Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma.

BACKGROUND: While neoadjuvant immunotherapy for melanoma has shown promising results, the data have been limited by a relatively short follow-up time, with most studies reporting 2-year outcomes. The goal of this study was to determine long-term outcomes for stage III/IV melanoma patients treated with neoadjuvant and adjuvant programmed cell death receptor 1 (PD-1) inhibition. PATIENTS AND METHODS: This is a follow-up study of a previously published phase Ib clinical trial of 30 patients with resectable stage III/IV cutaneous melanoma who received one dose of 200 mg IV neoadjuvant pembrolizumab 3 weeks before surgical resection, followed by 1 year of adjuvant pembrolizumab. The primary outcomes were 5-year overall survival (OS), 5-year recurrence-free survival (RFS), and recurrence patterns. RESULTS: We report updated results at 5 years of follow-up with a median follow-up of 61.9 months. No deaths occurred in patients with a major pathological response (MPR, <10% viable tumor) or complete pathological response (pCR, no viable tumor) (n = 8), compared to a 5-year OS of 72.8% for the remainder of the cohort (P = 0.12). Two of eight patients with a pCR or MPR had a recurrence. Of the patients with >10% viable tumor remaining, 8 of 22 patients (36%) had a recurrence. Additionally, the median time to recurrence was 3.9 years for patients with ≤10% viable tumor and 0.6 years for patients with >10% viable tumor (P = 0.044). CONCLUSIONS: The 5-year results from this trial represent the longest follow-up of a single-agent neoadjuvant PD-1 trial to date. Response to neoadjuvant therapy continues to be an important prognosticator with regard to OS and RFS. Additionally, recurrences in patients with pCR occur later and are salvageable, with a 5-year OS of 100%. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD-1 blockade in patients with a pCR and the importance of long-term follow-up for these patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02434354.

The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent.

This publication details the discovery of a series of selective transient receptor potential cation channel subfamily M member 5 (TRPM5) agonists culminating with the identification of the lead compound (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (39). We describe herein our biological rationale for agonism of the target, the examination of the then current literature tool molecules, and finally the process of our discovery starting with a high throughput screening hit through lead development. We also detail the selectivity of the lead compound 39 versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8, the drug metabolism and pharmacokinetics (DMPK) profile and in vivo efficacy in a mouse model of gastrointestinal motility.

[Delayed administration of thrombolytic therapy in minor stroke]. / Retraso en la administración de tratamiento trombolítico en el ictus minor.

INTRODUCTION: Minor strokes are considered to be those that present with few symptoms, although up to 40% of them entail long-term disability. The rate of thrombolysis in these patients is also lower than in other strokes. The aim of this study is to explore whether there are any differences in intravenous thrombolysis care times in minor strokes. PATIENTS AND METHODS: We conducted a retrospective review of strokes treated with intravenous thrombolysis at our centre and a comparative analysis of the care times in minor strokes and in the other types. RESULTS: Longer times were found in minor strokes in terms of door-to-CT scan and door-to-needle time. This was not the case, however, for the time from the onset of symptoms to arrival at the hospital. CONCLUSIONS: The presence of few symptoms in minor strokes can make them difficult to recognise and could be a reason for delaying treatment. Training among staff caring for these patients is essential to improve this aspect.

TITLE: Retraso en la administración de tratamiento trombolítico en el ictus minor.Introducción. Se considera ictus minor a aquel que se presenta con escasos síntomas; sin embargo, hasta un 40% presenta discapacidad a largo plazo. La tasa de trombólisis en estos pacientes también es inferior a la del resto de ictus. En este estudio se pretende explorar si existen diferencias en los tiempos de atención en la trombólisis intravenosa en los pacientes con ictus minor. Material y métodos. Revisión retrospectiva de los ictus tratados con trombólisis intravenosa en nuestro centro y análisis comparativo de los tiempos de asistencia entre ictus minor y el resto. Resultados. Se encontraron tiempos más alargados en los casos de ictus minor en cuanto al tiempo puerta-tomografía computarizada y puerta-aguja. No fue así, sin embargo, para el tiempo desde el inicio de los síntomas hasta la llegada al hospital. Conclusiones. La presencia de escasos síntomas en el ictus minor puede hacer difícil su reconocimiento y podría ser un motivo de retraso en el tratamiento. La formación entre el personal que atiende a estos pacientes es fundamental para mejorar este aspecto.

