Vivek Kumar

BACKGROUND: Worldwide, both the incidence and death rates of pancreatic cancer are increasing. Evaluation of pancreatic cancer burden and its global, regional, and national patterns is crucial to policy making and better resource allocation for controlling pancreatic cancer risk factors, developing early detection methods, and providing faster and more effective treatments. METHODS: Vital registration, vital registration sample, and cancer registry data were used to generate mortality, incidence, and disability-adjusted life-years (DALYs) estimates. We used the comparative risk assessment framework to estimate the proportion of deaths attributable to risk factors for pancreatic cancer: smoking, high fasting plasma glucose, and high body-mass index. All of the estimates were reported as counts and age-standardised rates per 100 000 person-years. 95% uncertainty intervals (UIs) were reported for all estimates. FINDINGS: In 2017, there were 448 000 (95% UI 439 000-456 000) incident cases of pancreatic cancer globally, of which 232 000 (210 000-221 000; 51·9%) were in males. The age-standardised incidence rate was 5·0 (4·9-5·1) per 100 000 person-years in 1990 and increased to 5·7 (5·6-5·8) per 100 000 person-years in 2017. There was a 2·3 times increase in number of deaths for both sexes from 196 000 (193 000-200 000) in 1990 to 441 000 (433 000-449 000) in 2017. There was a 2·1 times increase in DALYs due to pancreatic cancer, increasing from 4·4 million (4·3-4·5) in 1990 to 9·1 million (8·9-9·3) in 2017. The age-standardised death rate of pancreatic cancer was highest in the high-income super-region across all years from 1990 to 2017. In 2017, the highest age-standardised death rates were observed in Greenland (17·4 [15·8-19·0] per 100 000 person-years) and Uruguay (12·1 [10·9-13·5] per 100 000 person-years). These countries also had the highest age-standardised death rates in 1990. Bangladesh (1·9 [1·5-2·3] per 100 000 person-years) had the lowest rate in 2017, and São Tomé and Príncipe (1·3 [1·1-1·5] per 100 000 person-years) had the lowest rate in 1990. The numbers of incident cases and deaths peaked at the ages of 65-69 years for males and at 75-79 years for females. Age-standardised pancreatic cancer deaths worldwide were primarily attributable to smoking (21·1% [18·8-23·7]), high fasting plasma glucose (8·9% [2·1-19·4]), and high body-mass index (6·2% [2·5-11·4]) in 2017. INTERPRETATION: Globally, the number of deaths, incident cases, and DALYs caused by pancreatic cancer has more than doubled from 1990 to 2017. The increase in incidence of pancreatic cancer is likely to continue as the population ages. Prevention strategies should focus on modifiable risk factors. Development of screening programmes for early detection and more effective treatment strategies for pancreatic cancer are needed. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Oesophageal cancer is a common and often fatal cancer that has two main histological subtypes: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Updated statistics on the incidence and mortality of oesophageal cancer, and on the disability-adjusted life-years (DALYs) caused by the disease, can assist policy makers in allocating resources for prevention, treatment, and care of oesophageal cancer. We report the latest estimates of these statistics for 195 countries and territories between 1990 and 2017, by age, sex, and Socio-demographic Index (SDI), using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD). METHODS: We used data from vital registration systems, vital registration-samples, verbal autopsy records, and cancer registries, combined with relevant modelling, to estimate the mortality, incidence, and burden of oesophageal cancer from 1990 to 2017. Mortality-to-incidence ratios (MIRs) were estimated and fed into a Cause of Death Ensemble model (CODEm) including risk factors. MIRs were used for mortality and non-fatal modelling. Estimates of DALYs attributable to the main risk factors of oesophageal cancer available in GBD were also calculated. The proportion of oesophageal squamous cell carcinoma to all oesophageal cancers was extracted by use of publicly available data, and its variation was examined against SDI, the Healthcare Access and Quality (HAQ) Index, and available risk factors in GBD that are specific for oesophageal squamous cell carcinoma (eg, unimproved water source and indoor air pollution) and for oesophageal adenocarcinoma (gastro-oesophageal reflux disease). FINDINGS: There were 473 000 (95% uncertainty interval [95% UI] 459 000-485 000) new cases of oesophageal cancer and 436 000 (425 000-448 000) deaths due to oesophageal cancer in 2017. Age-standardised incidence was 5·9 (5·7-6·1) per 100 000 population and