Long-Term Safety of Teriflunomide in Multiple Sclerosis Patients: Results of Prospective Comparative Studies in Three European Countries.

BACKGROUND AND OBJECTIVES: Teriflunomide is a disease-modifying therapy (DMT) for multiple sclerosis (MS). This post authorisation safety study assessed risks of adverse events of special interest (AESI) associated with teriflunomide use. METHODS: Secondary use of individual data from the Danish MS Registry (DMSR), the French National Health Data System (SNDS), the Belgian national database of health care claims (AIM-IMA) and the Belgian Treatments in MS Registry (Beltrims). We included patients treated with a DMT at the date of teriflunomide reimbursement or initiating another DMT. Adjusted hazard rates (aHR) and 95% confidence intervals were derived from Cox models with time-dependent exposure comparing teriflunomide treatment with another DMT. RESULTS: Of 81 620 patients (72% women) included in the cohort, 22 324 (27%) were treated with teriflunomide. After a median follow-up of 4 years, teriflunomide use compared to other DMT was not associated with a risk of all-cause mortality, severe infection, pneumoniae, herpes zoster reactivation, pancreatitis, cardiovascular condition and cancers. For opportunistic infections, aHR for teriflunomide versus other DMT was 2.4 (1.2-4.8) in SNDS, which was not bound to a particular opportunistic agent. The aHR was 2.0 (1.1-3.7) for renal failures in the SNDS, but no association was found in other data sources. A total of 187 SNDS patients had a history of renal failure prior to cohort entry. None of these patients (0%) had a renal failure recurrence when treated with teriflunomide for 19 (13%) recurrences reported for patients on another DMT. DISCUSSION: We found no evidence that teriflunomide use would be associated with an increased risk of AESI. Trial Registration EUPAS register: EU PAS 19610.

Effect of screening mammography on the risk of breast cancer deaths and of all-cause deaths: a systematic review with meta-analysis of cohort studies.

OBJECTIVES: Observational cohort studies are used to evaluate the effectiveness of screening mammography in women offered screening. Because screening mammography has no effect on causes of death other than breast cancer (BC), cohort studies should show reductions in the risk of BC death substantially greater than possible reductions in the risk of all-cause death. We assessed the risk of BC deaths and of all-cause (or of nonBC) deaths associated with screening mammography attendance reported in cohort studies. STUDY DESIGN AND SETTING: Cohort studies published from 2002 to 2022 on women invited to screening mammography were searched in PubMed, Web of Sciences, Scopus, and in review articles. Random effect meta-analyses were performed using relative risks (RRs) of death between women who attended screening compared to women who did not attend screening. RESULTS: Eighteen cohort studies were identified, nine that reported RRs of BC deaths only, five that reported RRs of all-cause deaths only, and four that reported RRs for both BC deaths and all-cause deaths. The latter four cohort studies reported 12-76 times more all-cause deaths than BC deaths. The random-effect summary of RR for BC mortality in screening attendees vs nonattendees was 0.55 (95% CI: 0.50-0.60) in 13 cohort studies. The summary of RR for all-cause mortality was 0.54 (0.50-0.58) in 10 cohort studies. In the four cohort studies that evaluated both outcomes, the summary of RRs were 0.63 (0.43-0.83) for BC mortality and of 0.54 (0.44-0.64) for all-cause mortality. CONCLUSION: The similar relative reductions in breast- and all-cause (or nonBC) mortality indicates that screening mammography attendance is an indicator of characteristics associated with a lower risk of dying from any cause, including from BC, which observational studies have falsely interpreted as a screening effect.

Skin cancers are the most frequent cancers in fair-skinned populations, but we can prevent them.

