Gastrointestinal cancer precursor risk and mortality in pancreatic intraductal papillary mucinous neoplasms: a nationwide cohort study.

BACKGROUND AND AIMS: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection. The aim of the study was to examine absolute and relative risks of non-pancreatic gastrointestinal (GI) cancer precursors and mortality in histologically confirmed IPMN. METHODS: Through the nationwide ESPRESSO histopathology cohort, we retrieved data on IPMN between 1965 and 2016. Each index case was matched to ≤5 general population controls. Through Cox regression, we estimated hazard ratios (HRs) for future GI cancer precursors and death. RESULTS: A total of 117 patients with IPMN and 539 age- and sex-matched controls were included. Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI = 0.34-10.55). By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI = 1.79-7.27)). The most common cause of death in IPMN was pancreatic cancer (n = 14; 45.2% of all deaths). CONCLUSIONS: We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients. Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN. However, results should be confirmed in larger cohorts.

Factors associated with long-term benzodiazepine and Z-drug use across the lifespan and 5-year temporal trajectories among incident users: a Swedish nationwide register-based study.

PURPOSE: Despite being discouraged by guidelines, long-term use of benzodiazepines and related Z-drugs (BZDR) remains frequent in the real-world. An improved understanding of factors associated with the transition from new to long-term BZDR use and of temporal BZDR use trajectories is needed. We aimed to assess the proportion of long-term BZDR use (> 6 months) in incident BZDR-recipients across the lifespan; identify 5-year BZDR use trajectories; and explore individual characteristics (demographic, socioeconomic and clinical) and prescribing-related factors (pharmacological properties of the initial BZDR, prescriber's healthcare level, and concurrent dispensing of other medications) associated with long-term BZDR use and distinct trajectories. METHODS: Our nationwide register-based cohort included all BZDR-recipients in Sweden with first dispensation in 2007-2013. Trajectories of BZDR use days per year were built using group-based trajectory modelling. Cox regression and multinomial logistic regression were fitted to assess the predictors of long-term BZDR use and trajectories' membership. RESULTS: In 930,465 incident BZDR-recipients, long-term use increased with age (20.7%, 41.0%, and 57.4% in 0-17, 18-64, and ≥ 65-year-olds, respectively). Four BZDR use trajectories emerged, labelled 'discontinued', 'decreasing', 'slow decreasing' and 'maintained'. The proportion of the 'discontinued' trajectory members was the largest in all ages, but reduced from 75.0% in the youths to 39.3% in the elderly, whereas the 'maintained' increased with age from 4.6% to 36.7%. Prescribing-related factors, in particular multiple BZDRs at initiation and concurrent dispensing of other medications, were associated with increased risks of long-term (vs short-term) BZDR use and developing other trajectories (vs 'discontinued') in all age groups. CONCLUSIONS: The findings highlight the importance of raising awareness and providing support to prescribers to make evidence-based decisions on initiating and monitoring BZDR treatment across the lifespan.

Prenatal exposure to benzodiazepines and Z-drugs in humans and risk of adverse neurodevelopmental outcomes in offspring: A systematic review.

When used during pregnancy, benzodiazepines (BZDs) and related z-drugs could pass readily through the placenta and the foetal blood-brain barrier, where they can bind to γ-amino butyric acid (GABA) receptors in the developing foetal brain. Yet, data on long-term safety of prenatal BZD and z-drug use and its impact on offspring neurodevelopment are inconclusive. In this systematic review, we qualitatively synthetize the existing evidence on maternal exposure to various BZDs and z-drugs during pregnancy and offspring cognitive, emotional, behavioural, and motor skills developmental outcomes. Nineteen studies were included. We used harvest plots to visualize the directions of reported associations. Despite several associations between distinct types of BZDs and z-drugs and an increased risk of outcomes within different neurodevelopmental domains were observed, a remarkable scarcity of overall research on the topic and considerable discrepancies in methodology, particularly towards controlling for confounding by indication, precluded drawing conclusions with a reasonable degree of certainty. We outline various research strategies to mitigate methodological limitations and provide directions for future empirical studies on the topic.

Esophageal abnormalities and the risk for gastroesophageal cancers-a histopathology-register-based study in Sweden.