age-standardised mortality was 5·5 (5·3-5·6) per 100 000. Oesophageal cancer caused 9·78 million (9·53-10·03) DALYs, with an age-standardised rate of 120 (117-123) per 100 000 population. Between 1990 and 2017, age-standardised incidence decreased by 22·0% (18·6-25·2), mortality decreased by 29·0% (25·8-32·0), and DALYs decreased by 33·4% (30·4-36·1) globally. However, as a result of population growth and ageing, the total number of new cases increased by 52·3% (45·9-58·9), from 310 000 (300 000-322 000) to 473 000 (459 000-485 000); the number of deaths increased by 40·0% (34·1-46·3), from 311 000 (301 000-323 000) to 436 000 (425 000-448 000); and total DALYs increased by 27·4% (22·1-33·1), from 7·68 million (7·42-7·97) to 9·78 million (9·53-10·03). At the national level, China had the highest number of incident cases (235 000 [223 000-246 000]), deaths (213 000 [203 000-223 000]), and DALYs (4·46 million [4·25-4·69]) in 2017. The highest national-level age-standardised incidence rates in 2017 were observed in Malawi (23·0 [19·4-26·5] per 100 000 population) and Mongolia (18·5 [16·4-20·8] per 100 000). In 2017, age-standardised incidence was 2·7 times higher, mortality 2·9 times higher, and DALYs 3·0 times higher in males than in females. In 2017, a substantial proportion of oesophageal cancer DALYs were attributable to known risk factors: tobacco smoking (39·0% [35·5-42·2]), alcohol consumption (33·8% [27·3-39·9]), high BMI (19·5% [6·3-36·0]), a diet low in fruits (19·1% [4·2-34·6]), and use of chewing tobacco (7·5% [5·2-9·6]). Countries with a low SDI and HAQ Index and high levels of indoor air pollution had a higher proportion of oesophageal squamous cell carcinoma to all oesophageal cancer cases than did countries with a high SDI and HAQ Index and with low levels of indoor air pollution. INTERPRETATION: Despite reductions in age-standardised incidence and mortality rates, oesophageal cancer remains a major cause of cancer mortality and burden across the world. Oesophageal cancer is a highly fatal disease, requiring increased primary prevention efforts and, possibly, screening in some high-risk areas. Substantial variation exists in age-standardised incidence rates across regions and countries, for reasons that are unclear. FUNDING: Bill & Melinda Gates Foundation.

BACKGROUND: Stomach cancer is a major health problem in many countries. Understanding the current burden of stomach cancer and the differential trends across various locations is essential for formulating effective preventive strategies. We report on the incidence, mortality, and disability-adjusted life-years (DALYs) due to stomach cancer in 195 countries and territories from 21 regions between 1990 and 2017. METHODS: Estimates from GBD 2017 were used to analyse the incidence, mortality, and DALYs due to stomach cancer at the global, regional, and national levels. The rates were standardised to the GBD world population and reported per 100 000 population as age-standardised incidence rates, age-standardised death rates, and age-standardised DALY rates. All estimates were generated with 95% uncertainty intervals (UIs). FINDINGS: In 2017, more than 1·22 million (95% UI 1·19-1·25) incident cases of stomach cancer occurred worldwide, and nearly 865 000 people (848 000-885 000) died of stomach cancer, contributing to 19·1 million (18·7-19·6) DALYs. The highest age-standardised incidence rates in 2017 were seen in the high-income Asia Pacific (29·5, 28·2-31·0 per 100 000 population) and east Asia (28·6, 27·3-30·0 per 100 000 population) regions, with nearly half of the global incident cases occurring in China. Compared with 1990, in 2017 more than 356 000 more incident cases of stomach cancer were estimated, leading to nearly 96 000 more deaths. Despite the increase in absolute numbers, the worldwide age-standardised rates of stomach cancer (incidence, deaths, and DALYs) have declined since 1990. The drop in the disease burden was associated with improved Socio-demographic Index. Globally, 38·2% (21·1-57·8) of the age-standardised DALYs were attributable to high-sodium diet in both sexes combined, and 24·5% (20·0-28·9) of the age-standardised DALYs were attributable to smoking in males. INTERPRETATION: Our findings provide insight into the changing burden of stomach cancer, which is useful in planning local strategies and monitoring their progress. To this end, specific local strategies should be tailored to each country's risk factor profile. Beyond the current decline in age-standardised incidence and death rates, a decrease in the absolute number of cases and deaths will be possible if the burden in east Asia, where currently almost half of the incident cases and deaths occur, is further reduced. FUNDING: Bill & Melinda Gates Foundation.