Retraso en la administración de tratamiento trombolítico en el ictus minor / Delayed administration of thrombolytic therapy in minor stroke

Introducción: Se considera ictus minor a aquel que se presenta con escasos síntomas; sin embargo, hasta un 40% presenta discapacidad a largo plazo. La tasa de trombólisis en estos pacientes también es inferior a la del resto de ictus. En este estudio se pretende explorar si existen diferencias en los tiempos de atención en la trombólisis intravenosa en los pacientes con ictus minor. Material y métodos. Revisión retrospectiva de los ictus tratados con trombólisis intravenosa en nuestro centro y análisis comparativo de los tiempos de asistencia entre ictus minor y el resto. Resultados: Se encontraron tiempos más alargados en los casos de ictus minor en cuanto al tiempo puerta-tomografía computarizada y puerta-aguja. No fue así, sin embargo, para el tiempo desde el inicio de los síntomas hasta la llegada al hospital. Conclusiones: La presencia de escasos síntomas en el ictus minor puede hacer difícil su reconocimiento y podría ser un motivo de retraso en el tratamiento. La formación entre el personal que atiende a estos pacientes es fundamental para mejorar este aspecto.(AU)

Introduction: Minor strokes are considered to be those that present with few symptoms, although up to 40% of them entail long-term disability. The rate of thrombolysis in these patients is also lower than in other strokes. The aim of this study is to explore whether there are any differences in intravenous thrombolysis care times in minor strokes. Patients and methods: We conducted a retrospective review of strokes treated with intravenous thrombolysis at our centre and a comparative analysis of the care times in minor strokes and in the other types. Results: Longer times were found in minor strokes in terms of door-to-CT scan and door-to-needle time. This was not the case, however, for the time from the onset of symptoms to arrival at the hospital. Conclusions: The presence of few symptoms in minor strokes can make them difficult to recognise and could be a reason for delaying treatment. Training among staff caring for these patients is essential to improve this aspect.(AU)

UVA-activated riboflavin promotes collagen crosslinking to prevent root caries.

Root caries is an increasingly problem in aging societies with severe implications for the general health and wellbeing of large numbers of people. Strengthening type-I collagen, a major organic component of human dentin, has proved effective in preventing root caries. This study sought to determine whether exposure to riboflavin followed by UVA irradiation (RF/UVA) could promote additional collagen crosslinking, and thus improve the acid and enzymatic resistance of human dentin under simulated oral environments. If so, it could offer potential for treatment of the intractable problem of root caries. The greatest flexural strengths were found in dentin exposed to a 0.1% riboflavin solution for 1 minute followed by 1,600 mW/cm2 UVA irradiation for 10 minutes. Mineral loss and lesion depth were significantly lower in the RF/UVA group than in the control group. The microstructures of dentinal tubules and collagen networks after RF/UVA treatment retained their original forms after acidic and enzymatic degradation. In conclusion, RF/UVA treatment may be a new method for preventing root caries with promising prospects for clinical application.

Influence of Nonenzymatic Glycation in Dentinal Collagen on Dental Caries.

