From immune checkpoints to therapies: understanding immune checkpoint regulation and the influence of natural products and traditional medicine on immune checkpoint and immunotherapy in lung cancer.

Lung cancer is a disease of global concern, and immunotherapy has brought lung cancer therapy to a new era. Besides promising effects in the clinical use of immune checkpoint inhibitors, immune-related adverse events (irAEs) and low response rates are problems unsolved. Natural products and traditional medicine with an immune-modulating nature have the property to influence immune checkpoint expression and can improve immunotherapy's effect with relatively low toxicity. This review summarizes currently approved immunotherapy and the current mechanisms known to regulate immune checkpoint expression in lung cancer. It lists natural products and traditional medicine capable of influencing immune checkpoints or synergizing with immunotherapy in lung cancer, exploring both their effects and underlying mechanisms. Future research on immune checkpoint modulation and immunotherapy combination applying natural products and traditional medicine will be based on a deeper understanding of their mechanisms regulating immune checkpoints. Continued exploration of natural products and traditional medicine holds the potential to enhance the efficacy and reduce the adverse reactions of immunotherapy.

Lifetime excess absolute risk for lung cancer due to exposure to radon: results of the pooled uranium miners cohort study PUMA.

The Pooled Uranium Miners Analysis (PUMA) study is the largest uranium miners cohort with 119,709 miners, 4.3 million person-years at risk and 7754 lung cancer deaths. Excess relative rate (ERR) estimates for lung cancer mortality per unit of cumulative exposure to radon progeny in working level months (WLM) based on the PUMA study have been reported. The ERR/WLM was modified by attained age, time since exposure or age at exposure, and exposure rate. This pattern was found for the full PUMA cohort and the 1960 + sub-cohort, i.e., miners hired in 1960 or later with chronic low radon exposures and exposure rates. The aim of the present paper is to calculate the lifetime excess absolute risk (LEAR) of lung cancer mortality per WLM using the PUMA risk models, as well as risk models derived in previously published smaller uranium miner studies, some of which are included in PUMA. The same methods were applied for all risk models, i.e., relative risk projection up to <95 years of age, an exposure scenario of 2 WLM per year from age 18-64 years, and baseline mortality rates representing a mixed Euro-American-Asian population. Depending upon the choice of model, the estimated LEAR per WLM are 5.38 × 10-4 or 5.57 × 10-4 in the full PUMA cohort and 7.50 × 10-4 or 7.66 × 10-4 in the PUMA 1960 + sub-cohort, respectively. The LEAR per WLM estimates derived from risk models reported for previously published uranium miners studies range from 2.5 × 10-4 to 9.2 × 10-4. PUMA strengthens knowledge on the radon-related lung cancer LEAR, a useful way to translate models for policy purposes.

Lung Cancer in Women: The Past, Present, and Future.

Lung cancer is the leading cause of cancer death for women in multiple countries including the United States. Women are exposed to unique risk factors that remain largely understudied such as indoor pollution, second-hand tobacco exposure, biological differences, gender differences in tolerability and response to therapy in lung cancer, and societal gender roles, that create distinct survivorship needs. Women continue to lack representation in lung cancer clinical trials and are typically treated with data generated from majority male patient study populations, which may be inappropriate to extrapolate and generalize to females. Current lung cancer treatment and screening guidelines do not incorporate sex-specific differences and physicians also often do not account for gender differences when choosing treatments or discussing survivorship needs. To best provide targeted treatment approaches, greater representation of women in lung cancer clinical trials and further research is necessary. Clinicians should understand the unique factors and consequences associated with lung cancer in women; thus, a holistic approach that acknowledges environmental and societal factors is necessary.

Third mortality follow-up of the Mallinckrodt uranium processing workers, 1942-2019.

