels of CCR2 ligands had down-regulated CCR1. The results indicate that signaling chemokine receptors clear chemokines from circulation and tissues. These homeostatic functions of signaling chemokine receptors need to be integrated into safety and efficacy calculations when considering therapeutic receptor blockade.

No guidelines for supportive drug therapy have been established for oral mucositis occurring during cancer chemotherapy. We retrospectively examined the progression of oral mucositis in 91 patients with breast cancer who received the 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 regimen between September 2007 and August 2008. Daily rebamipide was administered to patients with oral mucositis as per hospital protocol to evaluate the hypothesized preventive and mucosal protective effects of rebamipide(Mucosta®). Oral mucositis was observed in 43 patients (47%)during 4 courses of FEC. The median age of the patients was 55 years(range, 32-76 years). Of the 91 patients, 49 patients who did not receive rebamipide during the 4 FEC courses were classified as group A, 14 patients who received rebamipide before the start of FEC were classified as group B, and 28 patients who received rebamipide after developing oral mucositis were classified as group C. The incidence of oral mucositis at the start of FEC with or without rebamipide administration was observed in 5 patients in group B (36%) and 38 patients in groups A and C (49%) (p=0.3472). The mucositis grade was G1 in 4 patients and G2 in 1 patient in group B, and G1 in 20 patients and G2 plus G3 in 18 patients in groups A and C (p=0.2467). In group C, the grade decreased in 25 patients (89%) and did not occur (G0) in 17 patients (61%) during the next course, and 15 patients (54%) continued to the final course without any occurrence of mucositis. These results suggest that rebamipide is effective for the treatment of oral mucositis. Although significant differences were not observed in the groups, rebamipide has the potential to prevent development of oral mucositis and alleviate its symptoms, and seems promising as a new supportive drug therapy. We hope to verify the preventive and protective effects of rebamipide by conducting a prospective, randomized trial while treating oral mucositis with basic oral care and appropriate interventions provided by a multidisciplinary team.

In Europe and the United States, beginning steroid treatment on the day before docetaxel(DTX)administration is recommended to reduce edema and/or hypersensitivity symptoms. In this study, we investigated the usefulness of starting steroid treatment on the day before DTX administration. Patients with breast cancer who received 4 or more cycles of DTX with or without trastuzumab or DTX and cyclophosphamide(TC)with or without trastuzumab as pre- or post-operative chemotherapy in our hospital between January 2010 and May 2012 were analyzed in this retrospective study. Patients were classified as those who started taking steroids on the day of DTX administration(GroupA: 62 patients)and those who started taking steroids on the day before DTX administration(GroupB: 47 patients). The incidence of edema and/or hypersensitivity was retrospectively compared between these groups after the completion of 4 cycles of chemotherapy. The incidence of edema was significantly lower in GroupB (n=12, 25.5%)than in GroupA (n=28, 45.2%; p=0.04). The onset of edema also tended to be later in GroupB. The incidence of hypersensitivity tended to be lower in GroupB(n=3, 6.4%)than in GroupA (n=8, 12.9%), although this difference was not statistically significant. These results suggest the benefit of steroid treatment started on the day before DTX administration in preventing the development of edema. Results also suggest that the onset of edema could be delayed by this administration method. We recommend that steroid premedication, which can lead to a reduction in adverse drug reactions to DTX, be used to help maintain patients' quality of life(QOL)and to support treatment continuation.

Primary chest wall abscess occurring after blunt chest trauma is rare. We present the case of a 50-year-old woman who presented with a swelling in her left breast. The patient had experienced blunt chest trauma 2 months back. Needle aspiration revealed pus formation in the patient’s chest. Computed tomography revealed a mass in the lower region of the left mammary gland, with thickening of the parietal pleura and skin and fracture of the fifth rib under the abscess. Following antibiotic administration and irrigation of the affected region, surgical debridement was performed. During surgery, we found that the pectoralis major muscle at the level of the fifth rib was markedly damaged, although the necrotic tissue did not contact the mammary gland. We diagnosed the lesion as a chest wall abscess that occurred in response to blunt chest trauma. Her postoperative course was uneventful. There has been no recurrence for six months after surgery.

