Severe Drug-Induced Interstitial Lung Disease After Administration of Osimertinib as Adjuvant Treatment for Resected EGFR-Mutated NSCLC: A Case Report.

Osimertinib administration has been approved as an adjuvant treatment after complete surgical resection in patients with EGFR-mutated NSCLC. This article presents the first report of life-threatening postoperative osimertinib-induced interstitial lung disease. An 83-year-old male patient underwent right upper lobectomy (pathologic stage IIA) and osimertinib (80 mg/d) was initiated on postoperative day 75. On day 44 of osimertinib administration, chest computed tomography revealed diffuse ground-glass opacities; accordingly, osimertinib-induced interstitial lung disease was diagnosed. Steroid pulse therapy was initiated using a high-flow nasal cannula to treat dyspnea and hypoxemia, rapidly improving the respiratory status and imaging findings; moreover, the patient's clinical course was excellent. This case report suggests that the postoperative occurrence of severe osimertinib-induced interstitial lung disease is a crucial factor that must be considered in patient decision-making regarding perioperative treatment.

Comparison Between Second- and Third-generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors as First-line Treatment in Patients With Non-small-cell Lung Cancer: A Retrospective Analysis.

BACKGROUND: For epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), administration of EGFR tyrosine kinase inhibitors (TKIs) is mandatory to prolong survival. To date, a comparison of second- and third-generation EGFR-TKIs has not been reported as far as we are aware. PATIENTS AND METHODS: We retrospectively investigated the survival time of patients diagnosed with EGFR-mutated advanced or recurrent NSCLC who had received afatinib, a second-generation EGFR-TKI, or osimertinib, a third-generation EGFR-TKI, as the first-line treatment. RESULTS: Among the 49 patients included in the study, 15 received afatinib and 34 received osimertinib. No significant differences in overall survival were observed between the two groups [afatinib vs. osimertinib=36 vs. 33 months (hazard ratio=2.917, 95% confidence interval=0.780-10.905; p=0.112)]. T790M mutation was detected in three of the patients in the afatinib group, and all three subsequently received osimertinib. The median overall survival of these three patients and of the 12 without the mutation were 63 and 36 months, respectively. CONCLUSION: There was no apparent difference in the effect on survival between second- and third-generation EGFR-TKIs, whereas the sequential administration of second- followed by third-generation EGFR-TKIs appeared to confer a better long-term prognosis.

Large cell neuroendocrine carcinoma of the lung with cancer-associated retinopathy.

We report a rare case of large cell neuroendocrine carcinoma (LCNEC) of the lung with cancer-associated retinopathy (CAR). To our knowledge, only two cases of LCNEC with CAR have been reported, one in 1995 and another in 2013. CAR, typically associated with small cell lung cancer (SCLC), is one of the paraneoplastic syndromes with deterioration of visual acuity, visual field constriction, and photophobia. CAR is caused by an autoimmune system reaction against the same antigen in the tumor and retinal photoreceptor cells. To diagnose CAR, genetic retinal dystrophies or any other medical causes of retinopathy should be excluded, but there are no standard diagnostic criteria. Anti-retinal antibodies are known to be positive in CAR patients, and anti-recoverin antibodies are thought to be sensitive and specific to CAR. In our case, anti-recoverin antibodies were not detected by serum tests, but CAR could be diagnosed on the basis of ophthalmological findings including clinical symptoms, electroretinographic findings, and visual field tests. CAR with clinical features of rapid visual disorder should be considered in LCNEC patients as well as in SCLC patients.

[Comparison of diagnostic criteria for the metabolic syndrome among Japanese university faculty].

OBJECTIVES: Diagnostic criteria for the metabolic syndrome (Mets) in Japan have been set by the Medical Committee of the Japanese Association of Medical Sciences (Med), the National Health and Nutrition Examination Survey (Nat), specific health checkups (Ckup), and second medical examination by Worker's Accident Compensation Insurance System (Wor). The purpose of this study was to compare classification of the metabolic syndrome by different organizational criteria and to investigate underlying differences. METHODS: All faculty members of a university in Osaka, Japan, underwent mandatory health checkups in September 2008. The demographic distribution included 769 males (mean age, 49 +/- 12 years) and 415 females (mean age, 43 +/- 10 years). Using the Med, Nat, Ckup and Wor criteria, individuals were assessed for the MetS and pre-metabolic syndrome (pre-Mets), strongly suspected metabolic syndrome (S-Mets) and assumed pre-metabolic syndrome (A-pre-Mets), as well as a positive support level (PSL) and a motivational support level (MSL). All faculty members were categorized into a morbid group (Mets, S-Mets, PSL, and FB) or a pre-morbid group (pre-Mets, A-pre-Mets, and MSL) based on medical data and smoking habits. The incidence of morbid and pre-morbid individuals was compared across the four criteria and analyzed based on gender and age (under 40 and 40 or over). RESULTS: Male incidences for the morbid and pre-morbid classifications were 17% and 20% with Med, 9% and 23% with Nat, 27% and 14% with Ckup, and 1.4% and 0% with Wor. There were significant differences across criteria sets in both the morbid and pre-morbid groups, with significantly greater numbers of males than females, and higher prevalences in those aged 40 or over than in their younger counterparts. Males aged under 40 classified into the pre-morbid group comprised 18% in Med, 16% in Nat, and 13% in Ckup. CONCLUSION: The different disease incidences found between Med and Ckup data in males aged 40 or over might be attributed to varying criteria for blood glucose levels, while Wor data may be influenced by the higher level of blood pressure set as a criterion with this approach. It will be important to continuously validate currently established criteria to identify the actual prevalence of MetS in Japan. Furthermore, incorporation of waist circumference and BMI for females, and a positive approach for young males, may be critical for future developments.

Toxicokinetics and metabolism deteriorated by acute nephrotoxicity after a single intravenous injection of hydrofluoric acid in rats.

OBJECTIVES: This study was designed to investigate the early dynamic state of hydrofluoric acid (HFA) in blood and urine as a model of accidental occupational exposure to a subtoxic dose of HFA. It was also aimed at determining the relationship between the kinetics and harmful effects of HFA on the kidney. METHODS: Rats received a single intravenous injection of HFA (3.2, 6.4, or 9.6 (LD(5)) mg/kg) or saline. The volume of each injection was 1 ml and the concentrations of HFA were 0.1, 0.2, and 0.3%, respectively. Ionized fluoride (F) was measured for the biological monitoring of HFA. Serum F concentrations were determined at 0, 5, 10, 30, 60, 120, and 300 min. Pharmacokinetic parameters were calculated with two-compartment modeling. Urine was directly collected from bladder for 300 min to determine the extent of the renal damage. RESULTS: AUC(0→300) values were significantly higher in the 9.6 mg/kg group than in the 3.2 and 6.4 groups. The total body clearance, V(1), V(2) and V(ss) were significantly lower in the 6.4 and 9.6 mg/kg groups than in the 3.2 mg/kg group. These results indicate that HFA was retained in blood. This could be a result of renal dysfunction. NAG/Cr and glucose excretion amount in urine were increased, and the clearance rate of F, urine volume and excretion amounts of electrolytes were decreased in the 9.6 mg/kg group compared with the saline group. These findings indicate renal tubular damage and a decrease in the amount of excretion of HFA from the kidney. CONCLUSIONS: We consider that acute nephrotoxicity of HFA caused renal injury, and the harmful effects of HFA were subsequently aggravated by its delayed metabolism.

Effects of sodium monofluoroacetate on glucose, amino-acid, and fatty-acid metabolism and risk assessment of glucose supplementation.

Sodium monofluoroacetate (SMFA; also known as compound 1080) is a highly toxic chemical; therefore, accidental exposure and intentional misuse are of great concern. SMFA intoxication is reportedly caused by the inhibition of aconitase. However, the pathogenesis underlying SMFA intoxication is not clear. This study was conducted to elucidate the acute effects of SMFA on glucose, amino-acid, and fatty-acid metabolism and to assess glucose supplementation as a possible alleviator or aggravator in SMFA intoxication. Rats were assigned to three groups: SMFA+saline, SMFA+glucose, and control (i.e., no SMFA), and blood samples were analyzed at 3 hours after SMFA or saline (control) administration. Additional rats were used for the monitoring of blood-glucose and lactate concentrations for 10 hour- and 14-day survival rates. SMFA increased the serum-citrate, serum-pyruvate, and blood-lactate concentrations. However, despite significant increases in these parameters when SMFA was administered with glucose, the effects on pH values were small and the survival rate was not changed. SMFA also increased the serum concentrations of free fatty acids, branched-chain amino acids, ammonia, urea, and calcium. The presence of glucose enhanced or suppressed these metabolic changes. Amphibolic intermediates in the tricarboxylic acid cycle might be supplied through the catabolism of proteins in SMFA intoxication. We conclude that other factors, in addition to the accumulation of lactate, citrate, and pyruvate, may affect survival rates, and that SMFA induces imbalances in glucose, amino-acid, and, fatty-acid metabolism. All these changes are inter-related and may contribute to SMFA intoxication.

Time-dependent changes of blood parameters and fluoride kinetics in rats after acute exposure to subtoxic hydrofluoric acid.

OBJECTIVES: In our previous study, we reported that even a sublethal dose of hydrofluoric acid (HFA) could cause acute toxic effects 60 min after intravenous injection. This study was designed to investigate the time- and dose-dependent changes associated with these disorders. The serum fluoride (F) kinetics are also considered in the discussion of the relationship between the concentrations of serum F and the disorders. METHODS: Rats were injected with HFA (1.6 or 9.6 mg/kg body weight) for the dose-response relationship study. For each dose, the rats were assigned to one of seven groups. Blood samples of the 0-min group were obtained from the carotid artery prior to injection as a control. The other six groups were labeled according to sampling times (5, 10, 30, 60, 120 and 300-min) in the time-dependent study. RESULTS: The 1.6 mg/kg dose decreased the ionized calcium (Ca2+) level significantly after 30 min, and it also decreased the total calcium (Ca) level after 300 min. The 9.6 mg/kg dose rapidly worsened renal dysfunction after 60 min. It increased the serum potassium level after 60 and 120 min and it decreased Ca and Ca2+ levels until 300 min. Although there was respiratory compensation, the base excess and HCO3(-) level and had not completely recovered by 300 min. CONCLUSIONS: Even low exposure to HFA caused renal dysfunction, and electrolyte abnormalities and metabolic acidosis lasted for several hours in rats. Therefore, persons involved in HFA accidental exposure should be closely monitored over time, even if the exposure is less than the sublethal dose.

Urinary scandium as predictor of exposure: effects of scandium chloride hexahydrate on renal function in rats.

Some of the rare earth elements such as Sc are believed to be non-toxic and, at present, are widely utilized for the replacement of toxic heavy metals in technological applications, but they are not entirely free of toxicity, with hidden potential health risks. In this animal experiment, we report the urinary scandium (Sc) excretion rate and nephrotoxiciy in male Wistar rats. For this purpose, the rats were given a single dose of a solution of scandium chloride by intraperitoneal injection. The Sc excretion (U-Sc) was determined in 24-h urine samples by inductively coupled plasma-argon emission spectrometry along with the Sc nephrotoxicity, urine volume (UV), creatinine (Crt), beta-2-microglobulin (beta2-MG) and N-acetyl-beta-D-glucosaminidase (NAG). A dose-dependent Sc excretion of 0.0063% (r = 0.97) via 24-h urine was confirmed. The administration of Sc induced a significant decrease of UV and Crt and a significant increase of NAG and beta2-MG. These results suggest that U-Sc can be a useful tool for monitoring Sc exposure. The formation of Sc colloidal conjugates that deposit in glomeruli may be the cause of a reduction of the glomerular filtration rate. We propose that the analytical method and results described in this study will be of great importance for future toxicological studies on Sc exposure.

Abnormalities in cadmium fluoride kinetics in serum, bile, and urine after single intravenous administration of toxic doses to rats.

Cadmium fluoride (CdF2, CdF for short) is the most lethal and hepatotoxic of all Cd-containing compounds. The toxic effects of CdF appear to depend on its detoxification and elimination. This study was designed to determine the early dynamics of the absorption, systemic distribution, and metabolism of CdF. The kinetics of cadmium and fluoride were investigated in the blood, bile, and urine of rats as a model of accidental occupational exposure to CdF. The serum concentration-time profiles measured after intravenous CdF (1.34, 2.67 or 4.01 mg/ per kg body weight) administration were analyzed by compartmental modeling using the WinNonlin program. Bile and urine were collected for 300 min after the administration. The kinetic profiles indicate that the clearance of Cd was diminished in the 2.67 and 4.01 mg/kg groups, leading to a persistently high serum Cd level. The mean total biliary excretions of Cd in the 2.67 and 4.01 mg/kg groups were significantly higher than that in the 1.34 mg/kg group. The abnormal kinetics of Cd was attributable to severe hepatic injury that diminished the capacity for Cd accumulation. The elimination of serum F was delayed in the 4.01 mg/kg group. The mean urinary F excretion amount was not significantly higher in the 4.01 mg/kg group than in the 2.67 mg/kg group. The abnormal kinetics of F was attributable to nephrotoxicity that diminished its elimination from the kidney.

Urinary fluoride reference values determined by a fluoride ion selective electrode.

As fluoride has a very short half-life in the body and the major route for fluoride excretion is via the kidney, human exposure is best measured in urine, where the concentration is expected to be highest. The urinary fluoride concentrations of 167 healthy Japanese adults were determined by means of a fluoride ion selective electrode. When the results were corrected for a specific gravity rho = 1.024 g cm-3, the histogram of urinary fluoride concentrations highly skewed toward low values with sharp peakedness (skewness = 1.56, kurtosis = 3.08). The normality of the log-transformed histogram (skewness = 0.12, kurtosis = 0.07) and the straight line on log-probability paper clearly showed a key feature of lognormal distribution of urinary fluoride. A geometric mean (GM) of 613.8 microg/l and 95% confidential interval (CI) of 241.0-1633.1 microg/l were established as reference values for urinary fluoride. The results presented in this study will be useful as guidelines for the biological monitoring of fluoride in normal subjects and individuals at risk of occupational or environmental fluoride exposure.