INTRODUCTION: Mallinckrodt Chemical Works was a uranium processing facility during the Manhattan Project from 1942 to 1966. Thousands of workers were exposed to low-dose-rates of ionizing radiation from external and internal sources. This third follow-up of 2514 White male employees updates cancer and noncancer mortality potentially associated with radiation and silica dust. MATERIALS AND METHODS: Individual, annualized organ doses were estimated from film badge records (n monitored = 2514), occupational chest x-rays (n = 2514), uranium urinalysis (n = 1868), radium intake through radon breath measurements (n = 487), and radon ambient measurements (n = 1356). Silica dust exposure from pitchblende processing was estimated (n = 1317). Vital status and cause of death determination through 2019 relied upon the National Death Index and Social Security Administration Epidemiological Vital Status Service. The analysis included standardized mortality ratios (SMRs), Cox proportional hazards, and Poisson regression models. RESULTS: Vital status was confirmed for 99.4% of workers (84.0% deceased). For a dose weighting factor of 1 for intakes of uranium, radium, and radon decay products, the mean and median lung doses were 65.6 and 29.9 mGy, respectively. SMRs indicated a difference in health outcomes between salaried and hourly workers, and more brain cancer deaths than expected [SMR: 1.79; 95% confidence interval (CI): 1.14, 2.70]. No association was seen between radiation and lung cancer [hazard ratio (HR) at 100 mGy: 0.93; 95%CI: 0.78, 1.11]. The relationship between radiation and kidney cancer observed in the previous follow-up was maintained (HR at 100 mGy: 2.07; 95%CI: 1.12, 3.79). Cardiovascular disease (CVD) also increased significantly with heart dose (HR at 100 mGy: 1.11; 95%CI: 1.02, 1.21). Exposures to dust ≥23.6 mg/m3-year were associated with nonmalignant kidney disease (NMKD) (HR: 3.02; 95%CI: 1.12, 8.16) and kidney cancer combined with NMKD (HR: 2.46; 95%CI: 1.04, 5.81), though without evidence of a dose-response per 100 mg/m3-year. CONCLUSIONS: This third follow-up of Mallinckrodt uranium processors reinforced the results of the previous studies. There was an excess of brain cancers compared with the US population, although no radiation dose-response was detected. The association between radiation and kidney cancer remained, though potentially due to few cases at higher doses. The association between levels of silica dust ≥23.6 mg/m3-year and NMKD also remained. No association was observed between radiation and lung cancer. A positive dose-response was observed between radiation and CVD; however, this association may be confounded by smoking, which was unmeasured. Future work will pool these data with other uranium processing worker cohorts within the Million Person Study.

Opportunities and Challenges of Kava in Lung Cancer Prevention.

Lung cancer is the leading cause of cancer-related deaths due to its high incidence, late diagnosis, and limited success in clinical treatment. Prevention therefore is critical to help improve lung cancer management. Although tobacco control and tobacco cessation are effective strategies for lung cancer prevention, the numbers of current and former smokers in the USA and globally are not expected to decrease significantly in the near future. Chemoprevention and interception are needed to help high-risk individuals reduce their lung cancer risk or delay lung cancer development. This article will review the epidemiological data, pre-clinical animal data, and limited clinical data that support the potential of kava in reducing human lung cancer risk via its holistic polypharmacological effects. To facilitate its future clinical translation, advanced knowledge is needed with respect to its mechanisms of action and the development of mechanism-based non-invasive biomarkers in addition to safety and efficacy in more clinically relevant animal models.

Radon and lung cancer in the pooled uranium miners analysis (PUMA): highly exposed early miners and all miners.

OBJECTIVES: Radon is a ubiquitous occupational and environmental lung carcinogen. We aim to quantify the association between radon progeny and lung cancer mortality in the largest and most up-to-date pooled study of uranium miners. METHODS: The pooled uranium miners analysis combines 7 cohorts of male uranium miners with 7754 lung cancer deaths and 4.3 million person-years of follow-up. Vital status and lung cancer deaths were ascertained between 1946 and 2014. The association between cumulative radon exposure in working level months (WLM) and lung cancer was modelled as the excess relative rate (ERR) per 100 WLM using Poisson regression; variation in the association by temporal and exposure factors was examined. We also examined analyses restricted to miners first hired before 1960 and with <100 WLM cumulative exposure. RESULTS: In a model that allows for variation by attained age, time since exposure and annual exposure rate, the ERR/100 WLM was 4.68 (95% CI 2.88 to 6.96) among miners who were less than 55 years of age and were exposed in the prior 5 to <15 years at annual exposure rates of <0.5 WL. This association decreased with older attained age, longer time since exposure and higher annual exposure rate. In analyses restricted to men first hired before 1960, we observed similar patterns of association but a slightly lower estimate of the ERR/100 WLM. CONCLUSIONS: This new large, pooled study confirms and supports a linear exposure-response relationship between cumulative radon exposure and lung cancer mortality which is jointly modified by temporal and exposure factors.

Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies.

BACKGROUND: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence. OBJECTIVES: We investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. METHODS: Data from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI). RESULTS: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1.5 RDA) and 1.01 (0.95-1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02-1.12) and 0.92 (0.84-1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements. CONCLUSIONS: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Association between ß-carotene supplementation and risk of cancer: a meta-analysis of randomized controlled trials.

CONTEXT: ß-Carotene, which is derived from most fruits and vegetables, is the most common type of carotenes. Existing studies have demonstrated that ß-carotene is associated with some positive health outcomes. However, results about the effects of supplemental ß-carotene on cancer are inconsistent. OBJECTIVE: To determine the association between supplemental ß-carotene intake and the risk of cancers. DATA SOURCES: Eight databases (PubMed, Web of Science, Embase, Cochrane, China National Knowledge Infrastructure, Wangfang, China Science and Technology Journal Database, and Chinese Biomedical Literature Database) were systematically searched until September 2022. DATA EXTRACTION: Only reports from randomized controlled trials in which an association between supplemental ß-carotene intake and the risk of cancer was found were included in the meta-analysis. DATA ANALYSIS: A total of 18 eligible studies based on 8 different randomized controlled trials were included in the meta-analysis, with varying sample sizes from 391 to 39 876 participants. There was no significant association between supplemental ß-carotene intake and overall cancer incidence rate after synthesizing all the results (risk ratio [RR]: 1.02; 95% confidence interval [CI], 0.99-1.05). Results from subgroup analysis indicated that intake of supplemental ß-carotene significantly increased the risk of lung cancer (RR: 1.19; 95%CI: 1.08-1.32), whereas no significant associations were observed for other site-specific cancers. In addition, smokers and the subgroup of participants with only low-dose ß-carotene intake had a risk increment of cancer if they took supplemental ß-carotene (RR: 1.16; 95%CI: 1.05-1.29). CONCLUSION: ß-Carotene supplementation has no beneficial or harmful effect on cancer incidence; moreover, it might have potentially harmful effects on lung cancer, especially for people who smoke. On the basis of the evidence from this study, supplemental intake of ß-carotene is not recommended for preventing cancer, and the establishment of a tolerable upper intake level of ß-carotene should be considered.

Reducing tobacco-associated lung cancer risk: a study protocol for a randomized clinical trial of AB-free kava.

BACKGROUND: Tobacco use is the leading cause of many preventable diseases, resulting in premature death or disease. Given that the majority of adult who smoke want to stop, this health burden could be significantly reduced if the success rate of tobacco cessation can be improved. In addition, most adults planning to quit were interested in trying complementary approaches to facilitating tobacco cessation, which is currently lacking. Therefore, there is an unmet and urgent need for novel interventions to improve the success of tobacco cessation. If such an intervention can reduce tobacco-associated lung carcinogenesis, that will be more desirable. The goal of this project is to develop a safe and effective kava-based intervention to enable tobacco cessation and reduce lung cancer risk, which will improve the health of smokers. METHODS: A randomized controlled trial will enroll 80 adults who currently smoke at least 10 cigarettes daily and randomize 1:1 into the placebo and AB-free kava arms, being exposed for 4 weeks, with a total of six visits (weeks 0, 1, 2, 4, 8, and 12) to evaluate the compliance and potential issues of AB-free kava use among the participants, explore the potential effect of the AB-free kava intervention on tobacco dependence, tobacco use, and lung carcinogenesis biomarkers. Participants will be enrolled during their primary care clinic visit. DISCUSSION: Primary care settings play a critical role in tobacco-related disease screening, counseling, and early intervention, as the majority of adults who smoke visit their physicians annually. Building upon our promising pilot human trial results in conjunction with ample compelling lab animal results, and consistent with evidence of kava's benefits from epidemiological data, this trial will evaluate the compliance of AB-free kava among adults who currently smoke with no intention to quit. The other exploratory aims include (1) whether AB-free kava intervention can reduce tobacco use and tobacco dependence; (2) whether AB-free kava use suppresses tobacco-induced carcinogenesis; and (3) the potential of the mechanism-based noninvasive biomarkers in precision AB-free kava intervention. The positive results from this study are expected to provide a great opportunity to effectively reduce smoking rates and tobacco-related diseases. TRIAL REGISTRATION: ClinicalTrials.gov with the identifier: NCT05081882. Registered on October 18, 2021.

