Female Non-smokers Research Articles

Effects of multiple-dose administration of zavegepant nasal spray on the single-dose pharmacokinetics of ethinyl estradiol-levonorgestrel.

The potential for drug-drug interaction of multiple-dose intranasal zavegepant on the single-dose oral contraceptive ethinyl estradiol and levonorgestrel (EE-LNG) was evaluated. Zavegepant (as a nasal spray) is a calcitonin gene-related peptide receptor antagonist approved in the United States for treatment of acute migraine in adults. This single-center, Phase 1, open-label, fixed-sequence study included healthy, nonsmoking females (18-45 years old). In treatment Period 1, a single oral dose of EE-LNG 0.02-0.10 mg was administered on Day 1. In treatment Period 2, intranasal zavegepant (20 mg daily; 10 mg per nostril separated by 1 h) was administered on Days 1-5; 1 oral dose of EE-LNG 0.02-0.10 mg was administered immediately after first 10 mg intranasal zavegepant dose on Day 2. Blood samples for EE-LNG concentrations were collected on Day 1, treatment Period 1, and Day 2, treatment Period 2, and zavegepant concentrations on Day 2, treatment Period 2. Noncompartmental pharmacokinetic parameters included maximum observed concentration (Cmax), area under the concentration-time curve (AUC) from Time 0 to last non-zero concentration (AUC0-t), and AUC from Time 0 to infinity (AUC0-inf). The safety and pharmacokinetic sample sizes were 26 and 23, respectively. Statistical comparisons of pharmacokinetic exposure parameters after co-administration of zavegepant and EE-LNG versus EE-LNG alone showed small, but statistically insignificant, changes in either EE or LNG exposure. EE comparison ratios (90% confidence intervals [CIs]) were 109.9% (105.3%, 114.8%) for AUC0-inf and 110.2% (104.6%, 116.1%) for Cmax. LNG comparison ratios (90% CIs) were 107.0% (100.2%, 114.3%) for AUC0-inf and 108.8% (99.9%, 118.4%) for Cmax. Frequently reported treatment-emergent adverse events included dysgeusia (n = 25, 96%), throat irritation (n = 11, 42%), headache (n = 10, 39%), nasal discomfort (n = 7, 27%), pharyngeal paresthesia (n = 5, 19%), and nausea (n = 4, 15%). Co-administration of zavegepant nasal spray with a single dose of an oral contraceptive resulted in no clinically meaningful changes (<12% increase) in EE-LNG exposure.

Effect of Valproate Coprescription on Clozapine Pharmacokinetics in Clinical Practice

Abstract Background Sodium valproate has been coprescribed with clozapine for seizure prophylaxis and for augmentation in treatment-refractory schizophrenia. However, the effect of valproate on clozapine metabolism and on the incidence of clozapine-related side effects is unclear. Methods We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in smokers and nonsmokers of both sexes in samples submitted for clozapine therapeutic drug monitoring, 1996–2017 in relation to valproate coprescription. Results There were 1217 (665 patients) and 3823 (1600 patients) samples from nonsmokers and from smokers, respectively, who were coprescribed valproate and clozapine. Data from 9774 (5065 patients) and 15,465 (7298 patients) samples from nonsmokers and from smokers, respectively, for whom drugs other than valproate were coprescribed were used as controls. Valproate coprescription in nonsmokers was associated with an increase in average plasma clozapine of 22.5%, suggesting moderate inhibition of clozapine metabolism, but there was no marked effect of valproate coprescription on plasma clozapine in smokers. In all the valproate-treated groups (male and female smokers and nonsmokers), the median plasma norclozapine concentration and the median plasma clozapine-to-norclozapine ratio were significantly lower and higher, respectively, as compared with the controls. Mixed-effects models showed a significant dose-response effect of valproate on lowering the plasma norclozapine concentration and on increasing the plasma clozapine-to-norclozapine ratio. Implications Given the complexity of the effect of valproate coadministration on clozapine pharmacokinetics and the possibility that the toxicity of clozapine may be enhanced in the presence of valproate, the use of these drugs in combination must now be questioned in all patients and not only in women of childbearing age.

The Factors Associated With Mutant Epidermal Growth Factor Receptor Positivity in Patients With Lung Cancer: A Study From a Tertiary Care Center in Pakistan.

