Impact of neoadjuvant chemotherapy on the safety and long-term outcomes of patients undergoing immediate breast reconstruction after mastectomy.

BACKGROUND: In breast cancer patients receiving neoadjuvant chemotherapy (NAC), immediate breast reconstruction (IBR) as a breast cancer treatment option remains controversial. We assessed the impact of NAC on surgical and oncological outcomes of patients undergoing IBR. METHODS: This was a retrospective multicenter study of 4726 breast cancer cases undergoing IBR. The rate of postoperative complications and survival data were compared between IBR patients who received NAC and those who did not receive NAC. Propensity score matching analysis was performed to mitigate selection bias for survival. RESULTS: Of the total 4726 cases, 473 (10.0%) received NAC. Out of the cases with NAC, 96 (20.3%) experienced postoperative complications, while 744 cases (17.5%) without NAC had postoperative complications. NAC did not significant increase the risk of complications after IBR (Odds ratio, 0.96; 95%CI 0.74-1.25). At the median follow-up time of 76.5 months, 36 patients in the NAC group and 147 patients in the control group developed local recurrences. The 5-year local recurrence-free survival rate was 93.1% in the NAC group and 97.1% in the control group. (P < 0.001). After matching, there was no significant difference between the two groups. CONCLUSION: IBR after NAC is a safe procedure with an acceptable postoperative complication profile.

Impact of radiation therapy for breast cancer with involved surgical margin after immediate breast reconstruction: A multi-institutional observational study.

INTRODUCTION: Involved surgical margins are risk factors for local recurrence and re-excision is often difficult, particularly in patients with breast cancer undergoing immediate breast reconstruction (IBR). However, the magnitude of the effect of radiation therapy on preventing local recurrence for breast cancers with involved margins has not been sufficiently assessed. MATERIALS AND METHODS: We retrospectively assessed sites of involved surgical margins and local recurrence after mastectomy with IBR in patients with early breast cancer between 2008 and 2016. The effect of postoperative radiation therapy was evaluated in patients with involved margins, adjusted for nuclear grade, lymphatic invasion, surgical procedures, and primary systemic therapy. RESULTS: A total of 274 (5.8 %) out of 4726 patients who underwent mastectomy with IBR had involved surgical margins: 133, 68, 88, and 26 had involvement of the skin, deep margin, lateral margins, and nipple, respectively (including duplicates). Radiation therapy was administered to 54 patients with involved margins. In patients with involved margins, 7-year cumulative incidences of local recurrence were 1.9 % and 12.6 % with and without radiation therapy, respectively (adjusted hazard ratio, 0.17; 95 % CI, 0.04-0.80). Local recurrence occurred in 28 patients, and the sites were skin, subcutaneous tissue, muscle, and nipple-areola complex in 7, 17, 1, and 3 patients, respectively. Among them, 23 (82.1 %) were associated with involved margin sites. CONCLUSIONS: Radiation therapy meaningfully reduced the incidence of local recurrence in patients with breast cancer with margin involvement after mastectomy with IBR. Most local recurrences occurred at involved margin-related sites.

Physicians' perception about the impact of breast reconstruction on patient prognosis: a survey in Japan.

BACKGROUND: One barrier to the widespread use of breast reconstruction (BR) is physicians' perception that BR adversely affects breast cancer prognosis. However, there is limited information regarding physicians' understanding of the impact of BR on patient prognosis and which physicians have misunderstandings about BR. METHODS: We conducted an e-mail survey regarding the impact of BR on the prognosis of patients with breast cancer among members of the Japanese Breast Cancer Society. RESULTS: Of 369 respondents, 99 (27%) said that they believe BR affects patient prognosis. Female respondents and those who treat fewer new breast cancer patients per year were more likely to state that they believe BR affects patient prognosis (P = 0.006 and 0.007). Respondents who believed that BR affects patient prognosis underestimated 5-year overall survival rates in patients who receive BR and subsequently have local or regional recurrence in different sites. CONCLUSION: Our survey demonstrated that a quarter of respondents believe that BR affects patient prognosis and underestimate survival rates in patients who receive BR and have subsequent local or regional recurrence. Because of the lack of evidence regarding the impact of BR on patient prognosis, educating physicians by providing accurate knowledge regarding BR and patient prognosis is highly recommended.