Advanced glycation end-products (AGEs) are generated via nonenzymatic glycation of dentinal collagen, resulting in accumulation of AGEs in dentin tissue. Since accumulated AGEs cause crosslinking between amino acid polypeptides in the collagen molecule and modify mechanical properties of dentinal collagen, the authors assumed that there would be a significant interaction between the generation of AGEs and progression of caries in dentin. To confirm such an interaction, spectroscopic imaging analyses (i.e., nanosecond fluorescence lifetime imaging and second harmonic generation light imaging) were performed in addition to biochemical and electron microscopic analyses in the present study. Seven carious human teeth were fixed in paraformaldehyde and cut longitudinally into 1-mm sections using a low-speed diamond saw for the following analyses. In transmission electron microscopy (TEM) analysis, nondecalcified specimens were embedded in epoxy resin and sliced into thin sections for observation. For the immunohistochemical analysis, the specimens were paraffin embedded after decalcification for 2 wk and sectioned with a microtome. Resultant sections were stained with anti-AGE and anticollagen antibodies. The demineralized specimens were used for spectroscopic analyses without additional treatment. For Western blotting analysis, specimens were separated into carious and sound dentin. Each specimen was homogenized with a bead crusher and an ultrasonic homogenizer and then treated with hydrochloric acid. In carious dentin, the collagen fibers showed an amorphous structure in the TEM image, and the AGEs were localized in the areas of bacterial invasion in the immunostaining image. The total amount of AGEs in carious dentin was higher than in sound dentin in Western blotting. The ultrastructure of type I collagen and total amount of AGEs varied markedly in the dentinal caries region. The fluorescence lifetime was shorter in the carious area than that in the sound areas, indicating an increase of AGEs in the carious area. The increase of AGEs could influence the progression of dentinal caries.

Impact of chemotherapy on survival in surgically resected retroperitoneal sarcoma.

BACKGROUND: The role of systemic chemotherapy (CT) in the multimodality treatment strategy for retroperitoneal sarcomas (RPS) remains controversial. We hypothesized that chemotherapy does not improve overall survival for patients with surgically resected RPS. METHODS: The National Cancer Database was used to identify all patients with RPS that underwent surgical resection from 1998 to 2011. Univariate and multivariable Cox proportional hazards modeling were used to assess overall survival (OS) and logistic regression was used for associations. Propensity score (PS) modeling was performed to create balanced cohorts for analysis. RESULTS: A total of 8653 patients with surgically resected RPS were identified; 1525 (17.6%) received CT; 10.6% of patients (n = 163) in the neoadjuvant setting. Factors associated with receipt of CT included moderate (OR 2.3) to poorly differentiated (OR 4.3) tumors, leiomyosarcoma (OR 1.8) or undifferentiated pleomorphic sarcoma (OR 2.3) histology, and R2 resection status (OR 2.2) (all p < 0.05). Unadjusted median OS for patients receiving CT compared to surgery alone was 40 vs 68.2 months respectively (p < 0.01). Following propensity score matching, worse median OS persisted among the CT cohort (40 vs 52 months, p = 0.002). Receipt of chemotherapy was not associated with improved long term survival in adjusted models for the raw and propensity matched cohorts (HR 1.17, 95% CI: 1.04-1.31; p = 0.009). CONCLUSION: Current available chemotherapy regimens for RPS do not confer a survival benefit. Routine use of chemotherapy for RPS should be discouraged until new effective systemic agents become available.

Effects of the tea catechin epigallocatechin gallate on Porphyromonas gingivalis biofilms.

AIMS: The aim of this study was to investigate the effects of tea catechin epigallocatechin gallate (EGCg) on established biofilms and biofilm formation by Porphyromonas gingivalis, a major pathogen of periodontal disease. METHODS AND RESULTS: Biofilm cell survival was measured using adenosine triphosphate (ATP) bioluminescence. In the presence of EGCg, the ATP level in cells of established biofilms was significantly decreased compared to the controls (P < 0·0001). Transmission electron microscopy revealed that EGCg damaged the cell membrane and cell wall of P. gingivalis. Confocal laser-scanning microscopy revealed that the proportion of dead cells was higher in biofilms treated with EGCg. Moreover, the effects of subminimal inhibitory concentrations (MICs) of EGCg on P. gingivalis biofilm formation were dose-dependent (P < 0·0001). CONCLUSION: Our results suggest that EGCg destroys established P. gingivalis biofilms and inhibits biofilm formation. SIGNIFICANCE AND IMPACT OF THE STUDY: Development of chemical control agents against oral biofilms is necessary, because oral biofilms can be only removed using mechanical debridement. This article indicates that EGCg may represent a novel antibiofilm agent that prevents infections involving bacterial biofilms such as periodontitis.

Pathological gambling associated with cabergoline in a case of recurrent depression.