Mortality among Tennessee Eastman Corporation (TEC) uranium processing workers, 1943-2019.

BACKGROUND: There are few occupational studies of women exposed to ionizing radiation. During World War II, the Tennessee Eastman Corporation (TEC) operated an electromagnetic field separation facility of 1152 calutrons to obtain enriched uranium (235U) used for the Hiroshima atomic bomb. Thousands of women were involved in these operations. MATERIALS AND METHODS: A new study was conducted of 13,951 women and 12,699 men employed at TEC between 1943 and 1947 for at least 90 days. Comprehensive dose reconstruction techniques were used to estimate lung doses from the inhalation of uranium dust based on airborne measurements. Vital status through 2018/2019 was obtained from the National Death Index, Social Security Death Index, Tennessee death records and online public record databases. Analyses included standardized mortality ratios (SMRs) and Cox proportional hazards models. RESULTS: Most workers were hourly (77.7%), white (95.6%), born before 1920 (58.3%), worked in dusty environments (57.0%), and had died (94.9%). Vital status was confirmed for 97.4% of the workers. Women were younger than men when first employed: mean ages 25.0 years and 33.0 years, respectively. The estimated mean absorbed dose to the lung was 32.7 mGy (max 1048 mGy) for women and 18.9 mGy (max 501 mGy) for men. The mean dose to thoracic lymph nodes (TLNs) was 127 mGy. Statistically significant SMRs were observed for lung cancer (SMR 1.25; 95% CI 1.19, 1.31; n = 1654), nonmalignant respiratory diseases (NMRDs) (1.23; 95% CI 1.19, 1.28; n = 2585), and cerebrovascular disease (CeVD) (1.13; 95% CI 1.08, 1.18; n = 1945). For lung cancer, the excess relative rate (ERR) at 100 mGy (95% CI) was 0.01 (-0.10, 0.12; n = 652) among women, and -0.15 (-0.38, 0.07; n = 1002) among men based on a preferred model for men with lung doses <300 mGy. NMRD and non-Hodgkin lymphoma were not associated with estimated absorbed dose to the lung or TLN. CONCLUSIONS: There was little evidence that radiation increased the risk of lung cancer, suggesting that inhalation of uranium dust and the associated high-LET alpha particle exposure to lung tissue experienced over a few years is less effective in causing lung cancer than other types of exposures. There was no statistically significant difference in the lung cancer risk estimates between men and women. The elevation of certain causes of death such as CeVD is unexplained and will require additional scrutiny of workplace or lifestyle factors given that radiation is an unlikely contributor since only the lung and lymph nodes received appreciable dose.

The Role of Neighborhood Air Pollution Exposure on Somatic Non-Small Cell Lung Cancer Mutations in the Los Angeles Basin (2013-2018).

Limited previous work has identified a relationship between exposure to ambient air pollution and aggressive somatic lung tumor mutations. More work is needed to confirm this relationship, especially using spatially resolved air pollution. We aimed to quantify the association between different air pollution metrics and aggressive tumor biology. Among patients treated at City of Hope Comprehensive Cancer Center in Duarte, CA (2013-2018), three non-small cell lung cancer somatic tumor mutations, TP53, KRAS, and KRAS G12C/V, were documented. PM2.5 exposure was assessed using state-of-the art ensemble models five and ten years before lung cancer diagnosis. We also explored the role of NO2 using inverse-distance-weighting approaches. We fitted logistic regression models to estimate odds ratio (OR) and their 95% confidence intervals (CIs). Among 435 participants (median age: 67, female: 51%), an IQR increase in NO2 exposure (3.5 µg/m3) five years before cancer diagnosis was associated with an increased risk in TP53 mutation (OR, 95% CI: 1.30, 0.99-1.71). We found an association between highly-exposed participants to PM2.5 (>12 µg/m3) five and ten years before cancer diagnosis and TP53 mutation (OR, 95% CI: 1.61, 0.95-2.73; 1.57, 0.93-2.64, respectively). Future studies are needed to confirm this association and better understand how air pollution impacts somatic profiles and the molecular mechanisms through which they operate.

Deep Breaths: A Systematic Review of the Potential Effects of Employment in the Nuclear Industry on Mortality from Non-Malignant Respiratory Disease.

Ionizing radiation is an established carcinogen, but its effects on non-malignant respiratory disease (NMRD) are less clear. Cohorts exposed to multiple risk factors including radiation and toxic dusts conflate these relationships, and there is a need for clarity in previous findings. This systematic review was conducted to survey the body of existing evidence for radiation effects on NMRD in global nuclear worker cohorts. A PubMed search was conducted for studies with terms relating to radiation or uranium and noncancer respiratory outcomes. Papers were limited to the most recent report within a single cohort published between January 2000 and December 2020. Publication quality was assessed based upon UNSCEAR 2017 criteria. In total, 31 papers were reviewed. Studies included 29 retrospective cohorts, one prospective cohort, and one longitudinal cohort primarily comprising White men from the U.S., Canada and Western Europe. Ten studies contained subpopulations of uranium miners or millers. Papers reported standardized mortality ratio (SMR) analyses, regression analyses, or both. Neither SMR nor regression analyses consistently showed a relationship between radiation exposure and NMRD. A meta-analysis of excess relative risks (ERRs) for NMRD did not present evidence for a dose-response (overall ERR/Sv: 0.07; 95% CI: -0.07, 0.21), and results for more specific outcomes were inconsistent. Significantly elevated SMRs for NMRD overall were observed in two studies among the subpopulation of uranium miners and millers (combined n = 4229; SMR 1.42-1.43), indicating this association may be limited to mining and milling populations and may not extend to other nuclear workers. A quality review showed limited capacity of 17 out of 31 studies conducted to provide evidence for a causal relationship between radiation and NMRD; the higher-quality studies showed no consistent relationship. All elevated NMRD SMRs were among mining and milling cohorts, indicating different exposure profiles between mining and non-mining cohorts; future pooled cohorts should adjust for mining exposures or address mining cohorts separately.

Association between exposures to radon and γ-ray radiation and histologic type of lung cancer in Eldorado uranium mining and milling workers from Canada.

BACKGROUND: The authors assessed the association between radon decay products (RDP) exposure and histologic types of incident lung cancer in a cohort of 16,752 (91.6% male) Eldorado uranium workers who were first employed from 1932 to 1980 and were followed through 1969-1999. METHODS: Substantially revised identifying information and RDP exposures were obtained on workers from the Port Radium and Beaverlodge uranium mines and from the Port Hope radium and uranium refinery and processing facility in Canada. Poisson regression was conducted using the National Research Council's Biological Effects of Ionizing Radiation (BEIR) VI-type models to estimate the risks of lung cancer by histologic type from RDP exposures and γ-ray doses. RESULTS: Lung cancer incidence was significantly higher in workers compared with the general Canadian male population. Radiation risks of lung cancer for all histologic types (n = 594; 34% squamous cell, 16% small cell, 17% adenocarcinoma) increased with increasing RDP exposure, with no indication of curvature in the dose response (excess relative risk per 100 working level months = 0.61; 95% confidence interval, 0.39-0.91). Radiation risks did not differ by histologic type (p = .144). The best-fitting BEIR VI-type model included adjustments for the significant modifying effects of time since exposure, exposure rate, and attained age. The addition of γ-ray doses to the model with RDP exposures improved the model fit, but the risk estimates remained unchanged. CONCLUSIONS: The first analysis of radiation risks of lung cancer histologic types in the Eldorado cohort supported the use of BEIR VI-type models to predict the future risk of histologic types of lung cancer from past and current RDP exposures. LAY SUMMARY: Lung cancer survival depends strongly on the cell type of lung cancer. The best survival rates are for patients who have the adenocarcinoma type. This study included 16,752 Eldorado uranium workers who were exposed to radon and γ-ray radiation during 1932-1980, were alive in 1969, and were followed for the development of new lung cancer during 1969-1999. One third of all lung cancers were of the squamous cell type, whereas the adenocarcinoma and small cell types accounted for less than 20% each. Radiation risks of lung cancer among men increased significantly with increasing radon exposure for all cell types, with the highest risks estimated for small cell and squamous cell lung cancers.

