Impact of Cytoreductive Nephrectomy Following Nivolumab Plus Ipilimumab Therapy for Patients With Advanced Renal Cell Carcinoma.

BACKGROUND/AIM: CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC. PATIENTS AND METHODS: Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy. RESULTS: The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR. CONCLUSION: Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

Methyl isobutyl ketone and methyl ethyl ketone in urine as biological markers of occupational exposure to these solvents at low levels.

OBJECTIVE: To examine whether unmetabolized methyl isobutyl ketone in urine is a useful marker of low-level occupational exposure to this ketone solvent, as is the case for methyl ethyl ketone. METHODS: The study was conducted in the second half of a working week. In total, 27 furniture-making workers (19 men and eight women) and 11 non-exposed controls (six men and five women) volunteered to participate in the study. Time-weighted average (TWA; 8-h) concentration of vapors of several solvents in air, including methyl isobutyl ketone (MIBK-A) and methyl ethyl ketone (MEK-A) was monitored by diffusive sampling. Urine samples collected at the end of the shift were subjected to head-space gas chromatography (GC) analysis for the unmetabolized solvents (i.e., MIBK-U and MEK-U). The relationship between the concentration of the solvent vapor and the corresponding solvent level in urine was examined by simple as well as multiple regression analysis. RESULTS: The exposures to MIBK and MEK were well below the current occupational exposure limit levels, but the maximum levels of exposure to toluene and ethylbenzene were around the corresponding exposure limit. The correlation of the TWA concentration of the solvent in air with the concentration of the corresponding solvent in the end-of-shift urine sample was significant both for MIBK and for MEK, and the correlation coefficient was larger for MIBK than for MEK. The slope in the exposure-excretion regression line was almost twice as steep for MEK than for MIBK, possibly due to the difference in water solubility. Approximately 0.12% of MIBK absorbed in the lungs will be excreted into urine, whereas the yield for MEK was somewhat higher (0.19%). CONCLUSION: MIBK in urine is a good marker of exposure to MIBK, as in the case of MEK in urine for MEK exposure.

Toluene, xylenes and xylene isomers in urine as biological indicators of low-level exposure to each solvent; a comparative study.

OBJECTIVE: To examine if xylenes and xylene isomers in end-of-shift urine are good biological indicators of low-level exposure to each solvent, similarly to toluene in urine. METHODS: The study was conducted in the latter half of a working week. Furniture makers, 86 subjects in total (76 men and ten women), participated in the study in combination with 11 non-exposed subjects. Time-weighted average (8-h TWA) exposures to mixtures of toluene (TOL-A), xylenes (XYLs-A), ethylbenzene (EB-A), acetone (ACE-A) etc. were monitored with diffusive samplers for lipophilic and hydrophilic solvents, respectively. Urine samples (i.e., TOL-U, XYLs-U, EB-U, ACE-U, etc.) were collected at the end of the shift and subjected to head-space gas chromatography analysis for each solvent. The exposure-excretion relationship was examined by simple as well as multiple regression analysis. RESULTS: The exposures to TOL and XYLs were around or below current occupational exposure limit levels. The exposures to other solvents [i.e., ACE, EB, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), etc.] were at substantially lower levels. The correlation of the TWA solvent exposure concentration with the concentration of the corresponding solvent in the end-of-shift urine sample was close for TOL, and also almost equally close in the case of XYLs and each of the three XYL isomers. Whereas the slope of the regression line for XYLs was significantly less steep than that for TOL when compared on an equi-molar basis, there was no difference among the three XYL isomers. No confounding effects of age, sex and co-exposure to other solvents were detected. The observation confirms previous reports that TOL-U is a good marker of TOL vapor exposure, indicates that XYL-U is also a reliable marker of exposure to vapors of XYLs or any of the three XYL isomers, and suggests that estimation of exposure to vapors of XYLs (i.e., three isomers in combination) is possible by the determination of one of the XYL isomers in urine, once the proportion of the isomers in air is known. Possible association of water solubility with solvent levels in urine is discussed. CONCLUSIONS: Biological monitoring of exposure by means of analysis of end-of-shift urine for mother solvent is possible, not only in the case of TOL as previously reported, but also in cases of XYLs, either for three isomers in combination or separately.

Urinary bromide levels probably dependent to intake of foods such as sea algae.

The purpose of the present study is to examine if the bromide (Br) level in urine (Br-U) varies substantially among adult general populations of either sex or of different dietary habits. For this purpose, morning spot urine samples (about 50 per group) were collected from six groups of people, i.e., one group each of men and women in a city in Japan (thus two groups in Japan) and one group each of women in two urban and two rural areas in central and northeast China (four groups in China). The samples were analyzed for Br by ECD-gas chromatography after derivatization to methyl bromide. Br-U essentially followed a normal distribution. Whereas there was only a marginal difference in Br-U between men (7.7 +/- 2.5 mg/L as an arithmetic mean and arithmetic standard deviation) and women (8.1 +/- 2.9 mg/L) in Japan, and no difference between the urban (2.3 +/- 0.8 mg/L) and rural women (2.6 +/- 1.1 mg/L) in China, the difference between Japanese (8.1 +/- 2.9 mg/L) and Chinese women (2.3 +/- 0.8 mg/L for two cities and 2.6 +/- 1.1 mg/L for two villages) was substantial. A literature survey suggested variation in dietary habits, especially that in sea algae intake, is a possible factor affecting the observed difference in Br-U between the two ethnic groups. Contribution of Br in cereals after fumigation with, e.g., methyl bromide, was also thought to be possible. The implication of difference in background Br-U levels is discussed in relation to biological monitoring of exposure to Br-containing industrial chemicals, such as 1- and 2-bromopropane.

Biological monitoring of occupational exposure to 1-bromopropane by means of urinalysis for 1-bromopropane and bromide ion.

The purposes of the present study are (1) to develop a sensitive analytical method to measure 1-bromopropane (1-BP) in urine, (2) to examine if 1-BP or bromide ion (Br) in urine is a useful biomarker of exposure to 1-BP, and (3) to identify the lowest 1-BP exposure concentration the method thus established can biomonitor. A factory survey was carried out on Friday, and 33 workers (all men) in cleaning and painting workshops participated; each worker was equipped with a diffusive sampler (carbon cloth KF-1500 as an adsorbent) to monitor 1-BP vapour for an 8-h shift, and offered a urine sample at the end of the shift for measurement of 1-BP and Br in urine. In addition, 10 non-exposed men offered urine samples as controls. The performance of the carbon cloth diffusive sampler was examined to confirm that the sampler is suitable for monitoring time-weighted average 1-BP vapour exposure. A head-space GC technique was employed for analysis of 1-BP in urine, whereas Br in urine was analysed by ECD-GC after derivatization to methyl bromide. The workers were exposed to vapours of seven other solvents (i.e. toluene, xylenes, ethylbenzene, acetone, etc.) in addition to 1-BP vapour; the 1-BP vapour concentration was 1.4 ppm as GM and 28 ppm as the maximum. Multiple regression analysis however showed that 1-BP was the only variable that influenced urinary 1-BP significantly. There was a close correlation between 1-BP in urine and 1-BP in air; the correlation coefficient (r) was >0.9 with a narrow variation range, and the regression line passed very close to the origin so that 2 ppm 1-BP exposure can be readily biomonitored. The correlation of Br in urine with 1-BP in air was also significant, but the r (about 0.7) was smaller than that for 1-BP, and the background Br level was also substantial (about 8 mg l(-1)). Thus, it was concluded that 1-BP in end-of-shift urine is a reliable biomarker of occupational exposure to 1-BP vapour, and that Br in urine is less reliable.

Possible metabolic interaction between hexane and other solvents co-exposed at sub-occupational exposure limit levels.

OBJECTIVE: To investigate whether metabolic interactions exist between hexane (HEX) and other solvents when co-exposed at the levels below occupational exposure limits. METHODS: Workers, 219 men in ten workshops in total, volunteered to participate in the study. They were occupationally exposed to mixtures of HEX and one or more of toluene (TOL), ethyl acetate (EA) and acetone (ACE). Time-weighted average intensity of vapor exposures was monitored by diffusive personal sampling. 'Free'- and 'total'-2,5-hexanedione (HD) levels in the end-of-shift urine samples were determined by gas chromatography (GC) before and after acid hydrolysis of urine, respectively, and expressed as observed (HDob) or after correction for creatinine concentration (HDcr) or urine specific gravity (HDsg). Possible interaction was examined by multiple regression analysis (MRA), taking either free- or total-HD as a dependent variable, and the four solvent concentrations as independent variables. RESULTS: In most cases, exposure intensity did not exceed the current occupational exposure limits even when additiveness was assumed. In addition that HEX was the most influential independent variable in all cases as expected, the MRA showed that, in cases of free-HD, ACE was also influential to HDob although weakly, but not to HDcr or HDsg. With regard to total-HD, ACE was weakly influential to HDob and HDsg, and EA also weakly to HDcr. The effect of ACE on free- or total-HD was not detected, however, when 22 men exposed only to HEX and ACE were subjected to the same analysis. Similarly, the effect of EA on total-HD was not observed among the remaining 197 men exposed to HEX, TOL and EA only. CONCLUSIONS: When the exposures were below occupational exposure limits, the free-HD levels in urine after HEX exposure will not be modified by co-exposures to TOL, EA or ACE.

Monitoring of occupational exposure to tetrachloroethene by analysis for unmetabolized tetrachloroethene in blood and urine in comparison with urinalysis for trichloroacetic acid.

OBJECTIVE: The present study was initiated to examine a quantitative relationship between tetrachloroethene (TETRA) in blood and urine with TETRA in air, and to compare TETRA in blood or urine with trichloroacetic acid (TCA) in urine as exposure markers. METHODS: In total, 44 workers (exposed to TETRA during automated, continuous cloth-degreasing operations), and ten non-exposed subjects volunteered to participate in the study. The exposure to vapor was monitored by diffusive sampling. The amounts of TETRA and TCA in end-of-shift blood and urine samples were measured by either head-space gas chromatography (HS-GC) or automated methylation followed by HS-GC. The correlation was examined by regression analysis. RESULTS: The maximum time-weighted average (TWA) concentration for TETRA-exposure was 46 ppm. Regression analysis for correlation of TETRA in blood, TETRA in urine and TCA in urine, with TETRA in air, showed that the coefficient was largest for the correlation between TETRA in air and TETRA in blood. The TETRA in blood, in urine and in air correlated mutually, whereas TCA in urine correlated more closely with TETRA in blood than with TETRA in urine. The TCA values determined by colorimetry and by the GC method were very similar. The biological marker levels at a hypothetical exposure of 25 ppm TETRA were substantially higher in the present study than were the levels reported in the literature. Possible reasons are discussed. CONCLUSIONS: Blood TETRA is the best marker of occupational exposure to TETRA, being superior to the traditional marker, urinary TCA.

Relationship between multidrug resistant gene expression and multidrug resistant-reversing effect of MS-209 in various tumor cells.

MS-209 is a novel quinoline compound which can overcome multidrug resistance (MDR) both in vitro and in vivo, while having a low level of side effects, and is now being evaluated in a clinical phase II study. Reverse transcription-polymerase chain reaction (RT-PCR) was used to quantitate the expression levels of MDR genes in various mouse and human tumor cell lines. The MDR gene and the beta actin gene, as the internal reference standard, were coamplified separately, and the relative expression of the MDR gene was represented by the MDR/beta actin ratio. The in vitro MDR-reversing effect of MS-209 was then compared with the MDR gene expression (MDR/beta actin ratio). We found a significant correlation between these two parameters. Moreover, a significant correlation was also observed between the level of expression of the MDR1 gene and that of P-glycoprotein in human cell lines. Therefore, the efficacy of MS-209 seems to specifically depend on the level of MDR gene expression (P-glycoprotein). From these observations, it is suggested that RT-PCR assays of MDR1 gene in tumor biopsy specimens might be an effective means to predict the response of tumor cells to combination therapy with MS-209.

Correlative regulation of nerve growth factor level and choline acetyltransferase activity by thyroxine in particular regions of infant rat brain.

Effects of thyroxine (T4) on nerve growth factor (NGF) level and choline acetyltransferase (ChAT) activity of rat brains were investigated. Repetitive intraperitoneal administration of T4 caused increases in both NGF level and ChAT activity in the frontal cortex, septum, hippocampus, and striatum and decreases in the cerebellum in 2-day-old rats. Only ChAT activity was elevated in the olfactory bulb, and the NGF level remained unchanged there. No changes were observed in the midbrain and pons/medulla. Furthermore, T4 was effective on the postnatal rats only up to day 11. These results suggest that T4 plays a role in the developmental regulation of NGF level and ChAT activity in rat brain in a region- and/or stage-specific manner. That (1) changes in NGF level and ChAT activity occurred in regions nearly identical to those that contained NGF-responding neurons, and (2) the change in NGF level in the hippocampus and frontal cortex was followed by the change of ChAT activity after a single injection of T4 suggest that the effects of T4 on cholinergic differentiation are, at least in part, mediated via NGF, which itself is quantitatively regulated by T4.

A questionnaire study on fatigue symptoms of municipal personnel.

The following questionnaire surveys were conducted on 390 male personnel who work in one of the public facilities of a certain city. 1) Fatigue surveys: Using the Fatigue Scale of Industrial Fatigue Research Committee, questionnaire investigations were carried out twice, before work and after work. 2) Health surveys: Using Cornell Medical Index, the neurotic tendency was examined. When the correlation factors of average complaints frequencies were analyzed, indoor workers showed a type of mental task before and after work, whereas outdoor workers showed a type of mental task before work, but showed a general type after work. The workers in generation below thirty-five years mainly showed a type of mental task, while complaints about physical disintegration were relatively frequent in generation above fifties. We consider such questionnaire researches at each work site will constitute a useful clue for examining and ameliorating workers' fatigued condition which may exist inordinately in daily duties.

Stimulatory effect of 4-alkylcatechols and their diacetylated derivatives on the synthesis of nerve growth factor.

A series of 4-alkylcatechols and 1,2-diacetoxy-4-alkylbenzenes (from methyl to butyl) were chemically synthesized for in vitro evaluation as stimulators of nerve growth factor (NGF) synthesis. All compounds were proven to be potent in stimulating NGF synthesis in L-M cells (a mouse fibroblast cell line) and mouse astroglial cells. In a series of 4-alkylcatechols, 4-methylcatechol and 4-ethylcatechol severely affected viability and cell adhesive properties. In a series of 1,2-diacetoxy-4-alkylbenzenes, the concentrations required for the maximal effect and the effective ranges of concentrations were higher than those in the 4-alkylcatechol series, and the cell adhesive properties or viabilities were not affected. Evidence is also presented to indicate that the elevation of NGF synthesis by these compounds was not associated with the cell growth.

Metabolic fate of 1-hexylcarbamoyl-5-fluorouracil in rats.

1. The metabolic fate of a new antitumour agent, 1-hexylcarbamoyl-5-fluoro [6-14C]uracil (14C-HCFU) in rats after oral administration was compared with that of 5-fluoro[6-14C]uracil (14C-FU). 2. Tissue radioactivity reached a max. 1 to 3 h after administration of 14C-HCFU and 0.5 h after 14C-FU. 3. Both drugs were excreted rapidly, mostly in urine. Expired 14CO2 from 14C-HCFU was significantly less than that from 14C-FU. 4. Unchanged FU was not detected in plasma 3 h after administration of 14C-FU, whereas FU was detected in plasma 5 h after 14C-HCFU. The pyrimidine ring of 14C-HCFU might be degradated more slowly than that of 14C-FU. 5. 1-(5-Carboxypentylcarbamoyl)-5-fluorouracil and 1-(3-carboxypropylcarbamoyl)-5-fluorouracil were identified as the major urinary metabolites of 14C-HCFU.