[Analgesic Effects of Mirogabalin for Cancer Pain].

Mirogabalin is a novel drug for alleviating peripheral neuropathic pain, available since April 2019 in Japan. Since cancer pain was not included as an outcome in clinical trials for product approval, there have been no reports on its effectiveness or safety for treating cancer pain. The purpose of this study was to evaluate the effectiveness and safety of mirogabalin for patients with cancer pain. During the 5 months from April to August 2019, our palliative care team prescribed mirogabalin to 34 patients who had not achieved effective analgesia even after opioid titration. Effectiveness was defined as(1)reduction in persistent pain of 50% or more on the numeric rating scale(NRS); or(2)reduction in the frequency of rescue medicine of 50% or more for breakthrough pain. Based on this definition, the rate of effectiveness of mirogabalin was 88.2%. Two patients experienced mild side effects in the central nervous system. However, these effects did not result in discontinuation of the medication. The results of the study showed that mirogabalin can be used effectively and safely for cancer pain relief.

Prevalence and Risk Factors of Urinary Incontinence and Overactive Bladder in Japanese Women.

OBJECTIVES: The prevalence of storage symptoms, including stress urinary incontinence (SUI) and overactive bladder (OAB), is high in women worldwide. In Japan, there have been few large-scale epidemiological surveys of lower urinary tract symptoms (LUTS), and the risk factors for these symptoms are unclear. The aim of this study was to explore the prevalence and risk factors of storage symptoms in Japanese women. METHODS: A cross-sectional Internet survey was conducted in Japan. Five thousand women aged 20-79 years were selected to answer demographic questionnaires, Japanese version of International Consultation on Incontinence Questionnaire-Short Form, and the Overactive Bladder Symptom Score (OABSS) pertaining to their symptoms in the previous month. Descriptive statistics were used to evaluate the prevalence of storage symptoms. Logistic regression analysis was performed to determine risk factors for SUI and OAB. RESULTS: The answers from 4804 women (average age, 40.4 years) were analyzed. The prevalence of SUI was 16.7% (SUI, 13.0%; mixed urinary incontinence, 3.7%). The prevalence of OAB diagnosed on OABSS was 8.1%. The prevalence of SUI and OAB symptoms increased with age, and 68.0% of women had one or more storage symptoms. Age ≥40 years, body mass index ≥25 kg/m2 , and constipation were common risk factors for SUI and OAB. Childbirth was an additional risk factor for SUI. CONCLUSIONS: The prevalence of storage symptoms in Japanese women was high, and risk factors associated with these symptoms were similar to those reported in studies in other countries.

[Persistent Chemotherapy-Induced Hiccups Successfully Treated with Pregabalin].

A 62-year-old male was diagnosed with large cell lung cancer(c-Stage IV)based on pathological examination of an anterior chest tumor. He received chemotherapy with cisplatin, pemetrexed, and bevacizumab. He suffered from persistent hiccups from day 2 of the first course of chemotherapy. He was unsuccessfully treated with chlorpromazine, shakuyakukanzoto, and gabapentin. Therefore, we administered pregabalin to him, and his hiccups subsided immediately. To prevent hiccups, he subsequently took pregabalin along with his chemotherapy regimen, and was able to receive 4 courses of chemotherapy without persistent hiccups. Pregabalin is a possible therapeutic option for treating persistent chemotherapy-induced hiccups.

Estrogen response element-GFP (ERE-GFP) introduced MCF-7 cells demonstrated the coexistence of multiple estrogen-deprivation resistant mechanisms.

