Risk of Esophageal Adenocarcinoma After Helicobacter pylori Eradication Treatment in a Population-Based Multinational Cohort Study.

BACKGROUND & AIMS: Helicobacter pylori infection is associated with a decreased risk of esophageal adenocarcinoma, and the decreasing prevalence of such infection might contribute to the increasing incidence of this tumor. We examined the hypothesis that eradication treatment of H pylori increases the risk of esophageal adenocarcinoma. METHODS: This population-based multinational cohort, entitled "Nordic Helicobacter Pylori Eradication Project (NordHePEP)," included all adults (≥18 years) receiving H pylori eradication treatment from 1995-2018 in any of the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) with follow-up throughout 2019. Data came from national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) by dividing the cancer incidence in the exposed cohort by that of the entire Nordic background populations of the corresponding age, sex, calendar period, and country. Analyses were stratified by factors associated with esophageal adenocarcinoma (ie, education, comorbidity, gastroesophageal reflux, and certain medications). RESULTS: Among 661,987 participants who contributed 5,495,552 person-years after eradication treatment (median follow-up, 7.8 years; range, 1-24 years), 550 cases of esophageal adenocarcinoma developed. The overall SIR of esophageal adenocarcinoma was not increased (SIR = 0.89; 95% CI, 0.82-0.97). The SIR did not increase over time after eradication treatment, but rather decreased and was 0.73 (95% CI, 0.61-0.86) at 11-24 years after treatment. There were no major differences in the stratified analyses. The overall SIR of esophageal squamous cell carcinoma, calculated for comparison, showed no association (SIR = 0.99; 95% CI, 0.89-1.11). CONCLUSIONS: This absence on an increased risk of esophageal adenocarcinoma after eradication treatment of H pylori suggests eradication is safe from a cancer perspective.

Outcome after surgery for invasive intraductal papillary mucinous neoplasia compared to conventional pancreatic ductal adenocarcinoma - A Swedish nationwide register-based study.

BACKGROUND: The clinical importance of intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Long-term survival after resection for invasive IPMN (inv-IPMN) compared to conventional pancreatic ductal adenocarcinoma (PDAC) is not thoroughly delineated. OBJECTIVE: This study, based on the Swedish national pancreatic and periampullary cancer registry aims to elucidate the outcome after resection of inv-IPMN compared to PDAC. METHODS: All patients ≥18 years of age resected for inv-IPMN and PDAC in Sweden between 2010 and 2019 were included. Clinicopathological variables were retrieved from the national registry. The effect on death was assessed in two multivariable Cox regression models, one for patients resected 2010-2015, one for patients resected 2016-2019. Median overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: We included 1909 patients, 293 inv-IPMN and 1616 PDAC. The most important independent predictors of death in multivariable Cox regressions were CA19-9 levels, venous resection, tumour differentiation, as well as T-, N-, M-stage and surgical margin. Tumour type was an independent predictor for death in the 2016-2019 cohort, but not in the 2010-2015 cohort. In Kaplan-Meier survival analysis, inv-IPMN was associated with longer median OS in stage N0-1 and in stage M0 compared to PDAC. However, in stage T2-4 and stage N2 median OS was similar, and in stage M1 even shorter for inv-IPMN compared to PDAC. CONCLUSION: In this population-based nationwide study, outcome after resected inv-IPMN compared to PDAC is more favourable in lower stages, and similar to worse in higher.

Sex differences in lymphoma incidence and mortality by subtype: A population-based study.

