Immunohistochemical study of basement membrane collagen IV in uterine cervix carcinoma

CONTEXT: The integrity of basement membrane (BM) is damaged during the evolution of a benign or potentially malignant lesion into a malignant one, in which it may undergo several degrees of discontinuity as a necessary condition for the invasive process. Immunostaining for collagen IV, which is exclusively found in BM, has been used to evaluate its formation in neoplastic and benign lesions of several organs.OBJECTIVE: To investigate BM continuity pattern in squamous carcinoma in situ (CIS), microinvasive (MIC) and invasive (IC) squamous cell carcinoma of the uterine cervix, and to find out if BM expression could be useful in the diagnosis of early stromal invasion (MIC).DESIGN: Archival material between 1988 and 1993 was studied at the Pathological Anatomy Department - Unicamp.PROCEDURES: The selected cases, previously formalin fixed and paraffin embedded, were reviewed retrospectively by submitting them to immunohistochemical study via the avidin-biotin-peroxidase method using a monoclonal antibody anticollagen IV.RESULTS: In all, 17 cases of CIS, 16 of MIC and 21 of IC were evaluated. All IC cases showed evident BM discontinuity, either focal or diffuse. In the CIS group, a continuous BM pattern was predominant, being focally disrupted in only 2/17 cases (11.8%). The MIC group showed an intermediate pattern, but with a clear tendency to BM discontinuity in 10/16 cases (62.5%). Inflammatory infiltrate, a variable also studied, cannot be considered responsible for BM discontinuity, since there was no statistical correlation between them.CONCLUSION: We conclude that immunostaining for collagen IV may contribute to the diagnosis of stromal invasion by BM discontinuity.CONTEXTO: A integridade da membrana basal (MB) é destruída no processo de evolução de uma lesão benigna ou potencialmente maligna para uma lesão maligna, onde ela pode sofrer vários graus de descontinuidade, como condição necessária para o processo de invasão. A imunocoloração para colágeno IV, que é exclusivamente encontrado na MB, tem sido utilizada para avaliar sua formação em processos benignos e neoplásicos de vários órgãos. OBJETIVO: Investigar o padrão de continuidade da MB no carcinoma in situ (CIS), microinvasivo (CMI) e epidermóide (CE) do colo uterino. Além disso, pretendeu-se verificar em que medida estes padrões poderiam ser úteis no diagnóstico de invasão estromal inicial (CMI). TIPO DE ESTUDO: Foi estudado o material do arquivo de tecidos dos anos de 1988 a 1993 do Departamento de Anatomia Patológica da UNICAMP. PROCEDIMENTOS: Os tecidos eram fixados em formalina e incluídos em parafina e foram revistos retrospectivamente para serem submetidos à reação imuno-histoquímica pelo método da avidina-biotina-peroxidase, com o anticorpo monoclonal anti-colágeno IV. RESULTADOS: Ao todo, foram avaliados 17 casos de CIS, 16 de CMI e 21 de CE. Todos os casos de CE mostraram evidente descontinuidade da MB, quer focal ou difusa. No grupo dos CIS foi observado um padrão contínuo de MB, sendo focalmente lesado em apenas 2/17 casos (11,8%). O grupo dos CMI mostraram um padrão intermediário, com clara tendência à descontinuidade da MB em 10/16 casos (62,5%). O infiltrado inflamatório, variável também estudada, não pode ser responsabilizado pela descontinuidade da MB, já que não houve correlação estatística entre eles. CONCLUSÃO: A imunocoloração para colágeno IV pode contribuir no diagnóstico de invasão estromal, quando houver lesão da MB.1846185

[preservation Of The Fertility And The Ovaries In Women With Benign Adnexal Tumors].

