Nipple reconstruction using spiral-peeling technique during oncoplastic breast-conserving surgery for a patient with small breasts.

Treatment of early breast cancer using breast-conserving surgery (BCS) commonly leads to local control and acceptable cosmetic results. We report a useful technique to achieve symmetry of the breast shape and nipple-areola, with excellent results. A Japanese patient with early breast cancer located in the inner central area of the breast was enrolled in this study. Intraductal spread of breast cancer to the nipple was suspected; however, no invasion was observed outside the nipple wall. We preserved the cylindrical surface, but resected the inner tissue with the top surface of the nipple. After coring the nipple, the remnant cylindrical surface was cut into a spiral shape. Nipple reconstruction using the spiral-peeling technique during oncoplastic breast-conserving surgery (OPBCS) may be useful for patients who desire nipple preservation.

Influence of Brain Metastasis on Analgesia-Related Outcomes in Patients with Lung and Breast Cancers Treated with Naldemedine: A Propensity Score-Matched Analysis.

Naldemedine is structurally designed to prevent passage across the blood-brain barrier (BBB), resulting in the attenuation of opioid-induced constipation without interfering with the analgesic effects of opioids. However, the influence of brain metastasis (BM), as one indicator of BBB disruption, on the analgesic effects of opioids in patients treated with naldemedine remains unclear. To examine whether the analgesic effects of opioids following naldemedine treatment are lower in patients with BM than in those without BM, we surveyed inpatients with lung and breast cancers treated with naldemedine at Fujita Health University Hospital between April 2017 and March 2022. Changes in the numeric rating scale (NRS) scores, morphine milligram equivalents (MMEs), and the number of rescues were assessed as analgesia-related outcomes during the first 7 days of naldemedine treatment in patients with or without BM, matched by the propensity score. In total, 172 patients were enrolled. After propensity-score matching, 30 patients with BM and 60 patients without BM were included in the analysis. Changes in NRS scores, MMEs, and the number of rescues did not differ between patients with and without BM. In the linear mixed-effects model, the coefficient of interaction between patients with or without BM and the days for each outcome was not statistically significant. BM does not influence the analgesic effect of opioids in patients with lung and breast cancers treated with naldemedine. Naldemedine may be useful for treating BM.

Cathepsin G-induced malignant progression of MCF-7 cells involves suppression of PAF signaling through induced expression of PAFAH1B2.

Breast cancer is primarily classified into ductal and lobular types, as well as into noninvasive and invasive cancer. Invasive cancer involves lymphatic and hematogenous metastasis. In breast cancer patients with distant metastases, a neutrophil-derived serine protease; cathepsin G (Cat G), is highly expressed in breast cancer cells. Cat G induces cell migration and multicellular aggregation of MCF-7 human breast cancer cells; however, the mechanism is not clear. Recently, platelet-activating factor (PAF)-acetylhydrolase (PAF-AH), the enzyme responsible for PAF degradation, was reported to be overexpressed in some tumor types, including pancreatic and breast cancers. In this study, we investigated whether PAF-AH is involved in Cat G-induced aggregation and migration of MCF-7 cells. We first showed that Cat G increased PAF-AH activity and elevated PAFAH1B2 expression in MCF-7 cells. The elevated expression of PAFAH1B2 was also observed in human breast cancer tissue specimens by immunohistochemical analysis. Furthermore, knockdown of PAFAH1B2 in MCF-7 cells suppressed the cell migration and aggregation induced by low concentrations, but not high concentrations, of Cat G. Carbamoyl PAF (cPAF), a nonhydrolyzable PAF analog, completely suppressed Cat G-induced migration of MCF-7 cells. In addition, PAF receptor (PAFR) inhibition induced cell migration of MCF-7 cells even in the absence of Cat G, suggesting that Cat G suppresses the activation of PAFR through enhanced PAF degradation due to elevated expression of PAFAH1B2 and thereby induces malignant phenotypes in MCF-7 cells. Our findings may lead to a novel therapeutic modality for treating breast cancer by modulating the activity of Cat G/PAF signaling.

Modification of oncoplastic breast surgery with immediate volume replacement using a thoracodorsal adipofascial flap.

BACKGROUND: The treatment of early breast cancer using breast conservation therapy (BCT) commonly ensures local control and acceptable cosmetic results. We report a useful technique including the use of a thoracodorsal adipofascial cutaneous flap for reconstructing defects in the outer quadrant area after partial mastectomy, which achieved excellent results. METHODS: During the past 15 years, some modifications have been added to the original method at a rate of one modification every 2-5 years. We classified these modifications into the original method and four modified methods. Modification I: addition of a crescent-shaped dermis on the distant edge of the thoracodorsal adipofascial flap (TDAFF), Modification II: addition of a crescent-shaped dermis on the proximal edge of the TDAFF, Modification III: addition of inframammary formation plus Modification II, and Modification IV: change of a crescent-shaped dermis to a Benz-shaped (shaped like the Mercedes Benz logo) one plus Modification III. We compared the plastic period, postoperative complications, oncological results, and cosmetic results among the original and four modified groups. RESULTS: The patient number was 26, 9, 15, 23, and 10 in the original and Modification I, II, III, and IV groups, respectively. The median observation period was 115, 92, 67, 51, and 32 months, respectively. Postoperative complications were seen in 5 (19%), 0, 2 (13%), 1 (5%), and 0 patients, respectively. Local recurrence was seen in 3 (12%), 0, 0, 0, and 0 patients, respectively. Distant recurrence was seen in 1 (4%), 1 (11%), 3 (20%), 0, and 0 patients, respectively. Cosmetic results evaluated as good-excellent were seen in 19 (73%), 5 (56%), 11 (73%), 19 (83%), and 10 (100%) patients, respectively. CONCLUSIONS: Oncoplastic surgery using an immediate volume replacement technique with a thoracodorsal adipofascial flap was improved by adding some modifications.

Oncoplastic breast surgery combining partial mastectomy with resection of double equilateral triangular skin flaps.

The treatment of early breast cancer using oncoplastic breast surgery (OBS) has been gradually increasing in popularity and is recognized for its efficacy in local control and excellent cosmetic results. We herein report a useful technique for obtaining symmetry of the breast shape for an early breast lesion located in an outer area, close to the nipple-areola, in a Japanese patient with ptotic, fatty breasts. We designed two equilateral triangles: one just upon the resected area and the other on the axilla. They were located on a straight line, with one top pointed to the cranial side and one to the caudal side. A crescent area around the areola was de-epithelialized in the 12 o'clock and 6 o'clock directions. Columnar-shaped breast tissue and an equilateral triangular skin flap and fatty tissue were removed together. To fill the defect, a skin-glandular flap was slid horizontally after suturing the inframammary line. Although an incision scar was formed on the breast and lateral chest wall in a Z-shape, this new technique was able to achieve not only cancer control but also excellent cosmetic results.

A Personal Breast Cancer Risk Stratification Model Using Common Variants and Environmental Risk Factors in Japanese Females.

Personalized approaches to prevention based on genetic risk models have been anticipated, and many models for the prediction of individual breast cancer risk have been developed. However, few studies have evaluated personalized risk using both genetic and environmental factors. We developed a risk model using genetic and environmental risk factors using 1319 breast cancer cases and 2094 controls from three case-control studies in Japan. Risk groups were defined based on the number of risk alleles for 14 breast cancer susceptibility loci, namely low (0-10 alleles), moderate (11-16) and high (17+). Environmental risk factors were collected using a self-administered questionnaire and implemented with harmonization. Odds ratio (OR) and C-statistics, calculated using a logistic regression model, were used to evaluate breast cancer susceptibility and model performance. Respective breast cancer ORs in the moderate- and high-risk groups were 1.69 (95% confidence interval, 1.39-2.04) and 3.27 (2.46-4.34) compared with the low-risk group. The C-statistic for the environmental model of 0.616 (0.596-0.636) was significantly improved by combination with the genetic model, to 0.659 (0.640-0.678). This combined genetic and environmental risk model may be suitable for the stratification of individuals by breast cancer risk. New approaches to breast cancer prevention using the model are warranted.

Immediate breast reconstruction with expander following recurrent lesion resection and exchange to silicon breast implant in a pregnant triple negative breast cancer patient: case report.

A 39-year-old gravida 1 para 1 pregnant Japanese woman underwent skin-sparing mastectomy and axillary lymph node dissection with immediate breast reconstruction (IBR) using a tissue expander (TE) at 32 weeks of pregnancy under general anesthesia. Inserted TE (300 cc) was expanded during breast feeding while the volume was 240 cc of the resected breast tissue. One month after delivery, 2 months after surgery, the contralateral healthy breast increased in size and the inframammary line was deviated toward a caudal site which was larger than 300 cc-inflated TE. She stopped breast feeding to receive a systemic chemotherapy after one months-breast feeding. At 3 months after delivery, the healthy breast size was smaller than the 250 cc-expanded breast and both the inframammary lines were at the same level. She was diagnosed local recurrence 3 month-postoperatively, so we resected the recurrent lesion and exchanged TE to silicon breast implant immediately. Finally, a good symmetry was obtained after insertion of the 220 cc SBI. At an IBR using TE, we should know the dynamic change of breast volume and the level of inframammary line of the healthy breast during those phases of pregnancy, delivery, and nursing.

Oncoplastic breast surgery combining partial mastectomy with V-rotation mammoplasty for breast cancer on the upper inner area of the breast.

The treatment of early breast cancer using breast conservation therapy (BCT) commonly ensures local control and acceptable cosmetic results. We herein report a useful technique for obtaining symmetry of the breast shape and a level inframammary line and nipple-areola that achieved excellent results. Four Japanese patients with early breast cancer located on the upper inner area of the breast were enrolled into this study. De-epithelialized skin close to the resected area and skin from the epigastric area with subdermal fatty tissue were moved to repair the defect. Oncoplastic breast surgery (OBS) combining partial mastectomy with the V-rotation mammoplasty technique was useful for patients with breast cancer on the upper inner area of minimal ptotic breasts.

Molecular pathogenesis of breast cancer: impact of miR-99a-5p and miR-99a-3p regulation on oncogenic genes.

Our recent research has revealed that passenger strands of certain microRNAs (miRNAs) function as tumor-suppressive miRNAs in cancer cells, e.g., miR-101-5p, miR-143-5p, miR-144-5p, miR-145-3p, and miR-150-3p. Thus, they are important in cancer pathogenesis. Analysis of the miRNA expression signature of breast cancer (BrCa) showed that the expression levels of two miRNAs derived from pre-miR-99a (miR-99a-5p and miR-99a-3p) were suppressed in cancerous tissues. The aim of this study was to identify oncogenic genes controlled by pre-miR-99a that are closely involved in the molecular pathogenesis of BrCa. A total of 113 genes were identified as targets of pre-miR-99a regulation (19 genes modulated by miR-99a-5p, and 95 genes regulated by miR-99a-3p) in BrCa cells. Notably, FAM64A was targeted by both of the miRNAs. Among these targets, high expression of 16 genes (C5orf22, YOD1, SLBP, F11R, C12orf49, SRPK1, ZNF250, ZNF695, CDK1, DNMT3B, TRIM25, MCM4, CDKN3, PRPS, FAM64A, and DESI2) significantly predicted reduced survival of BrCa patients based upon The Cancer Genome Atlas (TCGA) database. In this study, we focused on FAM64A and investigated the relationship between FAM64A expression and molecular pathogenesis of BrCa subtypes. The upregulation of FAM64A was confirmed in BrCa clinical specimens. Importantly, the expression of FAM64A significantly differed between patients with Luminal-A and Luminal-B subtypes. Our data strongly suggest that the aberrant expression of FAM64A is involved in the malignant transformation of BrCa. Our miRNA-based approaches (identification of tumor-suppressive miRNAs and their controlled targets) will provide novel information regarding the molecular pathogenesis of BrCa.

Upregulation of S100A10 in metastasized breast cancer stem cells.

Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44+ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell-related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.

Surgical Resection With Pedicled Rotation Flap for Post-mastectomy Locoregional Breast Cancer Recurrence.

BACKGROUND/AIM: Locoregional recurrence (LRR) of breast cancer is reported to occur at a rate of 5%-15%. Wide excision of LRR is the recommended treatment, which can increase the probability of subsequent local control. Herein, we describe a surgical technique wherein a pedicled skin and subcutaneous flap close the skin defect after resection of a breast cancer LRR without use of a skin graft. PATIENTS AND METHODS: We reviewed four patients who underwent surgical resection using a pedicled rotation flap for chest wall recurrence after mastectomy. RESULTS: The surgical margin was set 2 cm apart from the tumor margin. After resection of tumor from the chest wall, we formed an adjacent pedicled flap and rotated the flap to the skin defect. There were no post-operative complications, including wound necrosis. CONCLUSION: Surgical resection with a pedicled rotation flap for post-mastectomy breast cancer LRR is a highly feasible way to achieve complete resection.

Breast cancer with an intraductal component that was proven genetically to be metastasis of contralateral breast cancer: a case report.