It is well established that the male sex is associated with increased risk for, as well as poorer survival of, most cancers. A similar pattern has been described in lymphomas but has not yet been comprehensively assessed. In this nationwide population-based cohort study, we used the Swedish Lymphoma Register to investigate sex differences in lymphoma subtype incidence and excess mortality in adults (age 18-99) diagnosed in 2000-2019. Male-to-female incidence rate ratios (IRRs) and excess mortality ratios (EMRs) adjusted for age and calendar year were predicted using Poisson regression. We identified 36 795 lymphoma cases, 20 738 (56.4%) in men and 16 057 (43.6%) in women. Men were at significantly higher risk of 14 out of 16 lymphoma subtypes with IRRs ranging from 1.15 (95% confidence interval [CI] 1.09-1.22) in follicular lymphoma to 5.95 (95% CI 4.89-7.24) in hairy cell leukemia. EMRs >1 were seen in 13 out of 16 lymphoma subtypes indicating higher mortality in men, although only statistically significant for classical Hodgkin lymphoma 1.26 (95% CI 1.04-1.54), aggressive lymphoma not otherwise specified 1.29 (95% CI 1.08-1.55), and small lymphocytic lymphoma 1.52 (95% CI 1.11-2.07). A corresponding analysis using data from the Danish Lymphoma Register was performed with comparable results. In conclusion, we demonstrate a significantly higher incidence and trend toward higher mortality in men for most lymphoma subtypes. Future studies with large patient material that include detailed clinicopathological prognostic factors are warranted to further delineate and explain sex differences in lymphoma survival to enable optimal management of lymphoma patients regardless of sex.

Cohort profile: Nordic Helicobacter Pylori eradication project (NordHePEP).

PURPOSE: This cohort description presents the Nordic Helicobacter Pylori Eradication Project (NordHePEP), a population-based cohort of patients having received eradication treatment for Helicobacter pylori (HP). The cohort is created with the main purpose of examining whether and to what extent HP eradication treatment influences the risk of gastrointestinal cancer. PARTICIPANTS: NordHePEP includes all adults (aged ≥18 years) having been prescribed and dispensed HP eradication treatment according to the nationwide complete drug registries in any of the five Nordic countries (Denmark, Finland, Iceland, Norway, or Sweden) between 1994 and 2020 (start and end year varies between countries). We have retrieved and merged individual-level data from multiple national registries, including drug, patient, cancer, population, and death registries. FINDINGS: The cohort includes 674,771 patients having received HP eradication treatment. During up to 23 years of follow-up, 59,292 (8.8%) participants were diagnosed with cancer (non-melanoma skin cancer excluded), whereof 15,496 (2.3%) in the gastrointestinal tract. FUTURE PLANS: We will analyse HP eradication treatment in relation to gastrointestinal cancer risk. Standardised incidence ratios will be calculated as the observed cancer incidence in the cohort divided by the expected cancer incidence, derived from the background population of the corresponding age, sex, and calendar year.

Seasonal effects on cancer incidence and prognosis.

BACKGROUND: It is unknown if the reduction in the expected number of cancer cases diagnosed during Swedish holidays are due to diagnostic delays, how different cancers are affected, and if the season of diagnosis influences long-term cancer survival. We aimed to quantify seasonal trends in incidence and excess mortality for a wide range of malignancies, requiring more or less urgent clinical management. MATERIAL AND METHODS: This nationwide cohort study included all Swedish residents aged 20-84 in 1990-2019. Incidence and relative survival in pancreatic, colorectal, lung, urothelial, breast, and prostate cancer, together with malignant melanoma, non-Hodgkin lymphoma, and acute leukemia diagnosed during holiday and post-holiday were compared to working (reference) season. Incidence rate ratios (IRR) were estimated using Poisson regression and excess (cancer) mortality rate ratios using flexible parametric models. RESULTS: We identified 882,980 cancer cases. Incidence declined during holiday season for all malignancies and the IRR ranged from 0.58 (95% CI 0.57-0.59 in breast to 0.92 (95% CI 0.89-0.94) in pancreatic cancer. A post-holiday increase was noted for acute leukemia, pancreatic, and lung cancer. For all malignancies except lung cancer, non-Hodgkin lymphoma, and acute leukemia, the excess mortality at 2 years from diagnosis was higher among those diagnosed during the holiday season. A tendency toward elevated short-term (0.5 years) excess mortality was noted in the post-holiday group, but long-term effects only persisted in breast cancer. CONCLUSION: This study demonstrates lower holiday detection rates and higher mortality rates in various cancer types diagnosed during holiday season. Healthcare systems should offer a uniform level of cancer care independent of calendar season.

