Effects of polymorphisms in pregnane X receptor and ABC transporters on afatinib in Japanese patients with non-small cell lung cancer: pharmacogenomic-pharmacokinetic and exposure-response analysis.

PURPOSE: Because of the large interindividual variability of afatinib pharmacokinetics and adverse events, we evaluated the effects of polymorphisms in pregnane X receptor (NR1I2) and ABC transporters (ABCB1, ABCG2, and ABCC2) on the pharmacokinetics of afatinib. METHODS: The steady-state area under the concentration-time curve (AUC)0-24 of afatinib was analyzed using blood sampling just prior to and at 1, 2, 4, 6, 8, 12, and 24 h on day 15 after administration. RESULTS: The median oral clearance (CL/F) of afatinib in patients with the NR1I2 7635A allele was significantly lower than those in patients with the 7635G/G genotype (42.0 and 60.0 L/h, respectively, P = 0.025). There were no significant differences in afatinib CL/F between genotypes for NR1I2 8055C > T, -25385C > T, ABCB1, ABCG2, and ABCC2 polymorphisms. Based on the area under the receiver-operating characteristic curve, the threshold afatinib AUC0-24 value for prediction of dose reduction or withdrawal was 689 ng·h/mL at the best sensitivity (81.0%) and specificity (72.7%). In multivariate logistic regression analysis, an afatinib AUC0-24 above 689 ng·h/mL was independently associated with increased risk of dose reduction or withdrawal (OR: 11.66, P = 0.012). CONCLUSIONS: The NR1I2 7635A allele was related to a lower afatinib CL/F. Based on the AUC of 689 ng h/mL and CL/F, the optimal doses for patients with the NR1I2 7635G/G genotype and 7635A allele were recommended to be set at 40 and 30 mg/day, respectively, and subsequent adjustment of the maintenance dose based on the plasma concentrations of afatinib may be necessary to avoid afatinib-related adverse events.

Impact of the COVID-19 pandemic on the primary lung cancer screening program in Akita Prefecture, a region with the fastest aging population in Japan.

AIM: Akita Prefecture has the largest proportion of older inhabitants and the highest cancer mortality rate in Japan. Lung cancer is one of the biggest killers, and early detection is critical. Chest X-ray examinations are the main screening method for lung cancer; however, the COVID-19 pandemic has affected the screening system. Here, we evaluate how COVID-19 has affected lung cancer screening in Akita Prefecture. METHODS: Using the Akita General Health Corporation database, the average annual number of chest X-ray screening tests, close examinations and lung cancer diagnoses (stratified by sex and age) was evaluated during 2016-2019, and compared with the 2020 values. Furthermore, data on lung cancer registrations from 2018 to 2020 were obtained from the Collaborative Akita Prefecture Hospital-Based Cancer Registration System and analyzed. RESULTS: The average annual number of screening tests, close examinations and lung cancer diagnoses declined (by >50%) between 2016 to 2019 and 2020, especially among older people (aged ≥65 years). Furthermore, by stage, the number of patients with early-stage lung cancer (stage 0-I) decreased, and the number with advanced-stage cancer (stage IV) increased. CONCLUSIONS: The COVID-19 pandemic reduced lung cancer screening participation, especially among the older adult population in Akita Prefecture, resulting in a decrease in lung cancer diagnoses through screening. This might have reduced the number of early-stage cancer registrations. It is necessary to improve health education among the public regarding the importance of chest X-ray screening. Geriatr Gerontol Int 2023; 23: 622-627.

[An examination of the performance efficiency among dementia community support coordinators in Akita Prefecture].

AIM: To consider what is necessary to ensure the efficient performance of dementia community support coordinators. METHODS: In Akita Prefecture, we conducted a simple questionnaire survey of dementia community support coordinators in 25 municipalities to clarify the current status of their activities and examine what needs to be done to develop their projects more efficiently. RESULTS: It became clear that residents were not aware of the existence of these coordinators, underscoring the need to publicize their existence and activities. The lack of tools to improve the public's understanding of social resources for sharing information on building a support system was also demonstrated. In terms of cooperation, it was found that, despite the establishment of cooperation with IPIST and the medical center for dementia, cooperation with dementia support coordinators was insufficient. Furthermore, we confirmed that support coordinators were not very involved in the creation and activities of dementia care paths. CONCLUSIONS: Based on the above findings, we propose five points to support further efficient development. 1. Disseminate information to inform local residents about dementia community support coordinators, 2. Collaborate with dementia support coordinators and the welfare commissioner, 3. Create social resource maps and facilitate their understanding and establish dementia care path activities, 4. Create a work environment where dementia community support coordinators do not have to work concurrently, and 5. Create learning opportunities to improve understanding of the overall dementia policy.

Effects of CYP3A4/5 and ABC transporter polymorphisms on osimertinib plasma concentrations in Japanese patients with non-small cell lung cancer.

The effects of polymorphisms in CYP3A4 (20230G > A), CYP3A5 (6986A > G), ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and ABCC2 (-24C > T) on the area under the concentration-time curve (AUC) of osimertinib in 23 patients with non-small cell lung cancer were investigated. Blood sampling was performed just prior to and at 1, 2, 4, 6, 8, 12, and 24 h after osimertinib administration at the steady-state on day 15 after beginning therapy. The osimertinib AUC0-24 was significantly correlated with age (P = 0.038), serum albumin (P = 0.002), and serum creatinine (P = 0.012). Additionally, there were significant differences in the AUC0-24 of osimertinib among the groups administered vonoprazan, histamine 2-receptor antagonists or esomeprazole, and no acid suppressants (P = 0.021). By contrast, there were no significant differences in the AUC0-24 of osimertinib between genotypes of CYP3A4/5 or ABC transporters. Furthermore, there were no significant differences in the AUC0-24 of osimertinib between patients with diarrhea, skin rash, or hepatotoxicity and those without these conditions. In multivariate analysis, only serum albumin value was an independent factor predicting the AUC0-24 of osimertinib. Analysis of CYP3A4/5 and ABC transporter polymorphisms before osimertinib therapy may not predict the efficacy or side effects of osimertinib. The lower serum albumin values were associated with an increase in the AUC0-24 of osimertinib; however, further studies are needed to assess the factors contributing to the interindividual variability of osimertinib pharmacokinetics.

Relationship between Plasma Concentrations of Afatinib and the Onset of Diarrhea in Patients with Non-Small Cell Lung Cancer.

We evaluated the area under the plasma concentration-time curve (AUC) of afatinib required to avoid the onset of grade 2 or higher diarrhea. The C0 and AUC0-24 of afatinib were significant higher in patients with grade 2 diarrhea than in those with grade 0-1 diarrhea. The areas under the receiver operator curves were 0.795 with the highest sensitivity (89%) and specificity (74%) at an AUC0-24 threshold of 823.5 ng·h/mL, and 0.754 with the highest sensitivity (89%) and specificity (74%) at a C0 threshold of 28.5 ng/mL. In Kaplan-Meier analysis based on these cut-off AUC0-24 and C0 values, the median time to the incidence of grade 2 diarrhea was 16 days. The predicted AUC0-24 of afatinib from the single point of C6 showed the highest correlation with the measured AUC0-24 (r2 = 0.840); however, a significant correlation between the AUC0-24 and C0 was also observed (r2 = 0.761). C0 could be used as a marker of therapeutic drug monitoring because afatinib C0 was related to AUC0-24. Therefore, afatinib C0 should be monitored on day 8 after beginning therapy, and the daily dose of afatinib should be adjusted as an index with a cut-off value of 28.5 ng/mL.

Eosinophil extracellular traps in a patient with chronic eosinophilic pneumonia.

Eosinophils rapidly release extracellular filamentous chromatin fibers (extracellular traps, ETs) when they are stimulated. Reticulated ETs have been recently shown to affect secretion viscosity in eosinophilic inflammatory diseases. Here we report a 43-year-old woman with infiltrative shadows in both upper lungs that did not respond well to antibiotics. She admitted to occasional coughing and sputum, but had poor viscous regulation. Bronchoalveolar lavage fluid (BALF) collected from the upper left lobe showed many eosinophils (65%). She was diagnosed with chronic eosinophilic pneumonia, per previously reported criteria, and began treatment with prednisolone. The infiltration shadow gradually improved, and she was discharged 28 days after admission. Later, we immune-stained her BALF cell components with antibodies against major basic protein, an eosinophil granule protein, which showed a large number of agglomerating eosinophils; and antibodies against citrullinated histone H3 (CitH3-a marker for ETs), which showed CitH3-positive ETs, spread in a network. These findings confirmed that some BALF eosinophils released eosinophil ETs. This case shows the existence of ETs from BALF in patients with chronic eosinophilic pneumonia. Concentration of eosinophil ETs in eosinophilic inflammatory diseases may affect secretion viscosity in sputum, and so on.

[An examination for efficient project promotion of the initial-phase intensive support team for dementia in Akita Prefecture].

The purpose of this study was to clarify the trends in the activity of the initial-phase intensive support teams in Akita Prefecture and to, clarify the factors contributing to the more efficient promotion of future projects. A survey was conducted by questionnaire among 46 initial-phase intensive support team member for dementia. The results indicated that it is mostly maintained cooperation medical center for dementia and community support promoter for dementia. However, the question was insufficient cooperation with family doctor including visit the home. These findings suggest that it is important to disseminate information and improve awareness among the community as well as foster relationships of trust by families.

Effects of STAT3 polymorphisms and pharmacokinetics on the clinical outcomes of gefitinib treatment in patients with EGFR-mutation positive non-small cell lung cancer.

WHAT IS KNOWN AND OBJECTIVE: We investigated the correlations among signal transducer and activator of transcription 3 (STAT3) rs4796793C >G polymorphism, gefitinib pharmacokinetics and clinical responses in Japanese patients with non-small cell lung cancer receiving gefitinib therapy. METHODS: Forty-five patients were enrolled in this study. Plasma trough concentrations (C0 ) of gefitinib at the steady-state were measured by high-performance liquid chromatography. RESULTS AND DISCUSSION: Patients having a gefitinib C0 of at least ≥200 ng/mL had significantly longer PFS than patients having a C0 of <200 ng/mL (median [95% confidence interval (CI)] PFS: 11.0 [8.2-13.7] and 5.3 [0.0-12.0] months, respectively, P = .042). There were no significant differences in PFS between patients with STAT3 rs4796793C/C and G alleles; however, patients with STAT3 rs4796793C/C having a gefitinib C0 of ≥ 200 ng/mL had significantly longer progression-free survival (PFS) and overall survival (OS) than those with a C0 of <200 ng/mL (median [95% CI] PFS: 11.4 [4.1-18.6] and 3.0 [0.0-7.0] months, respectively, P = .008; median [95% CI] OS: 20.6 [7.4-33.7] and 12.6 [10.1-15.1] months, respectively, P = .042). In patients with the STAT3 rs4796793G allele, there were no significant differences in PFS and OS between the two gefitinib C0 groups. In addition, there were no significant differences in PFS or OS according to smoking, presence of proton pump inhibitor combination, or onset of side effects. WHAT IS NEW AND CONCLUSION: Clinical outcomes of gefitinib in patients with the STAT3 rs4796793C/C genotype depended on plasma concentrations of gefitinib. In addition to information regarding EGFR mutations, the STAT3 rs4796793C >G polymorphism and gefitinib C0 may be potential predictors of clinical outcomes after beginning of gefitinib therapy.

ABCG2 C421A polymorphisms affect exposure of the epidermal growth factor receptor inhibitor gefitinib.

ATP-binding castle protein G2 (ABCG2) is thought to inhibit the activities of certain gefitinib transporters, thereby affecting drug pharmacokinetics. The C421A polymorphism affects the function and expression of ABCG2 on the cell membrane. Previous studies have shown that proton-pump inhibitors (PPIs) inhibit gefitinib absorption, as well as the function of ABCG2. We evaluated the plasma concentrations of gefitinib in patients with and without the ABCG2 C421A polymorphism, who were or were not taking PPIs. In total, 61 patients with advanced epidermal-growth-factor-positive non-small-cell lung cancer were enrolled in this study. They were treated with gefitinib at a dose of 250 mg per day. Plasma gefitinib concentration and ABCG2 C421A status were determined after 2 weeks. The patients were divided into CC- and CA/AA genotype groups. We compared the trough and peak gefitinib levels and the area under the curve (AUC) values for 24-h gefitinib concentrations. We also compared these parameters among four groups distinguished according to the presence or absence of the polymorphism and PPI use. The mean trough gefitinib level and AUC value for 24-h gefitinib concentration were significantly lower in the CA/AA group compared to the CC group (mean trough level: 333.2 vs. 454.5 ng/mL, respectively, P = 0.021; AUC: 9949.9 vs. 13,085.4 ng・h/mL, respectively, P = 0.034). Among patients taking PPIs, the mean trough gefitinib level was significantly lower in the CA/AA group than the CC group (220.1 vs. 340.5 ng/mL, respectively, P = 0.033). The CA/AA-type of ABCG2 C421A polymorphism may be associated with lower gefitinib plasma concentrations.

An autopsy case of anaplastic lymphoma kinase-positive lung cancer exacerbated in a short period of time: a case report.

BACKGROUND: Anaplastic lymphoma kinase-positive lung cancer is a form of lung cancer that accounts for approximately 5% of non-small cell lung cancers. Recently, anaplastic lymphoma kinase inhibitors have been used for treatment of anaplastic lymphoma kinase-positive lung cancer, and their high clinical effect has also been demonstrated in cases of advanced stage lung cancer. Alectinib is an anaplastic lymphoma kinase inhibitor that it is recognized as a standard drug for primary therapy because of its superiority to crizotinib. CASE PRESENTATION: A 37-year-old Japanese man was admitted to our hospital due to multiple brain metastases. An autopsy report revealed that the cause of death was anaplastic lymphoma kinase-positive lung cancer, exacerbated in a short period despite treatment with alectinib. Necropsy revealed anaplastic lymphoma kinase-positive adenosquamous carcinoma of the lung, suggesting that it was involved in the prognosis of this patient. Based on the autopsy results, we reviewed the pathological tissue from transbronchial lung biopsy at the time of clinical diagnosis. The tissue specimen for clinical diagnosis in this case was a papillary adenocarcinoma. However, when this tissue was immunostained, thyroid transcription factor 1-negative and cytokeratin 5/6-positive parts were recognized. This result indicates that we could diagnose this patient as having had adenosquamous carcinoma of the lung. CONCLUSION: In cases of anaplastic lymphoma kinase-positive lung cancer poorly responsive to anaplastic lymphoma kinase inhibitors, re-examination of the tissue should be considered because there is a possibility of anaplastic lymphoma kinase-positive adenosquamous carcinoma.

Low-Dose Oral Immunotherapy Using Low-Egg-Allergen Cookies for Severe Egg-Allergic Children Reduces Allergy Severity and Affects Allergen-Specific Antibodies in Serum.

BACKGROUND: We evaluated the safety and efficacy of low-egg-allergen cookies (LAC) as low-dose oral immunotherapy (OIT) in children with severe egg allergy. We also examined the relationship between mild desensitization by low-dose OIT and serum biomarkers of allergy. METHODS: We enrolled 13 children with egg allergy who could not receive OIT with hard-boiled egg white (EW). For 11 participants, OIT was carried out using LAC for 3-4 months. Open food challenges with hard-boiled EW and blood samplings were performed before and after OIT. Participants were divided into 2 groups: high effect (H-E) and no/low effect (N/L-E). Serum levels of total IgE and egg yolk-, EW-, and ovomucoid (OM)-specific IgE, ovalbumin (OVA)- and OM-specific IgG4, IgA1, and IgA2, and the percentage of CD 203c+ were measured. RESULTS: Allergic severity was reduced in 7 patients, who were assigned to the H-E group. Moreover, no study participants were taken off the intake of LAC during OIT. In the H-E group, OVA-specific IgA2 levels after OIT were significantly higher than before OIT. The ratios of OM-specific IgG4/OM-specific IgE and OM-specific IgA2/OM-specific IgE in the H-E group after OIT were significantly higher than before OIT. CONCLUSION: Our findings suggest that low-dose OIT using LAC is an effective and safe treatment for patients with severe egg allergy.

Validity of Ultrasound Lung Comets for Assessment of the Severity of Interstitial Pneumonia.

OBJECTIVES: Ultrasound (US) lung comets are often observed in patients with interstitial lung disease or congestive heart failure, but few studies have explored the clinical importance of US lung comets in patients with the former condition. We explored whether the US lung comet number could be used to assess the severity of interstitial pneumonia. METHODS: Forty stable patients with interstitial pneumonia were examined. Lung comets evident on transthoracic US imaging in 12 selected regions of the posterior chest wall were analyzed. We defined lung comets accompanied by thickened and irregular pleural lines as interstitial US lung comets; these predominated in patients with interstitial pneumonia. The total number of interstitial US lung comets was correlated with the data from chest high-resolution computed tomography, pulmonary function tests, serologic tests, and the 6-minute walk test. RESULTS: The 40 patients included 16 with idiopathic pulmonary fibrosis and 24 with nonspecific interstitial pneumonia. Thirty-four patients had interstitial US lung comets, which were more common in the lower than the upper lung area. Good correlations were evident between the lung comet number and the extent of the reticular pattern on chest high-resolution computed tomography (r = 0.710; P < .01), predicted forced vital capacity (r = -0.614; P < .01), and lung diffusion capacity for carbon monoxide (r = -0.577; P < .01). Notably, the lung comet number had a strong negative correlation with the percutaneous oxygen saturation level after the 6-minute walk test (r = -0.751; P < .01). CONCLUSIONS: The number of interstitial US lung comets evident on transthoracic US imaging may be a valuable marker of disease severity in patients with interstitial pneumonia.

Association Between Endothelial Progenitor Cells and Treatment Response in Non-Squamous Non-small Cell Lung Cancer Treated with Bevacizumab.

BACKGROUND/AIM: To investigate the association between the number of circulating endothelial progenitor cells (EPCs) in non-squamous non-small cell lung cancer (NSCLC) and disease outcome, in combination chemotherapy with and without bevacizumab. MATERIALS AND METHODS: We retrospectively identified 25 non-squamous NSCLC cases, and divided them into high-EPC and low-EPC groups. Within each group, we compared disease outcomes, with or without the administration of bevacizumab. RESULTS: In the high-EPC group, chemotherapy with bevacizumab produced a significantly higher tumor reduction rate and objective response rate, with significantly longer progression-free survival, compared to chemotherapy without bevacizumab (p<0.001, p=0.010, and p<0.001, respectively). However, in the low-EPC group, there were no significant differences in disease outcomes in groups with versus those without bevacizumab. CONCLUSION: The number of EPCs may be a useful biomarker to guide decision-making in the use of bevacizumab in non-squamous NSCLC.

Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non-small-cell Lung Cancer.

INTRODUCTION: In this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non-small-cell lung cancer. METHODS: Retrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. RESULTS: The total area under the observed plasma concentration-time curve (AUC0-24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA. CONCLUSION: If the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.

Low plasma concentration of gefitinib in patients with EGFR exon 21 L858R point mutations shortens progression-free survival.

PURPOSE: The relationship between the pharmacokinetics and effects of gefitinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is unknown. In this study, we examined the correlation between gefitinib plasma concentration and progression-free survival (PFS) in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R. METHODS: The retrospective analysis examined 40 patients who were administered 250 mg of gefitinib daily. All patients were diagnosed with and treated for advanced non-small cell lung carcinoma with sensitive EGFR mutations between January 2011 and November 2013 at Akita University Hospital, Akita, Japan. The 40 patients were divided into four groups by trough plasma concentration (high or low) and mutation type (exon 19 deletions or exon 21 L858R point mutations). PFS, response rate, and toxic effects were analyzed in all four groups. RESULTS: After excluding 5 patients, the remaining 35 were successfully analyzed. For the patients with exon 19 deletions, there was no significant difference in PFS between the high and low plasma concentration groups (median survival: 12.0 vs. 17.0 months, P = 0.9548). In contrast, the PFS was significantly shorter for patients with exon 21 point mutations and low vs. high concentrations of gefitinib (median survival: 8.0 vs. 16.0 months, P < 0.05). CONCLUSIONS: The results suggest that low gefitinib plasma concentrations in patients with exon 21 L858R point mutations may be associated with shorter PFS in NSCLC patients.

Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib.

We investigated the effects of polymorphisms in CYP2D6, ABCB1, and ABCG2 and the side effects induced by gefitinib on the pharmacokinetics of O-desmethyl gefitinib, the active metabolite of gefitinib. On day 14 after beginning therapy with gefitinib, plasma concentrations of gefitinib and O-desmethyl gefitinib were measured. Patients were grouped into three groups according to their combination of CYP2D6 alleles: homozygous extensive metabolisers (EMs; *1/*1, *1/*2, and *2/*2; n = 13), heterozygous EMs (*1/*5, *2/*5, *1/*10, and *2/*10; n = 18), and intermediate metabolisers (IMs; *5/*10 and *10/*10; n = 5). The median AUC0-24 of O-desmethyl gefitinib in CYP2D6 IMs was 1460 ng h/mL, whereas that in homozygous EMs was 12,523 ng h/mL (P = 0.021 in univariate analysis). The median AUC ratio of O-desmethyl gefitinib to gefitinib differed among homozygous EMs, heterozygous EMs, and IMs at a ratio of 1.41:0.86:0.24 (P = 0.030). On the other hand, there were no significant differences in the AUC0-24 of O-desmethyl gefitinib between ABCB1 and ABCG2 genotypes. In a multivariate analysis, CYP2D6 homozygous EMs (P = 0.012) were predictive for a higher AUC0-24 of O-desmethyl gefitinib. The side effects of diarrhoea, skin rash, and hepatotoxicity induced by gefitinib were unrelated to the AUC0-24 of O-desmethyl gefitinib. CYP2D6 polymorphisms were associated with the formation of O-desmethyl gefitinib from gefitinib. In CYP2D6 homozygous EMs, the plasma concentrations of O-desmethyl gefitinib were higher over 24 h after taking gefitinib than those of the parent compound; however, side effects induced by gefitinib were unrelated to O-desmethyl gefitinib exposure.