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A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine mo...
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A lack of relevant genetic models and cell lines hampers our understanding of hepatoblastoma pathogenesis and the development of new therapies for this neoplasm. Here, we report an improved MYC-driven hepatoblastoma-like murine model that recapitulates the pathological features of embryonal type of hepatoblastoma, with transcriptomics resembling the high-risk gene signatures of the human disease. Single-cell RNA-sequencing and spatial transcriptomics identify distinct subpopulations of hepatoblastoma cells. After deriving cell lines from the mouse model, we map cancer dependency genes using CRISPR-Cas9 screening and identify druggable targets shared with human hepatoblastoma (e.g., CDK7, CDK9, PRMT1, PRMT5). Our screen also reveals oncogenes and tumor suppressor genes in hepatoblastoma that engage multiple, druggable cancer signaling pathways. Chemotherapy is critical for human hepatoblastoma treatment. A genetic mapping of doxorubicin response by CRISPR-Cas9 screening identifies modifiers whose loss-of-function synergizes with (e.g., PRKDC) or antagonizes (e.g., apoptosis genes) the effect of chemotherapy. The combination of PRKDC inhibition and doxorubicin-based chemotherapy greatly enhances therapeutic efficacy. These studies provide a set of resources including disease models suitable for identifying and validating potential therapeutic targets in human high-risk hepatoblastoma. The availability of relevant animal models that can recapitulate high-risk hepatoblastoma will help to better understand its pathogenesis. Here the authors report and characterize a hepatocyte-specific, MYC-driven hepatoblastoma mouse model and show it recapitulates the human hepatoblastoma pathophysiology.
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? 2023 Elsevier Inc.Using the OncoSim All Cancers Model, we estimated the annual cancer incidence, mortality and cancer management costs in Canada from 2020 to 2040. Incidence for each cancer type was estimated from logistic regre...
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? 2023 Elsevier Inc.Using the OncoSim All Cancers Model, we estimated the annual cancer incidence, mortality and cancer management costs in Canada from 2020 to 2040. Incidence for each cancer type was estimated from logistic regression analyses of the Canadian Cancer Registry (1992–2017), with province/territory, sex, five-year age groups and year as covariates. Deaths were estimated by sex and tumour site for cancers diagnosed between 2000 and 2017 (deaths to the end of 2017). The total cost of a cancer type was the sum of costs for individuals across four phases of cancer care. The projections presented in this study were generated based on a simulation of 32 million cases. The OncoSim All Cancers Model projects a 40% increase in the overall number of incident cancer cases from 2020 to 2040. The number of the four most commonly diagnosed cancers in Canada (breast, colorectal, lung, and prostate) are projected to increase annually. The overall number of cancer deaths is projected to increase by 44% from 2020 to 2040. More cancer deaths are projected in males than in females. The age-standardized mortality rate is expected to remain relatively stable over time. Overall cancer management costs are projected to increase from $20.6B in 2020 to $31.4B in 2040. Due mainly to an aging population and population growth in Canada, we estimate that cancer incidence, mortality and cancer management costs will increase considerably between 2020 and 2040. These results highlight the importance of planning for increasing investment and capacity in cancer control.
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This is a review of the epidemiologic literature on alcohol and risks of various cancers. Alcohol has consistently been related to risks of squamous cell carcinomas of the mouth, oral pharynx, larynx, and esophagus in multiple stu...
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This is a review of the epidemiologic literature on alcohol and risks of various cancers. Alcohol has consistently been related to risks of squamous cell carcinomas of the mouth, oral pharynx, larynx, and esophagus in multiple studies of varying design. The joint effects of alcohol and smoking are greater than additive, and. are probably multiplicative, suggesting biological synergism. All major types of alcoholic beverages have been causally implicated in the genesis of these diseases. The influence of alcohol on risks of upper aerodigestive tract cancers may be greater in persons with . marginal nutritional status than in better-nourished individuals. Alcohol also has been associated with an increased risk of adenocarcinomas of the esophagus, gastro-esophageal junction, and gastric cardia, but the relationship is not as strong as for squamous cell esophageal carcinomas. Alcohol and tobacco account for over 80% of the squamous carcinomas of the mouth, pharynx, larynx, and esophagus in the United States. Risks of cancers of the distal stomach, pancreas, colon, and rectum have not been consistently related to alcohol, although possible relationships between beer drinking and rectal cancer and between heavy use of alcohol and pancreatic cancer warrant further study. Studies of alcohol and liver cancer, in which the confounding influence of hepatitis B was considered, have yielded inconsistent results and should be replicated. An association between heavy alcohol use and breast cancer has been observed in most studies, even after controlling for known risk factors for breast cancer, and additional investigations of this issue are warranted.
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Background Although management guidelines exist for several genes associated with a 2‐fold to 5‐fold increase in the relative risk for certain cancers, the value of testing for them remains controversial. Methods De‐identified ...
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Background Although management guidelines exist for several genes associated with a 2‐fold to 5‐fold increase in the relative risk for certain cancers, the value of testing for them remains controversial. Methods De‐identified personal and family history data for 654 individuals?with pathogenic variants (PVs) in PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and/or RAD51D were analyzed for pretest and post‐test candidacy for guideline‐recommended management of cancer risk. These individuals were invited to complete a survey about provider recommendations and their adherence. Results Twenty‐four percent of CHEK2, ATM, PALB2, or NBN PV carriers were appropriate for consideration of annual breast magnetic resonance imaging screening before genetic testing, with the remaining 76% appropriate only after testing. No BRIP1, RAD51C, or RAD51D PV carriers were appropriate for consideration of risk‐reducing salpingo‐oophorectomy before genetic testing; 100% were appropriate only after testing. Seventeen percent of CHEK2 PV carriers were appropriate for earlier and more frequent colonoscopy before genetic testing, with the remaining 83% appropriate only after testing. Provider recommendations for annual breast magnetic resonance imaging, consideration of risk‐reducing salpingo‐oophorectomy, and earlier and more frequent colonoscopy were reported by 42%, 26%, and 66% of breast, ovarian, and colorectal cancer risk PV carriers, respectively, before genetic testing, versus 82%, 79%, and 81%, respectively, after testing. Nearly all respondents had planned or undertaken provider‐recommended management. Conclusions Testing for PALB2, ATM, CHEK2, NBN, BRIP1, RAD51C, and RAD51D changed management for those carrying PVs. Provider recommendations were aligned with guidelines, and patients adhered to recommendations,?both of which are critical for reducing both long‐term cancer morbidity and mortality.
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Background Although management guidelines exist for several genes associated with a 2‐fold to 5‐fold increase in the relative risk for certain cancers, the value of testing for them remains controversial. Methods De‐identified ...
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Background Although management guidelines exist for several genes associated with a 2‐fold to 5‐fold increase in the relative risk for certain cancers, the value of testing for them remains controversial. Methods De‐identified personal and family history data for 654 individuals?with pathogenic variants (PVs) in PALB2 , ATM , CHEK2 , NBN , BRIP1 , RAD51C , and/or RAD51D were analyzed for pretest and post‐test candidacy for guideline‐recommended management of cancer risk. These individuals were invited to complete a survey about provider recommendations and their adherence. Results Twenty‐four percent of CHEK2 , ATM , PALB2 , or NBN PV carriers were appropriate for consideration of annual breast magnetic resonance imaging screening before genetic testing, with the remaining 76% appropriate only after testing. No BRIP1 , RAD51C , or RAD51D PV carriers were appropriate for consideration of risk‐reducing salpingo‐oophorectomy before genetic testing; 100% were appropriate only after testing. Seventeen percent of CHEK2 PV carriers were appropriate for earlier and more frequent colonoscopy before genetic testing, with the remaining 83% appropriate only after testing. Provider recommendations for annual breast magnetic resonance imaging, consideration of risk‐reducing salpingo‐oophorectomy, and earlier and more frequent colonoscopy were reported by 42%, 26%, and 66% of breast, ovarian, and colorectal cancer risk PV carriers, respectively, before genetic testing, versus 82%, 79%, and 81%, respectively, after testing. Nearly all respondents had planned or undertaken provider‐recommended management. Conclusions Testing for PALB2 , ATM , CHEK2 , NBN , BRIP1 , RAD51C , and RAD51D changed management for those carrying PVs. Provider recommendations were aligned with guidelines, and patients adhered to recommendations,?both of which are critical for reducing both long‐term cancer morbidity and mortality.
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Background: Population-based data on the development of subsequent thoracic cancers following the initial diagnosis of lung cancer are scarce. We evaluated this clinical scenario in lung cancer patients registered within the Surve...
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Background: Population-based data on the development of subsequent thoracic cancers following the initial diagnosis of lung cancer are scarce. We evaluated this clinical scenario in lung cancer patients registered within the Surveillance, Epidemiology and End Results (SEER) database.Methods: The SEER database (1988-2013) was queried using the SEER*Stat program to determine the clinico-pathological features of lung cancer patients who develop subsequent thoracic cancers as well as the characteristics of these subsequent cancers. Associations were ascertained with chi-squared tests and survival analysis was performed using Kaplan-Meier methods. Standardized incidence ratios (SIRs) were calculated to determine the risk of each type of subsequent cancer.Results: A total of 223,274 lung cancer patients were identified and included in the current study. In this cohort, 6387 patients developed subsequent thoracic cancers. The following were associated with a higher likelihood of second cancers: female gender, younger age, white race, adenocarcinoma histology, married, lower AJCC stage, earlier year of diagnosis and local treatment with surgery rather than radiotherapy (p<.0001 for all parameters). In the subset of patients with subsequent thoracic cancers, survival was best for patients with second primary breast cancer followed by patients with lung or esophageal cancer (p<.0001). SIR analyses showed an excess risk for the development of esophageal cancer and second primary lung cancer following an initial diagnosis of lung cancer. This risk persists regardless of gender or receipt of radiotherapy (p<.05 for all scenarios).Conclusion: There is an excess risk for the development of esophageal cancer and second primary lung cancer following an initial lung cancer diagnosis. This risk is present irrespective of gender or receipt of radiotherapy.
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Background: The aim of this study was to analyse the association between pelvic radiation therapy (RT) and the development of rectal cancer as a second primary cancer.
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Limited health system capacities and competing health priorities in low and middle income countries (LMICs) necessitate apragmatic approach to population-based cancer screening. Thus, the challenges faced by LMICs to implement awe...
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Limited health system capacities and competing health priorities in low and middle income countries (LMICs) necessitate apragmatic approach to population-based cancer screening. Thus, the challenges faced by LMICs to implement awestern' model of screening for common cancers and the possible means to overcome these challenges are presented. Breast cancer is the number one cancer with arising trend in the majority of LMICs. Implementation of mass-scale mammography-based screening is not feasible and sustainable in most of them. While some LMICs have introduced breast cancer screening based on clinical breast examination (CBE), the programs need to be of appropriate quality. All LMICs should improve the capacity for early diagnosis of breast cancer along with other common cancers through community education, training of frontline health workers, facilitating prompt referrals and improving the infrastructure for cancer diagnosis and treatment. Resources permitting, the LMICs with high burden of cervical cancer may consider human papillomavirus (HPV) detection-based screening; asimple low-cost alternative is visual inspection with acetic acid (VIA). Regardless of the choice, astrong linkage should be established between screening and treatment with implementation of robust quality assurance. The few LMICs with arising trend of colorectal cancers and adequate resources may implement demonstration projects to screen with fecal immunochemical tests (FIT). Oral cancer screening of habitual tobacco and/or alcohol users using oral visual examination (OVE) may be implemented in countries with high burden of the cancer, but primary prevention (i.e., tobacco/alcohol cessation) should be prioritized. Screenings for other cancers are not recommended for LMICs.
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'The big C', a common euphemism for cancer, has loomed large on the collective psyche of the mankind for centuries, not least because of the relative dearth of effective treatment against this disease but its ability to relentless...
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'The big C', a common euphemism for cancer, has loomed large on the collective psyche of the mankind for centuries, not least because of the relative dearth of effective treatment against this disease but its ability to relentlessly evade them and come back to haunt us. However, the struggle against cancer took a decisive turn in 1971 when a relentless campaigning by health activists eventually led to signing of the National Cancer Act in the United States, an unprecedented event in the history of diseases. As we commemorate the 40th anniversary of the signing of that historic legislation, an assessment of the progress against cancer would naturally help us understand how we have fared so far in this struggle and guide us in our efforts to re-strategize and re-deploy our limited resources to their best use against this immortal enemy.
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