The clinical significance of preoperative chemotherapy, including trastuzumab for HER2-positive breast cancer, was examined based on hormone receptors(HR)to clarify future issues.104 HER2-positive breast cancer patients who completed preoperative chemotherapy and underwent surgery from May 2005 to August 2010. All patients received sequential treatment with taxane±trastuzumab for FEC(5-FU+epirubicin+cyclophosphamide)therapy, and from 2008 they received trastuzumab postoperatively for one year.Concerning the histological effects, the rate of comprehensive pCR(CpCR)in the 104 patients(31 HR-negative administered trastuzumab, 15 HR-negative not administered trastuzumab, 28 HR-positive administered trastuzumab, 30 HR-positive not administered trastuzumab)was 65%, 47%, 21% and 23% for each group, respectively CpCR was a significant factor(p0. 05)in prolonged distant disease-free survival(DDFS)in the HR-negative group. Distant metastasis occurred in 14 patients, namely, brain metastasis in 7 patients(4 HR-negative administered trastuzumab, 1 HR-negative not administered trastuzumab, 2 HR-positive administered trastuzumab). The therapeutic efficacy was pINV in 5 of these 7 patients(3HR-negative administered trastuzumab, 1 HR-negative not administered trastuzumab, 1 HR-positive administered trastuzumab), and 4 of those 5 patients received trastuzumab postoperatively.The responsiveness to preoperative chemotherapy including trastuzumab for HER2-positive breast cancer differs between HR-positive and HR-negative. pINV patients seem to be at a high risk for brain metastasis regardless of HR, and it may be difficult to suppress its occurrence only with trastuzumab adjuvant therapy.

Carcinoma of an accessory mammary gland is an extremely rare tumor. A 61-year-old male patient presented with a hard mass measuring 85 mm × 51 mm in the left axilla. Incisional biopsy histopathologically showed an adenocarcinoma compatible with breast carcinoma originating in an accessory mammary gland. Systemic examinations revealed no evidence of malignant or occult primary lesion in the bilateral mammary glands or in other organs. Neoadjuvant chemotherapy was performed for the locally advanced axillary tumor and reduced the tumor to 55 mm in size, and, then, he could undergo complete resection with a negative surgical margin in combination with reconstructive surgery to fill the resulting skin defect with a local flap of the latissimus dorsi muscle. The patient has presented with no metastatic lesion in four years since the operation. This unusual case shows that neoadjuvant chemotherapy is an effective and tolerated therapy for advanced accessory breast cancer in the axilla.

Triple-negative breast cancer (TNBC) is negative for all three markers, namely the hormone sensitivity receptors: estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). TNBC accounts for approximately 15% of all primary breast cancer cases. In general, patients with this disease have a higher risk of recurrence and a poorer prognosis compared with those with other subtypes of breast cancer. Patients with TNBC are defined as those for whom endocrine or anti-HER2 therapy are not indicated due to poor response. It is a heterogeneous disease group that shows various characteristics. There is a group that achieves a complete response to chemotherapy and has an excellent prognosis, a group that does not respond to chemotherapy and has a poor prognosis, and a group that has an excellent inherent prognosis and does not need chemotherapy. The subdivision of TNBC cases based on the prognosis and response to therapy is an issue for the future. In addition to classifying TNBC into basal and non-basal types by testing cytokeratin 5/6 (CK5/6) and epidemic growth factor receptors (EGFR) by the immunohistochemical staining method, Ki-67 may predict sensitivity to anticancer agents and a change in Ki-67 before and after therapy may potentially predict prognosis. Patients with a non-pathologic complete response (non-pCR) to preoperative chemotherapy have a high risk of early recurrence, and measures to deal with it are therefore needed. At present, the most commonly used perioperative chemotherapy is sequential combination therapy of an anthracycline drug and a taxane drug; however, it is limited because the pathologic complete response(pCR)rates following preoperative chemotherapy range from 30 to 40%. There is also an urgent need to develop a regimen that will overcome this problem. In association with BRCA gene mutations, sensitivity to DNA-damaging anticancer agents may lead to promising therapies. However, unfortunately, the use of DNA-damaging agents such as cisplatin and carboplatin is not covered by health insurance in Japan. Various new molecular targeted drugs aimed at blocking cell proliferation factors are expected to be developed in the future. Here we have summarized the current status and issues based on the clinical experience with the diagnosis and treatment of TNBC.

Summary The site of origin of ventricular premature beats (VPBs) was estimated by QRS maps and its distribution in two patient groups was studied. VPB origin was determined by comparing the body surface map of VPBs with that during electrical stimuli applied at various sites of the ventricle. Subjects were 100 patients without obvious underlying cardiovascular disease (Group N) and 289 patients with various heart diseases (Group D). Nine sites of origin of VPB were identified. In group N, VPBs of right ventricular origin were noted in 69%, those of left ventricular origin in 6%. There was a relatively high incidence of VPBs with foci estimated to be the divisions of the left bundle branch, and the age of patients with these VPBs was young. In Group D, VPBs of left ventricular origin showed a higher incidence (34.6%) and those of right ventricular origin a lower incidence (41.2%) than those in group N. The data suggest that VPBs originating from the apex and base of the ventricle strongly indicate the presence of basic heart disease and that VPBs originating in or near the divisions of the left bundle branch in younger subjects do not necessarily indicate cardiac disease.

