There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype ...adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic
variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver
mutations.
mutations were present in AAHs from 4 of 22 (18%) of patients.
mutations in AAH were only found in ever-smokers and were exclusive to
-mutant cases. Integrative analysis revealed profiles expressed in
-mutant cases (
) and
-mutant cases (
) of AAH, or common to both sets of cases (suppressed
). Gene sets associated with suppressed antitumor (Th1;
) and elevated protumor (
) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent
or
pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion.
.
The American College of Physicians (ACP) update of their standing guidance statement for colorectal-cancer screening in asymptomatic average-risk adults was recently published to assist clinicians ...with implementing evidence-based patient care. After assessing existing guideline literature, the ACP recommended five actions: consider not screening adults ages 45 to 49 years; stop screening adults older than 75 years; discuss benefits, harms, costs, availability, frequency, and patient values/preferences with patients prior to choosing a screening method; and when choosing, recommend biennial rather than annual use of a fecal immunochemical test or a guaiac fecal occult blood test and avoid recommending computed tomography colonography or stool DNA tests. While the ACP guidelines are rigorous, well-intended, and considerate of patients' input, their greatest impact may result from highlighting the need for researchers to help frontline clinicians to describe the risk, costs, and benefits/harms of various colorectal-cancer screening strategies in an effective, yet time-efficient, manner given the all-too-brief annual patient encounters. In the United States, reimbursement is still dependent on U.S. Preventive Services Task Force recommendations which are somewhat more liberal in contrast to the ACP's approach which strongly favors randomized, controlled trial evidence to guide the delivery of prevention and screening services to asymptomatic average-risk patients.
Various clinical and epidemiologic studies show that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase inhibitors (COXIBs) help prevent cancer. Since eicosanoid ...metabolism is the main inhibitory targets of these drugs the resulting molecular and biological impact is generally accepted. As our knowledge base and technology progress we are learning that additional targets may be involved. This review attempts to summarize these new developments in the field.
E-cigarettes have the ability to deliver nicotine in a manner that is similar to, and, theoretically, safer than, combusted tobacco. However, these devices are extremely heterogeneous and regulation ...has struggled to keep up with their rapid evolution. A compilation of early data suggest that e-cigarettes may contain numerous toxic substances, including known carcinogens. However, there are few data available on the short- and long-term health effects of e-cigarettes, including any potential effect on cancer risk. Until more is known, e-cigarettes should not be considered a safe alternative to combusted tobacco use.
Nearly all cancers have identifiable histologically defined precursors known as precancers. These precancers offer a window of opportunity to intercept the neoplastic process to prevent its ...development into invasive cancer. However, lack of knowledge regarding the evolution of precancers and the microenvironmental pressures shaping them precludes efforts to intercept them. Technological developments over the past decade have facilitated the study of precancers at a previously unattainable resolution. Calls for a national PreCancer Atlas effort incorporating these technologies were heeded in 2018, with the launch of the Human Tumor Atlas Network (HTAN) as part of the Beau Biden National Cancer Moonshot. Since then, five funded HTAN groups have focused their efforts on profiling precancers from breast, colon, skin, and lung. In this time, what progress has been made? What is next for HTAN and the field of premalignant biology? And are there lessons that individual investigators and the larger prevention field can learn from this initial effort to accelerate the development of novel early detection methods, risk prediction biomarkers, and interception agents? A special collection of invited reviews by experts in cancer evolution, systems biology, immunology, cancer genetics, preventive agent development, among other areas, attempts to answer these questions.
Colorectal Cancer Prevention HAWK, Ernest T; LEVIN, Bernard
Journal of clinical oncology,
01/2005, Volume:
23, Issue:
2
Journal Article
Peer reviewed
Colorectal cancer is the second leading cause of mortality in the United States. In the United States, the cumulative lifetime risk of developing colorectal cancer for both men and women is 6%. ...Despite advances in the management of this disease, the 5-year survival rate in the United States in only 62%. Because only 38% of patients are diagnosed when the cancers are localized to the bowel wall, it is likely that widespread implementation of screening could significantly improve the outcome. Colorectal cancer screening is cost effective, irrespective of the methods used. In addition to currently available methods (fecal occult blood, flexible sigmoidoscopy, colonoscopy, and double contrast barium enema), computed tomographic colonography (virtual colonoscopy) and stool-based molecular screening are under development. Four classes of chemopreventive compounds have demonstrated efficacy in reducing recurrent colorectal adenomas and/or cancer in randomized, controlled trials. They are selenium, calcium carbonate, hormone replacement therapy, and nonsteroidal anti-inflammatory drugs. The mechanisms of action of nonsteroidal anti-inflammatory drugs include inhibition of the cyclooxygenase system as well as cyclooxygenase-independent effects. Considerable effort is being expended to define chemopreventive activity, optimal dose, administration schedule, and toxicity for the coxibs in adenoma recurrence prevention trials. The threshold for tolerating toxicities is very low in asymptomatic individuals at minimally increased risk for colorectal neoplasia.
Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article ...examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds.
Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case‐control and cohort studies. These demonstrations of feasibility herald the ...potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation.
Minimally invasive, molecular biomarkers demonstrate feasibility for the early detection of multiple cancers in large‐scale case control and cohort studies. Here the paradigm‐changing opportunities and the challenges facing the preclinical development and clinical validation of multicancer early‐detection test strategies are discussed.
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