Selection of candidates for lung cancer screening based on individual risk has been proposed as an alternative to criteria based on age and cumulative smoking exposure (pack-years). Nine previously ...established risk models were assessed for their ability to identify those most likely to develop or die from lung cancer. All models considered age and various aspects of smoking exposure (smoking status, smoking duration, cigarettes per day, pack-years smoked, time since smoking cessation) as risk predictors. In addition, some models considered factors such as gender, race, ethnicity, education, body mass index, chronic obstructive pulmonary disease, emphysema, personal history of cancer, personal history of pneumonia, and family history of lung cancer.
Retrospective analyses were performed on 53,452 National Lung Screening Trial (NLST) participants (1,925 lung cancer cases and 884 lung cancer deaths) and 80,672 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) ever-smoking participants (1,463 lung cancer cases and 915 lung cancer deaths). Six-year lung cancer incidence and mortality risk predictions were assessed for (1) calibration (graphically) by comparing the agreement between the predicted and the observed risks, (2) discrimination (area under the receiver operating characteristic curve AUC) between individuals with and without lung cancer (death), and (3) clinical usefulness (net benefit in decision curve analysis) by identifying risk thresholds at which applying risk-based eligibility would improve lung cancer screening efficacy. To further assess performance, risk model sensitivities and specificities in the PLCO were compared to those based on the NLST eligibility criteria. Calibration was satisfactory, but discrimination ranged widely (AUCs from 0.61 to 0.81). The models outperformed the NLST eligibility criteria over a substantial range of risk thresholds in decision curve analysis, with a higher sensitivity for all models and a slightly higher specificity for some models. The PLCOm2012, Bach, and Two-Stage Clonal Expansion incidence models had the best overall performance, with AUCs >0.68 in the NLST and >0.77 in the PLCO. These three models had the highest sensitivity and specificity for predicting 6-y lung cancer incidence in the PLCO chest radiography arm, with sensitivities >79.8% and specificities >62.3%. In contrast, the NLST eligibility criteria yielded a sensitivity of 71.4% and a specificity of 62.2%. Limitations of this study include the lack of identification of optimal risk thresholds, as this requires additional information on the long-term benefits (e.g., life-years gained and mortality reduction) and harms (e.g., overdiagnosis) of risk-based screening strategies using these models. In addition, information on some predictor variables included in the risk prediction models was not available.
Selection of individuals for lung cancer screening using individual risk is superior to selection criteria based on age and pack-years alone. The benefits, harms, and feasibility of implementing lung cancer screening policies based on risk prediction models should be assessed and compared with those of current recommendations.
The US Preventive Services Task Force (USPSTF) is updating its 2013 lung cancer screening guidelines, which recommend annual screening for adults aged 55 through 80 years who have a smoking history ...of at least 30 pack-years and currently smoke or have quit within the past 15 years.
To inform the USPSTF guidelines by estimating the benefits and harms associated with various low-dose computed tomography (LDCT) screening strategies.
Comparative simulation modeling with 4 lung cancer natural history models for individuals from the 1950 and 1960 US birth cohorts who were followed up from aged 45 through 90 years.
Screening with varying starting ages, stopping ages, and screening frequency. Eligibility criteria based on age, cumulative pack-years, and years since quitting smoking (risk factor-based) or on age and individual lung cancer risk estimation using risk prediction models with varying eligibility thresholds (risk model-based). A total of 1092 LDCT screening strategies were modeled. Full uptake and adherence were assumed for all scenarios.
Estimated lung cancer deaths averted and life-years gained (benefits) compared with no screening. Estimated lifetime number of LDCT screenings, false-positive results, biopsies, overdiagnosed cases, and radiation-related lung cancer deaths (harms).