心室期外収縮96心拍と, 心室内変行伝導を伴う上室期外収縮29心拍のFrank法ベクトル心電図QRS環の特徴を分析し, 両者の鑑別基準の作成を試みた。心室期外収縮は心室変行伝導収縮に比してQRS時間および空間最大ベクトル到達時間の延長, 初期描記速度の低下, 正常伝導収縮との初期ベクトル空間夾角の開大という特徴を示した。心室期外収縮を心室変行伝導収縮から鑑別する基準として, (1) QRS時間≧120msec, (2) 空間最大ベクトル到達時間≧50msec, (3) 空間速度心電図初期30msec間のQRS環最大描記速度

The clinical usefulness of QRST isointegral maps (IQRST map) for detecting myocardial infarction that was complicated by intraventricular conduction disturbances was evaluated in patients with right bundle branch block (group RBBB, 64 patients) and left bundle branch block (group LBBB, 40 patients) by comparison with the normal mean IQRST map derived from 50 normal subjects. Myocardial infarction complicated the conduction disturbances in 24 of the 64 RBBB and in 18 of the 40 LBBB patients. A correlation coefficient was used for assessing the similarity of each map pattern with the normal mean IQRST map. The difference map was made by subtracting the average normal IQRST map from each abnormal IQRST map, and those differences that were less than 2 SD from the mean were retained as a significant area. The number of leads and their sum of differences were used to represent the size of the difference map. Correlation coefficients were significantly (p less than 0.001) smaller in patients with bundle branch block complicated by myocardial infarction than in patients with conduction disturbances not complicated by myocardial infarction. A significant area emerged in the difference map in all patients with myocardial infarction complicated by conduction disturbances. The emergence of a significant area revealed high diagnostic accuracy for detecting myocardial infarction in group RBBB (89.1%). The size of a significant area in a difference map was significantly larger in cases with complicated myocardial infarction than in cases with uncomplicated myocardial infarction in either group RBBB or group LBBB (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

標準12誘導心電図III誘導で0.2mV以上のQ波が存在する非梗塞群18例, 下壁梗塞群18例を対象として安静呼気および深吸気時のIII誘導Q波 (QIII) の電位, 前額面平均電気軸, QRS40isointegral MAPを比較検討した.その結果, (1) 深吸気によりQIIIの電位は両群ともに有意に減少したが, 0.2mV以下になるものは非梗塞群に多く, QIIIの減少率は非梗塞群で有意に大きかった. (2) 前額面平均電気軸は両群とも深吸気で20～30°垂直位方向への偏位を示した. (3) QRS40isointegral MAPにおける安静呼気時の負領域は非梗塞群では右胸背部にのみ存在する例が多く, 下壁梗塞群では左胸部下方にまで拡がる例が多かった.深呼気時の負領域は非梗塞群ではより上方に, 下壁梗塞群ではより下方に移動する例が多かった.従って, QRS40isointegral MAPおよびQIII電位の呼吸性変化は, 梗塞の有無により差があり, これらは両者の鑑別に有力な手がかりになることが示唆された.

体表面87点の単極誘導心電図から求めた, QRST isointegral map (I-map)と, QRST subtraction I-mapにより,前壁梗塞の診断および左室駆出率の推定を行なった.対象は陳旧性前壁梗塞47例であり,健常成人46例を正常対照群とした.前壁梗塞のQRST I-mapでは負領域が左胸部に張り出し,極大および極小の位置が健常人に比して有意に左下方に偏位した.またQRST subtraction I-mapにおけるn subtraction, ∑ subtraction, ∑ DIの指標は駆出率と比較的良い負相関を示した.また梗塞例の標準12誘導心電図V4誘導におけるQRST積分値と正常のそれとの差も駆出率と負相関を示し,簡便な方法として臨床応用が可能と考えられた.

脚ブロックを合併した心筋梗塞の診断を行なう場合のQRST isointegral map (I QRST map)の有用性を,右脚ブロック48例,左脚ブロック35例(心筋梗塞合併例はおのおの19例, 16例)を用い,健常成人46例を対象として検討した.梗塞合併の脚ブロック例のI QRST mapは脚ブロック単独例と異なり正常との相関係数は著しく低かった.また,これらの例の有意な積分値減少領域(差の領域)は梗塞部位毎に一定の部位に出現した.差の領域の大きさと,その領域内の各誘導点の積分値と正常平均値との差の総和は,梗塞合併群では非合併群に比して有意に大きかった.体表面電位図から求めたI QRST mapは脚ブロックにマスクされた心筋梗塞の有無とその部位診断に極めて有用であった.