A case of uterine adenomyoma of endocervical type that was suspected as minimal deviation adenocarcinoma on biopsy, MRI findings, and literature review.

Uterine adenomyomas of endocervical type are rare benign tumors of the uterine cervix commonly presented as cyst-like, dilated glandular structures within polypoid masses. A premenopausal woman in her 50s was referred to our hospital because of an increasing watery vaginal discharge. A multifocal cyst measuring 5 × 4.5 cm in size projecting into the endocervical canal was revealed on a contrast-enhanced MRI. The fluid within the tumor showed a hypointense signal on T1-weighted imaging (T1WI) and a hyperintense signal on T2-weighted imaging (T2WI). On T2WI, most of the septa within the tumor showed a slightly hyperintense to hypointense signal, whereas some areas revealed a strong hypointense signal; the contrast effect on the septum was satisfactory. On the T2WI taken 2 years previously, the tumor was a 4.5 × 3.5 cm polypoid mass protruding from the posterior endocervical wall. Contrastingly, the current T2WI showed that the stem was no longer identifiable because of tumor growth. Because previous imaging showed that the tumor was a stalked tumor protruding from the posterior endocervical wall, the imaging diagnosis was uterine adenomyoma of the endocervical type. A biopsy suggested the possibility of a minimal deviation adenocarcinoma (MDA). Hence, a total hysterectomy was performed. The final diagnosis confirmed the uterine adenomyoma of endocervical type. Uterine adenomyoma of the endocervical type might be difficult to differentiate from MDA in small biopsy specimens; therefore, evaluation of morphology by MRI is considered important in preoperative diagnosis.

Investigating the efficacy and safety of olanzapine prophylaxis for opioid-induced nausea and vomiting (JORTC-PAL20): a study protocol for an open-label, single-arm exploratory study.

INTRODUCTION: In opioid therapy for cancer pain, opioid-induced nausea and vomiting (OINV) occur in 20%-40% of patients during initial opioid treatment or increasing opioid doses. OINV result in failure to achieve pain relief due to poor opioid adherence. Therefore, antiemetics are used to prevent OINV, but their efficacy and safety in this context have not yet been fully elucidated. Olanzapine is a promising antiemetic for the prophylaxis of chemotherapy-induced nausea and vomiting. METHODS AND ANALYSIS: This single-arm, single-centre exploratory study will evaluate the prophylactic antiemetic efficacy and safety of 5 mg olanzapine in patients with cancer pain who are withholding initial regular opioid therapy. Thirty-five patients will be enrolled. The primary endpoint is the proportion of patients achieving complete control (CC) of OINV during 5 days of opioid treatment. CC was defined as the absence of emetic episodes, no need for rescue medication to treat nausea, and minimal or no nausea (3 or less on an 11-point categorical scale). Secondary endpoints include the complete response, defined as no emetic episodes and no use of rescue medication during the overall assessment period, the time from opioid initiation to first emetic episode, the time from opioid initiation to first rescue antiemetic administration, and adverse events graded by Patient-Reported Outcome (PRO) Common Terminology Criteria for Adverse Events (CTCAE) version 1.0 and CTCAE version 5.0. ETHICS AND DISSEMINATION: This study protocol was approved by National Cancer Center Hospital Certified Review Board. The results will be used as preliminary data to conduct a validation study. TRIAL REGISTRATION NUMBER: Japan Registry of Clinical Trials (jRCT) jRCTs031220008.

Malignancy-related ascites in palliative care units: prognostic factor analysis.

OBJECTIVES: The prognostic factors in patients with malignancy-related ascites (MA) have been poorly investigated. This study aimed to evaluate both the prognostic impact of MA on terminally ill patients with cancer and the prognostic factors in those with MA. METHODS: This was a post hoc analysis of a multicentre, prospective cohort study. Patients with advanced cancer admitted to palliative care units at 23 institutions and aged≥18 years were enrolled between January and December 2017. Overall survival (OS) was compared according to MA. A multivariate analysis was conducted to explore prognostic factors in patients with MA. RESULTS: Of 1896 eligible patients, gastrointestinal and hepatobiliary pancreatic cancers accounted for 42.5%. 568 (30.0%) of the total had MA. Patients with MA had significantly shorter OS than those without MA (median, 14 vs 22 days, respectively; HR, 1.55; 95% CI, 1.39 to 1.72; p<0.01). A multivariate analysis showed that MA was a poor prognostic factor (HR, 1.30; 95% CI, 1.13 to 1.50; p<0.01) and that among patients with MA, significant poor prognostic factors were liver metastasis, moderately to severely reduced oral intake, delirium, oedema, gastric cancer, high serum creatinine, high serum C reactive protein, high serum total bilirubin, dyspnoea and fatigue, while significant good prognostic factors were female sex, good performance status, high serum albumin and colorectal cancer. CONCLUSIONS: MA had a negative impact on survival in terminally ill patients with cancer. A multivariate analysis revealed several prognostic factors in patients with terminal cancer and MA.

Inhibition of MLCK­mediated migration and invasion in human endometriosis stromal cells by NF­κB inhibitor DHMEQ.

Endometriosis is initiated by the movement of endometrial cells in the uterus to the fallopian tubes, the ovaries and the peritoneal cavity after the shedding of the uterus lining. To cause endometriosis, it is often necessary for these endometrial cells to migrate, invade and grow at the secondary site. In the present study, immortalized human endometriosis stromal cells (HESC) were employed to look for the inhibitors of migration and invasion. Using a chemical library of bioactive metabolites, it was found that an NF­κB inhibitor, DHMEQ, inhibited the migration and invasion of HESC. Both whole­genome array and metastasis PCR array analyses suggested the involvement of myosin light chain kinase (MLCK) in the mechanism of inhibition. DHMEQ was confirmed to inhibit the expression of MLCK and small inhibitory RNA knockdown of MLCK reduced cellular migration and invasion. The addition of DHMEQ to the knockdown cells did not further inhibit migration and invasion. DHMEQ is particularly effective in suppressing disease models by intraperitoneal (IP) administration and this therapy is being developed for the treatment of inflammation and cancer. DHMEQ IP therapy may also be useful for the treatment of endometriosis.

Impact of Menopause and the Menstrual Cycle on Oxidative Stress in Japanese Women.

Although estrogen possesses both pro- and anti-oxidant properties, its overall role in oxidative stress among women remains unclear, particularly since the influence of exogenously administered estrogen during previous studies differed by dose, administration route, and estrogen type. The aim of this study was to elucidate the effects of endogenous estrogen on oxidative stress in women. Thus, we performed a non-interventional observational study of healthy postmenopausal (n = 71) and premenopausal (n = 72) female volunteers. Serum levels of derivatives of reactive oxygen metabolites (d-ROMs, which are collectively a marker of oxidative stress), as well as the biological antioxidant potential (BAP, an indicator of antioxidant capacity), were compared between (1) pre- versus post-menopausal women, and (2) premenopausal women in early follicular versus mid-luteal phases of their menstrual cycles. We found that serum d-ROMs and BAP values in postmenopausal women were significantly higher than those in premenopausal women. Moreover, the d-ROM levels were significantly correlated with serum copper concentrations. However, neither d-ROMs nor BAP values were significantly affected by the menstrual cycle phase, although changes in d-ROMs between the follicular and luteal phases were significantly correlated with copper concentration shifts. These data indicate that postmenopausal hypoestrogenism is associated with elevated oxidative stress, although regular fluctuations of estrogen levels during the menstrual cycle do not influence oxidative stress.

Development of a novel nonviral gene silencing system that is effective both in vitro and in vivo by using a star-shaped block copolymer (star vector).

The objective of our study was to develop a novel nonviral gene silencing system using small interfering RNA (siRNA) or short hairpin RNA (shRNA) complexes using star vector (SV), which is a star-shaped, four-branched, cationic-nonionic-blocked copolymer, as the water-soluble delivery system. This vector was previously designed as a carrier for high-efficiency gene delivery of plasmid DNA. The lamin gene was used as the target for developing siRNAs. SV was shown to condense and interact with siRNAs to yield SV/siRNA polyion complexes with a diameter of ca. 90 nm and having considerable stability. By using these complexes, siRNA was successfully delivered to almost all human hepatocellular carcinoma cells used in this study, and both siRNAs and shRNAs could produce significant gene silencing in these cells without affecting cell viability. The silencing efficacy of these complexes was similar to that of commercially available high-efficiency siRNA transfection reagent (Darmafect-4). After injecting SV/siRNA complexes into mice, effective gene silencing was also observed in vivo in the liver and lung, suggesting that the SV/siRNA complexes were stable under in vivo conditions, and their transfection efficiency was retained after intravenous administration. Thus, SV was a potential carrier for siRNA and shRNA delivery in both in vitro and in vivo conditions; this finding suggests that it may offer a new clinical therapeutic approach in gene therapy.

Improvement of hydrogelation abilities and handling of photocurable gelatin-based crosslinking materials.

Three types of eosin-derivatized gelatins (eosin-gelatins) with different molecular weights (M(w)) of ca. 15 kDa (low-molecular-weight eosin-gelatin, LEG), ca. 30 kDa (medium-molecular-weight eosin-gelatin, MEG), and ca. 95 kDa (high-molecular-weight eosin-gelatin, HEG) were prepared. All the eosin-gelatins except for HEG dissolved completely in water at 37 degrees C within several hours even at high concentrations of 35 or 40 wt % along with polyamine (poly(N,N-dimethylaminopropylacrylamide)) to produce photo-crosslinkable materials. The materials had appropriate viscosity for in situ molding at 37 degrees C and could be handled as a liquid at low temperatures of up to 25 degrees C. Upon photoirradiation for several tens of seconds, the materials were converted almost completely to hydrogels in the desired form with a microporous network structure by the radical coupling reaction. The mechanical strength of the produced hydrogels could be controlled by selecting a particular molecular weight or concentration of eosin-gelatins. The hydrogels obtained from LEG (40 wt %) or MEG (35 wt %) had elasticity similar to that of goat periodontal tissue. The handling of the photo-crosslinkable materials at room temperature and their photogelation ability were drastically improved by reducing the M(w) of eosin-gelatin. The potential usefulness of the photo-crosslinkable materials to periodontal regeneration has been discussed.

