Sequential Treatment with an Immune Checkpoint Inhibitor Followed by a Small-Molecule Targeted Agent Increases Drug-Induced Pneumonitis.

PURPOSE: Immune checkpoint inhibitors (ICI) and targeted small-molecule drugs are mainstay elements of lung cancer chemotherapy. However, they are associated with development of pneumonitis, a rare, but potentially life-threatening event. We analyzed lung cancer patients treated with ICI to evaluate the effect of sequential therapeutic administration on the incidence of pneumonitis. MATERIALS AND METHODS: In this retrospective study, 242 patients were included. Serial radiologic findings taken during and immediately after ICI treatment were reviewed. Factors that increased pneumonitis and the relationship between peri-ICI chemotherapy and the development of pneumonitis were evaluated. RESULTS: Pneumonitis developed in 23 patients (9.5%); severe pneumonitis (grade ≥ 3) occurred in 13 of 23 patients (56%); pneumonitis-related death occurred in six. High-dose thoracic radiation (≥ 6,000 cGy) revealed a tendency toward high risk of pneumonitis (odds ratio, 2.642; 95% confidence interval, 0.932 to 7.490; p=0.068). Among 149 patients followed for ≥ 8 weeks after the final ICI dose, more patients who received targeted agents within 8-weeks post-ICI experienced pneumonitis (3/16, 18.8%) compared with patients who received cytotoxic agents (4/54, 7.4%) or no chemotherapy (4/79, 5.1%) (p=0.162). Targeted therapy was associated with earlier-onset pneumonitis than treatment with cytotoxic agents (35 vs. 62 days post-ICI, p=0.007); the resulting pneumonitis was more severe (grade ≥ 3, 100% vs. 0%, p=0.031). CONCLUSION: Sequential administration of small-molecule targeted agents immediately after ICI may increase the risk of severe pneumonitis. The sequence of chemotherapy regimens that include ICI and targeted agents should be carefully planned to reduce the risk of pneumonitis in lung cancer patients.

Male patients presenting with rapidly progressive puberty associated with malignant tumors.

In males, precocious puberty (PP) is defined as the development of secondary sexual characteristics before age 9 years. PP is usually idiopathic; though, organic abnormalities including tumors are more frequently found in male patients with PP. However, advanced puberty in male also can be an important clinical manifestation in tumors. We report 2 cases of rapidly progressive puberty in males, each associated with a germ-cell tumor. First, an 11-year-old boy presented with mild fever and weight loss for 1 month. Physical examination revealed a pubertal stage of G3P3 with 10-mL testes. Investigations revealed advanced bone age (16 years) with elevated basal luteinizing hormone and testosterone levels. An anterior mediastinal tumor was identified by chest radiography and computed tomography, and elevated α-fetoprotein (AFP) and ß-human chorionic gonadotropin (ß-hCG) levels were noted. Histopathologic analysis confirmed a yolk-sac tumor. Second, a 12-year-old boy presented with diplopia, polydipsia, and polyuria for 4 months. Physical examination revealed a pubertal stage of G3P3 with 8-mL testes. Bone age was advanced (16 years) and laboratory tests indicated panhypopituitarism with elevated testosterone level. A mixed germ-cell tumor was diagnosed with elevated AFP and ß-hCG levels. Of course, these patients also have other symptoms of suspecting tumors, however, rapidly progressive puberty can be the more earlier screening sign of tumors. Therefore, in male patients with accelerated or advanced puberty, malignancy should be considered, with evaluation of tumor markers. In addition, advanced puberty in male should be recognized more widely as a unique sign of neoplasm.

High-Sensitivity C-Reactive Protein Can Reflect Small Airway Obstruction in Childhood Asthma.

PURPOSE: High-sensitivity assays enabled the identification of C-reactive protein (hs-CRP) at levels that were previously undetectable. We aimed to determine if hs-CRP could reflect airway inflammation in children, by comparing hs-CRP with spirometry and impulse oscillometry (IOS) parameters and symptomatic severities. MATERIALS AND METHODS: A total of 276 asthmatic children who visited Severance Children's Hospital from 2012-2014 were enrolled. Serum hs-CRP and pulmonary function tests were performed on the same day. Patients were divided into hs-CRP positive and negative groups (cut-off value, 3.0 mg/L). RESULTS: Of the 276 asthmatic children [median age 7.5 (5.9/10.1) years, 171 boys (62%)], 39 were hs-CRP positive and 237 were negative. Regarding spirometry parameters, we observed significant differences in maximum mid-expiratory flow, % predicted (FEF25₋75) (p=0.010) between hs-CRP positive and negative groups, and a negative correlation between FEF25₋75 and hs-CRP. There were significant differences in the reactance area (AX) (p=0.046), difference between resistance at 5 Hz and 20 Hz (R5-R20) (p=0.027), resistance at 5 Hz, % predicted (R5) (p=0.027), and reactance at 5 Hz, % predicted (X5) (p=0.041) between hs-CRP positive and negative groups. There were significant positive correlations between hs-CRP and R5 (r=0.163, p=0.008), and X5 (r=0.164, p=0.007). Spirometry and IOS parameters had more relevance in patients with higher blood neutrophil levels in comparison to hs-CRP. CONCLUSION: Hs-CRP showed significant correlation with FEF25₋75, R5, and X5. It can reflect small airway obstruction in childhood asthma, and it is more prominent in neutrophil dominant inflammation.

