Does proton pump inhibitors use increase risk of digestive tumors?: A 2-sample Mendelian randomization study.

The objective of this study was to explore the causal relationship between the use of proton pump inhibitors (PPIs) and 16 types of digestive system tumors. We utilized a 2-sample Mendelian randomization (MR) approach to investigate this relationship. We obtained exposure and outcome data from the UK Biobank and the Finland Biobank, respectively. The genetic data used in the analysis were derived from genome-wide association studies (GWAS) studies conducted on European populations. We screened single nucleotide polymorphisms significantly associated with the use of omeprazole, a commonly used PPIs, as instrumental variables. We then performed MR analyses using the inverse variance weighting (IVW) method, MR-Egger regression, and the weighted median method to evaluate the causal effect of omeprazole use on the 16 types of digestive system tumors. Our MR analysis revealed a significant causal relationship between the use of omeprazole and pancreatic malignancies, but not with any other types of digestive system tumors. The IVW analysis showed an odds ratio of 4.33E-05 (95%CI: [4.87E-09, 0.38], P = .03) and the MR-Egger analysis showed an odds ratio of 5.81E-11 (95%CI: [2.82E-20, 0.12], P = .04). We found no significant heterogeneity or pleiotropy, and sensitivity analysis confirmed the robustness of our results. Furthermore, statistical power calculations suggested that our findings were reliable. Conclusion The use of PPIs is a protective factor for pancreatic malignancies, but no causal relationship has been found with other digestive system tumors.

Exposure to weak opioids and risk of gastrointestinal tract cancers: A series of nested case-control studies.

AIMS: There is evidence gastrointestinal (GI) motility may play a role in the development of GI cancers. Weak opioids (codeine and dihydrocodeine) decrease GI motility, but their effect on GI cancer risk has not been assessed. We aim to assess the association between weak opioids and cancers of the GI tract. METHODS: A series of nested case-control studies was conducted using Scottish general practice records from the Primary Care Clinical Informatics Unit Research database. Oesophageal (n = 2432), gastric (n = 1443) and colorectal cancer (n = 8750) cases, diagnosed between 1999 and 2011, were identified and matched with up to five controls. Weak opioid use was identified from prescribing records. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, adjusting for relevant comorbidities and medication use. RESULTS: There was no association between weak opioids and colorectal cancer (adjusted OR = 0.96, CI 0.90, 1.02, P = 0.15). There was an increased risk of oesophageal (adjusted OR = 1.16, CI 1.04, 1.29, P = 0.01) and gastric cancer (adjusted OR = 1.26, CI 1.10, 1.45, P = 0.001). The associations for oesophageal cancer, but not gastric cancer, were attenuated when weak opioid users were compared with users of another analgesic (adjusted OR = 1.03 CI 0.86, 1.22, P = 0.76 and adjusted OR = 1.29 CI 1.02, 1.64, P = 0.04 respectively). CONCLUSIONS: In this large population-based study, there was no consistent evidence of an association between weak opioids and oesophageal or colorectal cancer risk, but a small increased risk of gastric cancer. Further investigation is required to determine whether this association is causal or reflects residual confounding or confounding by indication.

Genotype-based chemotherapy for patients with gastrointestinal tumors: focus on oxaliplatin, irinotecan, and fluoropyrimidines.

This review aimed to summarize the pharmacogenetic studies of the most commonly used drugs in the chemotherapy of gastrointestinal (GI) tumors: oxaliplatin, irinotecan, and fluoropyrimidines. So far, it has not been possible to develop an effective genotype-based approach for oxaliplatin. More and more evidence is emerging in favor of the fact that the choice of a dose of fluorouracil based on pharmacogenetic testing according to DPYD*2A, can be not only effective but also cost-effective. Additional, well-planned trials of the UGT1A1 genotype-based approach to irinotecan therapy are predicted to reduce adverse drug events in people with the UGT1A1*28/*28 genotypes and improve treatment efficacy in the rest of the patients, which might be cost-effective.

The Risk of Gastrointestinal Cancer on Daily Intake of Low-Dose BaP in C57BL/6 for 60 Days.

