Lung cancer screening with a low-dose chest CT scan can result in more benefit than harm when performed in settings committed to developing and maintaining high-quality programs. This project aimed ...to identify the components of screening that should be a part of all lung cancer screening programs. To do so, committees with expertise in lung cancer screening were assembled by the Thoracic Oncology Network of the American College of Chest Physicians (CHEST) and the Thoracic Oncology Assembly of the American Thoracic Society (ATS). Lung cancer program components were derived from evidence-based reviews of lung cancer screening and supplemented by expert opinion. This statement was developed and modified based on iterative feedback of the committees. Nine essential components of a lung cancer screening program were identified. Within these components 21 Policy Statements were developed and translated into criteria that could be used to assess the qualification of a program as a screening facility. Two additional Policy Statements related to the need for multisociety governance of lung cancer screening were developed. High-quality lung cancer screening programs can be developed within the presented framework of nine essential program components outlined by our committees. The statement was developed, reviewed, and formally approved by the leadership of CHEST and the ATS. It was subsequently endorsed by the American Association of Throacic Surgery, American Cancer Society, and the American Society of Preventive Oncology.
We have a limited understanding of the molecular underpinnings of early adenocarcinoma (ADC) progression. We hypothesized that the behavior of early ADC can be predicted based on genomic ...determinants.
To identify genomic alterations associated with resected indolent and aggressive early lung ADCs.
DNA was extracted from 21 ADCs
(AISs), 27 minimally invasive ADCs (MIAs), and 54 fully invasive ADCs. This DNA was subjected to deep next-generation sequencing and tested against a custom panel of 347 cancer genes.
Sequencing data was analyzed for associations among tumor mutation burden, frequency of mutations or copy number alterations, mutation signatures, intratumor heterogeneity, pathway alterations, histology, and overall survival. We found that deleterious mutation burden was significantly greater in invasive ADC, whereas more copy number loss was observed in AIS and MIA. Intratumor heterogeneity establishes early, as in AIS. Twenty-one significantly mutated genes were shared among the groups. Mutation signature profiling did not vary significantly, although the APOBEC signature was associated with ADC and poor survival. Subclonal KRAS mutations and a gene signature consisting of PIK3CG, ATM, EPPK1, EP300, or KMT2C mutations were also associated with poor survival. Mutations of KRAS, TP53, and NF1 were found to increase in frequency from AIS and MIA to ADC. A cancer progression model revealed selective early and late drivers.
Our results reveal several genetic driver events, clonality, and mutational signatures associated with poor outcome in early lung ADC, with potential future implications for the detection and management of ADC.
Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. ...Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed "neural" subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the "neural" LUSC. Forced expression of p63 downregulated Brn2 in the "neural" LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted. SIGNIFICANCE: Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.
http://cancerres.aacrjournals.org/content/canres/79/24/6084/F1.large.jpg.
Investigate racial disparities in outcomes and molecular features in Black and White patients with endometrioid endometrial carcinoma (EEC).
Black and White patients diagnosed with EEC who underwent ...hysterectomy ± adjuvant treatment in SEER, National Cancer Database (NCDB), the Genomics Evidence Neoplasia Information Exchange (GENIE) project (v.13.0), and eight NCI-sponsored randomized phase III clinical trials (RCTs) were studied. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for cancer-related death (CRD), non-cancer death (NCD), and all-cause death.
Black (n = 4397) vs. White (n = 47,959) patients in SEER had a HR (95% CI) of 2.04 (1.87–2.23) for CRD and 1.22 (1.09–1.36) for NCD. In NCDB, the HR (95% CI) for death in Black (n = 13,468) vs. White (n = 155,706) patients was 1.52 (1.46–1.58) dropping to 1.29 (1.23–1.36) after propensity-score matching for age, comorbidity, income, insurance, grade, stage, LVSI, and treatment. In GENIE, Black (n = 109) vs. White (n = 1780) patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR, CCND1, and PI3K-pathway-related gene mutations. In contrast, TP53 and DNA-repair-related gene mutation frequency as well as tumor mutational burden-high status were similar in Black and White patients. In RCTs, Black (n = 187) vs. White (n = 2877) patients were more likely to have advanced or recurrent disease, higher grade, worse performance status and progressive disease. Risk of death in Black vs. White patients in RCTs was 2.19 (1.77–2.71) persisting to 1.32 (1.09–1.61) after matching for grade, stage, and treatment arm while balancing age and performance status.
Differences exist in clinical presentation, outcomes, and molecular features in Black vs. White patients with EEC in real-world registries and RCTs. Targeted-drug development, strategies to modify social determinants, and diverse inclusion in RCTs are approaches to reduce disparities.
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•Risk of cancer-related and non-cancer-related death was 200% and 22% higher in Black vs. White patients with EEC in SEER.•Risk of all-cause death was 1.52 (1.46–1.58) dropping to 1.29 (1.23–1.36) in matched NCDB Black vs. White patients.•Black vs. White patients had fewer PTEN, PIK3R1, FBXW7, NF1, mTOR and CCND1 mutations and similar TMB-high status.•Advanced/recurrent disease, grade 3, and worse performance status were more common in Black vs. White EEC patients in RCTs.•Risk of death in Black vs. White patients in RCTs was 2.19 (1.77–2.71), persisting in matched analysis 1.32 (1.09–1.61).
•Drug-related interstitial lung disease (ILD)/pneumonitis diagnosis is challenging.•Careful monitoring, prompt diagnosis, and appropriate management are important.•Most events are low grade and can ...be managed safely.•Education is critical to ensure potential ILD/pneumonitis is proactively identified.•We suggest using a multidisciplinary approach.
Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd–related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd–related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd–related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms.
References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors’ own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.
Inequality between and within populations has origins in adverse early experiences. Developmental neuroscience shows how early biological and psychosocial experiences affect brain development. We ...previously identified inadequate cognitive stimulation, stunting, iodine deficiency, and iron-deficiency anaemia as key risks that prevent millions of young children from attaining their developmental potential. Recent research emphasises the importance of these risks, strengthens the evidence for other risk factors including intrauterine growth restriction, malaria, lead exposure, HIV infection, maternal depression, institutionalisation, and exposure to societal violence, and identifies protective factors such as breastfeeding and maternal education. Evidence on risks resulting from prenatal maternal nutrition, maternal stress, and families affected with HIV is emerging. Interventions are urgently needed to reduce children's risk exposure and to promote development in affected children. Our goal is to provide information to help the setting of priorities for early child development programmes and policies to benefit the world's poorest children and reduce persistent inequalities. PUBLICATION ABSTRACT
Women with persistent, recurrent, and/or metastatic cervical cancer have a poor prognosis. Even with the availability of cisplatin plus paclitaxel and bevacizumab, median overall survival (OS) is ...only 17.0 months, with median post-progression survival of approximately seven months. We studied the therapeutic vaccine, Axalimogene filolisbac (ADXS-HPV), in women who had progressed following at least one prior line of therapy (Gynecologic Oncology Group protocol 265/NCT01266460).
Volunteers ≥18 years with advanced cervical cancer and GOG performance status score of 0 or 1 were eligible for participation in this 2-stage, phase II trial. In stage 1, women received up to three doses of ADXS-HPV (1 × 109 colony-forming units in 250 mL IV over 15 min every 28 days) and were monitored for tumor progression. In stage 2, women were treated until progression, intolerable adverse events (AEs), or voluntary withdrawal of consent. Co-primary endpoints were safety and proportion of volunteers surviving ≥12 months. An estimated, combined (stages 1 + 2) 12-month OS of 35% was calculated from historical GOG cohorts to declare ADXS-HPV sufficiently active in this platinum-pre-treated population. Secondary endpoints were OS and progression-free survival (PFS).
Among 50 evaluable volunteers, the 12-month OS was 38% (n = 19). Median OS was 6.1 months (95% CI: 4.3–12.1) and median PFS was 2.8 months (95% CI: 2.6–3.0). The most common treatment-related AEs were fatigue, chills, fever, nausea, and anemia. The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment.
At the dose and schedule studied, ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity required to warrant further investigation in volunteers with cervical carcinoma.
•ADXS-HPV immunotherapy was tolerable and met the protocol-specified benchmark for activity.•Among 50 evaluable volunteers, the 12-month OS was 38%.•The majority of AEs were grade 1 or 2 and resolved spontaneously or with appropriate treatment.
Omicron variants are part of the "Coronavirus disease 2019 COVID-19 Variants of Concerns" and has the potential to spread around the world rapidly and can harm human life. We can anticipate that the ...endemic state of COVID-19 will be characterized by the development of new strains with surges that will predominate in unvaccinated and immunodeficient populations. Thus, there will be an important role in promoting vaccinations, boosters and accessible testing to prevent disease transmission and to rapidly detect surges. There is an urgent need to explore the virology and biology of Omicron variants, define clinical phenomes and therapies, monitor dynamics of genetic changes, and translate the knowledge of COVID-19 into new variants. Clinical and translational medicine will be impactful in addressing these challenges by providing new insights for understanding and predicting new variants-associated transmissibility, disease severity, immune escape, diagnostic or therapeutic failure.
Omicron variants are part of the “COVID‐19 variants of concerns” and have the potential to spread around the world rapidly and can harm human life. We can anticipate that the endemic state of ...COVID‐19 will be characterized by development of new strains with surges that will predominate in unvaccinated and immunodeficient populations. Thus, there will be an important role for promoting vaccinations, boosters and accessible testing to prevent disease transmission and to rapidly detect surges. There is an urgent need to explore the virology and biology of Omicron variants, define clinical phenomes and therapies, monitor dynamics of genetic changes and translate the knowledge of COVID‐19 into new variants. Clinical and translational medicine will be impactful in addressing these challenges by providing new insights for understanding and predicting new variants‐associated transmissibility, disease severity, immune escape, diagnostic, or therapeutic failure.
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