Influence of melanoma type on incidence and downstream implications of cutaneous immune-related adverse events in the setting of immune checkpoint inhibitor therapy.

BACKGROUND: Emerging evidence suggests that cutaneous immune-related adverse events (cirAEs) are associated with a survival benefit in the setting of advanced melanoma treated with immune checkpoint inhibitor (ICI) therapy. Previous studies have not examined the role of melanoma subtypes on cirAE development and downstream therapeutic outcomes. OBJECTIVE: Examine the impact of melanoma subtypes on cirAE onset and survival among ICI recipients. METHODS: Retrospective multi-institutional cohort study. Multivariate time-series regressions were utilized to assess relationships between melanoma subtype, cirAE development, and survival. RESULTS: Among 747 ICI recipients, 236 (31.6%) patients developed a cirAE. Patients with acral melanoma were less likely to develop a cirAE (hazard ratio [HR] = 0.41, P = .016) compared to patients with nonacral cutaneous melanoma. Across all melanoma subtypes, cirAEs were associated with reduced mortality (HR = 0.76, P = .042). Patients with acral (HR = 2.04, P = .005), mucosal (HR = 2.30, P < .001), and uveal (HR = 4.09, P < .001) primaries exhibited the worst survival. LIMITATIONS: Retrospective cohort study. CONCLUSION: This is the first study to demonstrate differences in cirAE development among melanoma subtypes. The presence of cirAEs was associated with better survival. Further, the lower incidence of cirAEs may be a marker of immunotherapy response, which is reflected in the association between acral melanoma and mortality.

Prediction of early-stage melanoma recurrence using clinical and histopathologic features.

Prognostic analysis for early-stage (stage I/II) melanomas is of paramount importance for customized surveillance and treatment plans. Since immune checkpoint inhibitors have recently been approved for stage IIB and IIC melanomas, prognostic tools to identify patients at high risk of recurrence have become even more critical. This study aims to assess the effectiveness of machine-learning algorithms in predicting melanoma recurrence using clinical and histopathologic features from Electronic Health Records (EHRs). We collected 1720 early-stage melanomas: 1172 from the Mass General Brigham healthcare system (MGB) and 548 from the Dana-Farber Cancer Institute (DFCI). We extracted 36 clinicopathologic features and used them to predict the recurrence risk with supervised machine-learning algorithms. Models were evaluated internally and externally: (1) five-fold cross-validation of the MGB cohort; (2) the MGB cohort for training and the DFCI cohort for testing independently. In the internal and external validations, respectively, we achieved a recurrence classification performance of AUC: 0.845 and 0.812, and a time-to-event prediction performance of time-dependent AUC: 0.853 and 0.820. Breslow tumor thickness and mitotic rate were identified as the most predictive features. Our results suggest that machine-learning algorithms can extract predictive signals from clinicopathologic features for early-stage melanoma recurrence prediction, which will enable the identification of patients that may benefit from adjuvant immunotherapy.

Polydeoxyribonucleotide improves tendon healing following achilles tendon injury in rats.

Tendon injuries are major musculoskeletal disorders. Polydeoxyribonucleotide activates the adenosine receptor subtype A2A, resulting in tissue growth and neogenesis. This experimental study confirms that polydeoxyribonucleotide can improve secretion of various growth factors, promote collagen synthesis, and restore tensile strength of the Achilles tendon in a rat model with Achilles tendon injury. Thirty-six male Sprague-Dawley rats, aged 7 weeks, were divided into two groups, and the Achilles tendon was transected and repaired using the modified Kessler's method. In the experimental group (n = 18), the rats received daily intraperitoneal administration of polydeoxyribonucleotide (8 mg/kg/day for 1, 2, or 4 weeks). The control groups received the same amount of normal saline. The rats were euthanized at 1, 2, and 4 weeks, and tissues from the repair site were harvested. The cross-sectional area of the tendon was significantly increased at 2 and 4 weeks in polydeoxyribonucleotide group (p = 0.008 and p = 0.017, respectively). Moreover, tendons in the polydeoxyribonucleotide group were more resistant to mechanical stress at 2 and 4 weeks (p = 0.041 and p = 0.041, respectively). The staining levels of collagen type I in the experimental group were significantly stronger at 2 and 4 weeks (p = 0.026 and p = 0.009, respectively). Furthermore, higher expression levels of fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor ß1 were detected in the experimental group at 4 weeks (p = 0.041, p = 0.026, and p = 0.041, respectively). This study confirms that polydeoxyribonucleotide can improve the tensile strength of the rats' Achilles tendon following injury and repair. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1767-1776, 2018.

Clinical Significance of Pre- and Post-Transplant BAFF Levels in Kidney Transplant Recipients.

It is well known that pre-transplant B cell activating factor (BAFF) levels are associated with the development of de novo anti-HLA antibodies and antibody mediated rejection post-transplant. However, the clinical significance of BAFF values at allograft rejection has not been determined. In this study, we investigated the clinical significance of pre-transplant BAFF level as well as post-transplant BAFF levels measured when indication biopsy was done. We checked for anti-HLA antibodies in 115 kidney transplant recipients who required allograft biopsy due to an increase in serum creatinine. With the same serum specimen, we measured BAFF levels, and in 78 of these patients, pre-transplant BAFF and anti-HLA antibody levels were detected as well. Patients in each group were divided into tertiles according to BAFF levels. We investigated the relationship between BAFF levels and the occurrence of anti-HLA antibodies. Pre-transplant BAFF levels showed significant association with pre-transplant sensitization, and also with early rejection (Tertile 3, 26.9% vs. Tertile 1, 11.5%; P<0.05). Post-transplant BAFF levels showed significant association with pre-transplant sensitization, but did not show association with anti-HLA antibodies and positive donor-specific antibodies at the time of biopsy. We did not find any association between post-transplant BAFF levels and allograft biopsy results, Banff scores and microvascular inflammation scores. In conclusion, pre-transplant BAFF levels are associated with pre-transplant sensitization and are useful in predicting allograft rejection. But post-transplant BAFF levels measured at the time of indication biopsy are not associated with the appearance of de novo HLA-DSA, allograft rejection, biopsy findings and other allograft outcomes.

Polycyclic aromatic hydrocarbons exposure in residents living near a cement factory with kilns.

PURPOSE: This study was performed to investigate polycyclic aromatic hydrocarbons (PAHs) exposure in the area around a cement factory with kilns using waste, including refuse plastic fuel. METHODS: Atmospheric total suspended particulates (TSPs) for each of an exposed area and a non-exposed area were collected. Similarly, urine samples were collected from 330 subjects in the exposed area and 126 subjects in the non-exposed area. Gas chromatography with mass spectrometry was used to analyze PAHs in the collected TSP samples and the PAH metabolites, urinary 2-naphthol (2-NAP) and 1-hydroxypyrene (1-OHP), of the residents. The concentrations of urinary 2-NAP and 1-OHP were adjusted by creatinine concentrations. RESULTS: The atmospheric concentrations of PAHs, including naphthalene and pyrene, were higher in the exposed area than those in the non-exposed area. The geometric means (GMs) of the urinary 2-NAP concentrations in the exposed and non-exposed groups without work experience were 4.06 and 1.55 µg/g creatinine, respectively. The GMs of the urinary 1-OHP concentrations were 0.26 and 0.14 µg/g creatinine, respectively. The results showed that the concentrations of PAH metabolites were significantly higher in the exposed group than those in the non-exposed group (p < 0.001). Multiple linear regression analysis with the log-transformed urinary 2-NAP and 1-OHP concentrations and other variables indicated a strong correlation of residence in the exposed area and smoking with an increase in the urinary 2-NAP and 1-OHP concentrations. CONCLUSIONS: In addition to the known risk factors, this study indicated that living near a cement factory with kilns is also a risk factor for PAH exposure.

Safety of dental extractions in coronary drug-eluting stenting patients without stopping multiple antiplatelet agents.

BACKGROUND: The risk of excessive bleeding prompts physicians to stop multiple antiplatelet agents before minor surgery, which puts coronary stenting patients at risk for adverse thrombotic events. HYPOTHESIS: We hypothesized that most dental extractions can be carried out safely without stopping multiple antiplatelet agents. METHODS: All dental extraction patients who had undergone coronary stenting and who were also on oral multiple antiplatelet agents therapy were enrolled. One hundred patients underwent dental procedures without stopping antiplatelet agents. All wounds were sutured and followed up at 24 hours, 1 week, and 1 month after the procedure. There were 2233 patients who had not taken oral antiplatelet agents from a health promotion center and had teeth extracted by the same method. After performing propensity-score matching for the entire population, a total of 100 matched pairs of patients were created. The primary outcome was a composite of excessive intraextraction blood loss, transfusion, and rehospitalization for bleeding, and the secondary outcome was a composite of death, nonfatal myocardial infarction, target lesion revascularization, and stent thrombosis within 1 month after the procedure. RESULTS: There were 2 excessive intraextraction bleeding cases that continued at the extraction site for 4 and 5 hours, respectively, in the coronary stenting patients, and 1 excessive intraextraction bleeding case that continued for 3 hours in the control patients. There were no cases of transfusion, rehospitalization for bleeding, or major cardiovascular events for the 2 propensity-matched groups. CONCLUSIONS: We found that most dental extractions in coronary stenting patients can be carried out safely without stopping multiple antiplatelet agents.

A comparison of triamcinolone acetonide and fibrin glue for seroma prevention in a rat mastectomy model.

