Efficacy of Mirogabalin for Taxane-associated Chemotherapy-induced Peripheral Neuropathy in Perioperative Chemotherapy for Early Breast Cancer.

BACKGROUND/AIM: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN. RESULTS: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects. CONCLUSION: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.

Characteristics of Patients With Metastatic Breast Cancer Who Survived more than 10 Years.

BACKGROUND/AIM: Despite advances in the treatment of breast cancer, metastatic breast cancer (MBC) remains difficult to cure, and few MBC patients survive 10 years after receiving a breast cancer metastasis diagnosis. We collected the cases of patients with MBC who survived >10 years post-metastasis diagnosis and assessed the patients' characteristics. PATIENTS AND METHODS: We retrospectively analyzed the cases of 245 consecutive patients diagnosed with MBC between January 2005 and December 2012 at our institution. Among them, 167 patients with confirmed survival of >10 years (i.e., long-term survival) or confirmed death at ≤10 years post-metastasis diagnosis were enrolled. RESULTS: There were 22 patients with MBC who survived >10 years. Regarding the cancer subtypes, 11 patients (50%) with long-term survival were HER2-positive. Seven of the 11 patients with HER2-positive MBC have been without recurrence although anti-HER2 therapy was discontinued. Triple-negative breast cancer (TNBC) was most common in the patients who survived ≤5 years but was not present in the >10-year survival group. In the HER2-negative cases, more cases in the long-term survival group were treated with local therapy (34.4% in the <5-year survival group, 43.8% in the 5-10-year group, and 72.7% in the >10-year group). CONCLUSION: MBC patients who survive >10 years after being diagnosed with metastasis are more likely to be HER2-positive and treated with local therapy. This suggests the efficacy of anti-HER2 therapy, and, conversely, clarifies unmet needs in TNBC and luminal-type MBC. The usefulness of local therapy was also supported by our findings.

Anxiety during pregnancy and autonomic nervous system activity: A longitudinal observational and cross-sectional study.

OBJECTIVES: To assess the longitudinal change in autonomic nervous system (ANS) activity during pregnancy and the association between anxiety during pregnancy and ANS activity. METHODS: Pregnant Japanese women with a singleton fetus and normal pregnancy were recruited (n=65). ANS activity and anxiety were measured using a self-rating questionnaire at approximately 20, 30, and 36weeks of gestation. Very low (VLF) and high (HF) frequency bands of heart rate variability spectrums were used. Anxiety was assessed using the Japanese version of the State-Trait Anxiety Inventory. A score of 45 or more on trait-anxiety and the other represent the trait-anxiety group and the non- trait-anxiety group, respectively. The state-anxiety group and the non-state-anxiety group were defined in the same manner. RESULTS: Longitudinal observation of individual pregnant women indicated the significant increasing trend (p=0.002) of VLF power and the significant decreasing trend (p<0.001) of HF power during 20 to 36 gestation weeks. Compared with the non-trait-anxiety group, the trait-anxiety group had significantly lower VLF values at 20 gestational weeks (p=0.033) and had significantly lower HF values at 30 and 36 gestational weeks (p=0.015 and p=0.044, respectively). The increasing rate of VLF from 20 to 36 gestational weeks was higher among the trait-anxiety group. The same associations were observed between the state-anxiety and non-state-anxiety groups at 20 gestational weeks. CONCLUSIONS: Anxiety during pregnancy decreased heart rate variability. Anxiety in second trimester pregnancy promoted a subsequent increase in sympathetic activity.

Learning disability in 10- to 16-year-old adolescents with very low birth weight in Japan.

In recent years, there has been an increase in the number of infants with very low birth weight (VLBW, i.e., weight less than 1,500 g) in Japan. However, the effect of VLBW on subsequent behavioral development and mental health remains unknown. Subjects enrolled were 57 individuals (13.4 ± 1.9 years old) with VLBW (VLBW group), including 23 small-for-gestational-age (SGA) infants (i.e., the SGA/VLBW group) and 34 appropriate-for-gestational-age (AGA) infants (the AGA/VLBW group). The control group was 29 individuals born AGA at term. We used the questionnaires, the Pupil Rating Scale Revised (PRS) to screen for learning disabilities and the Children's Depression Inventory (CDI) to examine the presence of depression. The PRS score in the VLBW group was significantly lower than that of the control group (p < 0.001). Suspected learning disabilities (LD, defined by a score below 65 points on the PRS) were found in 6 out of the 56 subjects in the VLBW group (10.7%), whereas none were found in the 29 control subjects (p = 0.074). The frequency of suspected LD children was higher in the SGA/VLBW group (4 out of 22 evaluated infants, 18.2%) than that in the AGA/VLBW group (2/34, 5.9%). The frequency of suspected LD in the non-verbal field was significantly higher (p = 0.02) in the SGA/VLBW group (18.2%) than in the AGA/VLBW group (0%). However, CDI score did not significantly differ between groups. These findings suggest that VLBW and fetal growth restriction may pose a risk for LD among adolescents with VLBW.

Association of women's birth weight with their blood pressure during pregnancy and with the body size of their babies.

The women's own intrauterine environment may influence their own pregnancy and their babies. The aim of our study was to investigate how a woman's birth weight affects the course of her pregnancy later in life as well as the body size of her babies; this study was based on the developmental origins of health and disease (DOHaD) concept. We collected Maternal and Child Health handbooks from 414 women and their biological mothers. They were classified into 3 categories based on the Fetal growth curve of Japan: light-for-date (LFD), which means birth weight is less than the -1.5SD; appropriate-for-date (AFD), which means it lies between the -1.5SD and +1.5SD; and heavy-for-date (HFD), which means it is in the +1.5SD, or higher. In the first trimester, systolic blood pressures (SBPs) were 117.6 (14.4 mmHg), 111.6 (12.4 mmHg), and 105.0 (11.6 mmHg), and diastolic blood pressures (DBP) were 71.0 (8.5 mmHg), 65.7 (9.4 mmHg), and 62.1 (8.7 mmHg) in women born LFD, AFD, and HFD, respectively (SBP: p for trend = 0.018, DBP: p for trend = 0.027). In the second and third trimesters, both SBP and DBP were higher for women born LFD than for those of the other 2 groups. Birth weights of the babies of women born LFD, AFD, and HFD were 2,791.1 (483.0 g), 3,043.4 (361.0 g), and 3,248.0 (431.5 g), respectively (p for trend < 0.01). Our findings support the DOHaD concept and suggest that intrauterine environment in fetal life may be passed down from generation to generation.

Overcoming hERG issues for brain-penetrating cathepsin S inhibitors: 2-cyanopyrimidines. Part 2.

We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K(+) channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain.

Discovery of orally bioavailable cathepsin S inhibitors for the reversal of neuropathic pain.

Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.

4-Amino-2-cyanopyrimidines: novel scaffold for nonpeptidic cathepsin S inhibitors.

We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine.

Discovery of selective and nonpeptidic cathepsin S inhibitors.

Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats.

Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins.

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrophin family, bind to and activate TrkA, TrkB and TrkC, respectively, members of the Trk receptor tyrosine kinase family, to exert various effects including promotion of differentiation and survival, and regulation of synaptic plasticity in neuronal cells. Many reports have suggested that different neurotrophins show distinct biological functions, although molecular mechanisms by which neurotrophins exert their different functions remain unclear. In the present study, we found distinct usages of phospholipase Cgamma (PLCgamma) and Shc in intracellular signaling stimulated by neurotrophins. BDNF stimulated much stronger interactions of PLCgamma with Trk than NGF and NT-3 in PC12 cells stably expressing TrkB and cultured cerebral cortical neurons, respectively, although BDNF, NGF and NT-3 induced similar levels of tyrosine phosphorylation of Trk. Furthermore, the cultured cortical neurons showed large PLCgamma-dependent increases in intracellular Ca(2+) levels in response to BDNF compared with NT-3. In Shc signaling, NGF, but not BDNF, displayed interactions between Trk and Shc in a phenylarsine oxide (PAO; an inhibitor of tyrosine phosphatase)-dependent manner in TrkB-expressing PC12 cells. These results indicated that neurotrophins stimulate distinct kinds of interactions between Trk and PLCgamma and between Trk and Shc. These differences may lead to the distinct biological functions of neurotrophins.