Hypotonic hyponatremia by primary polydipsia caused brain death in a 10-year-old boy.

Hypotonic hyponatremia by primary polydipsia can cause severe neurologic complications due to cerebral edema. A 10-year-and-4-month-old boy with a psychiatric history of intellectual disability and behavioral disorders who presented with chief complaints of seizure and mental change showed severe hypotonic hyponatremia with low urine osmolality (serum sodium, 101 mmol/L; serum osmolality, 215 mOsm/kg; urine osmolality, 108 mOsm/kg). The patient had been polydipsic for a few months prior, and this had been worse in the previous few days. A diagnosis of hypotonic hyponatremia caused by primary polydipsia was made. The patient was in a coma, and developed respiratory arrest and became brain death shortly after admission, despite the treatment. The initial brain magnetic resonance imaging showed severe brain swelling with tonsillar and uncal herniation, and the patient was declared as brain death. It has been reported that antidiuretic hormone suppression is inadequate in patients with chronic polydipsia, and that this inadequate suppression of antidiuretic hormone is aggravated in patients with acute psychosis. Therefore, hyponatremia by primary polydipsia, although it is rare, can cause serious and life-threatening neurologic complications.

IL-34 is associated with obesity, chronic inflammation, and insulin resistance.

OBJECTIVES: IL-34 is a recently identified alternative ligand for colony-stimulating factor-1 (CSF-1) receptor. IL-34 and CSF-1 are regulators of differentiation, proliferation, and survival in mononuclear phagocytes. Here, we investigated the IL-34 serum concentration and expression in human adipose tissues and any associations with insulin resistance. METHODS: We recruited 19 nondiabetic obese women, 9 type 2 diabetic women, and 27 normal-weight women. Metabolic parameters, abdominal fat distribution, serum IL-34 concentration, and IL-34 mRNA expression were measured in abdominal sc adipose tissue (SAT) and visceral adipose tissue (VAT). In addition, the expression/secretion and putative effects of IL-34 were assessed in human differentiated adipocytes. Serum IL-34 concentration was measured before and 5 to 9 months after laparoscopic Roux-en-Y gastric bypass surgery was performed on the 20 obese patients. RESULTS: Regardless of diabetes status, obese patients demonstrated significantly higher serum IL-34 concentrations than controls. Serum IL-34 was significantly and positively correlated with insulin resistance-related metabolic parameters. IL-34 mRNA was significantly higher in VAT than SAT. IL-34 was expressed in adipocytes as well as nonadipocytes, and expression was significantly higher during adipogenesis. In differentiated adipocytes, the expression/secretion of IL-34 was enhanced by TNFα and IL-1ß. In addition, IL-34 augmented fat accumulation and inhibited the stimulatory effects of insulin on glucose transport. Moreover, serum IL-34 was significantly decreased after Roux-en-Y gastric bypass-induced weight loss. CONCLUSION: The present study demonstrates, for the first time, that IL-34 is expressed in human adipose tissues and the circulating concentration is significantly elevated in obese patients. This suggests that IL-34 is associated with insulin resistance.

Development and clinical evaluation of a rapid serodiagnostic test for toxoplasmosis of cats using recombinant SAG1 antigen.

Rapid serodiagnostic methods for Toxoplasma gondii infection in cats are urgently needed for effective control of transmission routes toward human infections. In this work, 4 recombinant T. gondii antigens (SAG1, SAG2, GRA3, and GRA6) were produced and tested for the development of rapid diagnostic test (RDT). The proteins were expressed in Escherichia coli, affinity-purified, and applied onto the nitrocellulose membrane of the test strip. The recombinant SAG1 (rSAG1) showed the strongest antigenic activity and highest specificity among them. We also performed clinical evaluation of the rSAG1-loaded RDT in 182 cat sera (55 household and 127 stray cats). The kit showed 0.88 of kappa value comparing with a commercialized ELISA kit, which indicated a significant correlation between rSAG1-loaded RDT and the ELISA kit. The overall sensitivity and specificity of the RDT were 100% (23/23) and 99.4% (158/159), respectively. The rSAG1-loaded RDT is rapid, easy to use, and highly accurate. Thus, it would be a suitable diagnostic tool for rapid detection of antibodies in T. gondii-infected cats under field conditions.