Cancers of the skin are the most commonly occurring cancers in humans. In fair-skinned populations, up to 95% of keratinocyte skin cancers and 70-95% of cutaneous melanomas are caused by ultraviolet radiation and are thus theoretically preventable. Currently, however, there is no comprehensive global advice on practical steps to be taken to reduce the toll of skin cancer. To address this gap, an expert working group comprising clinicians and researchers from Africa, America, Asia, Australia, and Europe, together with learned societies (European Association of Dermato-Oncology, Euromelanoma, Euroskin, European Union of Medical Specialists, and the Melanoma World Society) reviewed the extant evidence and issued the following evidence-based recommendations for photoprotection as a strategy to prevent skin cancer. Fair skinned people, especially children, should minimise their exposure to ultraviolet radiation, and are advised to use protective measures when the UV index is forecast to reach 3 or higher. Protective measures include a combination of seeking shade, physical protection (e.g. clothing, hat, sunglasses), and applying broad-spectrum, SPF 30 + sunscreens to uncovered skin. Intentional exposure to solar ultraviolet radiation for the purpose of sunbathing and tanning is considered an unhealthy behaviour and should be avoided. Similarly, use of solaria and other artificial sources of ultraviolet radiation to encourage tanning should be strongly discouraged, through regulation if necessary. Primary prevention of skin cancer has a positive return on investment. We encourage policymakers to communicate these messages to the general public and promote their wider implementation.

The influence of breast screening on breast cancer incidence in England: observational study based on cancer registries and bulletins of the NHS Breast Screening Programme.

BACKGROUND: To assess the amount of breast cancer overdiagnosis associated with the National Health Service Breast Screening Programme (NHSBSP) that started in 1988 in England. METHODS: First, numbers of breast cancers in women eligible for breast screening not attending screening were estimated for the period 1995-2019, which were extrapolated to all women. A second method was based on ratios of incidence rates of breast cancers in women aged 50-69 to women aged 70 years or more in 1971-1985. The ratio was used for estimating expected numbers of cancers in 1988-2019, and 1995-2019. RESULTS: From 1995 to 2019, 506,607 non-invasive and invasive breast cancers were diagnosed among women aged 50-64 years (1995-2001) and 50-70 years (2002-2019). A first method estimated that 95,297 cancers were in excess to the number of cancers that would be expected had the NHSBSP not existed. 42,567 screen-detected non-invasive and micro-invasive cancers represented 45.8% of the total excess cancer. 18.8% of all cancers diagnosed among women invited to screening, 25.1% of cancers found in women attending screening, and 35.1% of cancers detected by screening would represent overdiagnosis. A second method estimated that, 18.0% of all cancers diagnosed in 1988-2019, and 18.2% of all cancers diagnosed in 1995-2019 among women invited to screening would represent overdiagnosis. CONCLUSION: The two independent methods obtained similar estimates of overdiagnosis. The NHS Breast Screening Programme in England is associated with substantial amount of overdiagnosis.

Change in effectiveness of mammography screening with decreasing breast cancer mortality: a population-based study.

BACKGROUND: Reductions in breast cancer mortality observed over the last three decades are partly due to improved patient management, which may erode the benefit-harm balance of mammography screening. METHODS: We estimated the numbers of women needed to invite (NNI) to prevent one breast cancer death within 10 years. Four scenarios of screening effectiveness (5-20% mortality reduction) were applied on 10,580 breast cancer deaths among Norwegian women aged 50-75 years from 1986 to 2016. We used three scenarios of overdiagnosis (10-40% excess breast cancers during screening period) for estimating ratios of numbers of overdiagnosed breast cancers for each breast cancer death prevented. RESULTS: Under the base case scenario of 20% breast cancer mortality reduction and 20% overdiagnosis, the NNI rose from 731 (95% CI: 644-830) women in 1996 to 1364 (95% CI: 1181-1577) women in 2016, while the number of women with overdiagnosed cancer for each breast cancer death prevented rose from 3.2 in 1996 to 5.4 in 2016. For a mortality reduction of 8.7%, the ratio of overdiagnosed breast cancers per breast cancer death prevented rose from 7.4 in 1996 to 14.0 in 2016. For a mortality reduction of 5%, the ratio rose from 12.8 in 1996 to 25.2 in 2016. CONCLUSIONS: Due to increasingly potent therapeutic modalities, the benefit in terms of reduced breast cancer mortality declines while the harms, including overdiagnosis, are unaffected. Future improvements in breast cancer patient management will further deteriorate the benefit-harm ratio of screening.

Efforts needed for preventing breast and colorectal cancer through changes in dietary patterns.

BACKGROUND: Prospective cohort studies on diet and cancer report risk associations as hazard ratios. But hazard ratios do not inform on the number of people who need to alter their dietary behaviours for preventing cancer. The objective of this study is to estimate the number of people that need to alter their diet for preventing one additional case of female breast or colorectal cancer. METHODS: Based on the largest prospective studies done in the USA and in Europe, we computed the number of subjects who need to alter their diet. RESULTS: For preventing one case of breast cancer, European women should increase their fruit consumption by 100 g/day during 33 000 person-years, and US women by 60 g/day during 10 600 person-years. For vegetables, European women should increase their consumption by 160 g/day during 26 900 person-years and US women by 100 g/day during 19 000 person-years. For preventing one case of colorectal cancer, European subjects should decrease their red meat consumption by 20 g/day during 26 100 person-years, and US subjects by 30 g/day during 8170 person-years. For processed meat, European subjects should decrease their consumption by 20 g/day during 17 400 person-years, and US subjects by 10 g/day during 7940 person-years. CONCLUSIONS: Large number of subjects would need to alter their intake of fruits, vegetables, red and processed meat during many years in order to prevent one additional breast or colorectal cancer.

AI for reading screening mammograms: the need for circumspection.

KEY POINTS: • The studies on AI reading of screening mammograms have methodological limitations that undermine the conclusion that AI could do better than radiologists. • These studies do not informon numbers of extra breast cancers found by AI that could represent overdiagnosis. • The ability of AI to detect breast cancers is overestimated because there are no result on biopsy procedures that should be performed when mammograms are positive at AI reading but not at radiology reading.

Ultraviolet radiation and cutaneous melanoma: a historical perspective.

In this article, we summarize the research that eventually led to the classification of the full ultraviolet (UV) radiation spectrum as carcinogenic to humans. We recall the pioneering works that led to the formulation of novel hypotheses on the reasons underlying the increasing burden of melanoma in light-skinned populations. It took long before having compelling evidence on the association between UV and melanoma, in particular, the importance of UV exposure during childhood for both the occurrence of melanoma and death. The role of UVA was established only after 2005. If molecular lesions caused by UV radiation are better known, the precise mechanism by which UV exposure drives melanoma occurrence and progression still needs to be elucidated. More research on the UV-melanoma relationships has led to more evidence-based sun-protection recommendations, especially for children, and to effective control of the artificial UV tanning fashion. Since around 1985-1995, the mortality because of melanoma has started to decrease in younger age groups in most light-skinned populations. If sun protection among children remain on top of public health agendas, there is a fairly great chance that melanoma mortality will stabilize and steadily decrease in all light-skinned populations. The introduction of effective therapies against metastatic disease will improve this reversal in mortality trends.

Alignment with Indices of A Care Pathway Is Associated with Improved Survival: An Observational Population-based Study in Colon Cancer Patients.

BACKGROUND: Causes of variations in outcomes from cancer care in developed countries are often unclear. Australia has developed health system pathways describing consensus standards of optimal cancer care across the phases of prevention through to follow-up or end-of-life. These Optimal Care Pathways (OCP) were introduced from 2013 to 14. We investigated whether care consistent with the OCP improved outcomes for colon cancer patients. METHODS: Colon patients diagnosed from 2008 to 2014 were identified from the Australian State of Victoria Cancer Registry (VCR) and cases linked with State and Federal health datasets. Surrogate variables describe OCP alignment in our cohort, across three phases of the pathway; prevention, diagnosis and initial treatment and end-of-life. We assessed the impact of alignment on (1) stage of disease at diagnosis and (2) overall survival. FINDINGS: Alignment with the prevention phase of the OCP occurred for 88% of 13,539 individuals and was associated with lower disease stage at diagnosis (OR = 0.33, 95% confidence interval 0.24 to 0.42), improved crude three-year survival (69.2% versus 62.2%; p < 0.001) and reduced likelihood of emergency surgery (17.7% versus 25.6%, p < 0.001). For patients treated first with surgery (n = 10,807), care aligned with the diagnostic and treatment phase indicators (44% of patients) was associated with a survival benefit (risk-adjusted HRnon-aligned vs aligned = 1.23, 95% confidence interval 1.13 to 1.35), better perioperative outcomes and higher alignment with follow-up and end-of-life care. The survival benefit persists adjusting for potential confounding factors, including age, sex, disease stage and comorbidity.Interpretation.This population-based study shows that care aligned to a pathway based on best principles of cancer care is associated with improved outcomes for patients with colon cancer. FUNDING: None.

Cancer prevention: cervical cancer.

Cervical cancer is the fourth most common cancer in women, and the seventh overall, with an estimated 528,000 new cases and 266,000 deaths in 2012 [1]. Almost nine out of ten (87%) cervical cancer deaths occur in the less-developed regions of the world. The cervical cancer incidence significantly increases after 20 years of age and peaks at 50 years of age. Because cervical cancer mainly affects African women at a relatively young age, the socio-economic consequences are enormous. The human papillomavirus (HPV) is central to the development of cervical neoplasia and can be detected in 99.7% of cervical cancers. Hence primary prevention aims at reducing human papillomavirus (HPV) infection by HPV vaccine administration. Secondary prevention involves cervical cancer screening and management of precancerous lesions via either Pap smear, visual inspection with acetic acid (VIA) or with lugols iodine (VILI) or HPV testing for high-risk HPV types. CONCLUSION: Sub-Saharan countries still have a long way to go in controlling the high burden of cervical cancer. Effective prevention methods exist, such as HPV vaccination and screening, but their affordability and implementation remain challenging for most of these countries. Despite that, there is still light on the horizon, as the cost of HPV vaccines has been steadily decreasing and most African countries are using the more cost-effective methods of cervical cancer screening.

Nationwide Incidence of Metastatic Cutaneous Squamous Cell Carcinoma in England.

Importance: Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential, but epidemiologic data are poor. Changes to the National Cancer Registration and Analysis Service (NCRAS) in England have allowed more accurate data analysis of primary and metastatic cSCC since 2013. Objective: To assess the national incidence of cSCC and metastatic cSCC (mcSCC) in England from 2013 through 2015. Design, Setting, and Participants: This national population-based study identified a cohort of patients with cSCC and mcSCC in England from January 1, 2013, through December 31, 2015. Patients were identified using diagnostic codes derived from pathology reports in the NCRAS. Data were analyzed from March 1, 2017, through March 1, 2018. Main Outcomes and Measures: Incidence rates across sex and risk factors for cSCC were derived from the NCRAS data. Risk of occurrence of mcSCC among the population with cSCC was assessed with Cox proportional hazards regression analysis to determine indicators of mcSCC. Results: Among the 76 977 patients with first primary cSCC in 2013 through 2015 (62.7% male; median age, 80 years [interquartile range, 72-86 years]), the age-standardized rates for the first registered cSCC in England from 2013 through 2015 were 77.3 per 100 000 person-years (PY) (95% CI, 76.6-78.0) in male patients and 34.1 per 100 000 PY (95% CI, 33.7-34.5) in female patients. Increased primary cSCC tumor count was observed in older, white male patients in lower deprivation quintiles. After a maximum follow-up of 36 months, cumulative incidence of mcSCC developed in 1.1% of women and 2.4% of men with a primary cSCC. Significant increases in the risk of metastasis with adjusted hazard rates of approximately 2.00 were observed in patients who were aged 80 to 89 years (hazard ratio [HR], 1.23; 95% CI, 1.07-1.43), 90 years or older (HR, 1.35; 95% CI, 1.09-1.66), male (HR, 1.79; 95% CI, 1.52-2.10), immunosuppressed (HR, 1.99; 95% CI, 1.64-2.42), and in higher deprivation quintiles (HR for highest quintile, 1.64; 95% CI, 1.35-2.00). Primary cSCC located on the ear (HR, 1.70; 95% CI, 1.42-2.03) and lip (HR, 1.85; 95% CI, 1.29-2.63) were at highest risk of metastasis. Conclusions and Relevance: This study presents the first national study of the incidence of mcSCC. With limited health care resources and an aging population, accurate epidemiologic data are essential for informing future health care planning, identifying high-risk patients, and evaluating skin cancer prevention policies.