BACKGROUND: The poor survival of patients with gastroesophageal cancers may improve if additional esophageal precursor lesions to Barrett's esophagus and squamous dysplasia are identified. We estimated the risk for gastroesophageal cancers among patients with various histopathological abnormalities in the esophagus, including Barrett's esophagus, subdivided by histopathological types. METHODS: Histopathology data from esophageal biopsies obtained 1979-2014 were linked with several national population-based registers in Sweden. Patients were followed from 2 years after the first biopsy date until cancer, death, emigration, esophagectomy/gastrectomy or end of follow-up, 31st of December 2016, whichever came first. We estimated standardized incidence ratios (SIRs) as measures of relative risk with the Swedish general population as reference. RESULTS: In total 367 esophageal adenocarcinoma (EAC) cases were ascertained during 831,394 person-years of follow-up. The incidence rate (IR) for EAC was 0.1 per 1000 person-years for normal morphology, 0.2-0.5 for inflammatory changes, and 0.8-2.9 for metaplasia. The IR was 1.0 per 1000 person-years (95% confidence interval 0.7-1.3) among patients with non-dysplastic intestinal metaplasia, 0.9 (0.8-1.1) in non-dysplastic gastric/glandular metaplasia and 2.9 (2.0-4.2) among columnar metaplasia patients with low-grade dysplasia. The SIRs were 11.7 (95% confidence interval 8.6-15.5), 12.0 (10.0-14.2) and 30.2 (20.5-42.8), respectively. The SIRs for gastric cardia adenocarcinoma (GCA) were moderately elevated. CONCLUSIONS: For the first time, we demonstrate that patients with esophageal inflammatory and other metaplastic abnormalities than Barrett's esophagus have an increased risk of EAC and GCA compared to the general population. Moreover, patients with different histopathologic subtypes of Barrett's esophagus have a comparable risk for EAC.

Gastric Mucosal Abnormality and Risk of Pancreatic Cancer: A Population-Based Gastric Biopsy Cohort Study in Sweden.

BACKGROUND: It remains open whether gastric precancerous lesions are associated with an elevated risk of pancreatic cancer. Our aim was to investigate the association between gastric mucosal status and pancreatic cancer risk. METHODS: Patients with gastric biopsies [normal, minor changes, superficial gastritis, and atrophic gastritis/intestinal metaplasia/dysplasia (AG/IM/Dys)] from the Swedish histopathology registers during 1979 to 2011 were included. Cross-linkages with several nationwide registries allowed complete follow-up and identification of pancreatic cancer cases until 2014. Standardized incidence ratios (SIR) and HRs were estimated. RESULTS: During 3,438,248 person-years of follow-up with 318,653 participants, 3,540 cases of pancreatic cancer were identified. The same pattern of excess risk of pancreatic cancer compared with the general population was observed across all groups: a peak of 12- to 21-fold excess risk in the first year after biopsy [e.g., normal: SIR = 17.4; 95% confidence interval (CI), 15.7-19.3; AG/IM/Dys: SIR = 11.5; 95% CI, 9.9-13.4], which dropped dramatically during the second and third years, followed by 20% to 30% increased risk after the third year (e.g., normal: SIR = 1.2; 95% CI, 1.1-1.4; AG/IM/Dys: SIR = 1.3; 95% CI, 1.1-1.5). However, no significant excess risk was observed with the normal gastric mucosa as reference. CONCLUSIONS: This unique, large pathologic cohort study did not find evidence that abnormal gastric mucosal status is causally associated with a long-term pancreatic cancer risk. However, a highly increased short-term risk was observed for people undergoing gastroscopy with biopsy sampling compared with the general population. IMPACT: Further studies for a long-term risk of pancreatic cancer in patients with gastric biopsies are needed, with further adjustments.

Establishing and Evaluating a Study Questionnaire on Knowledge and Attitudes of Healthcare Professionals Towards Recreational and Medical Cannabis Across Europe.