The acquisition of estrogen-deprivation resistance and estrogen receptor (ER) signal-independence in ER-positive breast cancer is one of the crucial steps in advancing the aggressiveness of breast cancer; however, this has not yet been elucidated in detail. To address this issue, we established several estrogen-deprivation-resistant (EDR) breast cancer cell lines from our unique MCF-7 cells, which had been stably transfected with an ERE-GFP reporter plasmid. Three cell lines with high ER activity and another 3 cell lines with no ER activity were established from cell cloning by monitoring GFP expression in living cells. The former three ERE-GFP-positive EDR cell lines showed the overexpression of ER and high expression of several ER-target genes. Further analysis of intracellular signaling factors revealed a marked change in the phosphorylation status of ERα on Ser167 and Akt on Thr308 by similar mechanisms reported previously; however, we could not find any changes in MAP-kinase factors. Comprehensive phospho-proteomic analysis also indicated the possible contribution of the Akt pathway to the phosphorylation of ERα. On the other hand, constitutive activation of c-Jun N-terminal kinase (JNK) was observed in ERE-GFP-negative EDR cells, and the growth of these cells was inhibited by a JNK inhibitor. An IGF1R-specific inhibitor diminished the phosphorylation of JNK, which suggested that a novel signaling pathway, IGF1R-JNK, may be important for the proliferation of ER-independent MCF-7 cells. These results indicate that ER-positive breast cancer cells can acquire resistance by more than two mechanisms at a time, which suggests that multiple mechanisms may occur simultaneously. This finding also implies that breast cancers with different resistance mechanisms can concomitantly occur and mingle in an individual patient, and may be a cause of the recurrence of cancer.

Femoral tunneled central venous catheters for terminally ill patients with cancer.

BACKGROUND: Oral administration of medication is often difficult in terminally ill patients with cancer. These patients require intravenous routes for high-dose opioid administration and/or parenteral nutrition. When the superior vena cava (SVC) is unsuitable for central vein catheter insertion (i.e., in patients with mediastinal masses involving the SVC), alternative access routes are needed. Of these, the femoral vein is most utilized. In our experience, the femoral tunneled catheter (FTC) is easy and safe to use. We retrospectively studied FTC outcomes in terminally ill patients with cancer. MATERIALS AND METHODS: Charts of consecutive patients admitted to the palliative care unit between April 2008 and December 2011 were reviewed. FTC is inserted into the vein by the single-puncture method using a 16-gauge catheter with a 14-gauge peel-away introducer. RESULTS: Eleven patients underwent FTC insertion. In total, there were 207 days of FTC placement; the mean period in place was 19±15 days. Eight patients received parenteral opioid therapy, high doses in four cases, via FTCs. Complications were incidental arterial puncture and poor infusion rate due to hip joint bending in one case each. Neither catheter-related infection nor clinical venous thrombosis occurred. CONCLUSIONS: FTCs were successfully inserted, with a low complication rate. FTC, a simple technique, might be an acceptable alternative in selected terminally ill patients with cancer, when SVC insertion is difficult or contraindicated.

Synthesis and biological evaluation of truncated α-galactosylceramide derivatives focusing on cytokine induction profile.

A series of truncated analogs of α-galactosylceramide with altered ceramide moiety was prepared, and evaluated for Th2-biased response in the context of IL-4/IFN-γ ratio. Phytosphingosine-modified analogs including cyclic, aromatic and ethereal compounds as well as the C-glycoside analog of OCH (2) with their cytokine inducing profile are disclosed.

Color auto-fluorescence from cancer lesions: improved detection of central type lung cancer.

A fluorescence endoscopic system, PDS-2000, enabled observation of color auto-fluorescence from the human body. We performed a clinical study to determine whether color auto-fluorescence bronchoscopy using PDS-2000 improved the accuracy of central type lung cancer diagnosis, as compared to white light bronchoscopy. White light bronchoscopy followed by auto-fluorescence bronchoscopy was performed in 71 subjects with either bronchogenic cancer, previous lung cancer, bloody sputum or who were at a high risk of developing lung cancer. Findings of white light bronchoscopy and auto-fluorescence bronchoscopy were classified into three categories. Two hundred eighty-eight biopsy specimens were taken from all sites which were considered to be abnormal by white light bronchoscopy as well as by auto-fluorescence bronchoscopy. The pathological findings were classified into nine categories. The sensitivity of only white light bronchoscopy (WLB) regarding the detection of severe dysplasia and cancer was compared with that of only auto-fluorescence bronchoscopy (AFB) and that of WLB+AFB. We quantified color endoscopic fluorescence images and compared the red/green signal intensity ratio (R/G ratio) according to the pathological diagnosis. The pathological diagnosis was normal in 123, inflammation, hyperplasia or metaplasia in 120, mild or moderate dysplasia in 8, severe dysplasia in 14 and cancer in 23. The sensitivity of WLB, AFB and WLB+AFB regarding the detection of severe dysplasia or cancer was 54.1%, 81.1% and 89.2%, respectively. The R/G ratio was significantly increased in the areas with severe dysplasia and cancer.

