[Effective Neo-Adjuvant Chemotherapy and Hormonal Therapy for Invasive Micro-Papillary Carcinoma of the Breast-Two Case Reports].

Case 1 involved a 54-year-old woman with a complaint of a lump in the left breast since October. A diagnosis of invasive micropapillary carcinoma(IMPC)was made by core needle biopsy. The profile of the carcinoma was as follows: ER(Allred 8=5+3), PgR(Allred 8=5+3), HER2(1+), Ki-67 index 30%. The patient underwent 4 courses of EC(epirubicin 90mg/ m2, cyclophosphamide 600 mg/m2), followed by 4 courses of triweekly docetaxel and nab-paclitaxel chemotherapy. Bp+Ax was underwent in May 2013. Pathologically, no residual tumor was observed. Case 2 involved a 61-year-old woman with the chief complaint of a lump in the right breast, diagnosed as IMPC by core needle biopsy. The profile of the carcinoma was as follows: ER(Allred 8=5+3), PgR(Allred 0=0+0), HER2(1+), Ki-67 index 30%. Pre-operative treatment consisted of letrozole(2.5mg/day)from May 2013 and hormone therapy for 6 months. Bp+SNB was performed in November 2013. Histopathologically, no remnant of IMPC component was observed apart from an 11mm papillo-tubular carcinoma. In spite of the fact that IMPC is considered highly malignant, pre-operative chemotherapy and hormonal therapy may be effective.

[Two Cases of ER-Positive Postmenopausal Breast Cancer That Increased in Size during Neoadjuvant Hormone Therapy].

The first patient was a 62-year-old woman who was referred to our hospital with the complaint of a left breast tumor. She was diagnosed with invasive ductal carcinoma(T1N0M0, stage I). The tumor was ER-positive, PgR-negative, and HER2- negative. She was treated with toremifene, letrozole, and anastrozole as neoadjuvant hormone therapy for 4 months, but the tumor increased in size. The clinical response was judged as progressive disease, and a left partial mastectomy and axillary lymph node dissection were performed. Chemotherapy and radiotherapy were performed after surgery. The second patient was a 68-year-old woman who was referred to our hospital with the complaint of a right breast tumor. She was diagnosed as invasive ductal carcinoma(T1N0M0, stage I). The tumor was ER-positive, PgR-negative, and HER2-negative. She was treated with letrozole as neoadjuvant hormone therapy for 4 months, but the tumor increased in size. The clinical response was judged as progressive disease, and a right partial mastectomy and axillary lymph node dissection were performed. Chemotherapy and radiotherapy were performed after surgery. Although the evidence is still insufficient, with neoadjuvant hormone therapy for hormone-sensitive breast cancer, improved tumor shrinkage and breast conservation have been reported. We experienced two cases in which the tumor increased in size during neoadjuvant hormone therapy; however, even though these cases showed no apparent effect, chemotherapy may be effective in future cases.

Ca2+ influx does not trigger glucose-induced traffic of the insulin granules and alteration of their distribution.

This study investigated mechanisms by which glucose increases readily releasable secretory granules via acting on preexocytotic steps, i.e., intracellular granule movement and granule access to the plasma membrane using a pancreatic beta-cell line, MIN6. Glucose-induced activation of the movement occurred at a substimulatory concentration with regard to insulin output. Glucose activation of the movement was inhibited by pretreatment with thapsigargin plus acetylcholine to suppress intracellular Ca2+ mobilization. Inhibitors of calmodulin and myosin light chain kinase also suppressed glucose activation of the movement. Simultaneous addition of glucose with Ca2+ channel blockers or the ATP-sensitive K+ channel opener diazoxide failed to suppress the traffic activation, and addition of these substances on top of glucose stimulation resulted in a further increase. Although stimulatory glucose had minimal changes in the intracellular granule distribution, inhibition of Ca2+ influx revealed increases by glucose of the granules in the cell periphery. In contrast, high K+ depolarization decreased the peripheral granules. Glucose-induced granule margination was abolished when the protein kinase C activity was downregulated. These findings indicate that preexocytotic control of insulin release is regulated by distinct mechanisms from Ca2+ influx, which triggers insulin exocytosis. The nature of the regulation by glucose may explain a part of potentiating effects of the hexose independent of the closure of the ATP-sensitive K+ channel.

Calmodulin overexpression causes Ca(2+)-dependent apoptosis of pancreatic beta cells, which can be prevented by inhibition of nitric oxide synthase.

We investigated the mechanism of beta-cell loss in transgenic mice with elevated levels of beta cell calmodulin. The transgenic mice experienced a sudden rise in blood glucose levels between 21 and 28 days of age. This change was associated with development of severe hypoinsulinemia and loss of beta cells from the islets. Ultrastructural analysis revealed that compromised granule formation and apoptotic changes in the transgenic beta cells preceded the onset of hyperglycemia. Intraperitoneal injection of tolbutamide, an antidiabetic sulfonylurea, decreased blood glucose levels but increased the number of apoptotic beta cells. Finally, injection of transgenic mice with N(omega)-nitro-L-arginine methyl ester, which inhibits nitric oxide synthase activity, prevented hyperglycemia and lessened the changes in number and size of beta cells. Because immunofluorescent staining revealed preferential distribution of neural nitric oxide synthase in pancreatic beta cells, we speculate that overexpression of calmodulin sensitizes the beta cells to Ca(2+)-dependent activation of neural nitric oxide synthase, which mediates apoptosis.