BACKGROUND AND OBJECTIVE: The present survey was a preliminary to a European research project on the attitude and knowledge of healthcare professionals towards the use of medical cannabis. The objective was to evaluate the readability, understandability, and relevance of a first version of the study questionnaire before preparing the finalized questionnaire, which will be subsequently proposed to European healthcare professionals on a large scale. METHODS: A cross-sectional study was conducted between December 2019 and May 2020. We established an electronic evaluation questionnaire relating to the study questionnaire. This evaluation questionnaire was proposed to multidisciplinary experts from all over Europe. Feedback from the evaluation questionnaire was considered for improving and finalizing the study questionnaire. RESULTS: 66 evaluation questionnaires were collected from nine European countries (Cyprus, France, Germany, Italy, Lithuania, Portugal, Spain, Sweden, United Kingdom), which corresponded to a participation rate of 41.5%. Most participants were women (65.2%, n = 43). The mean age was 39.5 years ± 11.6. Each participant could specify several occupations. There were 25 pharmacologists, 24 physicians, ten pharmacists, four university teachers, three epidemiologists or public health experts, one nurse, one biotechnologist, one microbiologist, and one police researcher. Overall, 84.8% of participants were interested in the topic of the survey on the knowledge and attitudes of healthcare professionals towards recreational and medical cannabis across Europe. Participants were satisfied with all but six of the proposed questions. In addition, two additional questions were subject for comments despite a high level of satisfaction. Consequently, the concerned questions (n = 8) were modified. CONCLUSION: This evaluation survey was a necessary step to improve the quality of the future research project. The positive feedback encourages the authors to proceed with the project on a European scale, scheduled for 2021.

Survival of esophageal and gastric cancer patients with adjuvant and palliative chemotherapy-a retrospective analysis of a register-based patient cohort.

PURPOSE: The survival of esophageal and gastric cancer patients treated with chemotherapy is rarely assessed outside of clinical trials. Therefore, we compared the effectiveness of various curative or palliative chemotherapy regimens on the survival of esophageal and gastric cancer patients in a "real world" clinical setting. METHODS: We identified a cohort of 966 incident esophageal and gastric cancer patients in Stockholm/Gotland County (a low-risk Western population) during 2008-2013. Patients who received chemotherapy with curative intention (n = 279) and palliative intention (n = 182) were analyzed separately. Using Cox proportional hazards regression models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for the potential confounding factors: age, sex, TNM stage, radiotherapy, comorbidity, marital status, education, income, and country of birth. RESULTS: In esophageal cancer patients with curative treatment intention, we observed a higher hazard for death among patients who received carboplatin-fluorouracil compared to patients who received cisplatin-fluorouracil, corresponding to a HR of 2.18 (95% CI 1.09-4.37). Conversely, in patients with cancer in the gastroesophageal junction who had a curative treatment intention at diagnosis, we observed a reduced hazard for death among those who received fluorouracil-oxaliplatin, compared to patients who received cisplatin-fluorouracil (HR 0.28; 95% CI 0.08-0.96). CONCLUSION: Among patients with esophageal cancer who received treatment with curative intention, cisplatin-fluorouracil was associated with better survival compared to carboplatin-fluorouracil, while patients with gastroesophageal junction cancer who were treated with cisplatin-fluorouracil had worse survival compared to fluorouracil-oxaliplatin.

Associations Between Gastric Atrophy and Its Interaction With Poor Oral Health and the Risk for Esophageal Squamous Cell Carcinoma in a High-Risk Region of China: A Population-Based Case-Control Study.

Previous findings concerning gastric atrophy as a potential risk factor for esophageal squamous cell carcinoma (ESCC) have been inconsistent. We aimed to test whether gastric atrophy and, further, its interaction with poor oral health elevated the risk of ESCC in a high-risk region of China. Our population-based case-control study in Taixing, China (2010-2014), recruited cases from local hospitals and the local cancer registry. Controls were selected randomly from the local population registry. Ultimately, 1,210 cases and 1,978 controls answered questionnaires and provided blood samples for assay of pepsinogens. Unconditional logistic regression models were used to estimate odds ratios and 95% confidence intervals. Gastric atrophy (defined as a serum level of pepsinogen I of <55 µg/L) was associated with an increased risk for ESCC (odds ratio = 1.61; 95% confidence interval: 1.33, 1.96), even after full adjustment for potential confounding factors. In addition, suggestion of an additive interaction between gastric atrophy and poor oral health was observed (relative excess risk due to interaction = 1.28, 95% confidence interval: 0.39, 2.18). We conclude that gastric atrophy appears to be a risk factor for ESCC in a high-risk region of China, and there is a suggested additive interaction with poor oral health that increases this risk even further.