The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma. More frequent use of ICIs has improved our understanding of their unique side effects, which are known as immune-related adverse events (irAEs). The spectrum of irAEs has expanded beyond more common manifestations such as dermatological, gastrointestinal and endocrine effects to rarer presentations involving nervous, hematopoietic and urinary systems. There are new safety data accumulating on ICIs in patients with previously diagnosed autoimmune conditions. It is challenging for clinicians to continuously update their working knowledge to diagnose and manage these events successfully. If diagnosed timely, the majority of events are completely reversible, and temporary immunosuppression with glucocorticoids, infliximab or other agents is warranted only in the most severe grade illnesses. The same principles of management will possibly apply as newer anti- cytotoxic T lymphocytes-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1/PD-L1) antibodies are introduced. The current focus of research is for prophylaxis and for biomarkers to predict the onset of these toxicities. In this review we summarize the irAEs of ICIs and emphasize their growing spectrum and their management algorithms, to update oncology practitioners.

Limited data exist on safety and efficacy of immune checkpoint inhibitors (ICIs) among organ transplant recipients. The objective of this study was to report a case series of two patients with renal transplant who received treatment with an ICI and to conduct a pooled analysis of published cases to describe the safety and efficacy of ICIs in organ transplant patients. A systematic search in the Google Scholar and PubMed databases was carried out to include all the published cases of organ transplant patients who received treatment with ICIs including programmed cell death protein 1 (PD-1), programmed death-ligand 1, or cytotoxic lymphocyte antigen-4 inhibitors since their inscription to January 31, 2019. In the present series of two cases with renal allografts who received pembrolizumab, one patient with squamous cell carcinoma of the skin experienced complete response (CR), whereas another patient with melanoma had a mixed response. Both patients experienced allograft rejection, but graft was salvaged. The pooled analysis of 64 patients published in literature showed that overall allograft rejection rate is 41% in organ transplant recipients following ICI therapy. The graft rejection rate was 44% (17/39) for renal, 39% (7/19) for liver, and 20% (1/5) for cardiac allografts. The highest risk was seen among patients who were treated with PD-1 inhibitors, 20/42 (48%)-13/24 (54%) on nivolumab and 7/18 (39%) on pembrolizumab. The risk was lowest with ipilimumab, 23% (3/13). The overall response rate (CR + partial response [PR]) was 20% with ipilimumab, 26% with nivolumab, and 53% with pembrolizumab, whereas disease control rate (CR + PR + stable disease) was 35% with ipilimumab, 37% with nivolumab, and 53% with pembrolizumab. None of the variables including age, gender, type of cancer, type of allograft, type of immunosuppression, time since transplantation to initiation of ICI, and prior history of rejection were significantly associated with the transplant rejection on univariate analysis. The efficacy of ICI among patients with organ transplant appears promising, warranting testing in prospective clinical trials. The risk of rejection and allograft loss is considerable; therefore, the risk and alternative form of therapies should be thoroughly discussed with the transplant patients prior to initiating ICI therapy. IMPLICATIONS FOR PRACTICE: Transplant recipients are at higher risk of developing cancers. Although immune checkpoint inhibitors have been shown to improve the outcome in more than one cancer type, transplant recipients were excluded from these trials. Most of the data on the safety and efficacy of immune checkpoint inhibitors in transplant patients are based upon case series and case reports. The pooled data from these reports suggest that anti-programmed death-ligand 1 inhibitors have reasonable safety and efficacy among organ transplant patients, which warrants testing in clinical trials.