BACKGROUND: When diagnosing patients with bilateral breast cancer, it is challenging to determine the relationship between multiple breast cancer lesions at the individual patient level with certainty. CASE PRESENTATION: A 35-year-old Japanese woman was diagnosed with a left breast cancer. She was previously diagnosed with right pT3N3M0 stage IIIC breast cancer and underwent chemotherapy with targeted therapy, radiotherapy, and endocrine therapy as adjuvant treatment after mastectomy and axillary lymph node dissection. Approximately 2 years after the first surgery, her left breast cancer was preoperatively diagnosed as a contralateral primary breast cancer, and left mastectomy and axillary lymph node dissection were performed. Histopathologically, the tumor was determined to be invasive ductal carcinoma accompanied with several intraductal components. After a second surgery, mutation analysis of her bilateral breast cancer was performed in a clinical study, which revealed that her metachronous bilateral breast tumors had the same GATA3 and CSMD1 mutations. Thus, mutation analysis strongly supported her latter left breast cancer being a metastatic lesion from the former right breast cancer. Some difficulties in diagnosing bilateral breast cancer exist when determining whether they are double primary cancers or represent contralateral breast metastasis. The existence of intraductal components is a critical piece of information for suspecting primary lesions. However, this case demonstrated that metastatic contralateral breast lesions can have intraductal components. CONCLUSION: Herein we report a genetically proven contralateral breast metastasis with some intraductal components.

Oncoplastic breast surgery combining partial mastectomy with a triangular skin resection and re-centralization of the nipple-areola.

The treatment of early breast cancer using breast conservation therapy (BCT) commonly ensures local control and acceptable cosmetic results. We herein report a useful technique to obtain symmetry of the breast shape and a level inframammary line and nipple-areola, which achieved excellent results. Six Japanese patients with early breast cancer located on the upper area of the breast were enrolled into this study. A triangle-shaped area of skin was removed together with cancerous and healthy-surrounding breast tissue. Two crescents were designed and de-epithelialized in the directions of 9 o'clock and 3 o'clock. The width of the crescent was decided to be the same as a half or the length of the base of a triangle to be removed. After partial mastectomy, the inner and outer glandular flaps were horizontally sutured. The operations were simple to perform and were not associated with any postoperative complications. Oncoplastic breast surgery combining partial mastectomy with triangular skin resection and re-centralization of the nipple-areola was useful for patients with breast cancer on the upper quadrant area of non-ptotic breasts.

FARP1 boosts CDC42 activity from integrin αvß5 signaling and correlates with poor prognosis of advanced gastric cancer.

Considering the poor prognosis of most advanced cancers, prevention of invasion and metastasis is essential for disease control. Ras homologous (Rho) guanine exchange factors (GEFs) and their signaling cascade could be potential therapeutic targets in advanced cancers. We conducted in silico analyses of The Cancer Genome Atlas expression data to identify candidate Rho-GEF genes showing aberrant expression in advanced gastric cancer and found FERM, Rho/ArhGEF, and pleckstrin domain protein 1 (FARP1) expression is related to poor prognosis. Analyses in 91 clinical advanced gastric cancers of the relationship of prognosis and pathological factors with immunohistochemical expression of FARP1 indicated that high expression of FARP1 is significantly associated with lymphatic invasion, lymph metastasis, and poor prognosis of the patients (P = 0.025). In gastric cancer cells, FARP1 knockdown decreased cell motility, whereas FARP1 overexpression promoted cell motility and filopodium formation via CDC42 activation. FARP1 interacted with integrin ß5, and a potent integrin αvß5 inhibitor (SB273005) prevented cell motility in only high FARP1-expressing gastric cancer cells. These results suggest that the integrin αvß5-FARP1-CDC42 axis plays a crucial role in gastric cancer cell migration and invasion. Thus, regulatory cascade upstream of Rho can be a specific and promising target of advanced cancer treatment.

RNA-sequence-based microRNA expression signature in breast cancer: tumor-suppressive miR-101-5p regulates molecular pathogenesis.

Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA-dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA-sequencing of breast cancer (BrCa) clinical specimens to identify tumor-suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor-suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre-miRNA were downregulated in BrCa tissues (e.g. miR-99a-5p/-3p, miR-101-5p/-3p, miR-126-5p/-3p, miR-143-5p/-3p, and miR-144-5p/-3p). Among these miRNA, we focused on miR-101-5p, the passenger strand of pre-miR-101, and investigated its tumor-suppressive roles and oncogenic targets in BrCa cells. Low expression of miR-101-5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR-101-5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine-Rich Splicing Factor Kinase 1, Vang-like protein 1, and Mago Homolog B) regulated by miR-101-5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor-suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

The Japanese Breast Cancer Society clinical practice guidelines for surgical treatment of breast cancer, 2018 edition.

We have prepared the Japanese Breast Cancer Society clinical practice guidelines (CPGs) for surgical treatment of breast cancer, 2018 update after a systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. The CPG committee for surgical treatment of breast cancer, composed of breast surgeons and plastic surgeons treating breast cancer, has developed the CPGs. Eight clinical questions (CQs) were selected and divided roughly into the following five categories: (1) breast surgery in initial therapy (CQs 1-3); (2) axillary surgery in initial therapy (CQs 4-5); (3) breast reconstruction in initial therapy (CQ 6); (4) surgical treatment for recurrent and metastatic breast cancer (CQs 7-8); and (5) others. Recommendations for these CQs were decided by the GRADE grid method. In addition, 4 outlines, 14 background questions (BQs), and 12 future research questions (FQs) were also selected. Statements for these BQs and FQs are provided. We developed the updated CPGs for surgical treatment of breast cancer, 2018, which include 8 CQs and recommendations. As a decision-making tool for the understanding and treatment of breast cancer, these guidelines will help surgical oncologists dealing with breast cancer, medical staff, and patients, along with their family members.

Clinical Features of Breast Cancer Patients with Human T-Cell Lymphotropic Virus Type-1 Infection.

Background: Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes adult T-cell leukemia/lymphoma (ATL), an aggressive form of T-cell malignancy. The relationship between HTLV-1 infection and cancer progression is controversial. HTLV-1 encodes oncogenic protein TAX1 and it is hypothesized that HTLV-1 infection is associated with breast cancer progression. In this study, we evaluated the relationship between HTLV-1 infection and clinicopathological factors in breast cancer patients. Methods: We retrospectively analyzed 610 patients with primary breast cancer who underwent surgical treatment without preoperative chemotherapy at Kagoshima University Hospital between January 2001 and January 2015. Results: When patients with and without HTLV-1 infection were compared, no differences in clinicopathological factors were observed, except for age. Disease-free survival and overall survival rates did not differ between groups. Conclusions: HTLV-1­positive patients were significantly older than HTLV-1­negative patients. It was supposed to be due to the fact that the HTLV-1 infection rate is decreasing. Any effect of HTLV-1 infection on breast cancer progression appears to be negligibly small.

Oncoplastic breast surgery combining partial mastectomy with immediate breast reshaping using multiple local flaps for a patient with slim body.

Oncoplastic breast surgery (OBS), which combines the concepts of oncologic and plastic surgery, is becoming more common worldwide. We report the results of OBS in a Japanese patient with early breast cancer located on the outer lower quadrant area. We performed OBS combining partial mastectomy with immediate breast reshaping using multiple adipofascial cutaneous flaps and free dermal fat graft because she refused any other OBS. We selected three local flaps to repair the defect. Perioperative and postoperative complications were not seen. The cosmetic findings 3 years after surgery were not excellent, but the patient was satisfied with the results. OBS combining partial mastectomy with immediate breast reshaping using a combination of several flaps was successfully performed in a patient with early breast cancer.

Significance of 18F-Fluorodeoxyglucose (FDG) Uptake in Response to Chemoradiotherapy for Pancreatic Cancer.

BACKGROUND: A metabolic shift to glycolysis is reportedly involved in radioresistance. We examined whether pretreatment 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), which can detect enhanced glucose uptake, was able to predict the therapeutic response to chemoradiotherapy (CRT) in patients with pancreatic cancer (PC). METHODS: Of 125 PC patients (75 unresectable and 50 borderline resectable), 37 and 26 underwent induction chemotherapy before CRT and surgical resection after CRT, respectively. FDG-PET was performed at three different institutions. RESULTS: Of the 88 patients who underwent upfront CRT, 31 (35%), 34 (39%), and 23 (26%) showed a partial response (PR), stable disease, and progressive disease, respectively. The tumor PR rate was an independent factor associated with longer overall survival (OS) on multivariate analysis. We evaluated the optimal cut-off of maximum standardized uptake values (SUVmax) at initial diagnosis to detect the tumor PR rate at the three institutions separately. The SUVmax was independently associated with tumor response rate on multivariate analysis. In the low SUVmax group, induction chemotherapy had no significant impact on OS. In contrast, induction chemotherapy was significantly associated with longer OS in the high SUVmax group. CONCLUSIONS: FDG-PET SUVmax was significantly associated with the therapeutic response to CRT in PC patients. Moreover, induction chemotherapy may improve the prognosis of patients with a high SUVmax tumor.