Classification of Local Recurrence After Nipple-Sparing Mastectomy Based on Location: The Features of Nipple-Areolar Recurrence Differ from Those of Other Local Recurrences.

BACKGROUND: Little information is available about the clinical and pathologic characteristics of local recurrence (LR) after nipple-sparing mastectomy according to the locations of LR. METHODS: This study classified 99 patients into the following two groups according to the location of LR after nipple-sparing mastectomy: nipple-areolar recurrence (NAR) group and other locations of LR (oLR) group. The study evaluated whether the location of LR was associated with disease-free survival (DFS) after LR resection. RESULTS: For about half of the patients (44.4 %) with NAR, the primary cancer was estrogen receptor (ER)-negative and human epidermal growth factor receptor 2 (HER2)-positive. Conversely, in most of the patients with oLR (79.2 %), the primary cancer was ER-positive and HER2-negative. Among the LR tumors, the frequency of noninvasive carcinoma in the NAR tumors was significantly higher than in the oLR tumors (51.9 % vs 4.2 %, respectively). During a median follow-up period of 46 months, the location of LR was not associated with DFS after LR. In the NAR group, the presence or absence of LR tumor invasiveness was the only factor associated with DFS. In the oLR group, age at primary surgery was the only factor associated with DFS. CONCLUSION: This multi-institutional retrospective study demonstrated that the features of NAR, such as the characteristics of the primary and recurrent tumors and the prognostic factors after LR resection, were quite different from those of oLR.

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

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 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.

Effect of denosumab on low bone mineral density in postmenopausal Japanese women receiving adjuvant aromatase inhibitors for non-metastatic breast cancer: 24-month results.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Erratum to immediate breast volume replacement using a free dermal fat graft after breast cancer surgery: multi-institutional joint research of short-term outcomes in 262 Japanese patients.

[This corrects the article on p. 179 in vol. 4, PMID: 26005649.].

Immediate breast volume replacement using a free dermal fat graft after breast cancer surgery: multi-institutional joint research of short-term outcomes in 262 Japanese patients.

BACKGROUND: Immediate volume replacement using a free dermal fat graft (FDFG) has been proven safe with early postoperative benefits. The aims of the present study were to clarify adequate indications and risk factors associated with operative morbidity. PATIENTS AND METHODS: A multi-institutional analysis of partial mastectomy with immediate volume replacement with FDFG was undertaken in 14 hospitals specializing in breast cancer treatment. Clinical and oncological variables were analyzed to identify factors associated with postoperative complications. RESULTS: A total of 262 cases were analyzed. Considering the observation period and overlap of patients, 13 (5.4%) out of 242 patients had complications within 1 month of surgery while 7 (4.6%) out of 151 patients developed complications 1-12 months after surgery. Two hundred and eleven out of 242 patients were statistically examined using a multivariate analysis, which revealed that the weight of resected breast tissue, size of implanted FDFG (cranio-caudal length), and weight of implanted FDFG were associated with a higher likelihood of postoperative complications. CONCLUSIONS: Immediate breast volume replacement using a FDFG after breast cancer surgery should be done for selected patients with breast cancer to avoid postoperative complications. The prospective and larger investigations are warranted for the establishment of appropriate guidelines.

Long-term follow-up of nipple-sparing mastectomy without radiotherapy: a single center study at a Japanese institution.