To evaluate the sparing of fertility and ovaries in women submitted to surgical treatment for benign adnexal tumors. Between February 2010 and January 2014, 206 patients were included in this observational study as they were submitted to surgical treatment for benign ovarian tumors at CAISM, a tertiary hospital. Fertility sparing surgery was defined as tumorectomy or unilateral salpingoophorectomy without hysterectomy in premenopausal women. Preservation of the ovary occurred when at least one ovary or part of it was mantained. Of the 206 women with benign tumors, 120 (58%) were premenopausal and 86 (42%) were postmenopausal. There were 36 (30%) ovarian germ cell tumors, 31 (26%) epithelial neoplasms and 11 (9%) sex-cord stromal tumors among premenopausal women. In the group of postmenopausal women, 35 (41%) epithelial neoplasms, 27 (31%) sex-cord stromal tumors and 8 (9%) ovarian germ cell tumors were identified. Among 36 women with non-neoplastic ovarian tumors, 21 (58%) had endometriomas and 8 (22%) functional cysts. Among 22 women with extra-ovarian tumors, uterine leiomyomatosis was the most frequent finding (50%). In the group of women who were ≤ 35 years old, 26 (57%) were treated by tumorectomy and 18 (39%) were submitted to unilateral salpingoophorectomy with sparing of the uterus and the contralateral ovary. Women who were ≤ 35 years old were more frequently operated by laparoscopy which was associated with a higher number of fertility sparing procedures when compared to laparotomy (p<0.01). Twenty-six (28%) women submitted to hysterectomy with bilateral salpingoophorectomy were premenopausal. Although there is a trend to perform only tumorectomy in women who are ≤ 35 years old, a significant number of young women is still treated by salpingoophorectomy. Among 36- to 45-year-old women, only 70% had their fertility spared, while 20% had both ovaries removed. However, whenever possible, we must try to preserve the ovaries, mainly in premenopausal women.3736-4

Preservation of the fertility and the ovaries in women with benign adnexal tumors

v. 37n.1364

Subdiagnóstico de neoplasia intraepitelial cervical (NIC) 2 ou lesão mais grave emmulheres combiópsia dirigida por colposcopia prévia mostrando NIC 1

sem informaçãosem informaçãoExpectant follow-up for biopsy-proven cervical intraepithelial neoplasia (CIN) 1 is the current recommendation for the management of this lesion. Nevertheless, the performance of the biopsy guided by colposcopy might not be optimal. Therefore, this study aimed to calculate the rate of underdiagnoses of more severe lesions in women with CIN 1 diagnosis and to evaluate whether age, lesion extent and biopsy site are factors associated with diagnostic failure. Methods Eighty women with a diagnosis of CIN 1 obtained by colposcopy-guided biopsy were selected for this study. These women were herein submitted to large loop excision of the transformation zone (LLETZ). The prevalence of lesions more severe than CIN 1 was calculated, and the histological diagnoses of the LLETZ specimens were grouped into two categories: "CIN 1 or less" and "CIN 2 or worse." Results The prevalence of lesions diagnosed as CIN 2 or worse in the LLETZ specimens was of 19% (15/80). Three women revealed CIN 3, and 1 woman revealed a sclerosing adenocarcinoma stage I-a, a rare type of malignant neoplasia of low proliferation, which was not detected by either colposcopy or previous biopsy. The underdiagnosis of CIN 2 was not associated with the women's age, lesion extension and biopsy site. Conclusions The standard methods used for the diagnosis of CIN 1 may underestimate the severity of the true lesion and, therefore, women undergoing expectant management must have an adequate follow-up393123127FAPESP - FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULOCNPQ – CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO CIENTÍFICO E TECNOLOGICOsem informaçãosem informaçãoO seguimento de mulheres com neoplasia intraepitelial cervical (NIC) 1 comprovada por biópsia é atualmente a recomendação de conduta para esta lesão. Entretanto, o desempenho da biópsia guiada por colposcopia pode falhar. Assim, este estudo teve como objetivo estimar a taxa de subdiagnóstico de lesões mais graves em mulheres com diagnóstico de NIC 1 e avaliar se a idade, a extensão da lesão e o local da biópsia são fatores associados à falha do diagnóstico. Métodos Foram selecionadas 80 mulheres com diagnóstico de NIC 1 obtido por biópsia dirigida por colposcopia. Estas mulheres foram submetidas a excisão da zona de transformação por alça diatérmica (EZTAD). A prevalência de lesões mais graves do que NIC 1 foi calculada, e os diagnósticos histológicos feitos nas amostras obtidas por EZTAD foram agrupados em duas categorias: “NIC 1 ou menos grave” e “NIC 2 ou mais grave”. Resultados A prevalência de lesões diagnosticadas como NIC 2 ou mais grave nas amostras de EZTAD foi de 19% (15/80). Três mulheres apresentaram NIC 3, e uma mulher revelou adenocarcinoma esclerosante estágio I-a, um tipo raro de neoplasia maligna de baixa proliferação, que não foi detectado por qualquer exame de colposcopia ou biópsia anterior. O subdiagnóstico de NIC 2 não foi associado à idade, à extensão da lesão ou ao local da biópsia. Conclusão Os métodos de referência utilizados para o diagnóstico da NIC 1 podem subestimar a gravidade da lesão verdadeira e, portanto, as mulheres submetidas a conduta expectante devem ter um seguimento adequad

Survival Of Women With Ovarian Carcinomas And Borderline Tumors Is Not Affected By Estrogen And Progesterone Receptor Status.

To examine the patterns of estrogen receptor (ER) and progesterone receptor (PR) expression in borderline ovarian tumors (BOTs) and ovarian carcinomas. We also assessed the disease-free survival (DFS) and overall survival (OS) in women with ovarian carcinoma, in relation to ER and/or PR expression. We examined ER/PR expression in 38 BOTs and 172 ovarian carcinomas removed from patients treated at the State University of Campinas-UNICAMP (Brazil), from 1993 to 2008 and followed for up to 60 months using tissue microarray-based immunohistochemistry. Twenty-eight (73.7%) mucinous and 10 (26.3%) serous BOTs were included. Ovarian carcinomas consisted mainly of 79 (46.0%) serous, 44 (25.5%) mucinous, 17 (9.8%) endometrioid, 10 (5.8%) clear-cell types. There was no significant difference of the ER/PR expression between BOT and ovarian carcinoma (p=0.55 for ER alone, 0.90 for PR alone, and 0.12 for combined expression). The level of ER/PR expression in BOTs was significantly higher in serous than in mucinous tumors (p<0.01). In carcinomas, ER/PR was higher in serous tumors than in mucinous (p<0.01) and clear cell tumors (p=0.02), and higher in endometrioid tumors than in mucinous tumors (p<0.01). DFS was affected neither by the clinical characteristics nor by combined steroid receptor status. OS was found to be significantly worse (p<0.01) only in women with stages II-IV tumors and those with residual disease after surgery (p<0.01). Overall, serous and endometrioid tumors were predominantly ER/PR positive, whereas mucinous and clear-cell tumors were preponderantly ER/PR negative. DFS and OS were not affected by ER/PR expression.24167-7

Symptoms, Ca125 And He4 For The Preoperative Prediction Of Ovarian Malignancy In Brazilian Women With Ovarian Masses.

This manuscript evaluates whether specific symptoms, a symptom index (SI), CA125 and HE4 can help identify women with malignant tumors in the group of women with adnexal masses previously diagnosed with ultrasound. This was a cross-sectional study with data collection between January 2010 and January 2012. We invited 176 women with adnexal masses of suspected ovarian origin, attending the hospital of the Department of Obstetrics and Gynecology of the Unicamp School of Medicine. A control group of 150 healthy women was also enrolled. Symptoms were assessed with a questionnaire tested previously. Women with adnexal masses were interviewed before surgery to avoid recall bias. The Ward Agglomerative Method was used to define symptom clusters. Serum measurements of CA125 and HE4 were made. The Risk of Ovarian Malignancy Algorithm (ROMA) was calculated using standard formulae. Sixty women had ovarian cancer and 116 benign ovarian tumors. Six symptom clusters were formed and three specific symptoms (back pain, leg swelling and able to feel abdominal mass) did not agglomerate. A symptom index (SI) using clusters abdomen, pain and eating was formed. The sensitivity of the SI in discriminating women with malignant from those with benign ovarian tumors was 78.3%, with a specificity of 60.3%. Positive SI was more frequent in women with malignant than in women with benign tumors (OR 5.5; 95% CI 2.7 to 11.3). Elevated CA125 (OR 11.8; 95% CI 5.6 to 24.6) or HE4 (OR 7.6; 95% CI 3.7 to 15.6) or positive ROMA (OR 9.5; 95% CI 4.4 to 20.3) were found in women with malignant tumors compared with women with benign tumors. The AUC-ROC for CA125 was not different from that for HE4 or ROMA. The best specificity and negative predictive values were obtained using CA125 in women with negative SI. Women diagnosed with an adnexal mass could benefit from a short enquiry about presence, frequency and onset of six symptoms, and CA125 measurements. Primary care physicians can be thereby assisted in deciding as to whether or not reference the woman to often busy, congested specialized oncology centers.1342

Serous and non-serous ovarian carcinoma: histological tumor type as related to the grade of differentiation and disease prognosis