Efficient screening programs estimated to yield the most benefits for a given number of screenings were identified. Most of the efficient risk factor-based strategies started screening at aged 50 or 55 years and stopped at aged 80 years. The 2013 USPSTF-recommended criteria were not among the efficient strategies for the 1960 US birth cohort. Annual strategies with a minimum criterion of 20 pack-years of smoking were efficient and, compared with the 2013 USPSTF-recommended criteria, were estimated to increase screening eligibility (20.6%-23.6% vs 14.1% of the population ever eligible), lung cancer deaths averted (469-558 per 100 000 vs 381 per 100 000), and life-years gained (6018-7596 per 100 000 vs 4882 per 100 000). However, these strategies were estimated to result in more false-positive test results (1.9-2.5 per person screened vs 1.9 per person screened with the USPSTF strategy), overdiagnosed lung cancer cases (83-94 per 100 000 vs 69 per 100 000), and radiation-related lung cancer deaths (29.0-42.5 per 100 000 vs 20.6 per 100 000). Risk model-based vs risk factor-based strategies were estimated to be associated with more benefits and fewer radiation-related deaths but more overdiagnosed cases.
Microsimulation modeling studies suggested that LDCT screening for lung cancer compared with no screening may increase lung cancer deaths averted and life-years gained when optimally targeted and implemented. Screening individuals at aged 50 or 55 years through aged 80 years with 20 pack-years or more of smoking exposure was estimated to result in more benefits than the 2013 USPSTF-recommended criteria and less disparity in screening eligibility by sex and race/ethnicity.
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We ...identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
Display omitted
•Pediatric HGG and DIPG comprise a diverse set of clinical and biological subgroups•Somatic coding mutations per tumor range from none to among the highest seen in human cancer•Histone mutations co-segregate with distinct alterations and downstream pathways•H3/IDH1 WT tumors may resemble low-grade lesions and have targetable alterations
Mackay et al. perform an integrated analysis of >1,000 cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma. They identify co-segregating mutations in histone-mutant subgroups and show that histone wild-type subgroups are molecularly more similar to lower-grade tumors.
Gain-of-function mutations in the Type I Bone Morphogenic Protein (BMP) receptor ACVR1 have been identified in two diseases: Fibrodysplasia Ossificans Progressiva (FOP), a rare autosomal dominant ...disorder characterized by genetically driven heterotopic ossification, and in 20–25% of Diffuse Intrinsic Pontine Gliomas (DIPGs), a pediatric brain tumor with no effective therapies and dismal median survival. While the ACVR1 mutation is causal for FOP, its role in DIPG tumor biology remains under active investigation. Here, we discuss cross-fertilization between the FOP and DIPG fields, focusing on the biological mechanisms and principles gleaned from FOP that can be applied to DIPG biology. We highlight our current knowledge of ACVR1 in both diseases, and then describe the growing opportunities and barriers to effectively investigate ACVR1 in DIPG. Importantly, learning from other seemingly unrelated diseases harboring similar mutations may uncover novel mechanisms or processes for future investigation.
•Fibrodysplasia Ossificans Progressiva (FOP) and Diffuse Intrinsic Pontine Gliomas (DIPGs) share ACVR1 mutations.•While ACVR1 mutations underlie FOP, their functional role in DIPG remains unclear.•Developmental biology provides a context of shared biology among diverse diseases.•Intersecting Mendelian disorders and cancer genomics can elucidate potential cancer genes.
Abstract
Background
Risk-prediction models have been proposed to select individuals for lung cancer screening. However, their long-term effects are uncertain. This study evaluates long-term benefits ...and harms of risk-based screening compared with current United States Preventive Services Task Force (USPSTF) recommendations.
Methods
Four independent natural history models were used to perform a comparative modeling study evaluating long-term benefits and harms of selecting individuals for lung cancer screening through risk-prediction models. In total, 363 risk-based screening strategies varying by screening starting and stopping age, risk-prediction model used for eligibility (Bach, PLCOm2012, or Lung Cancer Death Risk Assessment Tool LCDRAT), and risk threshold were evaluated for a 1950 US birth cohort. Among the evaluated outcomes were percentage of individuals ever screened, screens required, lung cancer deaths averted, life-years gained, and overdiagnosis.
Results
Risk-based screening strategies requiring similar screens among individuals ages 55–80 years as the USPSTF criteria (corresponding risk thresholds: Bach = 2.8%; PLCOm2012 = 1.7%; LCDRAT = 1.7%) averted considerably more lung cancer deaths (Bach = 693; PLCOm2012 = 698; LCDRAT = 696; USPSTF = 613). However, life-years gained were only modestly higher (Bach = 8660; PLCOm2012 = 8862; LCDRAT = 8631; USPSTF = 8590), and risk-based strategies had more overdiagnosed cases (Bach = 149; PLCOm2012 = 147; LCDRAT = 150; USPSTF = 115). Sensitivity analyses suggest excluding individuals with limited life expectancies (<5 years) from screening retains the life-years gained by risk-based screening, while reducing overdiagnosis by more than 65.3%.
Conclusions
Risk-based lung cancer screening strategies prevent considerably more lung cancer deaths than current recommendations do. However, they yield modest additional life-years and increased overdiagnosis because of predominantly selecting older individuals. Efficient implementation of risk-based lung cancer screening requires careful consideration of life expectancy for determining optimal individual stopping ages.
The discovery of nanodipolar π‐conjugated oligomer‐containing polymers as high performance nanodielectric materials with high permittivity and low dielectric loss over a wide range of frequency (100 ...Hz–4 MHz) is reported. Terthiophene‐containing methacrylate polymers are synthesized by reversible addition fragmentation transfer (RAFT) polymerization. Both X‐ray and thermal studies indicate the formation of small crystalline domains of terthiophene side chains dispersed in amorphous matrix. The highly polarizable and fast‐responsive nanodipoles from the nanoscale crystalline domains (<2 nm) are believed to dictate the performance. These polymers uniquely satisfy nanodipole architectures conjectured two decades ago to guide the design of high performance nanodielectric materials. This unprecedented approach can be generalized to a variety of π‐conjugated oligomer‐containing polymers for the development of high energy density capacitor materials.
A new series of polymers containing π‐conjugated oligomer as side chains show great promise as candidates for high performance nanodielectric materials. The oligomer‐based highly polarizable side chains can self‐organize to form nanoscale, conjugated, electrically conductive domains, which uniquely meet the requirement for nanodipole architecture, resulting in high permittivity and low dielectric loss across a wide range of frequency (100 Hz–4 MHz).
The optimum screening policy for lung cancer is unknown.
To identify efficient computed tomography (CT) screening scenarios in which relatively more lung cancer deaths are averted for fewer CT ...screening examinations.
Comparative modeling study using 5 independent models.
The National Lung Screening Trial; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial; the Surveillance, Epidemiology, and End Results program; and the U.S. Smoking History Generator.
U.S. cohort born in 1950.
Cohort followed from ages 45 to 90 years.
Societal.
576 scenarios with varying eligibility criteria (age, pack-years of smoking, years since quitting) and screening intervals.
Benefits included lung cancer deaths averted or life-years gained. Harms included CT examinations, false-positive results (including those obtained from biopsy/surgery), overdiagnosed cases, and radiation-related deaths.
The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer model ranges, 1.4% to 8.3%).
The number of cancer deaths averted for the scenario varied across models between 177 and 862; the number of overdiagnosed cases of cancer varied between 72 and 426.
Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to lifetime follow-up.
Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-years' exposure to smoking.
National Cancer Institute.
Early, longitudinal integration of palliative care (PC) is recommended for patients with advanced cancer, in both inpatient and outpatient settings. Despite the growth of specialty PC teams in the ...last decade, the majority of PC is still delivered in the inpatient setting using a traditional referral-based consult delivery model. However, traditional consultation can lead to significant variation or delay in inpatient PC utilization. New care delivery models and strategies are emerging to deliver PC to hospitalized oncology patients who would most benefit from their services and to better align with professional society recommendations.
To identify different care models to deliver PC to ho`spitalized oncology patients and summarize their impact on patient and health system-related outcomes.
We conducted a scoping review of peer-reviewed articles from 2006 to 2021 evaluating delivery of PC to oncology patients in acute inpatient care. We abstracted study characteristics, the study's intervention and comparison arms, and outcomes related to specialty PC intervention.
We identified four delivery models that have been reported to deliver PC: 1) traditional referral-based consultation, 2) criterion-based or “triggered” consultation, 3) co-rounding with primary inpatient team, and 4) PC clinicians serving as the primary team. We summarize the known outcomes data from each model, and compare the benefits and limitations of each model.
Our findings provide guidance to health systems about care delivery models to deploy and implement inpatient PC resources to best serve their unique populations.
In their 2021 lung cancer screening recommendation update, the U.S. Preventive Services Task Force (USPSTF) evaluated strategies that select people based on their personal lung cancer risk (risk ...model-based strategies), highlighting the need for further research on the benefits and harms of risk model-based screening.
To evaluate and compare the cost-effectiveness of risk model-based lung cancer screening strategies versus the USPSTF recommendation and to explore optimal risk thresholds.
Comparative modeling analysis.
National Lung Screening Trial; Surveillance, Epidemiology, and End Results program; U.S. Smoking History Generator.
1960 U.S. birth cohort.
45 years.
U.S. health care sector.
Annual low-dose computed tomography in risk model-based strategies that start screening at age 50 or 55 years, stop screening at age 80 years, with 6-year risk thresholds between 0.5% and 2.2% using the PLCOm2012 model.
Incremental cost-effectiveness ratio (ICER) and cost-effectiveness efficiency frontier connecting strategies with the highest health benefit at a given cost.
Risk model-based screening strategies were more cost-effective than the USPSTF recommendation and exclusively comprised the cost-effectiveness efficiency frontier. Among the strategies on the efficiency frontier, those with a 6-year risk threshold of 1.2% or greater were cost-effective with an ICER less than $100 000 per quality-adjusted life-year (QALY). Specifically, the strategy with a 1.2% risk threshold had an ICER of $94 659 (model range, $72 639 to $156 774), yielding more QALYs for less cost than the USPSTF recommendation, while having a similar level of screening coverage (person ever-screened 21.7% vs. USPSTF's 22.6%).
Risk model-based strategies were robustly more cost-effective than the 2021 USPSTF recommendation under varying modeling assumptions.
Risk models were restricted to age, sex, and smoking-related risk predictors.
Risk model-based screening is more cost-effective than the USPSTF recommendation, thus warranting further consideration.
National Cancer Institute (NCI).
Transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) is one of the mechanisms responsible for acquired EGFR-TKIs resistance. Although it rarely happens this event ...determines a rapid disease deterioration and needs specific treatment.
We report a case of 75-year-old LUAD female with a p.L858R mutation in Epidermal Growth Factor Receptor (EGFR) who presented with SCLC transformation after responding to first line osimertinib treatment for only 6 months. To understand the underlying molecular mechanism, we retrospectively sequenced the first (LUAD) and the second (SCLC) biopsy using a 56 multi-gene panel. Immunohistochemistry (IHC) staining and Fluorescence In Situ Hybridization (FISH) was applied to confirm the genetic aberrations identified.
EGFR p.E709A and p.L858R, Tumor Protein p53 (TP53) p.A159D and Retinoblastoma 1 (RB1) c.365-1G>A were detected in both the diagnostic LUAD and transformed SCLC samples. A high copy number gain for Proto-Oncogene C-Myc (MYC) and a Phosphoinositide 3-Kinase Alpha (PIK3CA) p.E545K mutation were found in the transformed sample specifically. Strong TP53 staining and negative RB1 staining were observed in both LUAD and SCLC samples, but FISH only identified MYC amplification in SCLC tissue.
We consider the combined presence of MYC amplification with mutations in TP53 and RB1 as drivers of SCLC transformation. Our results highlight the need to systematically evaluate TP53 and RB1 status in LUAD patients to offer a different therapeutic strategy.
PDF