Minimum structure requirement of immunomodulatory glycolipids for predominant Th2 cytokine induction and the discovery of non-linear phytosphingosine analogs.

Analogs of immunomodulatory glycolipid OCH (2) were prepared and minimum structure requirement to exhibit equivalent profiles was disclosed. Analogs bearing non-linear hydrocarbon chain in the phytosphingosine moiety (18, 19) were shown for the first time to possess comparable cytokine inducing profile to 2. Molecular modeling of 2/hCD1d complex based on the crystal structure of alpha-GalCer (1)/hCD1d complex is also described.

Total synthesis of an immunosuppressive glycolipid, (2S,3S,4R)-1-O- (alpha-d-galactosyl)-2- tetracosanoylamino-1,3,4-nonanetriol.

[reaction: see text] A practical and efficient total synthesis of (2S,3S,4R)-1-O-(alpha-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonanetriol, OCH 1b, a potential therapeutic candidate for Th1-mediated autoimmune diseases, is described. The synthesis incorporates direct alkylation onto epoxide 5 and stereospecific halide ion catalyzed alpha-glycosidation reaction. A key intermediate 10 was obtained in only eight steps and 37% overall yield from commercially available d-arabitol 2, and the total synthesis of 1b was accomplished in 12 steps and 19% overall yield. This method will enable the synthesis of a variety of phytosphingolipids, especially that with the shorter sphingosine side chain than 1a, in a highly stereoselective manner.

Small cell lung cancer cells express EGFR and tyrosine phosphorylation of EGFR is inhibited by gefitinib ("Iressa", ZD1839).

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib ("Iressa", ZD1839) has demonstrated anti-tumor activity in non-small cell lung cancer (NSCLC) and has been approved in over 20 countries. NSCLC has been reported to express high levels of EGFR. However, gefitinib appears to be more effective against adenocarcinoma than squamous cell carcinoma, the latter expressing more EGFR. In the present study, we evaluated the effect of gefitinib against the small cell lung cancer (SCLC) cell lines NCI-H82, NCI-H209, NCI-H510, NCI-H526 and NCI-H660. SCLC has been reported to express a low to undetectable level of EGFR. We compared the effects of gefitinib between cell lines with detectable and undetectable EGFR expression. First, we evaluated expression levels of EGFR and HER2/neu by Western blotting and immunoprecipitation respectively; EGFR protein was detected in two of the five SCLC cell lines, whereas HER2/neu was not detected in any. Next, we analyzed expression levels of phosphorylated ERK1/2 and compared these results with EGFR (HER-1/ErbB1) and HER2/neu (ErbB2) expression levels, as EGFR conducts signals through Ras-Raf-MAPK pathway; gefitinib inhibited phosphorylation of ERK1/2 by EGF addition in cell lines with detectable and undetectable EGFR expression. These data suggest that gefitinib is potentially effective against cancers with low EGFR expression such as SCLC.

Human small cell lung cancer cells express functional VEGF receptors, VEGFR-2 and VEGFR-3.

Studies have suggested that the vascular endothelial growth factors (VEGFs)/VEGF receptors (VEGF-Rs) system plays an important role in tumour growth and metastasis. We conducted the present study to clarify whether small cell lung cancer (SCLC) cells express functional VEGF-Rs and VEGFs, and their biological significance in the SCLC progression. We examined expression of VEGF and VEGF-C, and their receptors, VEGFR-2 and VEGFR-3, in five SCLC cell lines, NCI-H82, H209, H510, H526 and H660, by Western blotting. We evaluated whether hypoxic conditions up-regulate these protein expressions. We also examined whether VEGF addition and VEGF-D addition cause phosphorylation of the mitogen-activated protein kinase (MAPK) as well as VEGFR-2 and VEGFR-3. Further, we investigated whether VEGF addition and VEGF-D addition induced the proliferation and migration of the SCLC cells. VEGF, VEGF-C, VEGFR-2 and VEGFR-3 were detectable by Western blotting in all five SCLC cell lines,. The VEGF-Rs and VEGFs expression levels were increased by an incubation under hypoxic conditions in NCI-H82. VEGF addition and VEGF-D addition caused phosphorylation of MAPK as well as the VEGF-Rs themselves, and induced proliferation and migration of the SCLC cells. These results suggested potential of VEGF signal-pathway inhibitors as anti-cancer agents in SCLC treatment disturbing growth and migration of the cancer cells.

Alterations in penicillin binding protein gene of Streptococcus pneumoniae and their correlation with susceptibility patterns.

Penicillin binding protein (pbp) gene alterations of 328 clinical isolates of Streptococcus pneumoniae were examined for a correlation with their antibiotic-resistance. The frequency of penicillin G (PEN-G) resistance was determined to clarify susceptibility to several antibiotics, namely PEN-G, ampicillin, sulbactam/ampicillin, cefozopram, panipenem (PAPM), clarithromycin (CLR), azithromycin (AZM) and levofloxacin (LVX). Oligonucleotide primers for three pbp genes (pbp1a, pbp2x and pbp2b) were used to detect mutations in pbp. Of the strains, 25.9% were classified as Pen-Gs, 68.0% as Pen-Gir and 6.1% as Pen-Gr. The polymerase chain reaction product for wild-type pbp1a was found in 185 isolates, that for wild-type pbp2x was found in 66 isolates and that for wild-type pbp2b was found in 213 isolates. None of these three genes was detectable in 100 isolates while all of them were detected in 64 isolates (1aw/2xw/2bw). Of those 64 isolates with 1aw/2xw/2bw, the minimum inhibitory concentration (MIC) of PEN-G was < or =0.06 mg/l for 54 isolates and 0.12 mg/l for 10 isolates. Of the 272 strains for which the MIC of PAPM was < or =0.03 mg/l, there were 85 Pen-Gs, 184 Pen-Gir and three Pen-Gr isolates. Three strains for which the MIC of LVX was > or =4.0 mg/l included one Pen-Gs and two Pen-Gir isolates. The MICs of CLR correlated significantly with those of AZM. The MIC of CLR was > or =1 mg/l for 216 isolates, and the MIC of AZM was > or =1 mg/l for 244 of them. These data suggested that PAPM may be effective against S. pneumoniae infection, although acquisition of resistance should be considered. LVX also seemed to be effective against S. pneumoniae.

[A case of pulmonary hamartoma and sclerosing hemangioma in the same lung].

A 49-year-old woman was referred to our hospital because abnormal masses had been found in the left lung on chest radiography. This examination and CT scanning on admission both revealed a 12 x 8 mm mass in the left S5 and a 31 x 25 mm mass in the left S8. Calcification was not found in the tumors. Bronchoscopy showed narrowing of the left B5 and B8 bronchi by irregularity of the mucous membrane. No malignant cells were found in the cytological specimens, which were obtained by brushing and washing of the bronchi. Although the radiological findings suggested benign tumors, surgical resection was performed to confirm the diagnosis. The tumor in the left S5 was diagnosed as a hamartoma because it contained cartilage, lipoid tissue and lymphatic follicles. The tumor in the left S8 was diagnosed as a sclerosing hemangioma because vasculo-capillary formation by the cells with epithelial origin was seen. The pathological diagnosis of the two tumors differed, but a similar mechanism of tumorigenesis was suggested.

Synthesis and biological evaluation of new 4-arylpiperidines and 4-aryl-4-piperidinols: dual Na(+) and Ca(2+) channel blockers with reduced affinity for dopamine D(2) receptors.

A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a-f and 4a-f) was synthesized and evaluated for blocking effects on both neuronal Na(+) and T-type Ca(2+) channels and binding affinity for dopamine D(2) receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D(2) receptors which is common in this class of structure. Compounds 2a-f, 3a-f and 4a-f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO model but only 1/20 the affinity for dopamine D(2) receptors of 1a. The superposition of 2a, 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D(2) receptors since only biphenyl compounds such as 2f had high affinity similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases.