Potential of TAK-593 Ophthalmic Emulsion for the Treatment of Age-Related Macular Degeneration.

Intravitreal injection therapy of anti-vascular endothelial growth factor (VEGF) antibody or steroids is the mainstream for patients with age-related macular degeneration (AMD). However, since intravitreal injection is invasive administration, side effects such as endophthalmitis are major problems. In this study, we selected eye drops as a non-invasive treatment method, and aimed to develop eye drops that can deliver TAK-593 (VEGF receptor tyrosine kinase inhibitor) to the posterior segment of the eye. Since TAK-593 is a poorly water-soluble drug, the TAK-593 emulsion was formulated. The solubility of TAK-593 in various oils was measured, and the oil used for the emulsion was selected. Furthermore, viscosity enhancers were added to the emulsion in order to improve the drug delivery into the eye. As viscosity enhancer, xanthan gum was selected based on the properties and the viscosity of the emulsion. The delivery of TAK-593 to the posterior eye was increased by the formulation concentration and the addition of viscosity enhancers. In the laser-induced choroidal neovascularization model, TAK-593 emulsion eye drops showed the same angiogenesis-suppression efficacy as anti-VEGF antibody intravitreal injection. From these results, it was revealed that TAK-593 with an effective drug concentration can be delivered to the posterior eye by non-invasive eye drop administration.

Application of Convolutional Long Short-Term Memory Neural Networks to Signals Collected from a Sensor Network for Autonomous Gas Source Localization in Outdoor Environments.

Convolutional Long Short-Term Memory Neural Networks (CNN-LSTM) are a variant of recurrent neural networks (RNN) that can extract spatial features in addition to classifying or making predictions from sequential data. In this paper, we analyzed the use of CNN-LSTM for gas source localization (GSL) in outdoor environments using time series data from a gas sensor network and anemometer. CNN-LSTM is used to estimate the location of a gas source despite the challenges created from inconsistent airflow and gas distribution in outdoor environments. To train CNN-LSTM for GSL, we used temporal data taken from a 5 × 6 metal oxide semiconductor (MOX) gas sensor array, spaced 1.5 m apart, and an anemometer placed in the center of the sensor array in an open area outdoors. The output of the CNN-LSTM is one of thirty cells approximating the location of a gas source. We show that by using CNN-LSTM, we were able to determine the location of a gas source from sequential data. In addition, we compared several artificial neural network (ANN) architectures as well as trained them without wind vector data to estimate the complexity of the task. We found that ANN is a promising prospect for GSL tasks.

The rate of facial nerve dysfunction and time to recovery after intraparotid and extraparotid facial nerve exposure and protection in head and neck cutaneous tumor surgery.

BACKGROUND: Most patients with head and neck skin tumors present with normal facial nerve function. A common treatment strategy for these patients is facial nerve preservation surgery, although the degree to which the nerve is successfully preserved is still unclear. Data on the incidence and recovery of facial nerve dysfunction are woefully lacking in the field of dermato-oncology. METHODS: In 23 patients with normal preoperative facial nerve function, we retrospectively reviewed twenty-six head and neck surgical interventions that included facial nerve exposure and protection, focusing particularly on the differences in outcome between intraparotid and extraparotid exposure of the facial nerve branches. RESULTS: Eleven of the 26 cases (42.4%) developed transient paresis, but only one (3.8%) developed permanent paresis. Of 41 dissected facial nerve branches, 14 developed transient paresis (34.1%) and one, a marginal mandibular branch, developed permanent paresis (2.4%). The branches most susceptible to developing paresis were the temporal (4/6 branches, 66.7%) and marginal mandibular branches (8/17 branches, 47.1%). Although the rate of paresis was higher, and ensuing recovery period slightly longer in the extraparotid dissection group compared to the intraparotid dissection group, there were no statistically significant differences between the two groups. The extraparotid and intraparotid rates of paresis were 48% (11/23 branches) and 21.1% (4/19 branches), respectively, P = 0.139; and the average recovery periods were 10.3 and 9.3 weeks, respectively, P = 0.64. CONCLUSIONS: The functional outcome, regardless of the different sites of facial nerve exposure, was almost always either complete facial nerve sparing or transient dysfunction that resolved within 6 months.

A Rare Case of a Primary Cutaneous Desmoplastic Atypical Granular Cell Tumor.

Granular cell tumors are uncommon neoplasms and a small number of these neoplasms have been reported as showing malignant behavior. Here, we report a rare case of a solitary granular cell tumor that exhibited atypical histology, including an extensive desmoplastic stroma, in a 69-year-old woman. The surgical specimen revealed localized areas of spindling cells, areas of cellular pleomorphism, and p53 overexpression. Based on previously published criteria, we classified this lesion as an atypical granular cell tumor. To date, only very few case reports have documented this desmoplastic variant of granular cell tumor. However, the classifications of benign, atypical, and malignant granular cell tumors are still controversial, owing to an overlap of morphological and immunohistochemical profiles and lack of consistent histological criteria. Additionally, it is unknown whether the histology of the desmoplastic variant in the present case is significant for the classification of granular cell tumors and prediction of patient prognosis. Regardless of these issues, awareness, and close follow-up are required because of potential recurrences of this rare variant of granular cell tumor.

Japanese Society of Clinical Oncology clinical practice guidelines 2010 for antiemesis in oncology: executive summary.

The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT3) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT3 receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT3 receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.

[Immune Checkpoint Inhibitors for Advanced Melanoma - Evidences and Future Perspectives].

Recently developed immune checkpoint inhibitors, such as anti-PD-1 antibodies, have shown a clear improvement in clinical efficacy compared with conventional cytotoxic chemotherapy in the treatment of patients with advanced melanoma. Treatment with anti-PD-1 antibodies has resulted in improved objective response rates, longer durations of response, and longer overall survival rates. Although the incidence rate of adverse events associated with anti-PD-1 antibodies is lower than that associated with cytotoxic agents, characteristic severe adverse events such as pneumonia, endocrinopathy, and colitis can occur. A recent clinical trial that evaluated the utility of an anti-PD-1 antibody in combination with an anti-CTLA-4 antibody reported that the treatment enhanced clinical efficacy in terms of response rate and progression-free survival. However, the incidence of adverse events and treatment discontinuation also increased. For optimal selection of immune checkpoint inhibitors for treating patients with advanced melanoma, biomarkers capable of predicting clinical efficacy, prognosis, and adverse events in each patient need to be identified. In addition, novel combination therapies, including immune checkpoint inhibitors and MAP kinase pathway-targeting agents, should result in more favorable clinical responses and prolonged overall survival rates.

A novel approach for inguinal lymph node dissection without inguinal skin incision for invasive extramammary Paget disease.

Inguinal lymph node dissection (ILND) for skin cancer is associated with a high incidence of wound complications. The traditional skin approaches are associated with a high risk of wound/flap necrosis of the inguinal skin, which leads to wound dehiscence and wound infection. We report a novel approach for ILND without inguinal skin incision for patients with invasive extramammary Paget disease (EMPD) to minimize the wound complications inherent in conventional ILND. We totally performed this procedure in 3 patients with invasive EMPD with inguinal nodal metastases. No patient had complications, including flap necrosis, wound dehiscence, or wound infection. Our novel surgical approach would retain the vascular supply because there was no inguinal skin incision, preventing postoperative wound complications. In addition, ILND was easily performed with satisfactory exposure of the surgical field. However, the number of patients was small and the follow-up period was short. Further evaluation of a larger case series with longer follow-up is essential to investigate the effect, safety, and indications for this novel approach.

Case of alcoholic ketoacidosis accompanied with severe hypoglycemia.

We report a 55 year old Japanese man with a history of alcohol abuse, who was in a near fasting state for the previous few days.He was admitted to our hospital with abrupt disturbance of consciousness. He presented disturbance of consciousness with extreme hypoglycemia and ketoacidosis with high ß-hydroxybutyric acid concentration. Taking into account his living history, we diagnosed with alcoholic ketoacidosis (AKA). Symptoms ameliorated with glucose injection and fluid loading. AKA patients show abdominal pain, nausea or vomiting, but they are usually alert and lucid despite the severe acidosis. This case, however, presented comatose status caused by hypoglycemia. Poor oral intake of this patient was assumed to be the cause of hypoglycemia. Alcoholism may cause hypoglycemia accompanying with AKA, due to a low carbohydrate intake, the inhibition of gluconeogenesis, and reduced hepaticglycogen storage as seen in this case. Here, we report a case of AKA that demonstrated hypoglycemia with the literature review.

Comprehensive analysis of mitochondria in roots and hypocotyls of soybean under flooding stress using proteomics and metabolomics techniques.

Flooding is a serious problem for soybeans because it reduces growth and grain yield. Proteomic and metabolomic techniques were used to examine whether mitochondrial function is altered in soybeans by flooding stress. Mitochondrial fractions were purified from the roots and hypocotyls of 4-day-old soybean seedlings that had been flooded for 2 days. Mitochondrial matrix and membrane proteins were separated by two-dimensional polyacrylamide gel electrophoresis and blue-native polyacrylamide gel electrophoresis, respectively. Differentially expressed proteins and metabolites were identified using mass spectrometry. Proteins and metabolites related to the tricarboxylic acid cycle and γ-amino butyrate shunt were up-regulated by flooding stress, while inner membrane carrier proteins and proteins related to complexes III, IV, and V of the electron transport chains were down-regulated. The amounts of NADH and NAD were increased; however, ATP was significantly decreased by flooding stress. These results suggest that flooding directly impairs electron transport chains, although NADH production increases in the mitochondria through the tricarboxylic acid cycle.

[Management of extravasation of chemotherapeutic agents].

Extravasation of chemotherapeutic agents can potentially cause severe skin damage such as ulceration, resulting in a dramatic decrease in quality of life in patients receiving chemotherapy. Although guidelines for treating extravasation were published in Japan a few years ago, practical procedures on how to deal with it, have not been presented in the guidelines yet due to a lack of supporting evidence. Therefore, each hospital should provide its own procedures to manage the extravasation of chemotherapeutic agents. We describe here the treatment of extravasation by topical injection of steroids. We have never experienced significant skin damage in patients after treatment with topical steroid injections.

Synthesis of Disk-Shaped Tungsten(VI) Oxide Particles with Various Physical Properties for Mineralization of Acetic Acid in Water Under Irradiation of Visible Light.

Disk-shaped tungsten(VI) oxide (D-WO3) particles were synthesized according to a previously reported method consisting of pyrolysis, precipitation, and calcination, and the calcination temperature was changed (200-600 °C). The samples were characterized by field-emission scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction, the Brunauer- Emmett-Teller single-point method, and diffuse reflectance spectroscopy. In addition, to evaluate the photocatalytic activities of the samples, the mineralization of acetic acid to carbon dioxide (CO2) was measured by loading Pt particles onto the surface of the samples by photodeposition and irradiating them in an aqueous suspension with a blue light-emitting diode. Increasing the calcination temperature was associated with several changes: the crystallites grew larger, increasing the crystallinity; the specific surface area decreased, decreasing the adsorption capacity; and the rate of the photocatalytic CO2 evolution reaction increased. Pt-loaded (0.1 wt%) D-WO3 calcined at 600 °C showed the highest activity with a CO2 evolution rate of 5.9 µmol h-1. These results indicated that improving the crystallinity of the D-WO3 samples was effective in increasing their photocatalytic activities.

Vitiligo expansion and extent correlate with durable response in anti-programmed death 1 antibody treatment for advanced melanoma: A multi-institutional retrospective study.

Vitiligo is an autoimmune disorder resulting from the destruction of melanocytes. Several reports indicate the association between vitiligo and treatment response in advanced melanoma during immunotherapy. It has not been investigated, however, if an increase of vitiligo while on treatment with anti-programmed death 1 (PD-1) antibodies is associated with more durable responses. The aim of this study is to evaluate the correlation between the vitiligo dynamics and clinical efficacy of anti-PD-1 antibodies. This study included advanced melanoma patients who were treated with nivolumab or pembrolizumab and developed vitiligo thereafter. Correlation between vitiligo expansion (defined as an increase of lesion size at two separate time points at least 4 weeks apart) as well as vitiligo extent (body surface area [BSA] affected) and clinical efficacy based on response rate, progression-free survival and overall survival was assessed. We retrospectively reviewed 29 patients. The median time from the initiation of anti-PD-1 antibody to vitiligo onset was 4.3 months in patients who showed a response and 5.5 months in patients who showed no response (P = 0.31). Twelve patients showed vitiligo expansion, and in nine of these patients, vitiligo increased to grade 2 (covering ≥ 10% BSA). Vitiligo expansion and grade 2 vitiligo showed no improvement in treatment response (P = 0.59 and 0.25) but were associated with prolonged progression-free survival (P = 0.019 and 0.04). Grade 2 vitiligo also showed a trend for prolonged overall survival (P = 0.07). Trend of expansion and larger vitiligo extent may be predictive factors of prolonged survival during anti-PD-1 antibody in melanoma patients.

Characterization of cytomegalovirus pp65-HLA-A24 peptide-specific CTL lines from metastatic melanoma patients.

Because of advances in immunological technology for detecting a very small number of blood CTL cells, clinicians have been able to monitor cellular immunity against CMV and evaluate the status of CMV infections in highly advanced cancer patients or transplant recipients. Our previous study using healthy volunteer PBLs revealed a significant increase in CMV HLA-A24 tetramer+ CTLs after stimulation in vitro with autologous DCs. However, the efficiency of CMV A24 peptide-specific CTL expansion in highly advanced cancer patients has yet to be studied in detail. In the present study, we tried to characterize and expand HLA-A*2402 CMVpp65 peptide (QYDPVAALF)-specific tetramer+ CTLs from HLA-A*2402+ metastatic melanoma patients, and eventually demonstrated that expansion efficiency was closely related to both post-stimulation CMV tetramer frequency and anti-CMV IgG titer. This is a novel finding regarding in vitro CMVpp65-A24 peptide-specific CTL expansion based on metastatic cancer patient-derived PBLs. Interestingly, the current results using metastatic melanoma PBLs showed a much higher frequency of CMVpp65-A24 tetramer+ CTLs and expansion efficiency than in healthy volunteers. Finally, we were successful in cloning CMVpp65 HLA-A24 peptide-specific TCR cDNAs from in vitro expanded CTL lines derived from melanoma patients. Additionally, CMVpp65 HLA-A24 peptide-specific TCR cDNA was transduced into naive T cells from patients and functionally reconstructed. The results showed that cloned CMV-specific TCR genes were efficient in reconstituting specific anti-CMV activity and might be good tools for adoptive immunotherapy against CMV infections.