Lung Cancer Screening by Race and Ethnicity in an Integrated Health System in Hawaii.

Importance: Racial and ethnic differences in lung cancer screening (LCS) completion and follow-up may be associated with lung cancer incidence and mortality rates among high-risk populations. Aggregation of Asian American, Native Hawaiian, and Pacific Islander racial and ethnic groups may mask the true underlying disparities in screening uptake and diagnostic follow-up, creating barriers for targeted, preventive health care. Objective: To examine racial and ethnic differences in LCS completion and follow-up rates in a multiethnic population. Design, Setting, and Participants: This population-based cohort study was conducted at a health maintenance organization in Hawaii. LCS program participants were identified using electronic medical records from January 1, 2015, to December 31, 2019. Study eligibility requirements included being aged 55 to 79 years, a 30 pack-year smoking history, a current smoker or having quit within the past 15 years, at least 5 years past any lung cancer diagnosis and treatment, and cancer free. Data analysis was performed from June 2019 to October 2020. Exposure: Eligible for LCS. Main Outcomes and Measures: Screening rates were analyzed by self-reported race and ethnicity and completion of a low-dose computed tomography (LDCT) test. Diagnostic follow-up results were based on the Lung Imaging Reporting and Data System (Lung-RADS) staging system. Results: A total of 1030 eligible LCS program members had an order placed; their mean (SD) age was 65.5 (5.8) years, and 633 (61%) were men. The largest racial and ethnic groups were non-Hispanic White (381 participants [37.0%]), Native Hawaiian or part Native Hawaiian (186 participants [18.1%]), and Japanese (146 participants [14.2%]). Men and Filipino, Chinese, Japanese, and non-Hispanic White individuals had a higher proportion of screen orders for LDCT compared with women and individuals of the other racial and ethnic groups. The overall LCS completion rate was 81% (838 participants). There was a 14% to 15% screening completion rate gap among groups. Asian individuals had the highest screening completion rate (266 participants [86%]) followed by Native Hawaiian (149 participants [80%]) and non-Hispanic White individuals (305 participants [80%]), Pacific Islander (50 participants [79%]) individuals, and individuals of other racial and ethnic groups (68 participants [77%]). Within Asian subgroups, Korean (31 participants [94%]) and Japanese (129 participants [88%]) individuals had the highest completion rates followed by Chinese individuals (28 participants [82%]) and Filipino individuals (78 participants [79%]). Of the 54 participants with Lung-RADS stage 3 disease, 93% (50 participants) completed a 6-month surveillance LDCT test; of 37 individuals with Lung-RADS stage 4 disease, 35 (97%) were followed-up for additional procedures. Conclusions and Relevance: This cohort study found racial and ethnic disparities in LCS completion rates after disaggregation of Native Hawaiian, Pacific Islander, and Asian individuals and their subgroups. These findings suggest that future research is needed to understand factors that may be associated with LCS completion and follow-up behaviors among these racial and ethnic groups.

Updated mortality analysis of the Mallinckrodt uranium processing workers, 1942-2012.