Objective In this study, we sought to elucidate the relationship between demographic and clinical factors and epidermal growth factor receptor tyrosine kinase (EGFR-TK) positivity in patients with advanced-stage lung cancer at a tertiary care center in Pakistan. Methods This analytical cross-sectional study was conducted from February 2020 to July 2023 at Shaikh Zayed Hospital, Lahore, Pakistan, in collaboration with the Centre of Excellence in Molecular Biology (CEMB), University of the Punjab. The study included 70 consecutive patients with advanced-stage lung cancer, and aimed to identify common EGFR mutations (Exon 19 deletion and Exon 21 L858R mutation), determine their frequency, and correlate EGFR-TK mutation positivity with clinical and non-clinical factors. Tissue acquisition and processing involved bronchoscopy, pleuroscopy, or percutaneous ultrasound-guided lung mass biopsy, followed by molecular analysis using polymerase chain reaction (PCR) extraction, amplification, and sequencing. The study employed convenient sampling and included adults aged over 18 years with histologically confirmed lung cancer. Results We enrolled 70 lung cancer patients, with a mean age of 60.87 years, and a male-to-female ratio of 1.4:1. The majority (61.4%) had adenocarcinoma, and 34.3% harbored a mutant EGFR-TK. EGFR mutations were more common in adenocarcinoma (91.7%) and associated with female non-smokers. Binary logistic regression analysis revealed that age <50 years and adenocarcinoma type were significant predictors of EGFR mutations. We found no significant associations with gender, smoking status, or other variables. These findings have implications for personalized treatment approaches in lung cancerpatients. Conclusions Our study reveals a high frequency of occult EGFR mutations (Exon 19 deletion and Exon 21 L858R mutation) in non-small cell lung cancer (NSCLC) patients, particularly among male smokers and female non-smokers. These findings emphasize the importance of routine EGFR mutation testing to identify patients who may benefit from targeted therapies, ultimately improving treatment outcomes.

Sex disparity, prediagnosis lifestyle factors, and long-term survival of gastric cancer: a multi-center cohort study from China

BackgroundThis multi-center cohort study aimed to investigate whether sex and prediagnosis lifestyle affect the prognosis of gastric cancer.MethodsPatients with gastric cancer were from four gastric cancer cohorts of the National Cancer Center of China, The First Hospital of Lanzhou University, Lanzhou University Second Hospital, and Gansu Provincial Cancer Hospital. Prediagnosis lifestyle factors in our study included body mass index (BMI) at diagnosis, usual BMI, weight loss, the history of Helicobacter pylori (Hp) infection, and the status of smoking and drinking.ResultsFour gastric cancer cohorts with 29,779 gastric cancer patients were included. In total patients, female patients had a better prognosis than male patients (HR = 0.938, 95%CI: 0.881–0.999, P = 0.046). For prediagnosis lifestyle factors, BMI at diagnosis, usual BMI and the amount of smoking were statistically associated with the prognosis of gastric cancer patients. Female patients with smoking history had a poorer survival than non-smoking females (HR = 0.782, 95%CI: 0.616–0.993, P = 0.044). Tobacco consumption > 40 cigarettes per day (HR = 1.182, 95%CI: 1.035–1.350, P = 0.013) was independent adverse prognostic factors in male patients. Obesity paradox was observed only in male patients (BMI < 18.5, HR = 1.145, 95%CI: 1.019–1.286, P = 0.023; BMI: 23–27.4, HR = 0.875, 95%CI: 0.824–0.930, P < 0.001; BMI ≥ 27.5, HR = 0.807, 95%CI: 0.735–0.886, P < 0.001).ConclusionsSex and some prediagnosis lifestyle factors, including BMI at diagnosis, usual BMI and the amount of smoking, were associated with the prognosis of gastric cancer.

Gender-specific outcomes of low-dose computed tomography screening for lung cancer detection: A retrospective study in Chinese never-smoker population.

Low-dose computed tomography (LDCT) has emerged as a pivotal tool for detecting lung cancer among ever-smokers. This study aims to evaluate the gender-specific outcomes of LDCT screening within the Chinese never-smoking population. We conducted a single-center, retrospective cohort study, which analyzed LDCT screening outcomes for 42,018 asymptomatic participants. Specifically, we focused on assessing gender-specific differences in the prevalence of pulmonary nodules, and the incidence of lung cancer diagnosis among never-smokers. Among the 42,018 eligible participants, 41.50% were females and 58.50% were males. Most participants were non-smokers (77.57%), with a significantly higher proportion of non-smokers among females than males (99.33% vs. 62.14%). Pulmonary nodules were identified in 2.66% of participants, with a higher prevalence in females (2.99%) than males (2.43%) (p < 0.001). Non-smoking females had a higher incidence of positive nodules than non-smoking males (2.98% vs. 2.38%, p < 0.001). Invasive biopsies were performed in 334 individuals with nodules, confirming lung cancer in 258 cases. The majority of these cancer cases were non-smokers (212), with non-smoking females showing a higher incidence (0.85%) compared to males (0.43%) (p < 0.001). There was no significant difference in the false-positive rates between non-smoking females (0.14%) and males (0.13%). Multivariate analysis showed that never-smoking women were more likely to undergo biopsies (OR 1.65, p = 0.0016) and had a higher, though not statistically significant, probability of lung cancer diagnosis (OR 1.84, p = 0.06). This study elucidates sex-based differences within the Chinese population, revealing a higher prevalence of pulmonary nodules and lung cancers among non-smoking females. These findings offer valuable reference for both clinical practice and future research initiatives.

The clinical significance of endoplasmic reticulum stress related genes in non-small cell lung cancer and analysis of single nucleotide polymorphism for CAV1.

In recent years, protein homeostasis imbalance caused by endoplasmic reticulum stress has become a major hallmark of cancer. Studies have shown that endoplasmic reticulum stress is closely related to the occurrence, development, and drug resistance of non-small cell lung cancer, however, the role of various endoplasmic reticulum stress-related genes in non-small cell lung cancer is still unclear. In this study, we established an endoplasmic reticulum stress scores based on the Cancer Genome Atlas for non-small cell lung cancer to reflect patient features and predict prognosis. Survival analysis showed significant differences in overall survival among non-small cell lung cancer patients with different endoplasmic reticulum stress scores. In addition, endoplasmic reticulum stress scores was significantly correlated with the clinical features of non-small cell lung cancer patients, and can be served as an independent prognostic indicator. A nomogram based on endoplasmic reticulum stress scores indicated a certain clinical net benefit, while ssGSEA analysis demonstrated that there was a certain immunosuppressive microenvironment in high endoplasmic reticulum stress scores. Gene Set Enrichment Analysis showed that scores was associated with cancer pathways and metabolism. Finally, weighted gene co-expression network analysis displayed that CAV1 was closely related to the occurrence of non-small cell lung cancer. Therefore, in order to further analyze the role of this gene, Chinese non-smoking females were selected as the research subjects to investigate the relationship between CAV1 rs3779514 and susceptibility and prognosis of non-small cell lung cancer. The results showed that the mutation of rs3779514 significantly reduced the risk of non-small cell lung cancer in Chinese non-smoking females, but no prognostic effect was found. In summary, we proposed an endoplasmic reticulum stress scores, which was an independent prognostic factor and indicated immune characteristics in the microenvironment of non-small cell lung cancer. We also validated the relationship between single nucleotide polymorphism locus of core genes and susceptibility to non-small cell lung cancer.

Exploring the Disparity in Indoor/Outdoor Time and Radon Exposure as Possible Factors Contributing to the Unexpected Increase in Lung Cancer Risk among Non-Smoking Women.

According to a NIH study, Lung cancer among individuals who have never smoked is more prevalent in women and occurs at an earlier age than in smokers. The rise in lung cancer rates among female non-smokers might be linked to radon inhalation and should be further investigated. Our theory is based on the differences in radon exposure between males and females, which can be attributed to the variations in time spent indoors versus outdoors. Over the past few years, the smoking rates have shown a steady decline in the United States and other developed countries. This decrease in smoking prevalence has led to a new shift in the primary risk factors associated with lung cancer. Although tobacco smoke historically served as the primary cause of lung cancer, the reduction in smoking rates has allowed other risk factors, such as radon exposure, to come to the forefront. Given that women in certain countries, on average, might spend more time indoors compared to men, they are potentially exposed to higher levels of radon. This increased exposure could explain the rising rates of lung cancer among female non-smokers. The theory is still in its nascent stages and requires further research and validation. However, if proven correct, it could significantly alter our understanding of lung cancer risk factors and lead to new prevention. It is therefore crucial to expedite the review and publication of this theory, given its potential implications for public health.

Coexistence of Bronchiectasis Related with Rheumatoid Arthritis and Posttuberculosis Lung Disease - An Everpresent Issue

Abstract The lung is a common site of involvement both in TB and rheumatoid arthritis (RA) disease, caused by disease itself or therapy. After completion of antiTB treatment, post TB lung disease (PTLD) residual changes persist and affect heath, survival and quality of life, mainly in patients with associated collagen diseases, as RA. Bronchiectasis are described in both RA and PTLD. The purpose of this prevalence study of bronchiectasis, performed among 92 RA hospitalized patients, from June 2017 to June 2019, consists in a pictorial assessment of the lung involvement changes, noticed on chest radiography and/or computed tomography, described in relation with TB sequelae, severity and duration of RA disease. Results. A high prevalence of imagistic abnormalities was found in 77.2% of cases (n=71/92). Bronchiectasis was a frequent imagistic chest finding (24/71; 33.8%), having a lower frequency among all study group patients (n=24/92; 26%), mostly older nonsmoker females. Conclusions. In a high TB burden, as Romania, the prevalence of bronchiectasis is related with advanced RA disease, being strongly correlated with persistent respiratory symptoms (p=0.009), and coexisting PTLD calcified nodular lung sequelae (p=0.001).

Exposure to second-hand smoke and breast cancer risk in non-smoking women: a comprehensive systematic review and meta-analysis.

Through the use of an innovative method to identify original publications, we conducted ameta-analysis of all epidemiological studies evaluating the association between second-hand smoke (SHS) exposure and breast cancer risk among female non-smokers published in English up to October 2022. Pooled relative risks (RR) were obtained through the use of random-effects models. Dose-response relationships were derived using log-linear functions. Out of 73 identified eligible studies, 63 original articles were included in the meta-analysis. The pooled RR for breast cancer for overall exposure to SHS was 1.24 (95% confidence interval, CI, 1.15-1.34, number of articles, n = 52). Regarding the setting of exposure, RRs were 1.17 (95% CI 1.08-1.27, n = 37) for SHS exposure at home, 1.03 (95% CI 0.98-1.08, n = 15) at the workplace, 1.24 (95% CI 1.11-1.37, n = 16) at home or workplace, and 1.45 (95% CI 1.16-1.80, n = 13) for non-specified settings. The risk of breast cancer increased linearly with higher duration (RR 1.29;95% CI 1.04-1.59 for 40 years of SHS exposure, n = 12), intensity (RR 1.38;95% CI 1.14-1.67 for 20 cigarettes of SHS exposure per day, n = 6), and pack-years (RR 1.50;95% CI 0.92-2.45 for 40 SHS pack-years, n = 6) of SHS exposure. This meta-analysis shows a statistically significant excess risk of breast cancer in women exposed to SHS.

A population level study on smoking and radon induced adenocarcinoma and small-cell carcinoma among males and females in Canada

ObjectiveTo assess if there is a relationship between residential radon exposure and two lung cancer histological types, small-cell carcinoma (diagnosed in people with a smoking history) and adenocarcinoma (the most commonly diagnosed histologic type in people who have never smoked) among males and females in Canada. MethodsWith survey data of long-term radon measurements in residential homes, long-term averaged tobacco consumption rates in the units of cigarettes per day per person and long-term averaged age-standardized lung cancer incidence rates at provincial level, simple linear fitting (ANOVA linear regression) was applied in this study to determine the effect on lung cancer induction by smoking and exposure to indoor radon, and to assess if there is a relationship between residential radon exposure and lung cancer histological types. ResultsLung cancer incidence rates correlate very well with the tobacco consumption rates (P ​< ​0.05). However, females appear to be more likely than males to develop lung cancer at a given amount of cigarette consumption. For both small-cell carcinoma and adenocarcinoma, a statistically significant correlation between incidence rate and mean radon concentration was observed for females, the correlation was much stronger for adenocarcinoma (P ​= ​0.0057) than small-cell carcinoma (P ​= ​0.0483). However, there was no such correlation for males. ConclusionIt is possible that female non-smokers are more susceptible to radon-induced lung cancer, and the joint effect of radon exposure and tobacco smoking may be worse in female smokers compared to males, such that higher incidence rate of adenocarcinoma among females compared to males were observed in recent decades, even though females never smoked more than males.

Participant adherence in a lung cancer screening (LCS) program in a non-smoking population.

10556 Background: LCS guidelines in smoking populations includes an annual low-dose CT Chest (LDCT) scan. Historically, real-world adherence to repeat imaging following the baseline LDCT has been low at 22% (Silvestri et al. Chest 2023). Various reasons for non-adherence have been cited and can be amplified in populations where English is not the primary language, low health literacy, or logistical reasons that interfere with scheduling. We are conducting the Female Asian Nonsmoker Screening Study (FANSS), which is a pilot study for Asian women with no smoking history to provide LDCTs to this population. We describe the strategies utilized to address potential barriers to adherence and report the participant (pt) adherence observed to date for this population. Methods: FANSS is an IRB-approved trial that provides LDCTs annually for 3 years and has an interim follow-up phone call every 6 months. All aspects of the study other than the LDCT could be conducted virtually pending pt preference. All pt interactions were conducted in the pt’s requested language. LDCTs were interpreted according to Lung-RADS. Review of the LDCT results were available in-person or virtually by a nurse practitioner or the principal investigator. The timeline for the 2nd and 3rd LDCT after the baseline scan was determined as follows: pts with negative findings were recommended for a repeat LDCT in 1 year; pts with suspicious findings were reviewed at the NYU Multidisciplinary Nodule Board and recommended for a repeated LDCT in a 3 or 6 month interval. A bilingual (English and Chinese speaking) research coordinator and medical secretaries reached out to pts at their preferred contact (email, phone, or text) for scheduling the follow-up LDCT. Up to three attempts to reach pts to schedule their follow-up LDCT were made. Results: From 3/5/21 to 1/27/24, 634 subjects completed their baseline LDCTs. Language interpretation services were utilized in 30% of pts. As of 1/27/24, 215 pts were due for their 2nd LDCT: 195 (91%) completed (186) or scheduled (9) the LDCT, 5 pts withdrew their consent, and 15 did not complete the scan. The main reasons for not completing the scans were: living outside New York City, other health concerns, and lost to follow-up. As of 1/27/24, 95 pts were due for their 3rd LDCT: 87 (92%) completed (82) and scheduled (5) the LDCT, and 8 did not complete the scan due to being lost to follow-up. Conclusions: The FANSS population is a unique pt cohort comprised of all Asian women who do not qualify for current LCS guidelines. Interventions to address potential adherence issues were implemented. In our research-based setting, virtual conduct of most of the study procedures allowed pt flexibility. Pt outreach to ensure follow-up by contacting through various methods also ensured adherence of &gt;90%. These interventions can be considered for use in other LCS programs to improve adherence to LCS follow-up.

Recruitment strategies in a lung cancer screening program for Asian women with no smoking history.

e22514 Background: The Female Asian Nonsmoker Screening Study (FANSS) is a pilot study for eligible Asian women with no smoking history to provide low-dose CT (LDCT) Chest scans for lung cancer screening annually for 3 years. To recruit for the study, we took into consideration several factors including potential language barriers, low awareness of lung cancer incidence in non-smoking populations, and participant (pt) availability. Here we describe the use of various recruitment strategies to support enrollment to the FANSS study. Methods: Multimodal recruitment strategies for enrollment into FANSS were used. A dedicated phone line answered by receptionists able to speak English and several Chinese dialects was created. Research staff are bilingual or utilized telephonic interpretation services in all pt interactions. Informational flyers available in both English and Chinese were mailed to primary care physicians serving primarily Asian communities and posted in pharmacies and storefronts in NYC Chinatown. A website was developed for interested individuals to submit their contact information for further information. Working with our institutional Epic EMR, a list of all pts with active MyChart accounts was created with criteria “Asian,” “female,” “OK to contact for Research recruitment,” “age 40-74,” and excluded anyone with a smoking history and “Cancer” in the past 5 years. From this list, pts then were sent an IRB-approved recruitment message through MyChart from 3/2023-6/2023. Interested pts who reached out through the above methods were contacted by research staff to determine eligibility. All eligible pts who agreed to participate were consented either in-person or virtually to allow for schedule flexibility to review the consent. Results: From 3/5/21 to 1/27/24, 1518 women inquired about FANSS through our website, dedicated phone line or MyChart messages and were directly contacted by our team. After determination of eligibility, 760 pts had an informed consent discussion either virtually or in-person. From 3/5/21 to 3/2023, 247 pts underwent the consent process and 229 pts had a baseline LDCT. Following the intervention of directed MyChart messaging in 3/2023, 568 pts responded to the MyChart message indicating interest, however 102 pts were not eligible due to inaccurate info in their Epic medical record (i.e. ethnicity or smoking history). Overall, from 3/2023 to 1/27/24, 513 pts underwent the consent process. Among these, 90 subjects (18%) were recruited via MyChart. Conclusions: Recruitment to a lung cancer screening program in non-smokers is feasible, and specific considerations tailored to engage minority populations can improve enrollment such as bilingual staff and translated materials. The use of directed messaging through the Epic EMR is an important tool to identify potential pts which may be applied to aid in recruitment to other clinical trials or lung cancer screening programs.

Résistance aux anti-EGFR via l’acquisition successive et cumulée de deux nouvelles addictions oncogénique BRAF et ALK

Targeted therapies are the standard first-line treatment for metastatic lung adenocarcinoma with certain molecular abnormalities. These abnormalities are particularly common in Southeast Asia and French Polynesia. A 51-year-old Tahitian female non-smoker was diagnosed in 2018with stage IV lung adenocarcinoma harboring a p.L858R EGFR mutation. She received gefitinib as first-line treatment. Due to locoregional progression and the presence of a resistance mutation (p.T790M of EFGR), she received osimertinib as second-line treatment, after which chemotherapy was proposed as 3rd-line treatment. An additional biopsy detected not only the previously known EGFR mutation, but also a BRAF p.V600E mutation. Following disease progression during chemotherapy, the patient received targeted therapies combining dabrafenib, trametinib and osimertinib. Due to a dissociated response after four months of treatment, a 5th line of paclitaxel bevacizumab was initiated. Subsequent to additional progression and given the ALK rearrangement shown on the re-biopsy, 6th-line treatment with alectinib was proposed. As the response was once again dissociated, a final line was proposed before stopping active treatments due to their toxicity and overall deterioration in the patient's state of health. This exceptional case is characterized by resistance to anti-EGFR through the successive and cumulative acquisition of two new oncogene addictions. The authors underline the importance of re-biopsy at each progression, leading (if at all feasible) to yet around round of targeted therapy.

Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.

The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.

Oxidative stress and pro-inflammatory cytokines following perchloroethylene exposure in young female dry-cleaning workers.

The involvement of Perchloroethylene (PCE) in the development of autoimmune diseases has been reported. However, few studies investigated immunotoxicity in PCE-exposed workers. To study changes in the oxidative stress and cytokine profile of young female dry-cleaning workers exposed to PCE. Thirty-eight exposed workers and 38 unexposed controls were recruited. All the participants were young nonsmoker females. Individual interviews were conducted by a physician. Blood samples were collected and hematological tests were performed by an automated Coulter Counter. Plasma PCE levels were determined using gas chromatography/flame ionization detection. Plasma total antioxidant capacity (TAC), Catalase (CAT), Superoxide dismutase (SOD), and Malondialdehyde (MDA) levels were measured using the colorimetric method. The levels of plasma cytokines interleukin-1β (IL-1β), IL-2, IL-4, IL-6, IL-8, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) were measured by commercially kits. The levels of plasma PCE averaged 561±96 ng/ml in the exposed group compared with 1.3±0.5 ng/ml in the controls. The hematological tests failed to find abnormalities in the exposed workers. Exposed workers presented significantly increased plasma levels of MDA, SOD and CAT. There were no significant differences between the two groups for level of plasma TAC. Significantly increased plasma IL-1β and TNF-α and decreased IL-2 and IL-8 levels were seen in the exposed workers. There were no significant differences between the two groups for IL-4, IL-6, and IFN-γ. PCE exposure resulted in changed cytokine profile in dry-cleaning workers, suggesting the potential immunotoxicity of PCE at low exposure levels.

Baseline data and associations between urinary biomarkers of polycyclic aromatic hydrocarbons, blood pressure, hemogram, and lifestyle among wildland firefighters.

Available literature has found an association between firefighting and pathologic pathways leading to cardiorespiratory diseases, which have been linked with exposure to polycyclic aromatic hydrocarbons (PAHs). PAHs are highlighted as priority pollutants by the European Human Biomonitoring Initiative in occupational and non-occupational contexts. This cross-sectional study is the first to simultaneously characterize six creatinine-adjusted PAHs metabolites (OHPAHs) in urine, blood pressure, cardiac frequency, and hemogram parameters among wildland firefighters without occupational exposure to fire emissions (> 7 days), while exploring several variables retrieved via questionnaires. Overall, baseline levels for total OHPAHs levels were 2 to 23-times superior to the general population, whereas individual metabolites remained below the general population median range (except for 1-hydroxynaphthalene+1-hydroxyacenaphtene). Exposure to gaseous pollutants and/or particulate matter during work-shift was associated with a 3.5-fold increase in total OHPAHs levels. Firefighters who smoke presented 3-times higher total concentration of OHPAHs than non-smokers (p < 0.001); non-smoker females presented 2-fold lower total OHPAHs (p = 0.049) than males. 1-hydroxypyrene was below the recommended occupational biological exposure value (2.5 μg/L), and the metabolite of carcinogenic PAH (benzo(a)pyrene) was not detected. Blood pressure was above 120/80 mmHg in 71% of subjects. Firefighters from the permanent intervention team presented significantly increased systolic pressure than those who performed other functions (p = 0.034). Tobacco consumption was significantly associated with higher basophils (p = 0.01-0.02) and hematocrit (p = 0.03). No association between OHPAHs and blood pressure was found. OHPAHs concentrations were positively correlated with monocyte, basophils, large immune cells, atypical lymphocytes, and mean corpuscular volume, which were stronger among smokers. Nevertheless, inverse associations were observed between fluorene and pyrene metabolites with neutrophils and eosinophils, respectively, in non-smokers. Hemogram was negatively affected by overworking and lower physical activity. This study suggests possible associations between urinary PAHs metabolites and health parameters in firefighters, that should be further assessed in larger groups.

Effect of Coffee and Chocolate Ingestion on Clozapine Dose and on Plasma Clozapine and Norclozapine Concentrations in Clinical Practice.

Some reports point to dietary caffeine intake as a cause of increased plasma clozapine concentrations in certain patients. We compared clozapine dose and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in male and female smokers and nonsmokers in relation to reported (i) coffee (caffeine) and (ii) chocolate (caffeine and theobromine) intake in samples submitted for clozapine therapeutic drug monitoring, 1993-2017. There was information on coffee ingestion for 16,558 samples (8833 patients) from males and 5886 samples (3433 patients) from females and on chocolate ingestion for 12,616 samples (7568 patients) from males and 4677 samples (2939 patients) from females. When smoking was considered, there was no discernible effect of either coffee or chocolate ingestion either on the median dose of clozapine or on the median plasma clozapine and norclozapine concentrations in men and in women. However, cigarette smoking was associated with higher coffee and chocolate consumption. Although male nonsmokers who reported drinking 3 or more cups of coffee daily had significantly higher median plasma clozapine and norclozapine concentrations than those who drank less coffee, they were also prescribed a significantly higher clozapine dose. There was no clear effect of coffee ingestion on plasma clozapine and norclozapine in female nonsmokers. Inhibition of clozapine metabolism by caffeine at the doses of caffeine normally encountered in those treated with clozapine is unlikely even in male nonsmokers. Measurement of plasma caffeine in an appropriate sample should be considered in any future investigation into a presumed clozapine-caffeine interaction.

Clinicopathological and genomic features of superficial esophageal squamous cell carcinomas in nondrinker, nonsmoker females.

Esophageal squamous cell carcinoma (ESCC) is sometimes detected in non-drinker and non-smoker females who are considered to have very low risk of ESCC development in daily practice. This study examined the clinicopathological and genomic characteristics of ESCCs in females with no history of drinking and smoking. The sample comprised 118 ESCC lesions occurring in 95 female patients who underwent endoscopic submucosal dissection at our department between January 2008 and December 2019. The patients were categorized into two groups: 51 lesions in 49 patients with no history of drinking and smoking (nondrinker/nonsmoker [NDNS] group) and 69 lesions in 45 patients with a history of drinking or smoking (drinker/smoker [DS] group). We analyzed the differences in clinicopathological and cancerous genomic characteristics between the groups. Significant genomic alterations were validated using immunohistochemistry. Multiple logistic regression revealed that older age, fewer multiple Lugol-voiding lesions (LVLs), and reflux esophagitis (RE) were independently associated with the occurrence of ESCCs in the NDNS group. ESCC lesions in the NDNS group were predominantly located in the mid-thoracic esophagus, posterior wall side, with 0-IIa, the aspect ratio of the lesion >2 (vertical/horizontal), and endoscopic keratinization. Genetic analysis showed that CDKN2A driver alterations were significantly more frequent and KMT2D alterations were significantly less frequent in the NDNS group than in the DS group. KMT2D alterations were strongly correlated with immunostaining. Older nondrinker, nonsmoker females with RE and fewer multiple LVLs may develop longitudinal 0-IIa ESCC with keratinization of the posterior wall of the mid-thoracic esophagus. ESCCs in nondrinker, nonsmoker females had fewer KMT2D alterations and more CDKN2A alterations, which may be a biomarker for treatment.

Opportunistic lung cancer screening with low-dose computed tomography in National Cancer Center of China: The first 14 years' experience.

In China, over 50% of lung cancer cases occur in nonsmokers. Thus, identifying high-risk individuals for targeted lung cancer screening is crucial. Beyond age and smoking, determining other risk factors for lung cancer in the Asian population has become a focal point of research. Using 30,000 participants in the prospectively enrolled cohort at China's National Cancer Center (NCC) over the past 14 years, we categorized participants by risk, with an emphasis on nonsmoking females. Between November 2005 and December 2019, 31,431 individuals voluntarily underwent low-dose computed tomography (LDCT) scans for lung cancer screening at the NCC. We recorded details like smoking history, exposure to hazards, and family history of malignant tumors. Using the 2019 NCCN criteria, participants were categorized into high-, moderate-, and low-risk groups. Additionally, we separated non-high-risk groups into female never smokers (aged over 40) exposed to second-hand smoke (SHS) and others. Any positive results from initial scans were monitored per the I-ELCAP protocol (2006), and suspected malignancies were addressed through collaborative decisions between patients and physicians. We analyzed and compared the detection rates of positive results, confirmed lung cancers, and cancer stages across risk, age, and gender groups. Out of 31,431 participants (55.9% male, 44.1% female), 3695 (11.8%) showed positive baseline LDCT scans with 197 (0.6%; 106 females, 91 males) confirmed as lung cancer cases pathologically. Malignancy rate by age was 0.1% among those aged under 40 years, 0.4% among those aged 40-49 years, 0.8% among those aged 50-59 years, and 1.2% among those aged 60 years and older. From the 25,763 participants (56.9% male, 43.1% female) who completed questionnaires, 1877 (7.3%) were categorized as high risk, 6500 (25.2%) as moderate risk, and 17,386 (67.5%) as low risk. Of the 23,886 in the non-high-risk category, 8041 (33.7%) were females over 40 years old exposed to SHS. The high-risk group showed the highest lung cancer detection rate at 1.4%. However, females exposed to SHS had a notably higher detection rate than the rest of the non-high-risk group (1.1% vs. 0.5%; p < 0.0001). In this cohort, 84.8% of the detected lung cancers were at an early stage. In our study, using LDCT for lung cancer screening proved significant for high-risk individuals. For non-high-risk populations, LDCT screening could be considered for nonsmoking women with exposure to SHS.

Machine learning-based prediction of abdominal aortic aneurysms for individualized patient care

ObjectiveThe United States Preventative Services Task Force guidelines for screening for abdominal aortic aneurysms (AAA) are broad and exclude many at risk groups. We analyzed a large AAA screening database to examine the utility of a novel machine learning (ML) model for predicting individual risk of AAA. MethodsWe created a ML model to predict the presence of AAAs (>3 cm) from the database of a national nonprofit screening organization (AAAneurysm Outreach). Participants self-reported demographics and comorbidities. The model is a two-layered feed-forward shallow network. The ML model then generated AAA probability based on patient characteristics. We evaluated graphs to determine significant factors, and then compared those graphs with a traditional logistic regression model. ResultsWe analyzed a cohort of 10,033 patients with an AAA prevalence of 2.74%. Consistent with logistic regression analysis, the ML model identified the following predictors of AAA: Caucasian race, male gender, advancing age, and recent or past smoker with recent smoker having a more profound affect (P < .05). Interestingly, the ML model showed body mass index (BMI) was associated with likelihood of AAAs, especially for younger females. The ML model also identified a higher than predicted risk of AAA in several groups, including female nonsmokers with cardiac disease, female diabetics, those with a family history of AAA, and those with hypertension or hyperlipidemia at older ages. An elevated BMI conveyed a higher than expected risk in male smokers and all females. The ML model also identified a complex relationship of both diabetes mellitus and hyperlipidemia with gender. Family history of AAA was a more important risk factor in the ML model for both men and women too. ConclusionsWe successfully developed an ML model based on an AAA screening database that unveils a complex relationship between AAA prevalence and many risk factors, including BMI. The model also highlights the need to expand AAA screening efforts in women. Using ML models in the clinical setting has the potential to deliver precise, individualized screening recommendations.