Adrenal insufficiency after curative-intent gastric cancer treatment: a case report.

BACKGROUND: Adrenal insufficiency is a life-threatening condition, and advanced gastric cancer is associated with very poor prognosis. Adrenalectomy and/or metastatic invasion of the adrenal glands can cause primary adrenal insufficiency, which in turn can present with symptoms mimicking advanced cancer. CASE PRESENTATION: Herein we report of a 68-year-old White male with a history of left adrenalectomy in conjunction with distal gastrectomy due to gastric adenocarcinoma. At the 2-year follow-up visit after cancer surgery, the patient presented with fatigue, unintentional weight loss, hyperkalemia, and a computed tomography scan with a right adrenal mass. Primary adrenal insufficiency caused by gastric cancer metastatic invasion of the remaining right adrenal gland was established and glucocorticoid therapy initiated. The patient received first line palliative chemotherapy with systemic disease control and subsequent stereotactic body radiotherapy to the right adrenal gland. More than 17 months after pathology-confirmed gastric cancer relapse, there is no clinical nor radiological evidence of active malignant disease and the patient is doing well on glucocorticoid replacement therapy. CONCLUSIONS: This case does not only illustrate the importance of prompt and correct clinical management of adrenal insufficiency, but also that selected patients with advanced gastric cancer can gain from and achieve long-term survival using a multimodal treatment approach.

Incidence Trends and Survival in Early-Onset Esophagogastric Adenocarcinoma: A Swedish Population-Based Cohort Study.

BACKGROUND: Early-onset adenocarcinomas of different sites are increasing in high-income countries, data on esophagogastric adenocarcinoma are sparse. METHODS: We performed a Swedish population-based cohort study over 1993 to 2019 to delineate differences in incidence and survival in early-onset (age 20-54 years) compared with later-onset (55-99 years) esophageal, cardia, and noncardia gastric adenocarcinoma. Temporal incidence trends were quantified as annual percentage changes (APC) and survival differences as excess mortality rate ratios (EMRR) using Poisson regression and including 95% confidence intervals (CI). RESULTS: Among 27,854 patients with esophagogastric adenocarcinoma, 2,576 were early-onset whereof 470 were esophageal, 645 were cardia, and 1,461 were noncardia gastric. Except noncardia gastric, the male predominance was larger in early-onset compared with later-onset disease. Advanced stage and signet ring cell morphology were more common among early-onset patients. Early-onset and later-onset APC estimates were comparable and esophageal adenocarcinoma incidence increased, cardia remained stable, and noncardia gastric decreased. Early-onset patients had better survival than later-onset, which was amplified when adjusting for prognostic factors including stage [adjusted EMRR 0.73 (95% CI, 0.63-0.85) in esophageal, 0.75 (95% CI, 0.65-0.86) in cardia, and 0.67 (95% CI, 0.61-0.74) in noncardia gastric adenocarcinoma]. The early-onset survival advantage was more pronounced in localized stages 0 to II (all sites) and women (esophageal and noncardia gastric). CONCLUSIONS: We found no major differences in incidence trends comparing early-onset and later-onset esophagogastric adenocarcinoma. Despite unfavorable prognostic features, early-onset esophagogastric adenocarcinoma survival was better than later-onset, particularly in localized stages and women. IMPACT: Our findings suggest delayed diagnosis in younger individuals and especially men.

Reranking cancer mortality using years of life lost.

Incidence and mortality are default measures to describe cancer trends. Mortality compounds incidence and survival but not age at death. We calculated years of life lost (YLL) due to 1 of the 10 solid tumors causing most deaths (lung, colorectal, prostate, pancreatic, breast, hepatobiliary, urinary, central nervous system, gastric, melanoma) using Swedish National Cancer and Cause of Death Registers. Comparing YLL with mortality in 2019, lung (43 152 YLL) and colorectal (32 340 YLL) cancer remained at the top, pancreatic cancer was upranked fourth to third (22 592 YLL) and breast cancer fifth to fourth (21 810 YLL), while prostate cancer was downranked third to fifth (17 380 YLL). Assessing YLL over 2010-2019, women lost consistently more life years because of lung and pancreatic cancer. A downward colorectal cancer mortality trend was reflected as a YLL decline only in women. YLL is simple to calculate, is intuitive to interpret, and expands the understanding of the cancer burden on society.

Declining Cancer Incidence in the Elderly: Decreasing Diagnostic Intensity or Biology?

BACKGROUND: Advanced age is a consistent risk factor for cancer; nonetheless, cancer incidence typically declines after age 75-85 for most solid tumors. METHODS: To delineate the true cancer age-incidence pattern, we performed a population-based cohort study using Swedish Cancer Register data from 1970-2014 on nine common, adult (age 20-99) cancers categorized as requiring high (pancreatic, lung, non-meningioma brain), medium (anorectal, urinary bladder, non-Hodgkin lymphoma), and low (melanoma skin, breast, prostate) diagnostic invasiveness based on the perceived risk of complications associated with histopathologic verification. We estimated the reported incidence and the proportion of autopsy-detected cancers by age but also projected a corrected incidence assuming the same proportion of unexpected cancer findings if all deaths underwent autopsy. RESULTS: The registered cancer incidence dropped after peak age around 65-84, with the exception of melanoma skin. This pattern was attenuated when exploring the proportion of incident, unexpected cancer findings in autopsy material by age. The "total" cancer incidence, reported plus projected incident autopsy cases, increased monotonously with age. CONCLUSIONS: The long-established cancer incidence decline in elderly is most probably an artifact due to reduced diagnostic intensity. IMPACT: Biological drivers to the cancer incidence decline in elderly are unlikely and resources are better allocated to prepare for the anticipated cancer pandemic when numbers of healthy elderly increase. Cancer alarm symptoms in elderly fit for cancer therapy should be investigated promptly and clinical cancer trials focus to also include elderly to set updated standards for cancer therapy in the dominating age group.

Age trends in biliary tract cancer incidence by anatomical subtype: A Swedish cohort study.

AIM: Studies from Western countries suggest that early-onset biliary tract cancer, a rare malignancy originating from the bile ducts (cholangiocarcinoma) or gallbladder, is increasing. We performed a population-based cohort study to outline age trends in biliary tract cancer incidence in Sweden. METHODS: All patients with biliary tract cancer, excluding non-biliary chiefly hepatocellular histopathology, recorded in the Swedish Cancer Register in year 1993-2019 and at age 20-84 were included. Analyses were stratified by anatomical subtype; intrahepatic, gallbladder, perihilar, distal, and not specified. We analyzed absolute incidence rates by calendar period (1993-2001, 2002-2010, and 2011-2019) and annual percentage change (APC) including 95% confidence intervals (CI) across 1993-2019 for all ages and stratified into younger (20-54 years) and older (55-84 years) patients. RESULTS: Among 14,083 patients with biliary tract cancer, 1377 (9.8%) were younger. Gallbladder cancer incidence decreased (APC -2.82, 95% CI: -3.18--2.46), while intrahepatic cholangiocarcinoma increased (APC 1.74, 95% CI: 1.30-2.18), and the latter surpassed gallbladder as the most common subtype during the study period. While both intrahepatic and perihilar cholangiocarcinoma increased in both age groups, the rise was most prominent in younger adults, APC 3.01, 95% CI: 1.84-4.20 and 3.93, 95% CI: 2.08-5.81, respectively. CONCLUSION: Intrahepatic and perihilar cholangiocarcinoma are increasing in Sweden and more so younger adults. Further studies are needed to elucidate the underlying reasons behind the observed trends.

Gall Bladder Disease and the Risk of Small Bowel Cancer-Results from a Nationwide Swedish Cohort Study.

BACKGROUND AND AIMS: Small bowel cancer is a rare but rising malignancy. The etiology is poorly understood and there is a need for large-scale studies. Gallbladder disease (GBD), inducing localized inflammation, has been suggested to increase small bowel cancer risk. METHODS: We retrieved nationwide data from Sweden's 28 pathology departments on all adults (age 20-79) with pathology-confirmed GBD diagnosed in 1965-2017. In total 156,390 GBD patients were matched with up to 5 matched comparators from the general population and follow-up started one year after GBD diagnosis. We used stratified Cox regression to calculate hazard ratios (HRs) for small bowel adenocarcinoma, adenomas, and carcinoids. RESULTS: During a median follow-up of 12 years, we identified 92 small bowel adenocarcinomas, 132 adenomas, and 81 carcinoid tumors in the GBD cohort. Corresponding incidence rates were 4.8, 6.9, and 4.2 per 100,000 person-years (PY), compared to 3.2, 3.2, and 1.8 in matched comparators. The adjusted HR was 1.42 (95% CI = 1.08-1.87) for small bowel adenocarcinoma, 1.79 (95% CI = 1.41-2.27) for adenoma, and 2.07 (95% CI = 1.52-2.81) for carcinoid. The excess cancer risk was most pronounced during the first year of follow-up for adenocarcinomas and during the first six years for adenomas while for carcinoids the HR peaked 10-15 years after start of follow-up. CONCLUSIONS: In this nationwide cohort study, GBD was associated with an increased risk of small bowel cancer. The excess risk of small bowel adenocarcinoma was mainly seen during the first years of follow-up while small bowel carcinoid risk peaked 11-16 years after GBD diagnosis.

Implications for Efficacy and Safety of Total Dose and Dose-Intensity of Neoadjuvant Gemcitabine-Cisplatin in Muscle-Invasive Bladder Cancer: Three-Week Versus Four-Week Regimen.

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy is standard care prior to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: To assess efficacy and safety of two commonly used neoadjuvant schedules with different total doses and dose-intensities of gemcitabine and cisplatin (GC). METHODS: Data were collected retrospectively from all patients treated between 2010 and 2018 with neoadjuvant chemotherapy according to clinical routine at seven centres in Sweden and Denmark. Patients in Sweden received three cycles of a 4-week schedule (GC-4w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, 15, q 28 days) and in Denmark four cycles of a 3-week schedule (GC-3w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, q 21 days). Primary endpoint was pathological response at cystectomy (pT0N0 and < pT2N0). RESULTS: A total of 251 patients were treated with GC-4w and 455 with GC-3w. pT0N0 was significantly higher for patients treated with GC-3w compared to GC-4w, 46% versus 32% (adjusted odds ratio [aOR] 1.80; 95% confidence interval [CI] 1.16-2.80; P = 0.009); and for < pT2N0 60% versus 47% (aOR 1.08; 95% CI 0.70-1.66; P = 0.743). There were no significant differences between GC-4w and GC-3w regarding survival parameters. GC-3w patients discontinued treatment more frequently and showed a higher degree of neutropenia. CONCLUSIONS: A significantly higher complete response-rate was observed in the patient group treated with the more cisplatin-dose-intense 3-week schedule. The side-effect profile was in favor of the 4-week approach while relapse-free and overall survival were similar.

Sex Differences in Urothelial Bladder Cancer Survival.

BACKGROUND: While urinary bladder cancer is consistently more common in men worldwide, women have poorer prognosis. The aim of this study was to outline sex differences in prognostic factors and clinical management and to explore whether these can explain the poorer urinary bladder cancer outcome in women. PATIENTS AND METHODS: We performed a population-based cohort study including all patients diagnosed with urothelial bladder cancer between 1997 and 2014 at age 18 to 89 who had data recorded in the Swedish Urinary Bladder Cancer Register (n = 36,344). Female-to-male odds ratios for clinical management parameters were estimated by logistic regression. To quantify sex differences in bladder cancer-specific survival, we estimated empirical survival proportions and mortality rates as well as applied flexible parametric models to estimate female-to-male hazard ratios and survival proportions over follow-up. Adjusted models included age, year, World Health Organization grade, stage, marital status, education, health care region, birth country, and comorbidity. RESULTS: Except for an adverse stage distribution in women, we found no evidence of unequal clinical management. Among those diagnosed with bladder cancer, women had a higher bladder cancer mortality (adjusted hazard ratio, 1.15; 95% confidence interval, 1.08-1.23) driven by muscle-invasive tumors (adjusted hazard ratio, 1.24; 95% confidence interval, 1.14-1.34). The female survival disadvantage was confined to the first 2 years after diagnosis. CONCLUSION: The excess bladder cancer mortality in women is limited to those diagnosed with muscle-invasive tumors and cannot be explained by the examined clinicopathologic factors. Further investigations of sex differences in therapeutic procedures and outcomes, including complications, of muscle-invasive bladder cancer, must be performed.

Sex and survival in non-small cell lung cancer: A nationwide cohort study.

AIM: To in detail delineate sex differences in non-small cell lung cancer outcome and investigate possible underlying drivers. METHODS: We performed a nationwide, population-based cohort study using data on all incident cases of lung squamous cell carcinoma (n = 10,325) and adenocarcinoma (n = 23,465) recorded in the Swedish Lung Cancer Register in 2002-2016. Flexible parametric models were applied to compute adjusted female-to-male hazard ratios (aHRs) and standardized survival proportions over follow-up including age, calendar year, education, marital status, birth country, health care region, performance status, smoking history, comorbidities, and tumor location in the final model. RESULTS: Women presented with better performance status, were younger, and more often never-smokers. Women with adenocarcinoma also had lower comorbidity burden, less advanced stage, and were more often EGFR positive. Men with adenocarcinoma had a consistently poorer lung cancer-specific survival across stage; HR 0.69; 95% CI 0.63-0.76 (stage IA-IIB) to 0.94; 95% CI 0.88-0.99 (stage IIIB-IV), remaining largely unchanged after adjustments; aHR 0.74; 95% CI 0.66-0.82 to 0.84; 95% CI 0.81-0.87. The same pattern was observed in squamous cell carcinoma, except in stage IIIA disease, where we found no sex differences in survival. CONCLUSIONS: Men with non-small cell lung cancer have a consistently poorer prognosis, even after careful adjustments for a wide range of prognostic factors. While the pattern was similar in both squamous cell and adenocarcinoma, it was larger and more consistent in the latter.

Sex differences in cancer risk and survival: A Swedish cohort study.

AIM: The aim of this study is to firmly delineate temporal and age trends regarding sex discrepancies in cancer risk and survival as well as quantifying the potential gain achieved by eliminating this inequality. METHODS: We performed a population-based cohort study using data on all adult incident cancer cases (n = 872,397) recorded in the Swedish Cancer Register in 1970-2014. To assess the associations between sex and cancer risk and sex and survival, male-to-female incidence rate ratios (IRRs) and excess mortality ratios (EMRs) adjusted for age and year of diagnosis were estimated using Poisson regression. RESULTS: Men were at increased risk for 34 of 39 and had poorer prognosis for 27 of 39 cancers. Women were at increased risk for 5 of 39 and had significantly poorer survival for 2 of 39 cancers. IRRs among male predominant sites ranged from 1.05; 95% confidence interval (CI), 1.03--1.1 (lung adenocarcinoma) to 8.0; 95% CI, 7.5-8.5 (larynx). EMRs among sites with male survival disadvantage ranged from 1.1; 95% CI, 1.03-1.1 (colon) to 2.1; 95% CI, 1.5--2.8 (well-differentiated thyroid). CONCLUSION: Male sex is associated with increased risk and poorer survival for most cancer sites. Identifying and eliminating factors driving the observed sex differences may reduce the global cancer burden.