Recent reports have suggested that nipple-sparing mastectomy (NSM) is a potential alternative to mastectomy (MT). The aim of our study was to investigate the oncological and technical outcomes of NSM compared with MT using long-term follow-up data. A total of 932 patients between April 1985 and March 2004 were enrolled in our study. Among them, 788 patients received NSM, whereas 144 patients received the routine mastectomy. The median follow-up time was 78 months. No significant difference in the probability of local recurrence between the NSM cohort and the MT cohort was found (8.2 vs. 7.6 %, p = 0.81). The rate of nipple-areola complex (NAC) relapse was low (3.7 %), and all of the nipple and/or areola recurrence cases were treated with NAC removal. Furthermore, nipple and/or areola recurrence was associated with a significantly better prognosis than that of skin flap recurrences and local lymph node recurrences. For the 21-year disease-free survival and the 21-year overall survival, no significant difference between the NSM and MT cohorts was observed. There was no occurrence of nipple necrosis in our trial. This was the first study to investigate the long-term follow-up of NSM in a large Japanese population. We reported the NSM could be performed without nipple necrosis and is oncologically as safe as mastectomy without radiotherapy. Therefore, we suggest that NSM without radiotherapy is a potential alternative to mastectomy for breast cancer patients for both outcome and aesthetic benefits.

[Bi-weekly nab-paclitaxel and trastuzumab therapy effective against recurrent breast cancer with multiple lung metastases in elderly patient who had previously undergone two chemotherapeutic regimens for treatment of metastatic disease-a case Report].

We herein report a 75-year-old patient with recurrent hormone-nonresponsive, HER2-positive breast cancer who presented with multiple lung metastases. She had undergone a mastectomy followed by adjuvant chemotherapy with FEC, CMF, and UFT. Forty-six months after the surgery, multiple lung, liver, and bone metastases were observed. Docetaxel and trastuzumab were administered as first-line chemotherapy for 13 months. A partial response and stable disease were observed, but progressive disease in the lung and brain was subsequently revealed. The patient then underwent g-knife treatment for brain metastasis. Lapatinib and capecitabine treatment was administered as second-line chemotherapy for 9 months. Stable disease was observed, but progressive disease in the lung metastases with clinical symptoms including cough, exertional dyspnea, and general malaise was revealed. As third-line chemotherapy, the patient was administered low-dose, bi-weekly nab-paclitaxel(150mg/m2)and trastuzumab therapy. Four weeks after beginning the nab-paclitaxel and trastuzumab treatment, the cough disappeared; 2 months after beginning the therapy, a partialresponse in the lung metastases was seen. The patient is well and the treatment has been continued for 50 weeks. No progression has been seen. Bi-weekly nab-paclitaxel treatment appears to have few side effects and might be an effective treatment option for patients with recurrent breast cancer.

Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain.

Bone pain is one of the most common complications in cancer patients with bone metastases. Although the mechanism of cancer-associated bone pain is poorly understood, clinical observations that inhibitors of osteoclasts such as bisphosphonates (BPs) efficiently reduce bone pain suggest a potential role of osteoclasts, which play a central role in the development and progression of bone metastasis. Osteoclasts dissolve bone minerals by releasing protons through the a3 isoform of the vacuolar-H(+)-ATPase, creating acidic microenvironments. In addition, cancer cells, inflammatory cells and immune cells that reside in bone metastases also produce acidic conditions by releasing protons. It has been well-known that acidic conditions due to proton release cause pain. Our study showed that the sensory nociceptive neurons innervate bone and these neurons express acid-sensing nociceptors such as the acid-sensing ion channels and transient receptor potential channel-vanilloid subfamily members. Acid signals received by these nociceptors subsequently activate intracellular signaling pathways and transcription factors in sensory neurons. The understanding of the nociceptive events following proton release and subsequent creation of acidic microenvironments leads us to design novel molecular-based approaches for reducing bone pain associated with cancer and inflammation.

Acid activation of Trpv1 leads to an up-regulation of calcitonin gene-related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: a potential mechanism of inflammatory pain.

Increased production of calcitonin gene-related peptide (CGRP) in sensory neurons is implicated in inflammatory pain. The inflammatory site is acidic due to proton release from infiltrating inflammatory cells. Acid activation of peripheral nociceptors relays pain signals to the CNS. Here, we examined whether acid activated the transient receptor potential vanilloid subtype 1 (Trpv1), a widely recognized acid-sensing nociceptor and subsequently increased CGRP expression. Chemically induced inflammation was associated with thermal hyperalgesia and increased CGRP expression in dorsal root ganglion (DRG) in rats. In organ cultures of DRG, acid (pH 5.5) elevated CGRP expression and the selective Trpv1 antagonist 5'-Iodoresiniferatoxin decreased it. Trpv1-deficient DRG showed reduced CGRP increase by acid. Of note, many of CGRP/Trpv1-positive DRG neurons exhibited the phosphorylation of cAMP response element-binding protein (CREB), a nociceptive transcription factor. Knockdown of CREB by small interfering RNA or a dominant-negative form of CREB diminished acid-elevated CGRP expression. Acid elevated the transcriptional activity of CREB, which in turn stimulated CGRP gene promoter activity. These effects were inhibited by a Ca(2+)/calmodulin-dependent protein kinase (CaMK) inhibitor KN-93. In conclusion, our results suggest that inflammatory acidic environments activate Trpv1, leading to an up-regulation of CGRP expression via CaMK-CREB cascade, a series of events that may be associated with inflammatory pain.

[Nineteen years postoperatively, anastrozole, UFT and cyclophosphamide combination therapy remained effective against recurrent hormone responsive breast cancer with intraabdominal lymphnode, pleural, skin and bone metastases in old age following sixteen-year tamoxifen treatment - a case report].

We report an 89-year-old patient with recurrent hormone-responsive breast cancer who presented with pleural, skin and bone metastases. Nineteen years previously, she had undergone a mastectomy and then for 16 years received adjuvant hormone therapy. The patient was orally administered a combination therapy of anastrozole, UFT and cyclophosphamide. A remarkable response was seen after 5 months, and no side effects were observed. The patient became well and the treatment was continued without relapse at 8 months. Oral anti-cancer treatments in combination with hormone therapy appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients.

[Doxifluridine, medroxyprogesterone acetate and cyclophosphamide (DMpC) combination therapy is effective against recurrent triple negative breast cancer--a case report].

We report a postmenopausal recurrent breast cancer patient with triple negative disease who presented with right recurrent nerve palsy. Nine years previously, she had undergone a mastectomy. FDG-PET scan revealed neck lymph node metastases from the breast cancer. The recurrent nerve palsy was thus considered to have been caused by the lymph node metastases. The patient was orally administered DMpC (doxifluridine, medroxyprogesterone acetate and cyclophosphamide) combination therapy. This resulted in a remarkable response after five months, with the recurrent nerve palsy completely disappearing at six months. No side effects from the treatment were observed. The patient was well and the treatment was being continued without relapse at nine months. Oral anti-cancer treatments such as DMpC appear to have few side effects and might be an effective treatment option for recurrent breast cancer patients with triple negative disease.

[Therapeutic agents for disorders of bone and calcium metabolism: Zoledronic acid].

Intervenous (IV) bisphosphonates are used for cancer patients with hypercalcemia of malignancy (HCM) and breast cancer bone metastases (BM). Recently, zoledronic acid, the most potent third generation bisphosphonate, has been approved for both HCM and BM of broad tumors. It showed 850-fold stronger activity than pamidronate in bone resorption assay, and clinical efficacy against multiple cancer bone lesion has been confirmed in randomized clinical trials. Zoledronic acid becomes one of the most used bisphosphonate for cancer patients in the world, and the results of clinical trials for cancer treatment-induced bone loss or postmenopausal osteoporosis are now updating.

[Anastrozole-resistant breast cancer responsive to exemestane--a case report].