BACKGROUND: Seroma formation is one of the most common complications after flap surgery during the postoperative period. Various methods have been developed to overcome this problem, but none of them have been used successfully. Authors used topical triamcinolone acetonide to reduce seroma formation in a rat mastectomy model and compared its effectiveness with fibrin glue. METHODS: In the rat mastectomy model, the authors administered triamcinolone acetonide (experimental group I, n=12), fibrin glue (experimental group II, n=12), and saline (control group, n=12) beneath the skin flap just before closure of the skin. Seroma collections were aspirated and quantified after 7 days, and histologic analysis of the skin flaps and chest walls of the rats was performed. RESULTS: The experimental group I had a reduced mean seroma volume of 1.79±1.32 mL, whereas the experimental group II and control group had mean seroma volumes of 4.04±1.43 mL and 8.51±2.60 mL, respectively (P<0.05). In semiquantitative analysis of inflammation, inflammatory cell count in experimental group I was significantly fewer than in the other 2 groups (P<0.001). In addition, seroma capsule formation did not occur. CONCLUSIONS: Seroma prevention using triamcinolone acetonide is simpler, more economical, and more effective than fibrin glue. In proper concentrations, triamcinolone acetonide can be used to prevent seroma formation in clinical practice.

Prevalence of electrocardiographic findings suggestive of sudden cardiac death risk in 10,867 apparently healthy young Korean men.

BACKGROUND: The objective of this study was to determine the prevalence of electrocardiographic (ECG) findings suggestive of sudden cardiac death risk in apparently healthy young Korean men. METHODS: We administered questionnaires that elicited personal and family histories and performed ECGs on 10,867 male subjects (mean age, 20.9 years). The subjects with abnormal ECG findings underwent echocardiography, a treadmill test, Holter monitoring, a flecainide provocation test, or an electrophysiologic study (EPS) according to the ECG findings and histories. RESULTS: Of the subjects, 5.95% had left ventricular hypertrophy on ECG, but no subjects had hypertrophic cardiomyopathy by echocardiography. The percentage of subjects with a Brugada ECG pattern was 0.90%. We identified one subject with a positive result on the flecainide provocation test. The percentage of subjects with a preexcitation ECG was 0.17%. In two of the subjects, supraventricular tachycardia was induced in the EPS. Of the subjects, 0.05% had epsilon waves, but there were no subjects with arrhythmogenic right ventricular dysplasia/cardiomyopathy by echocardiography. The percentage of subjects with long QT intervals was 0.02%, but there were no arrhythmias on the treadmill test or Holter monitoring. CONCLUSIONS: The prevalence of a Brugada ECG pattern in apparently healthy young men is higher in Korea than other countries.

Ultra-trace determination of plutonium in marine samples using multi-collector inductively coupled plasma mass spectrometry.

Sources of plutonium isotopes to the marine environment are well defined, both spatially and temporally, which makes Pu a potential tracer for oceanic processes. This paper presents the selection, optimisation and validation of a sample preparation method for the ultra-trace determination of Pu isotopes ((240)Pu and (239)Pu) in marine samples by multi-collector (MC) ICP-MS. The method was optimised for the removal of the interference from (238)U and the chemical recovery of Pu. Comparison of various separation strategies using AG1-X8, TEVA, TRU, and UTEVA resins to determine Pu in marine calcium carbonate samples is reported. A combination of anion-exchange (AG1-X8) and extraction chromatography (UTEVA/TRU) was the most suitable, with a radiochemical Pu yield of 87+/-5% and a U decontamination factor of 1.2 x 10(4). Validation of the method was accomplished by determining Pu in various IAEA certified marine reference materials. The estimated MC-ICP-MS instrumental limit of detection for (239)Pu and (240)Pu was 0.02 fg mL(-1), with an absolute limit of quantification of 0.11 fg. The proposed method allows the determination of ultra-trace Pu, at femtogram levels, in small size marine samples (e.g., 0.6-2.0 g coral or 15-20 L seawater). Finally, the analytical method was applied to determining historical records of the Pu signature in coral samples from the tropical Northwest Pacific and (239+240)Pu concentrations and (240)Pu/(239)Pu atom ratios in seawater samples as part of the 2008 GEOTRACES intercalibration exercise.

Soybean oil-degrading bacterial cultures as a potential for control of green peach aphids (Myzus persicae).

Microorganisms capable of degrading crude oil were isolated and grown in soybean oil as a sole carbon source. The microbial cultures were used to control green peach aphids in vitro. Approximately 60% mortality of aphids was observed when the cultures were applied alone onto aphids. To examine the cultures as a pesticide formulation mixture, the cultures were combined with a low dose of the insecticide imidacloprid (one-fourth dose of recommended field-application rate) and applied onto aphids. The cultures enhanced significantly the insecticidal effectiveness of imidacloprid, which was higher than imidacloprid alone applied at the low dose. The isolated microorganisms exhibited high emulsifying index values and decreased surface tension values after being grown in soybean oil media. GC/MS analyses showed that microorganisms degraded soybean oil to fatty acids. The cultures were suggested to play the roles of wetting, spreading, and sticking agents to improve the effectiveness of imidacloprid. This is the first report on the control of aphids by using oil-degrading microbial cultures.