Maintained seroprevalence of toxoplasmosis among the residents of Jeju island, Korea.

Seroepidemiological status of toxoplasmosis among the residents of Jeju island was surveyed and evaluated by ELISA with crude extract of Toxoplasma gondii. The sera of 2,348 residents (male 1,157 and female 1,191) were collected and checked for the IgG antibody titers, which showed 13.2% positive rate (309 sera). The positive rates were increasing gradually according to the age from 4.3% in teenage to 20.6% in seventies. The positive rates were significantly different between the sex by 16.2% for male and 10.2% for female (P<0.05). This positive rate of toxoplasmosis in Jeju island residents is regarded relatively higher than any other regions of Korea. And the high positive rate may be maintained continuously among Jeju island residents without any clear reasons until now but due to some parts peculiar socio-cultural tradition of Jeju island. Therefore, it is necessary to study further the epidemiology of toxoplasmosis of Jeju island.

Template-free synthesis and characterization of mesoporous tungsten nitride nanoplates.

We report well-defined mesoporous ß-W(2)N nanoplates prepared by using layered WO(3)·H(2)O without templates. The tungsten nitride nanoplates exhibit typical mesoporous structures with size-controlled monomodal pore distributions.

Synthesis of octahedral Pt-Pd alloy nanoparticles for improved catalytic activity and stability in methanol electrooxidation.

We report Pt-Pd nanoparticles synthesized by means of a polyol process with glycerol as a reducing agent. The Pt-Pd nanoparticles exhibit dominantly exposed {111} facets in octahedral shape with complete alloy formation between Pt and Pd. Furthermore, the octahedral Pt-Pd alloy catalysts show improved catalytic activity and stability in methanol electrooxidation.

High-performance hydrogen fuel cell using nitrate reduction reaction on a non-precious catalyst.

The H(2)-NO(3)(-) electrochemical cell using nitrate reduction on a non-precious cathode catalyst shows much improved efficiency despite ∼75% reduction of Pt metal loading as compared to typical PEMFCs using typical ORR on precious catalysts.

Cuboctahedral Pd nanoparticles on WC for enhanced methanol electrooxidation in alkaline solution.

We report cuboctahedral Pd nanoparticles on WC synthesized by the polyol process using ethylene glycol with NO(3)(-) and Fe(3+)/Fe(2+) ions. The cuboctahedral Pd/WC shows much improved electrocatalytic activity for methanol electrooxidation in alkaline solution.

Synergy effect of nanostructure electrodes supported by tungsten carbide and oxide for methanol electrooxidation.

We report nanostructure electrodes for methanol electrooxidation by means of the co-sputtering deposition method. The Pt-WC-WO(3) three-phase electrode has higher I(f)/I(b) and oxidation current density i.e. improved electrocatalytic activity in comparison with those of pure Pt and two-phase electrodes because of both catalysis of tungsten carbide and size-control by tungsten oxide.

Hypoxia switches glucose depletion-induced necrosis to phosphoinositide 3-kinase/Akt-dependent apoptosis in A549 lung adenocarcinoma cells.

In solid tumours, necrosis is commonly found in the core region in response to metabolic stress that results from oxygen and glucose depletion (OGD) due to insufficient vascularization and has been implicated in tumour progression. We have previously shown that metabolic stress due to glucose depletion (GD) induces necrosis and HMGB1 release through mitochondrial ROS production in A549 lung adenocarcinoma cells. In this study, we examined the effects of hypoxia on GD-induced necrosis and show that hypoxia prevented GD-induced mitochondrial ROS production, HMGB1 release, and necrosis and switched the cell death mode to apoptosis that is dependent on caspase-3 and -9. We further found that inhibition of ERK1/2 by U0126 abolished the effects of hypoxia to switch the cell death mode and to suppress mitochondrial ROS production, indicating an important role(s) of the ERK pathway in cell death mode determination. We also found that during OGD-induced apoptosis the prosurvival protein kinase Akt is activated and inhibition of Akt by the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and wortmannin prevent OGD-induced apoptosis, caspase-3 and -9 activation, and nuclear translocation of AIF and EndoG. Similar inhibitory effects of PI3K inhibitors were observed in A549 cells that underwent apoptosis when treated with GD in the presence of NAC (a general antioxidant) or catalase (a H(2)O(2) scavenger), or in the presence of active PKC by treatment with phorbol-12-myristate-13-acetate, indicating a crucial role(s) of the PI3K-Akt pathway in OGD-indcued apoptosis. In conclusion, our results demonstrate that hypoxia switches GD-induced necrosis to apoptosis and ERK1/2 and PI3K-Akt exert anti-necrotic and pro-apoptotic activities in the cell death, respectively.