We describe a postmenopausal woman suffering from advanced breast cancer with pleural effusion. She had prior anastrozole therapy, and was referred to our hospital with dyspnea. The use of exemestane, a highly selective steroidal aromatase inhibitor (25 mg daily), successfully induced remission of pleural effusion. Exemestane is a useful treatment for postmenopausal woman with advanced breast cancer, which is refractory to anastrozole.

A case of serum CEA disappearance curve after resection of breast carcinoma.

Carcinoembryonic antigen (CEA) elimination kinetics after tumor resection were measured in a case of breast cancer. A 45-year-old woman with a left breast carcinoma underwent surgery after neoadjuvant chemotherapy. The serum CEA level before surgery was 34.3 ng/ml. After sequential monitoring of serum CEA levels, postoperative serum CEA elimination kinetics were calculated using non-linear least square analysis with the fitting equation C(t)=(C0-Cp)exp(-kt)+Cp, where C(t) was the postoperative CEA level, t was the number days after surgery, C0 was the CEA level at postoperative time zero, Cp was the CEA at plateau, and k was the rate constant of elimination. Cp was calculated as 6.9 ng/ml, which was above the cut-off level and indicated residual malignancy. After adjuvant chemotherapy, CEA normalized to 1.8 ng/ml. In breast cancer patients with high preoperative serum CEA levels, our analytical method for CEA elimination might be useful for the detection of residual malignancies.

Combined large cell neuroendocrine carcinoma.

We report a case of combined large cell neuroendocrine carcinoma. A 78-year-old man with vertigo was referred to our hospital where chest X-ray revealed a tumor shadow in the right lung. A transbronchial lung biopsy specimen verified a diagnosis of non-small cell lung carcinoma (cT1N0M0). Right lower lobectomy with mediastinal lymph node dissection (#7, 8, 9) was performed. A postoperative histological diagnosis was combined large cell neuroendocrine carcinoma of a component of squamous cell carcinoma [pT4 (pm) N2M0]. The patient received concurrent chemoradiotherapy due to upper mediastinal lymph node metastasis 4 months after surgery. The chemoradiotherapy well responded and the patient remains well 9 months after surgery.

[Histoculture drug response assay for solitary fibrous tumor--a case report].

A 49-year-old male was referred to our hospital because of an abnormal shadow in his left lower lung field on chest X-ray. Magnetic resonance imaging scans revealed a large mass on the left diaphragm. The tumor was surgically extirpated. The tumor, encapsulated and growing from the center of the left diaphragm, measured 18 x 8 x 4 cm and weighed 440 g. Microscopic examination revealed a solitary fibrous tumor with mitotic activity of 7/ 50 hpf. Immunohistochemically, the tumor was negative for cytokeratin, s-100 protein, desmin, and alpha-smooth muscle actin, while positive for vimentin and CD34. On a histoculture drug response assay using the resected tissue, the tumor was sensitive to 5-FU, adriamycin, mitomycin C and docetaxel, and resistant to cisplatin, irinotecan, and gemcitabine.

[Histoculture drug response assay guided concurrent chemoradiotherapy for lung metastasis from adrenocortical carcinoma--a case report].

A 50-year-old woman underwent surgical resection of a left adrenocortical carcinoma in April 2000. Bilateral pulmonary metastases and abdominal lymph node metastasis were detected in June 2001. After radiation therapy for the abdominal lymph node metastasis, a pulmonary metastatic lesion was thoracoscopically resected. The specimen was subjected to histoculture drug response assay (HDRA), and results revealed that this tumor was sensitive for cisplatin. We therefore performed concurrent chemoradiotherapy including cisplatin for the residual pulmonary metastatic lesion; a complete response was then obtained. Standard protocols of chemotherapy are often absent for malignant tumors, such as in this case, with low incidences. HDRA seems useful for chemotherapy agent selection in cases of rare malignant tumors.