Enhancement of star vector-based gene delivery to endothelial cells by addition of RGD-peptide.

This study aimed to investigate the feasibility of using a cationic nonviral gene carrier in endothelial cells for enhancing gene expression by the addition of an integrin-binding RGD peptide. A 4-branched cationic polymer of poly( N,N-dimethylaminopropylacrylamide) (star vector), developed as a gene carrier, could complex with the luciferase-encoding plasmid DNA under a charge ratio of 5 (vector/pDNA) to form polymer/DNA complexes (polyplexes). The addition of the RGD-containing peptide (GRGDNP) to the polyplex solution led to a decrease in the zeta-potential from ca. +30 to +20 mV along with the reduction in the particle size from ca. 300 to 200 nm. Additionally, a marked inhibition of polyplex aggregation was observed, indicating the coating of the polyplex surface with RGD peptides. A transfection study on endothelial cells showed that the luciferase activity increased with the amount of RGD peptides added to the polyplexes and exhibited minimal cellular cytotoxicity. The transfection activity further increased when cyclic RGD peptides (RGDFV) were used; the activity with RGD peptide addition was approximately 8-fold compared to that without RGD peptide addition. Gene delivery to endothelial cells was significantly enhanced by only the addition of RGD peptides to star vector-based polyplexes.

Synthesis and in vitro evaluation of novel star-shaped block copolymers (blocked star vectors) for efficient gene delivery.

Novel 4-branched diblock copolymers consisting of cationic chains as an inner domain and nonionic chains as an outer domain were prepared by iniferter-based living radial polymerization and evaluated as a polymeric transfectant. The cationic polymerization of 3-(N,N-dimethylamino)propyl acrylamide (DMAPAAm) using 1,2,4,5-tetrakis( N,N-diethyldithiocarbamylmethyl)benzene as a 4-functional iniferter followed by the nonionic block polymerization of N,N-dimethylacrylamide (DMAAm) afforded 4-branched diblock copolymers with controlled compositions. By changing the solution or irradiation conditions, 4-branched PDMAPAAms with molecular weights of 10,000, 20,000, and 50,000 were synthesized. In addition, by graft polymerization, PDMAPAAm-PDMAAm blocked copolymers with copolymer composition (unit ratio of DMAAm/DMAPAAm) ranging from 0.18 to 1.0 for each cationic polymer were synthesized. All polymers were shown to interact with and condense plasmid DNA to yield polymer/DNA complexes (polyplexes). A transfection study on COS-1 cells showed that the polyplexes from block copolymers with cationic chain length of approximately 50,000 and a nonionic chain length of 30,000, which were approximately 200 nm in diameter and very stable in aqueous media, had the most efficient luciferase activity with minimal cellular cytotoxicity under a charge ratio of 20 (vector/pDNA). The PDMAPAAm-PDMAAm-blocked, star-shaped polymers are an attractive novel class of nonviral gene delivery systems.

Deposition transfection technology using a DNA complex with a thermoresponsive cationic star polymer.

A novel non-viral gene transfection method in which DNA complexes were kept in contact with a deposition surface (deposition transfection) was developed. We designed a novel aqueous thermoresponsive adsorbent material for DNA deposition, which was a star-shaped copolymer with 4-branched chains. Each chain is comprised of a cationic poly(N,N-dimethylaminopropyl acrylamide) (PDMAPAAm) block (Mn: ca. 3000 g x mol(-1)), which formed an inner domain for DNA binding and a thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) block (Mn: ca. 6000 g x mol(-1)), which formed an outer domain for surface adsorption. Complex formation between the copolymer and the luciferase-encoding plasmid DNA occurred immediately upon simple mixing in an aqueous medium; polyplexes approximately 100 nm in size were formed. Because the lower critical solution temperature of the polyplexes was approximately 35 degrees C, they could deposit on the substrate by precipitation from an aqueous solution upon warming, which was confirmed by quartz crystal microbalance (QCM) method and water contact angle measurement. When COS-1 cells were cultured on the polyplex-deposited substrate in a culture medium, the luciferase activity observed was higher than that observed on a DNA-coated substrate with or without the cationic polymer before and after complete adhesion and by conventional solution transfection using the polyplexes. The activity was enhanced with an increase in the charge ratio (surfactant/pDNA) with permissible cellular cytotoxicity.