PURPOSE: To compare the clinical-pathological features of women with serous and non-serous ovarian tumors and to identify the factors associated with survival. METHODS: In this reconstructed cohort study, 152 women with ovarian carcinoma, who attended medical consultations between 1993 and 2008 and who were followed-up until 2010 were included. The histological type was clearly established for all women: 81 serous carcinomas and 71 non-serous tumors (17 endometrioid, 44 mucinous and 10 clear cell carcinomas). The crude and adjusted odds ratios (OR), with the respective 95% confidence intervals (95%CI), were calculated for the clinical and pathological features, comparing serous and non-serous histological types. The Hazard Ratios (HR) with 95%CI was calculated for overall survival, considering the clinical and pathological features. RESULTS: Comparison of serous to non-serous tumor types by univariate analysis revealed that serous tumors were more frequently found in postmenopausal women, and were predominantly high histological grade (G2 and G3), advanced stage, with CA125&gt;250 U/mL, and with positive peritoneal cytology. After multivariate regression, the only association remaining was that of high histological grade with serous tumors (adjusted OR 15.1; 95%CI 2.9-77.9). We observed 58 deaths from the disease. There was no difference in overall survival between women with serous carcinoma and women with non-serous carcinoma (HR 0.4; 95%CI 0.1 - 1.1). It was observed that women aged 50 years or less (HR 0.4; 95%CI 0.1-0.9) and those who were in menacne (HR 0.3; 95%CI 0.1-0.9) had a longer survival compared respectively to those above 50 years of age and menopaused. High histological grade (G2 and G3) (p<0.01), stages II-IV (p<0.008) and positive cytology (p<0.001) were significantly associated with worse prognosis. CA125 and the presence of ascites did not correlate with survival. Survival was poor when the disease was diagnosed in stages II to IV and compared to stage I (log-rank p<0.01) regardless of histological type (serous and non-serous). CONCLUSIONS: The proportion of high histological grade (G2 and G3) was significantly higher among serous than non-serous carcinomas. Serous and non-serous histological types were not related to overall survival.OBJETIVO: Comparar as características clinicopatológicas de mulheres com carcinoma seroso e não seroso de ovário e identificar os fatores associados à sobrevida. MÉTODOS: Foram incluídas, neste estudo de coorte reconstituída, 152 mulheres com carcinoma de ovário, atendidas entre 1993 e 2008 e seguidas até 2010, nas quais o tipo histológico foi claramente estabelecido: 81 pacientes com carcinoma seroso e 71 pacientes com tumores não serosos (17 com carcinoma endometrioide, 44 com carcinoma mucinoso e 10 com carcinoma de células claras). Foram calculados os odds ratios (OR) brutos e os OR ajustados com os respectivos intervalos de confiança (IC95%) para as características clínicas e patológicas, comparando tumores serosos e não serosos. Foram calculados os Hazard Ratios (HR) com os respectivos IC95% em relação à sobrevida geral, para as variáveis clínicas e patológicas. RESULTADOS: Comparando os tipos seroso e não seroso, na análise univariada, os tumores serosos foram mais frequentes na pós-menopausa e eram preponderantemente carcinomas de alto grau histológico (G2 e G3), em estádios avançados, com CA125&gt;250 U/mL e citologia peritoneal positiva. Após regressão múltipla, apenas o alto grau histológico se manteve associado com tumores serosos (OR ajustado 15,1; IC95% 2,9-77,9). Observamos 58 óbitos pela doença. O tipo histológico (seroso ou não seroso) não esteve associado com a sobrevida (HR 0,4; IC95% 0,1-1,1). Mulheres com idade de 50 anos ou menos (HR 0,4; IC95% 0,1-0,9) e aquelas que estavam em menacme (HR 0,3; IC95% 0,1-0,9) tiveram maior sobrevida quando comparadas, respectivamente, àquelas com idade acima de 50 anos e na menopausa. Carcinomas de alto grau histológico (G2 e G3) (p<0,01), estádio II a IV (p<0,008) e citologia peritoneal positiva (p<0,001) estiveram significativamente relacionados com pior prognóstico. O nível sérico de CA125 e a presença de ascite não se relacionaram com a sobrevida. A sobrevida foi menor quando a doença foi diagnosticada em estágios II a IV em comparação àquela das mulheres diagnosticadas no estádio I (log-rank p<0,01) independentemente do tipo histológico (seroso ou não seroso). CONCLUSÕES: A proporção de carcinomas de alto grau histológico (G2 ou G3) foi significativamente maior entre os carcinomas serosos comparados com não serosos. O tipo histológico seroso ou não seroso não esteve associado à sobrevida total.19620

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions