Risk-based lung cancer screening performance in a universal healthcare setting.

Globally, lung cancer is the leading cause of cancer death. Previous trials demonstrated that low-dose computed tomography lung cancer screening of high-risk individuals can reduce lung cancer mortality by 20% or more. Lung cancer screening has been approved by major guidelines in the United States, and over 4,000 sites offer screening. Adoption of lung screening outside the United States has, until recently, been slow. Between June 2017 and May 2019, the Ontario Lung Cancer Screening Pilot successfully recruited 7,768 individuals at high risk identified by using the PLCOm2012noRace lung cancer risk prediction model. In total, 4,451 participants were successfully screened, retained and provided with high-quality follow-up, including appropriate treatment. In the Ontario Lung Cancer Screening Pilot, the lung cancer detection rate and the proportion of early-stage cancers were 2.4% and 79.2%, respectively; serious harms were infrequent; and sensitivity to detect lung cancers was 95.3% or more. With abnormal scans defined as ones leading to diagnostic investigation, specificity was 95.5% (positive predictive value, 35.1%), and adherence to annual recall and early surveillance scans and clinical investigations were high (>85%). The Ontario Lung Cancer Screening Pilot provides insights into how a risk-based organized lung screening program can be implemented in a large, diverse, populous geographic area within a universal healthcare system.

Integrating Smoking Cessation Into Low-Dose Computed Tomography Lung Cancer Screening: Results of the Ontario, Canada Pilot.

INTRODUCTION: Low-dose computed tomography screening in high-risk individuals reduces lung cancer mortality. To inform the implementation of a provincial lung cancer screening program, Ontario Health undertook a Pilot study, which integrated smoking cessation (SC). METHODS: The impact of integrating SC into the Pilot was assessed by the following: rate of acceptance of a SC referral; proportion of individuals who were currently smoking cigarettes and attended a SC session; the quit rate at 1 year; change in the number of quit attempts; change in Heaviness of Smoking Index; and relapse rate in those who previously smoked. RESULTS: A total of 7768 individuals were recruited predominantly through primary care physician referral. Of these, 4463 were currently smoking and were risk assessed and referred to SC services, irrespective of screening eligibility: 3114 (69.8%) accepted referral to an in-hospital SC program, 431 (9.7%) to telephone quit lines, and 50 (1.1%) to other programs. In addition, 4.4% reported no intention to quit and 8.5% were not interested in participating in a SC program. Of the 3063 screen-eligible individuals who were smoking at baseline low-dose computed tomography scan, 2736 (89.3%) attended in-hospital SC counseling. The quit rate at 1 year was 15.5% (95% confidence interval: 13.4%-17.7%; range: 10.5%-20.0%). Improvements were also observed in Heaviness of Smoking Index (p < 0.0001), number of cigarettes smoked per day (p < 0.0001), time to first cigarette (p < 0.0001), and number of quit attempts (p < 0.001). Of those who reported having quit within the previous 6 months, 6.3% had resumed smoking at 1 year. Furthermore, 92.7% of the respondents reported satisfaction with the hospital-based SC program. CONCLUSIONS: On the basis of these observations, the Ontario Lung Screening Program continues to recruit through primary care providers, to assess risk for eligibility using trained navigators, and to use an opt-out approach to referral for cessation services. In addition, initial in-hospital SC support and intensive follow-on cessation interventions will be provided to the extent possible.

Delivery of Cancer Care in Ontario, Canada, During the First Year of the COVID-19 Pandemic.

Importance: The COVID-19 pandemic has impacted cancer systems worldwide. Quantifying the changes is critical to informing the delivery of care while the pandemic continues, as well as for system recovery and future pandemic planning. Objective: To quantify change in the delivery of cancer services across the continuum of care during the COVID-19 pandemic. Design, Setting, and Participants: This population-based cohort study assessed cancer screening, imaging, diagnostic, treatment, and psychosocial oncological care services delivered in pediatric and adult populations in Ontario, Canada (population 14.7 million), from April 1, 2019, to March 1, 2021. Data were analyzed from May 1 to July 31, 2021. Exposures: COVID-19 pandemic. Main Outcomes and Measures: Cancer service volumes from the first year of the COVID-19 pandemic, defined as April 1, 2020, to March 31, 2021, were compared with volumes during a prepandemic period of April 1, 2019, to March 31, 2020. Results: During the first year of the pandemic, there were a total of 4 476 693 cancer care services, compared with 5 644 105 services in the year prior, a difference of 20.7% fewer services of cancer care, representing a potential backlog of 1 167 412 cancer services. While there were less pronounced changes in systemic treatments, emergency and urgent imaging examinations (eg, 1.9% more parenteral systemic treatments) and surgical procedures (eg, 65% more urgent surgical procedures), major reductions were observed for most services beginning in March 2020. Compared with the year prior, during the first pandemic year, cancer screenings were reduced by 42.4% (-1 016 181 screening tests), cancer treatment surgical procedures by 14.1% (-8020 procedures), and radiation treatment visits by 21.0% (-141 629 visits). Biopsies to confirm cancer decreased by up to 41.2% and surgical cancer resections by up to 27.8% during the first pandemic wave. New consultation volumes also decreased, such as for systemic treatment (-8.2%) and radiation treatment (-9.3%). The use of virtual cancer care increased for systemic treatment and radiation treatment and psychosocial oncological care visits, increasing from 0% to 20% of total new or follow-up visits prior to the pandemic up to 78% of total visits in the first pandemic year. Conclusions and Relevance: In this population-based cohort study in Ontario, Canada, large reductions in cancer service volumes were observed. While most services recovered to prepandemic levels at the end of the first pandemic year, a substantial care deficit likely accrued. The anticipated downstream morbidity and mortality associated with this deficit underscore the urgent need to address the backlog and recover cancer care and warrant further study.

Adherence to guidance for prioritizing higher risk groups for breast cancer screening during the COVID-19 pandemic in the Ontario Breast Screening Program: a descriptive study.

BACKGROUND: Breast cancer screening in Ontario, Canada, was deferred during the first wave of the COVID-19 pandemic, and a prioritization framework to resume services according to breast cancer risk was developed. The purpose of this study was to assess the impact of the pandemic within the Ontario Breast Screening Program (OBSP) by comparing total volumes of screening mammographic examinations and volumes of screening mammographic examinations with abnormal results before and during the pandemic, and to assess backlogs on the basis of adherence to the prioritization framework. METHODS: A descriptive study was conducted among women aged 50 to 74 years at average risk and women aged 30 to 69 years at high risk, who participated in the OBSP. Percentage change was calculated by comparing observed monthly volumes of mammographic examinations from March 2020 to March 2021 with 2019 volumes and proportions by risk group. We plotted estimates of backlog volumes of mammographic examinations by risk group, comparing pandemic with prepandemic screening practices. Volumes of mammographic examinations with abnormal results were plotted by risk group. RESULTS: Volumes of mammographic examinations in the OBSP showed the largest declines in April and May 2020 (> 99% decrease) and returned to prepandemic levels as of March 2021, with an accumulated backlog of 340 876 examinations. As of March 2021, prioritization had reduced the backlog volumes of screens for participants at high risk for breast cancer by 96.5% (186 v. 5469 expected) and annual rescreens for participants at average risk for breast cancer by 13.5% (62 432 v. 72 202 expected); there was a minimal decline for initial screens. Conversely, the backlog increased by 7.6% for biennial rescreens (221 674 v. 206 079 expected). More than half (59.4%) of mammographic examinations with abnormal results were for participants in the higher risk groups. INTERPRETATION: Prioritizing screening for those at higher risk for breast cancer may increase diagnostic yield and redirect resources to minimize potential long-term harms caused by the pandemic. This further supports the clinical utility of risk-stratified cancer screening.

Measuring the impact of the COVID-19 pandemic on organized cancer screening and diagnostic follow-up care in Ontario, Canada: A provincial, population-based study.

It is essential to quantify the impacts of the COVID-19 pandemic on cancer screening, including for vulnerable sub-populations, to inform the development of evidence-based, targeted pandemic recovery strategies. We undertook a population-based retrospective observational study in Ontario, Canada to assess the impact of the pandemic on organized cancer screening and diagnostic services, and assess whether patterns of cancer screening service use and diagnostic delay differ across population sub-groups during the pandemic. Provincial health databases were used to identify age-eligible individuals who participated in one or more of Ontario's breast, cervical, colorectal, and lung cancer screening programs from January 1, 2019-December 31, 2020. Ontario's screening programs delivered 951,000 (-41%) fewer screening tests in 2020 than in 2019 and volumes for most programs remained more than 20% below historical levels by the end of 2020. A smaller percentage of cervical screening participants were older (50-59 and 60-69 years) during the pandemic when compared with 2019. Individuals in the oldest age groups and in lower-income neighborhoods were significantly more likely to experience diagnostic delay following an abnormal breast, cervical, or colorectal cancer screening test during the pandemic, and individuals with a high probability of living on a First Nation reserve were significantly more likely to experience diagnostic delay following an abnormal fecal test. Ongoing monitoring and management of backlogs must continue. Further evaluation is required to identify populations for whom access to cancer screening and diagnostic care has been disproportionately impacted and quantify impacts of these service disruptions on cancer incidence, stage, and mortality. This information is critical to pandemic recovery efforts that are aimed at achieving equitable and timely access to cancer screening-related care.

Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis.

BACKGROUND: Diamond-Blackfan anemia is a fatal congenital anemia characterized by a specific disruption in erythroid progenitor cell development. Approximately 25% of patients have mutations in the ribosomal protein RPS19 suggesting that Diamond-Blackfan anemia may be caused by a defect in ribosome biogenesis and translation. However, it is unclear how these defects specifically disrupt early erythropoiesis. Recent studies have shown that the retroviral receptor/heme exporter FLVCR1 is critical for early erythropoiesis. FLVCR1 null mice, despite dying in utero and having reduced myeloid and lymphoid cell growth, show a disruption in early erythropoiesis and have craniofacial and limb deformities similar to those found in some Diamond-Blackfan anemia patients. DESIGN AND METHODS: In this study, we recapitulated the Diamond-Blackfan anemia hematologic features of reduced erythropoiesis but normal myelopoiesis by disrupting FLVCR1 in human hematopoietic stem cells. RESULTS: We found that CD71(high) cells, which are enriched for immature erythroid cells, from Diamond-Blackfan anemia patients negative for RPS19 gene mutations express alternatively spliced isoforms of FLVCR1 transcript which encode proteins whose expression and function are disrupted. More importantly, our results suggest alternative splicing of FLVCR1 is significantly enhanced in Diamond-Blackfan anemia immature erythroid cells. Furthermore, we also observed enhanced FLVCR1 alternative splicing and a dramatic reduction of FLVCR1 protein expression in RPS19 down-regulated human K562 cells, which were used as a model to represent RPS19 gene mutated Diamond-Blackfan anemia. CONCLUSIONS: Taken together, our results suggest enhanced alternative splicing of FLVCR1 transcripts and subsequent FLVCR1 insufficiency as an additional contributing factor to the erythropoietic defect observed in Diamond-Blackfan anemia.

The C domain in the surface envelope glycoprotein of subgroup C feline leukemia virus is a second receptor-binding domain.

The receptor-binding domain (RBD) in the surface (SU) subunit of gammaretrovirus envelope glycoprotein is critical for determining the host receptor specificity of the virus. This domain is separated from the carboxy terminal C domain (Cdom) of SU by a proline-rich region. In this study, we show that the Cdom region in the SU from subgroup C feline leukemia virus (FeLV-C) forms a second receptor-binding domain that is distinct from its RBD, and which can independently bind to its host receptor FLVCR1, in the absence of RBD. Furthermore, our results suggest that residues located in the C2 disulfide-bonded loop in FeLV-C Cdom are critical for SU binding to FLVCR1 and for virus infection. We propose that binding of FeLV-C SU to FLVCR1 involves interaction of two receptor-binding domains (RBD and Cdom) with FLVCR1, and that this mechanism of interaction is conserved for other gammaretroviruses. Our results could have important implications for designing gammaretrovirus vectors that can efficiently infect specific target cells.

The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent intramolecular autolysis.

Limb girdle muscular dystrophy type 2A is linked to a skeletal muscle-specific calpain isoform known as p94. Isolation of the intact 94-kDa enzyme has been difficult to achieve due to its rapid autolysis, and uncertainty has arisen over its Ca2+-dependence for activity. We have expressed a C-terminally truncated form of the enzyme that comprises the protease core (domains I and II) along with its insertion sequence, IS1, and N-terminal leader sequence, NS. This 47-kDa p94I-II mini-calpain was stable during purification. In the presence of Ca2+, p94I-II cleaved itself within the NS and IS1 sequences. Mapping of the autolysis sites showed that NS and IS1 have the potential to be removed without damage to the protease core. Ca2+-dependent autolysis must be an intramolecular event because the inactive p94I-II C129S mutant was not cleaved by incubation with wild-type p94I-II. In addition, the rate of autolysis of p94I-II was independent of the concentration of the enzyme.