Family history of gastric mucosal abnormality and the risk of gastric cancer: a population-based observational study.

Background: An increased prevalence of gastric premalignant abnormalities was reported among relatives of gastric cancer (GC) patients, with rather unexplored clinical significance. Methods: In Swedish computerized pathology registers, we identified, as 'index' persons, 232 681 patients who were born after 1931 and underwent endoscopic examination with stomach biopsy between 1979 and 2014. Through linkage with the Multi-Generation Register, we compiled a cohort consisting of 903 337 first-degree relatives of these biopsied patients. The relatives were grouped according to their 'family histories', defined as the first gastric mucosal diagnosis of the index person or GC family history known before that. Standardized incidence ratios (SIRs) provided comparisons with the matched general population. For internal comparisons with relatives with 'normal/minor changes' mucosal family history, hazard ratios (HRs) were derived from adjusted Cox regression modelling. Results: During follow-up, 1302 relatives developed GC. Crude incidence rates of non-cardia GC were 7.7 × 10-5 year-1 for the 'normal/minor changes' family history group (SIR = 1.0), 11.2 to 12.6 × 10-5 year-1 for precancerous changes groups (atrophic gastritis/intestinal metaplasia/dysplasia, SIR = 1.5 to 1.6), and 18.4 × 10-5 year-1 for those with a family history of GC (SIR = 2.3). HRs derived from Cox models corroborated the family history-related risk pattern, with the most conspicuous trend observed among siblings-a family history of any precancerous changes and GC was associated with, respectively, a 2.5-fold and a 3.8-fold increment in non-cardia GC hazard, compared with siblings of index persons with 'normal/minor mucosal changes'. Conclusions: The precancerous mucosal abnormalities recorded in a person's first-degree relatives may improve GC risk stratification for this person.

Incidence of gastric cancer among patients with gastric precancerous lesions: observational cohort study in a low risk Western population.

OBJECTIVE: To accurately measure the incidence of gastric cancer among patients with gastric precancerous lesions, and to quantify the excess incidence in comparison with people with normal mucosa on endoscopy and a general population. DESIGN: Population based cohort study. SETTING: Population of Sweden using data from its national disease registers. PARTICIPANTS: 405,172 patients who had gastric biopsy samples taken for non-malignant indications between 1979 and 2011. MAIN OUTCOME MEASURES: Incidence of gastric cancer, reported separately for patients with different mucosal changes in biopsy samples. Standardised incidence ratios provided estimation of the relative risk, using the general Swedish population as reference; and hazard ratios were derived from Cox regression modelling for internal comparisons with patients with normal gastric mucosa. RESULTS: After excluding the first two years of follow-up, 1599 cases of gastric cancer were identified. The annual crude incidence of gastric cancer was 20 × 10(-5) for those in the normal mucosa group (standardised incidence ratio 1.0), 42 × 10(-5) for those with minor changes (1.5), 59 × 10(-5) for the gastritis group (1.8), 100 × 10(-5) for the atrophic gastritis group (2.8), 129 × 10(-5) for the intestinal metaplasia group (3.4), and 263 × 10(-5) for the dysplasia group (6.5). Cox regression modelling confirmed that excess risks increased monotonically with progressive severity of gastric lesions, with the highest hazard ratio of 10.9 (dysplasia versus normal mucosa, 95% confidence interval 7.7 to 15.4). The increased incidence was stable throughout the follow-up period, and the gaps between cumulative incidence curves grew continuously. CONCLUSIONS: Among patients who undergo gastroscopy with biopsy for clinical indications, approximately 1 in 256 with normal mucosa, 1 in 85 with gastritis, 1 in 50 with atrophic gastritis, 1 in 39 with intestinal metaplasia, and 1 in 19 with dysplasia will develop gastric cancer within 20 years. These numbers, along with cost-benefit analyses, should guide future surveillance policies for these particular patient groups.