A case of primary breast angiosarcoma with multiple discontinuous small lesions.

BACKGROUND: Angiosarcoma of the breast is rare. It carries a poor prognosis because of its high risk of local recurrence and distant metastases. Presently, there are still no established systemic therapies. Thus, the main treatment strategy for breast angiosarcoma is complete resection. This underscores the importance of closely monitoring the spread of the tumor lesion, particularly for multifocal angiosarcoma, and to plan an optimal operative procedure. We herein present the successful surgical treatment of a rare case of multifocal primary breast angiosarcoma. CASE PRESENTATION: A 43-year-old woman visited our hospital with a growing lump on her right breast accompanied by pain. Clinical and radiological examinations revealed a well-circumscribed 40-mm-diameter tumor at the inner lower quadrant of her right breast. Histological examination of a needle biopsy specimen revealed angiosarcoma. Based on a precise evaluation of the tumor by contrast-enhanced MRI and contrast-enhanced CT scan, a wide local excision with sufficient margins was performed. In the resected specimen, three discontinuous small lesions of angiosarcoma were observed around the main tumor. Therefore, total mastectomy was additionally performed. Pathological examination revealed two other small nodules of angiosarcoma in the remnant right breast, which appeared to be close but not continuous to the defective part of the initial resection. Postoperative follow-up at 1 year showed no signs of recurrence or distant metastasis. Multifocal primary breast angiosarcoma is extremely rare with only two previous reports describing its multifocality. CONCLUSIONS: Owing to its rarity, a standardized surgical treatment for breast angiosarcoma remains controversial. Our case suggests that primary breast angiosarcoma may occasionally present with multifocal tumor. Thus, it is important to keep in mind the multifocality of breast angiosarcoma when assessing its spread by diagnostic imaging and when planning the surgical strategy.

Cinacalcet corrects biased allosteric modulation of CaSR by AHH autoantibody.

Biased agonism is a paradigm that may explain the selective activation of a signaling pathway via a GPCR that activates multiple signals. The autoantibody-induced inactivation of the calcium-sensing receptor (CaSR) causes acquired hypocalciuric hypercalcemia (AHH). Here, we describe an instructive case of AHH in which severe hypercalcemia was accompanied by an increased CaSR antibody titer. These autoantibodies operated as biased allosteric modulators of CaSR by targeting its Venus flytrap domain near the Ca2+-binding site. A positive allosteric modulator of CaSR, cinacalcet, which targets its transmembrane domain, overcame this autoantibody effect and successfully corrected the hypercalcemia in this patient. Hence, this is the first study to our knowledge that identifies the interaction site of a disease-causing GPCR autoantibody working as its biased allosteric modulator and demonstrates that cinacalcet can correct the AHH autoantibody effects both in vitro and in our AHH patient. Our observations provide potentially new insights into how biased agonism works and how to design a biased allosteric modulator of a GPCR. Our observations also indicate that the diagnosis of AHH is important because the severity of hypercalcemia may become fatal if the autoantibody titer increases. Calcimimetics may serve as good treatment options for some patients with severe AHH.

A multicenter, observational study of metastatic breast cancer patients who were treated with eribulin mesylate or taxane-based regimens.

AIM: This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting. METHODS: This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post-progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics. RESULTS: In total, 216 patients receiving eribulin monotherapy (n = 101), taxane monotherapy (n = 73) or taxane plus bevacizumab (n = 42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events. CONCLUSION: In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports.

Serum TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Breast cancer remains a common malignancy in women, but the take-up for breast cancer screening programs in Japan is still low, possibly due to its perceived inconvenience. TFF1 and TFF3 are expressed in both breast cancer tissue and normal breast. Serum trefoil proteins were reported as cancer screening markers for gastric, prostate, lung, pancreatic cancer and cholangio carcinoma. The purpose of this study was to examine whether serum trefoil proteins could be screening biomarkers for breast cancer. Serum trefoil proteins in 94 breast cancer patients and 84 health check females were measured by ELISA. Serum TFF1 and TFF3 were significantly higher and serum TFF2 was significantly lower in breast cancer patients. Area under the curve of receiver operating characteristic of TFF1, TFF2, and TFF3 was 0.69, 0.83, and. 0.72, respectively. AUC of the combination of TFF1, TFF2, and TFF3 was 0.96. Immunohistochemically, TFF1 expression was positive in 56.5% and TFF3 was positive in 73.9% of breast cancers, while TFF2 was negative in all tumors. Serum TFF1 had positive correlation with expression of TFF1 in breast cancer tissue. Serum concentrations of TFF1 and TFF3 but not TFF2 are higher in women with breast cancer than in women without breast cancer.

Post-mastectomy radiation therapy in breast cancer with 1-3 involved lymph nodes: the Pros.

In 2014, the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) reported that post-mastectomy radiation therapy (PMRT) for breast cancer patients with 1-3 cancer-positive lymph nodes is associated with a survival benefit. However, it is not known whether this applies to Japanese patients in daily clinical practice, because this conclusion was based on the results of older, western trials. Therefore, we studied the differences between PMRT results in western breast cancer patients and current practice in Japanese patients. Although we identified three differences, they do not appear to strongly impact the results of EBCTCG. We conclude that Japanese breast cancer patients with 1-3 positive lymph nodes should receive PMRT in daily clinical practice.

Intratumoral bidirectional transitions between epithelial and mesenchymal cells in triple-negative breast cancer.

Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition MET, are crucial in several stages of cancer metastasis. Epithelial-mesenchymal transition allows cancer cells to move to proximal blood vessels for intravasation. However, because EMT and MET processes are dynamic, mesenchymal cancer cells are likely to undergo MET transiently and subsequently re-undergo EMT to restart the metastatic process. Therefore, spatiotemporally coordinated mutual regulation between EMT and MET could occur during metastasis. To elucidate such regulation, we chose HCC38, a human triple-negative breast cancer cell line, because HCC38 is composed of epithelial and mesenchymal populations at a fixed ratio even though mesenchymal cells proliferate significantly more slowly than epithelial cells. We purified epithelial and mesenchymal cells from Venus-labeled and unlabeled HCC38 cells and mixed them at various ratios to follow EMT and MET. Using this system, we found that the efficiency of EMT is approximately an order of magnitude higher than that of MET and that the two populations significantly enhance the transition of cells from the other population to their own. In addition, knockdown of Zinc finger E-box-binding homeobox 1 (ZEB1) or Zinc finger protein SNAI2 (SLUG) significantly suppressed EMT but promoted partial MET, indicating that ZEB1 and SLUG are crucial to EMT and MET. We also show that primary breast cancer cells underwent EMT that correlated with changes in expression profiles of genes determining EMT status and breast cancer subtype. These changes were very similar to those observed in EMT in HCC38 cells. Consequently, we propose HCC38 as a suitable model to analyze EMT-MET dynamics that could affect the development of triple-negative breast cancer.

Virtual Touch tissue quantification cannot assess breast cancer lesions except for ductal carcinomas in situ and small invasive cancers: a retrospective study.

BACKGROUND: Virtual Touch tissue quantification (VTTQ) is a promising new technology that quantitatively determines the stiffness of tissue. However, the clinical impact of this device on the assessment of breast cancer is unclear. METHODS: This study aimed to review the ultrasound records of patients with breast lesions where VTTQ was used to assess 123 normal breast tissues, 18 benign tumors, and 117 histopathologically confirmed breast cancers in a total of 129 patients. To determine the VTTQ value, a 5×5 mm region of interest was placed in the center of the area of interest, and the target lesion was measured at least three times by VTTQ. RESULTS: Seventy-six percent of the malignant lesions could not be assessed using VTTQ. Among the malignant lesions, ductal carcinomas in situ (DCIS) and invasive breast cancers smaller than 1.6 cm tended to be 'measurable.' Only 17 and 1% of benign breast lesions and areas of normal breast tissue, respectively, were considered to be 'unmeasurable' (P<0.001). CONCLUSIONS: A breast lesion that could not be quantitatively assessed by VTTQ was suspicious for malignancy. By contrast, DCIS lesions and small invasive breast cancers tended to be 'measurable.' These findings indicate that VTTQ may be a useful application for assessing breast tumors.

Aberrantly methylated genes in human papillary thyroid cancer and their association with BRAF/RAS mutation.

Cancer arises through accumulation of epigenetic and genetic alteration. Aberrant promoter methylation is a common epigenetic mechanism of gene silencing in cancer cells. We here performed genome-wide analysis of DNA methylation of promoter regions by Infinium HumanMethylation27 BeadChip, using 14 clinical papillary thyroid cancer samples and 10 normal thyroid samples. Among the 14 papillary cancer cases, 11 showed frequent aberrant methylation, but the other three cases showed no aberrant methylation at all. Distribution of the hypermethylation among cancer samples was non-random, which implied existence of a subset of preferentially methylated papillary thyroid cancer. Among 25 frequently methylated genes, methylation status of six genes (HIST1H3J, POU4F2, SHOX2, PHKG2, TLX3, HOXA7) was validated quantitatively by pyrosequencing. Epigenetic silencing of these genes in methylated papillary thyroid cancer cell lines was confirmed by gene re-expression following treatment with 5-aza-2'-deoxycytidine and trichostatin A, and detected by real-time RT-PCR. Methylation of these six genes was validated by analysis of additional 20 papillary thyroid cancer and 10 normal samples. Among the 34 cancer samples in total, 26 cancer samples with preferential methylation were significantly associated with mutation of BRAF/RAS oncogene (P = 0.04, Fisher's exact test). Thus, we identified new genes with frequent epigenetic hypermethylation in papillary thyroid cancer, two subsets of either preferentially methylated or hardly methylated papillary thyroid cancer, with a concomitant occurrence of oncogene mutation and gene methylation. These hypermethylated genes may constitute potential biomarkers for papillary thyroid cancer.

Classification of Epstein-Barr virus-positive gastric cancers by definition of DNA methylation epigenotypes.

Epstein-Barr virus (EBV) is associated with Burkitt lymphoma, nasopharyngeal carcinoma, opportunistic lymphomas in immunocompromised hosts, and a fraction of gastric cancers. Aberrant promoter methylation accompanies human gastric carcinogenesis, though the contribution of EBV to such somatic methylation changes has not been fully clarified. We analyzed promoter methylation in gastric cancer cases with Illumina's Infinium BeadArray and used hierarchical clustering analysis to classify gastric cancers into 3 subgroups: EBV(-)/low methylation, EBV(-)/high methylation, and EBV(+)/high methylation. The 3 epigenotypes were characterized by 3 groups of genes: genes methylated specifically in the EBV(+) tumors (e.g., CXXC4, TIMP2, and PLXND1), genes methylated both in EBV(+) and EBV(-)/high tumors (e.g., COL9A2, EYA1, and ZNF365), and genes methylated in all of the gastric cancers (e.g., AMPH, SORCS3, and AJAP1). Polycomb repressive complex (PRC) target genes in embryonic stem cells were significantly enriched among EBV(-)/high-methylation genes and commonly methylated gastric cancer genes (P = 2 × 10(-15) and 2 × 10(-34), respectively), but not among EBV(+) tumor-specific methylation genes (P = 0.2), suggesting a different cause for EBV(+)-associated de novo methylation. When recombinant EBV was introduced into the EBV(-)/low-methylation epigenotype gastric cancer cell, MKN7, 3 independently established subclones displayed increases in DNA methylation. The promoters targeted by methylation were mostly shared among the 3 subclones, and the new methylation changes caused gene repression. In summary, DNA methylation profiling classified gastric cancer into 3 epigenotypes, and EBV(+) gastric cancers showed distinct methylation patterns likely attributable to EBV infection.

Primary non-Hodgkin's lymphoma of the breast treated nonsurgically: report of three cases.

Extranodal non-Hodgkin's lymphoma (NHL) is a rare breast disease. Here we report three cases of primary NHL of the breast. The first patient was a 29-year-old woman with a firm mass in her right breast with ipsilateral axillary lymphadenopathy. An excisional biopsy revealed NHLs. Clinical stage was IIAE. The tumor and enlarged lymph nodes had successfully been treated following the combination therapy. The second patient was a 70-year-old women with an elastic hard mass in her left breast. An excisional biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following the combination therapy. The third patient was a 67-year-old women with a hard mass in her left breast. Core needle biopsy revealed NHLs and clinical stage was 1AE. The tumor disappeared following chemotherapy. All patients are alive with no evidence of recurrence 4-8 years after the initial treatment. Although a standard treatment has yet to be established, an initial treatment with combination therapy without surgical intervention including axillary dissection appears to be appropriate for this rare disease.

[Results of chemotherapy using new anti-cancer drugs since S-1 for advanced or recurrent gastric cancer in our institute].

In many medical institutes the treatment for advanced (not resectable or radical grade C) or recurrent gastric cancer seems to be based on a regional perspective or prognostic restriction, and rarely on large-scale clinical studies; instead the selection is based on effective cases reported in the literature or on own.s own. In the current situation, chemotherapy using new anti-cancer drugs since S-1 has actually appeared to improve the prognosis or to maintain better QOL. We examined 46 cases (28 advanced (not resectable or radical grade C) cases and 18 recurrent cases after curative operation) during the period from January 2001 to December 2005. In 27 chemotherapy cases (1-year survival 52.5%, 2-year survival 31.5%, 3-year survival 19.5%, and MST=344 day), the survival time was significantly extended compared to 19 cases without chemotherapy (1-year survival 10.5% and MST=102 day) (p<0.0001). In the 27 chemotherapy cases, between 5 performance status (PS) 0 cases and 8 PS 1 cases, there was no significant difference in survival. But in 12 PS 2 cases, survival was significantly shorter smaller than that of PS 0 or PS 1 cases (p<0.05, p<0.001). Also, the period in the hospital during survival time of 6 cases, 2-year survival or more, was significantly shorter than that of 10 less than 1-year survival cases treated with chemotherapy. These findings led us to conclude that chemotherapy using new anti-cancer drug since S-1 showed excellent QOL in addition to longer survival benefits at the present time, when a standard treatment for to advanced or recurrent gastric cancer has not yet been established. It seemed that prognostic improvement by maintaining further excellent QOL could be expected if standard treatments based on the results of large-scale clinical studies were established.

Encoding richness of self-generated elaboration and spacing effects on incidental memory.

The present study investigated encoding variability in self-generated elaboration on incidental memory as a function of the type of presentation which was either massed or spaced. The subjects generated different answers to a "why" question for the first and the second presentations of a target sentence in a self-generated elaboration condition. In an experimenter-provided elaboration condition they then rated the appropriateness of the different answers provided by the experimenter for the first and second presentations. This procedure was followed by two free recall tests, one of which was immediate and the other delayed. A self-generated elaboration effect was observed in both the spaced and the massed presentations. These results indicated that the self-generated elaboration effect was facilitated, even in the massed presentation because the different answers to the first and the second presentations led to a richer encoding of each target.

[A case of gastric cancer with liver invasion responding to TS-1/low-dose CDDP chemotherapy].

We report the case of a 79-year-old female with gastric cancer accompanied by liver invasion. She underwent simple subtotal gastrectomy in another hospital. Five months after surgery, combination chemotherapy with TS-1 (100 mg/body/day, 3 weeks) and CDDP (10 mg/body/day, day 1, 8, 15 drip infusion) in 1 course was performed, and complete response (CR) was noted. No severe adverse effects were observed during this combined therapy. TS-1 and low-dose CDDP therapy may prove effective for treating gastric cancer with liver invasion in advanced age.

Self-generated elaboration and spacing effects on incidental memory.

The purpose of the present study was to investigate the effect of self-generated elaboration on incidental memory as a function of type of presentation (massed vs spacing). Subjects generated answers to "why" questions for target sentences in a self-generated elaboration condition. They then rated the appropriateness of the answers to the questions presented by the experimenter in an experimenter-provided elaboration condition. This procedure was followed by free recall tests. The target sentences were presented twice, in either a massed presentation without intervening items between the first and the second presentation or spaced presentation in which 5 items appeared between the two presentations. The self-generated elaboration effect, namely, higher recall, of self-generated elaboration over experimenter-provided elaboration, occurred with spaced but not with massed presentation. So, self-generated elaboration was facilitated in the spaced presentation because the time between the first and the second presentations led to richer encoding of each target.