Pathological gambling has been described frequently in patients with Parkinson disease or other movement disorders who were treated with dopamine agonists. Here, we report a patient with recurrent depression who developed pathological gambling after administration of the dopamine agonist cabergoline. A 36-year-old male Japanese patient presented with his third episode of depression. His depressive symptoms responded minimally to fluvoxamine. Cabergoline was then added to augment the antidepressant's efficacy. Although this regimen resulted in dramatic improvement, he started to spend considerable money and time every day in pachinko parlors and go to the horse racing track every weekend. He spent more than twenty thousand US dollars in total. He tried to stop gambling many times but failed to control his urge. His gambling behavior did not stop even though he was experiencing a marital crisis. He had not displayed any manic symptoms during this entire period. This complication fulfilled the criteria for pathological gambling according to the Diagnostic and Statistical Manual of MentalDisorders, Fourth Edition, Text Revision edition. The patient's perplexing behavior did not end until cabergoline was discontinued. Thus far, pathological gambling associated with cabergoline has rarely been reported while gambling associated with pramipexole and ropinirole, dopamine agonists, has frequently been documented. In addition, this is the first case of depression in which the patient developed pathological gambling during treatment with a dopamine agonist. In conclusion, clinicians should be aware of the potential for pathological gambling when prescribing cabergoline to patients with depression.

Effects of acute citalopram treatment on the methamphetamine-induced locomotor activity.

1. Previously the authors have shown that acute citalopram treatment increased the dopamine D2 receptor expression in rat brain striatum (Kameda et al., 2000). In the present study, the authors attempted to determine whether these effects of citalopram influence the methamphetamine-induced locomotor activity. 2. The pretreatment with a single administration of citalopram (10 mg/kg, i.p.) resulted in the significant enhancement of the locomoter activity induced by methamphetamine treatment (1 mg/kg, i.p.). The enhancement was observed 30 min, 12 hours, 24 hours, but not 7 days after withdrawal of citalopram administration. 3. Then the authors determined the methamphetamine concentration in rat brain striatum by gas chromatography-mass spectrometry (GC-MS) The results showed that the concentration of methamphetamine wars significantly higher in the rats 24 hours, and also 7 days after withdrawal of citalopram administration, compared to the control rats. 4. These results emphasized the involvement of the high methamphetamine concentration, caused by the pretreatment with citalopram, in the enhancement of the methamphetamine-induced locomotor activity. However high methamphetamine concentration alone could not account for this enhancement, since the high concentration of methamphetamine observed 7 days after withdrawal of citalopram administration did not appear to enhance the methamphetamine-induced locomotor activity. Another mechanism through which the pretreatment with citalopram enhanced the methamphetamine-induced locomotor activity, such as the increased expression of the dopamine D2 receptors, could not be excluded.

Effects of lithium on dopamine D2 receptor expression in the rat brain striatum.

Effects of lithium on the dopamine D2 receptor expression in the rat brain striatum were studied. Feeding the chow containing 0.2% LiCO3 for 6 days increased the level of the dopamine D2 receptor mRNA, and the transcription rate of the dopamine D2 receptor gene, indicating the stimulatory effects of lithium on the transcription of the dopamine D2 receptor gene. [3H] Spiperone binding to the striatal membranes increased in the rats treated with lithium, while the Western blotting analysis showed no change of the amount of the dopamine D2 receptors. These results suggested that lithium might induce the conformational changes of the dopamine D2 receptors. The methamphetamine-induced locomotor activity was enhanced by the pretreatment with lithium, whereas simultaneous increase in the methamphetamine concentration in the striatum was also observed. These observations suggested that the stimulation of methamphetamine-induced locomotor activity by lithium might be, at least partly, due to either increased sensitivity of the dopamine receptors, or increased concentration of methamphetamine in brain, or combination of both.

Transplanted peripheral blood stem cells, mobilized by chemotherapy alone, can induce persistent hematopoiesis in children with acute leukemia.

Three patients with leukemia were transplanted with peripheral blood stem cells mobilized by intensification or maintenance chemotherapy alone. They maintained persistent reconstituted hematopoiesis for at least 9 years. The experience provides evidence that long-term marrow repopulating cells can be mobilized into the blood to an adequate repopulating extent by chemotherapy alone.

Characterization of the gammac chain among 27 unrelated Japanese patients with X-linked severe combined immunodeficiency (X-SCID).

X-linked severe combined immunodeficiency (X-SCID) is a rare fatal disease that is caused by mutations in the gene encoding the gammac chain. In this study, 27 unrelated Japanese patients with X-SCID were examined in terms of their genetic mutations and surface expression of the gammac chain. Among 25 patients examined, excluding two patients with large deletions, 23 different mutations were identified in the IL2RG gene, including 10 novel mutations. One patient bearing an extracellular mutation and all three of the patients bearing intracellular mutations after exon 7 expressed the gammac chain on the cell surface. Overall, 84% of patients lacked surface expression of the gammac chain leading to a diagnosis of X-SCID.

Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan.

BACKGROUND: Whether the type of diabetes, race, and year and age of diagnosis affect the incidence of diabetic vascular complications is unknown. That both type 1 and type 2 diabetes occur in the young Japanese population prompted us to investigate whether the type of diabetes and the year of diagnosis are related to the incidence of nephropathy. METHODS: Of the 17,256 diabetic patients who visited the outpatient clinic at our diabetes center between 1965 and 1990, 1578 (9.1%) had early-onset diabetes (diagnosed before the age of 30); of these, 620 (39%) had type 1, and 958 (61%) had type 2 diabetes. The incidence of nephropathy was analyzed in the patients according to postpubertal duration and year of diagnosis. RESULTS: The cumulative incidence of nephropathy after 30 years of postpubertal diabetes was significantly higher (P < 0.0001) in type 2 diabetic patients (44.4%, 95% CI, 37.0 to 51.8%) than in type 1 diabetic patients (20.2%, 95% CI, 14.9 to 25.8%). The incidence of nephropathy among type 1 diabetic patients has declined during the past two decades, whereas it has not among type 2 diabetic patients. The rate ratio for type 2 diabetic patients diagnosed between 1980 and 1984 relative to type 1 diabetic patients diagnosed in the same period was 2.74 (95% CI, 1. 17 to 6.41). CONCLUSIONS: The incidence of nephropathy has declined in Japanese patients with type 1 but not in those with type 2 diabetes. In young Japanese patients, because of the higher incidence of nephropathy in type 2 diabetes and the higher prevalence of type 2 than type 1 diabetes, type 2 diabetes is likely the major cause of diabetic nephropathy.

Effects of citalopram on dopamine D2 receptor expression in the rat brain striatum.

Effects of citalopram on dopamine D2 receptor expression in the rat brain striatum were studied. Repeated administration of citalopram increased the amount of dopamine D2 receptors, the level of dopamine D2 receptor mRNA, and the transcription rate of the dopamine D2 receptor gene. Single administration of citalopram also increased the level of dopamine D2 receptor mRNA with a maximum effect in 2-4 h after the treatment, and the transcription rate of the dopamine D2 receptor gene. The administration of 5-hydroxytryptophan (5-HTP) also increased the level of dopamine D2 receptor mRNA. These results suggest that the increase in the dopamine D2 receptor expression induced by citalopram may be owing, at least partially, to the stimulation of the dopamine D2 receptor gene transcription, and that serotonin (5-HT) may mediate the effects of citalopram in the induction of dopamine D2 receptor expression.

Polymyalgia rheumatica and type 2 diabetes mellitus complicated with electromyographic abnormalities that responded well to corticosteroid therapy.

A 62-year-old man who had a 14-year history of diabetes complained of low-grade fever, general malaise, pain of bilateral femurs and hip girdle, and was adniitted to our hospital. The diagnosis of polymyalgia rheumatica (PMR) was made from the clinical symptoms, elevated C-reactive protein and erythrocyte sedimentation rate. Electromyography revealed abnormalities that suggested diabetic peripheral neuropathy. However, the abnormalities were improved after starting treatment with corticosteroids (PSL). After stopping PSL, electric nerve conduction disturbance developed; therefore, it was suggested that peripheral nerve involvement due to PMR was improved by administration of PSL regardless of the existence of diabetic peripheral neuropathy.