PURPOSE: Mallinckrodt Chemical Works (MCW) was the earliest uranium processing facility in the United States, and in 1942 produced the uranium oxide used for the first sustained and controlled nuclear fission chain-reaction at the University of Chicago. A second follow-up through 2012 was conducted of 2514 White male workers employed 1942-1966 at the MCW for dose-response analyses for selected causes of death. MATERIALS AND METHODS: Organ/tissue-specific dose reconstruction included both external (12,686 MCW film badge records, 210 other facility film badge records, and 31,297 occupational chest x-rays) and internal sources of uranium and radium (39,451 urine bioassays, 2341 breath radon measurements, and 6846 ambient radon measurements). Dust measurements from pitchblende facilitated quantitative risk estimates for non-radiogenic effects on the lung and kidney. Vital status was determined from multiple sources including the National Death Index and the Social Security Administration. Cox regression models were used for dose response analyses. RESULTS: Vital status was determined for 99% of the workers, of whom 75% had died. The mean lung dose from all sources of external and internal radiation combined was 69.9 mGy (maximum 885 mGy; percent workers >100 mGy, 10%) and there was no evidence for a dose response for lung cancer (Hazard Ratio (HR) of 0.95 (95% CI = 0.81-1.12) at 100 mGy). A significant association with radiation was found for kidney cancer (HR of 1.73 (95% CI = 1.04-2.79) at 100 mGy) and suggested for nonmalignant kidney diseases (HR of 1.30 (95% CI = 0.96-1.76) at 100 mGy). A non-radiation etiology could not be discounted, however, because of the possible renal toxicities of uranium, a heavy metal, and silica, a component of pitchblende dust. Non-significant HRs at 100 mGy for other sites of a priori interest were 0.36 (0.06-2.03) for leukemia other than CLL, 0.68 (0.17-2.77) for liver cancer, and 1.23 (0.79-1.90) for non-Hodgkin lymphoma. The HR at 100 mGy was 1.09 (0.99-1.20) for ischemic heart disease. An association was seen between dust and combined malignant and non-malignant lung disease, HR at 10 mgm-3year-1 of 1.01 (1.00-1.02). CONCLUSIONS: A positive radiation dose response was observed for malignant and non-malignant kidney disease, and a negative dose response for malignant and non-malignant lung disease. Cumulative measures of dust were significantly associated with malignant and non-malignant lung disease and suggested for malignant and non-malignant kidney disease. Small numbers preclude definitive interpretations which will await the combination with similar studies of early uranium processing workers.

Fish Intake, Dietary Polyunsaturated Fatty Acids, and Lung Cancer: Systematic Review and Dose-Response Meta-Analysis of 1.7 Million Men and Women.

To determine the association between fish intake and dietary polyunsaturated fatty acids (PUFA) and incidence of lung cancer. We systematically reviewed and meta-analyzed all available studies to quantify the associations of fish and PUFA consumption with risk of lung cancer. Relative risk (RR) with 95% confidence interval (CI) was calculated. 13 population-based prospective cohort studies involving 1,785,000 participants and two randomized control trials were included. Our study demonstrated that dietary PUFA significant reduced risk of lung cancer for men (RR 0.99, 95%CI 0.98 to 1.00) and the U.S. population (RR 0.99, 95%CI 0.98 to 1.00). Dose-response analysis indicated that a 5 g/day increment of dietary PUFA was associated with 5% lower risk of lung cancer (RR 0.95, 95%CI 0.91 to 0.99). In addition, PUFA supplementation is significant improved overall survival in patients with lung cancer (RR 1.98, 95%CI 1.09 to 3.59). Our study showed an inverse association between dietary PUFA and risk of lung cancer in males and among the U.S. population. Although smoking cessation is the single biggest factor associated with lung cancer risk reduction, this study adds to a growing body of evidence that diet may have a role in modestly reducing lung cancer risk.

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.

BACKGROUND: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. OBJECTIVE: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women. METHODS: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models. RESULTS: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. CONCLUSIONS: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

Early discontinuation of induction therapy in chemoimmunotherapy as an effective alternative to the standard regimen in patients with non-small cell lung cancer: a retrospective study.

PURPOSE: We aimed to investigate whether induction chemotherapy with less than four courses is as effective as induction chemotherapy with more than four courses in non-small cell lung cancer (NSCLC) patients receiving chemoimmunotherapy. METHODS: We retrospectively enrolled 249 patients with NSCLC who received chemoimmunotherapy at 12 centers in Japan between January and December 2019. The patient group that completed less than four courses owing to adverse events (AEs), and received subsequent maintenance therapy was compared to the group that received at least four courses of induction chemotherapy followed by maintenance therapy. RESULTS: On univariate and multivariate analyses, the patient group that transitioned to maintenance therapy after completing less than four courses of induction chemotherapy had significantly shorter progression-free survival (PFS) than those who completed at least four courses (hazard ratio [HR] 2.15, 95% confidence interval: 1.38-3.37, p < 0.001 and HR 2.32, 95% confidence interval: 1.40-3.84, p = 0.001, respectively). There was no obvious difference in PFS between the group in which induction chemotherapy ended in two or three courses leading to partial or complete response, and the group that continued at least four courses of induction chemotherapy (log-rank test p = 0.53). CONCLUSION: Treatment efficacy may be maintained if induction chemotherapy is completed in less than four courses owing to development of AEs, and is administered for more than two courses with partial or complete response; efficacy is maintained even on transitioning to maintenance therapy.

LncRNA PKMYT1AR promotes cancer stem cell maintenance in non-small cell lung cancer via activating Wnt signaling pathway.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common type of human lung cancers, which has diverse pathological features. Although many signaling pathways and therapeutic targets have been defined to play important roles in NSCLC, limiting efficacies have been achieved. METHODS: Bioinformatics methods were used to identify differential long non-coding RNA expression in NSCLC. Real-time RT-PCR experiments were used to examine the expression pattern of lncRNA PKMYT1AR, miR-485-5p. Both in vitro and in vivo functional assays were performed to investigate the functional role of PKMYT1AR/miR-485-5p/PKMYT1 axis on regulating cell proliferation, migration and tumor growth. Dual luciferase reporter assay, fluorescent in situ hybridization (FISH), immunoblot, co-immunoprecipitation experiments were used to verify the molecular mechanism. RESULT: Here, we identify a human-specific long non-coding RNA (lncRNA, ENST00000595422), termed PKMYT1AR (PKMYT1 associated lncRNA), that is induced in NSCLC by Yin Yang 1 (YY1) factor, especially in cancerous cell lines (H358, H1975, H1299, H1650, A549 and SPC-A1) compared to that in normal human bronchial epithelium cell line (BEAS-2B). We show that PKMYT1AR high expression correlates with worse clinical outcome, and knockdown of PKMYT1AR inhibits tumor cell proliferation, migration and xenograft tumor formation abilities. Bioinformatic analysis and a luciferase assay demonstrate that PKMYT1AR directly interacts with miR-485-5p to attenuate the inhibitory role on its downstream oncogenic factor PKMYT1 (the protein kinase, membrane-associated tyrosine/threonine 1) in NSCLC. Furthermore, we uncover that miR-485-5p is downregulated in both cancerous cell lines and peripheral blood serum isolated from NSCLC patients compared to reciprocal control groups. Consistently, forced expression of miR-485-5p inhibits the proliferation and migration abilities of tumor cells. Moreover, we provide evidence showing that PKMYT1AR targeting antisense oligonucleotide (ASO) dramatically inhibit tumor growth in vivo. Mechanistic study shows that PKMYT1AR/ miR-485-5p /PKMYT1 axis promotes cancer stem cells (CSCs) maintenance in NSCLC via inhibiting ß-TrCP1 mediated ubiquitin degradation of ß-catenin proteins, which in turn causes enhanced tumorigenesis. CONCLUSIONS: Our findings reveal the critical role of PKMYT1AR/miR-485-5p /PKMYT1 axis during NSCLC progression, which could be used as novel therapeutic targets in the future.

Chimeric Antigen Receptor T-Cell Therapy in Lung Cancer: Potential and Challenges.

Chimeric antigen receptor T (CAR-T) cell therapy has exhibited a substantial clinical response in hematological malignancies, including B-cell leukemia, lymphoma, and multiple myeloma. Therefore, the feasibility of using CAR-T cells to treat solid tumors is actively evaluated. Currently, multiple basic research projects and clinical trials are being conducted to treat lung cancer with CAR-T cell therapy. Although numerous advances in CAR-T cell therapy have been made in hematological tumors, the technology still entails considerable challenges in treating lung cancer, such as on-target, of-tumor toxicity, paucity of tumor-specific antigen targets, T cell exhaustion in the tumor microenvironment, and low infiltration level of immune cells into solid tumor niches, which are even more complicated than their application in hematological tumors. Thus, progress in the scientific understanding of tumor immunology and improvements in the manufacture of cell products are advancing the clinical translation of these important cellular immunotherapies. This review focused on the latest research progress of CAR-T cell therapy in lung cancer treatment and for the first time, demonstrated the underlying challenges and future engineering strategies for the clinical application of CAR-T cell therapy against lung cancer.