BACKGROUND: Benzo(a)pyrene (BaP) is a carcinogenic compound in contaminated foodstuffs. The effect of oral intake of the environmental carcinogen BaP under low doses and frequent exposure on a digestive system has not been thoroughly verified. METHODS: In this regard, this study was conducted to prove the toxicity effects of BaP on the stomach and colon tissue after exposure to C57BL/6 mouse (3 and 6 µg/kg) following daily oral administration for 60 days. This study investigated acute gastric mucosal injury, severe gastric edema, cell infiltration, and mononuclear cells, multifocal cells, and tumoral inflammatory cells. RESULTS: The results of ELISA showed that the expression of serum interleukin (IL)-6 and tumor necrosis factor-α in the BaP exposure group were significantly increased, and a high level of DNA adduct distribution in their stomach and colon. Moreover, this study has confirmed the expression of early carcinogenesis markers: nuclear factor (NF)-κB, p53, IL-6, superoxide dismutase 1 (SOD1), mucin (MUC1 and MUC2), and ß-catenin in the stomach and colon, and showed that there was a significant increase in IL-6, NF-κB, SOD1, ß-catenin, and MUC1 (P < 0.05). At the same time, there was a significant decrease in MUC2 and p53 (P < 0.05). Thus, even in low doses, oral intake of BaP can induce DNA damage, increasing the potential risk of gastrointestinal cancer. CONCLUSION: This study will provide a scientific basis for researching environmental contaminated food and intestinal health following daily oral administration of BaP.

Safety and immunogenicity of inactivated SARS-CoV-2 vaccines in people with gastrointestinal cancer.

OBJECTIVES: This study aimed to evaluate the safety and immunogenicity of inactivated COVID-19 vaccines in patients with gastrointestinal cancer (GI) cancer. The role of memory B cells (MBCs) in the humoral response to COVID-19 vaccination was also investigated. METHODS: In this prospective observational study, GI cancer patients and healthy individuals who had received 2 doses of inactivated COVID-19 vaccines were included. The data regarding adverse effects, serum anti-receptor binding domain (RBD)-IgG, neutralizing antibodies (NAbs), and frequencies of MBCs were collected prospectively. RESULTS: The inactivated COVID-19 vaccines were safe and well tolerated. Serum anti-RBG-IgG and NAbs were lower for cancer patients. Old age, high ASA score, and receiving active chemotherapy were risk factors for lower antibody titers. The frequencies of activated and resting MBCs decreased in (17.45% vs 38.11%, P = 0.002; 16.98% vs 34.13%, P = 0.023), while the frequencies of intermediate and atypical MBCs increased in cancer patients (40.06% vs 19.87%, P = 0.010; 25.47% vs 16.61%, P = 0.025). The serum antibody titer decreased gradually during follow-up but increased when a booster vaccine was given. CONCLUSION: The inactivated COVID-19 vaccines were well tolerated in patients with GI cancer but with lower immunogenicity. The subpopulations of MBCs were disordered in cancer patients, and a booster vaccine may be prioritized for them.

Ranitidine Use and Risk of Upper Gastrointestinal Cancers.

BACKGROUND: The discovery that ranitidine is contaminated with N-nitrosodimethylamine, a suspected human carcinogen, raises the hypothesis of a gastrointestinal carcinogenic effect; however, evidence remains inconclusive. METHODS: We used the nationwide Danish Prescription Registry to identify a cohort of incident ranitidine users and two active comparator cohorts comprising users of other histamine-2 receptor blockers (H2RB) and users of proton pump inhibitors (PPI). All Danish adults with a first prescription of ranitidine, other H2RBs, or PPIs in 1996 through 2008 were followed virtually completely through 2018 for incidence of esophageal, stomach, liver, and pancreatic cancers. We used Cox regression with propensity-score weighting to calculate hazard ratios and 10-year cumulative risk with 95% confidence intervals. RESULTS: We ascertained 276 newly diagnosed esophageal, 342 stomach, 133 hepatocellular, and 517 pancreatic cancers among ranitidine users during follow-up (median 14 years). In comparison with use of other H2RBs or PPIs, we found no consistent evidence of increased HRs or excess 10-year cumulative risk of any upper gastrointestinal cancer following ranitidine use. We observed no association after restriction to subjects with at least 5 or 10 prescriptions or those with 10 prescriptions and at least 10 years of follow-up. CONCLUSIONS: Our large prospective study using high-quality prescription and cancer incidence data, with two active comparator groups, provides no compelling evidence that ranitidine increases the risk of upper gastrointestinal cancers. IMPACT: Our results, which do not support any carcinogenic effect on esophagus, stomach, liver or pancreas, should be reassuring for millions of concerned past users of ranitidine.

Association of the Frequency and Quantity of Alcohol Consumption With Gastrointestinal Cancer.

Importance: Although total alcohol consumption is a known risk factor for gastrointestinal (GI) cancers, few studies have attempted to assess the pattern of alcohol drinking in association with GI cancers. Objective: To evaluate the relative association of the frequency of drinking vs the amount of alcohol consumed per occasion with the development of GI cancers. Design, Setting, and Participants: A population-based retrospective cohort study used data from the Korean National Health Insurance System database on 11 737 467 participants without cancer who underwent a national health screening program from January 1, 2009, to December 31, 2010. Participants were followed up from the year after their health screening date until they received a diagnosis of GI cancer, death, or December 31, 2017. The median follow-up duration was 6.4 years (interquartile range, 6.4-7.4 years). Statistical analysis was performed from January 1, 2019, to March 31, 2020. Exposures: Weekly alcohol consumption (nondrinker [0 g/week], mild drinker [0-104 g/week], moderate drinker [105-209 g/week], and heavy drinker [≥210 g/week]), drinking frequency, and amount per occasion. Main Outcomes and Measures: Incident GI cancers at 6 specific sites (esophagus, stomach, colorectal, liver, biliary, and pancreas). Results: Among 11 737 467 participants (6 124 776 women [52.2%]; mean [SD] age, 54.6 [10.4] years), 319 202 (2.7%) developed GI cancer. Compared with nondrinkers, the risk of GI cancer was higher for mild drinkers (adjusted hazard ratio [aHR], 1.04; 95% CI, 1.03-1.05), moderate drinkers (aHR, 1.14; 95% CI, 1.12-1.15), and heavy drinkers (aHR, 1.28; 95% CI, 1.26-1.29). The risk of GI cancer increased linearly with the frequency of drinking in a dose-dependent manner (aHR, 1.39; 95% CI, 1.36-1.41 for individuals who drink every day). In contrast, the risk of GI cancer appeared to increase with consumption up to 5 to 7 units per occasion (aHR, 1.15; 95% CI, 1.14-1.16), and then the HRs were no higher for those with a higher intake per session than 5 to 7 units (8-14 units per occasion: aHR, 1.11; 95% CI, 1.09-1.12; >14 units per occasion: aHR, 1.11; 95% CI, 1.08-1.14). Given similar weekly alcohol consumption levels, the risk of GI cancer increased with a higher frequency of drinking and decreased with a higher amount per occasion. Risk patterns for 6 specific cancers were generally similar to that of all GI cancers. Conclusions and Relevance: In this cohort study, frequent drinking was a more important risk factor for incident GI cancers than the amount of alcohol consumed per occasion. Individuals should be cautioned about regular consumption of small amounts of alcohol in addition to the total amount of alcohol consumption or amount per occasion.

Consumption of artificially sweetened soft drinks and risk of gastrointestinal cancer: a meta-analysis of observational studies.

OBJECTIVE: There remain inconclusive findings from previous observational epidemiological studies on whether consumption of artificially sweetened soft drinks (ASSD) increases the risk of gastrointestinal (GI) cancer. We investigated the associations between the consumption of ASSD and the risk of GI cancer using a meta-analysis. DESIGN: Systematic review and meta-analysis. SETTING: PubMed and EMBASE were searched using keywords until May 2020 to identify observational epidemiological studies on the association between the consumption of ASSD and the risk of GI cancer. SUBJECTS: Twenty-one case-control studies and seventeen cohort studies with 12 397 cancer cases and 2 474 452 controls. RESULTS: In the random-effects meta-analysis of all the studies, consumption of ASSD was not significantly associated with the risk of overall GI cancer (OR/relative risk (RR), 1·02; 95 % CI, 0·92, 1·14). There was no significant association between the consumption of ASSD and the risk of overall GI cancer in the subgroup meta-analyses by study design (case-control studies: OR, 0·95; 95 % CI, 0·82, 1·11; cohort studies: RR, 1·14; 95 % CI, 0·97, 1·33). In the subgroup meta-analysis by type of cancer, consumption of ASSD was significantly associated with the increased risk of liver cancer (OR/RR, 1·28; 95 % CI, 1·03, 1·58). CONCLUSIONS: The current meta-analysis of observational epidemiological studies suggests that overall, there is no significant association between the consumption of ASSD and the risk of GI cancer.

Evaluation of potential gastrointestinal carcinogenicity associated with the ingestion of asbestos.

The inhalation of asbestos, depending on the fiber type and dose, may be associated with the development of mesothelioma and other asbestos-related diseases. However, little is known about the potential adverse effects associated with the ingestion of asbestos. Evidence of asbestos fibers released from asbestos-cement pipes used in water distribution systems has led to concerns of potentially contaminated drinking water. The purpose of this study is to determine whether ingestion of asbestos fibers may lead to cancerous effects on the gastrointestinal (GI) tract. Data from animal and human studies were analyzed using a weight-of-evidence approach to evaluate the potential risk of GI cancers associated with asbestos ingestion. Seventeen human and 23 animal studies were identified and evaluated in this study. Animal studies were conducted in multiple species with inconsistent dosing protocols. Overall, animal studies reported that the asbestos fibers, irrespective of fiber type and dose, failed to produce any definitive GI carcinogenic effect. The 17 identified human epidemiological studies reported the ingestion of asbestos-contaminated water with concentrations from 1 to 71,350 million fibers per liter (MFL). A majority of the epidemiology studies reported statistically significant increases in multiple GI-specific cancers. However, these findings are confounded due to several critical study limitations including flawed study design, small sample size, selection bias, lack of individual exposure history, lack of adequate latency, and the inability to account for confounders including occupational history, diet, and smoking history. Based on our weight-of-evidence assessment, there is insufficient evidence of causality between the ingestion of asbestos and an increased incidence of GI cancers.

Outcomes of Patients With Advanced Gastrointestinal Cancer in Relationship to Opioid Use: Findings From Eight Clinical Trials.

BACKGROUND: This study assessed the patterns of opioid use among patients with advanced gastrointestinal cancers who were included in 8 clinical trials and evaluated the impact of opioid use on survival outcomes of included patients. METHODS: Deidentified datasets from 8 clinical trials evaluating first-line systemic treatment of advanced gastrointestinal cancers were accessed from the Project Data Sphere platform (ClinicalTrial.gov identifiers: NCT01124786, NCT00844649, NCT00290966, NCT00678535, NCT00699374, NCT00272051, NCT00305188, and NCT00384176). These trials evaluated patients with pancreatic carcinoma, gastric carcinoma, hepatocellular carcinoma (HCC), and colorectal carcinoma. Multivariable logistic regression analysis was used to evaluate factors predicting the use of opioids. Kaplan-Meier survival estimates were used to compare survival outcomes in each disease entity among patients who did or did not receive opioid treatment. Multivariable Cox regression analysis was then used to further assess the impact of opioid use on survival outcomes in each disease entity. RESULTS: A total of 3,441 participants were included in the current analysis. The following factors predicted a higher probability of opioid use within logistic regression analysis: younger age at diagnosis (odds ratio [OR], 0.990; 95% CI, 0.984-0.997; P=.004), nonwhite race (OR for white vs nonwhite, 0.749; 95% CI, 0.600-0.933; P=.010), higher ECOG score (OR for 1 vs 0, 1.751; 95% CI, 1.490-2.058; P<.001), and pancreatic primary site (OR for colorectal vs pancreatic, 0.241; 95% CI, 0.198-0.295; P<.001). Use of opioids was consistently associated with worse overall survival (OS) in Kaplan-Meier survival estimates of each disease entity (P=.008 for pancreatic cancer; P<.001 for gastric cancer, HCC, and colorectal cancer). In multivariable Cox regression analysis, opioid use was associated with worse OS among patients with pancreatic cancer (hazard ratio [HR], 1.245; 95% CI, 1.063-1.459; P=.007), gastric cancer (HR, 1.725; 95% CI, 1.403-2.122; P<.001), HCC (HR, 1.841; 95% CI, 1.480-2.290; P<.001), and colorectal cancer (HR, 1.651; 95% CI, 1.380-1.975; P<.001). CONCLUSIONS: Study findings suggest that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers. Further studies are needed to understand the underlying mechanisms of this observation and its potential implications.

Across-Site Differences in the Mechanism of Alcohol-Induced Digestive Tract Carcinogenesis: An Evaluation by Mediation Analysis.

A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case-control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43-2.36) for head and neck cancer, 21.15 (9.11-49.12) for esophageal cancer, and 1.65 (1.38-1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers. SIGNIFICANCE: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.

Exposure to oral bisphosphonates and risk of gastrointestinal cancer.

Few studies have explored the association of oral bisphosphonate exposure and gastrointestinal cancer within Asian populations. In this study, we investigated 45,397 Korean women from the nationwide population-based cohort from 2002 to 2013. Oral bisphosphonate exposure did not appear to be associated with elevated or reduced risk for gastrointestinal cancer. INTRODUCTION: While several studies suggested increased risk in upper gastrointestinal (GI) cancer or reduced risk in colorectal cancer upon bisphosphonate exposure, the association is less explored within Asian populations. We investigated the effect of oral bisphosphonate exposure on the risk of GI cancers within a nationwide population-based cohort. METHODS: This study used two separate cohorts. The first cohort included 45,397 women aged 60 years or older from the National Health Insurance Service-Health Screening Cohort during 2002-2013. Participants were classified into bisphosphonate users and non-users based on drug exposure during 2002-2007, and followed-up from the index date of January 1, 2008. The second cohort included 25,665 newly diagnosed osteoporosis patients who started taking oral bisphosphonate during 2003-2008. After 4 years of drug exposure period, patients were separated into quartiles based on cumulative oral bisphosphonate exposure. Participants were followed-up until December 31, 2013 for GI cancer, stomach cancer, and colorectal cancer. Cox proportional hazard regression models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for the cancer risks. RESULTS: Compared to bisphosphonate non-users, no significant risk difference was observed among bisphosphonate users on GI (HR 1.06; 95% CI 0.87-1.28), stomach (HR 1.11; 95% CI 0.85-1.47) and colorectal cancers (HR 1.04; 95% CI 0.79-1.37). Among bisphosphonate users, increasing doses of bisphosphonate exposure was not associated with elevated or reduced risk for GI cancer (p for trend 0.573). CONCLUSION: Oral bisphosphonate use did not appear to be associated with elevated or reduced risk for GI cancers.

[Proton pump inhibitors and cancers: A hazardous association?] / Inhibiteurs de la pompe à protons (IPP) et cancers : une association à risques ?

Proton pump inhibitors, a major progress in gastro-enterology, are globally among the most widely prescribed drugs. But, due to their strong gastric acid inhibition, they can be responsible for side effects, particularly in cancer patients. They are involved in renal function impairment, bone fractures, digestive bacterial overgrowth, particularlyclostridium difficile infections, anemia and hypomagnesemia. Long term use can increase the risks of gastric, pancreatic and liver cancers. They decrease absorption of weak bases drugs, particularly tyrosine kinase inhibitors and capecitabine and are responsible for a poorer prognosis if taken concomitantly with erlotinib, gefitinib and pazopanib. Modification of cyclin dependent kinases is also possible as well as decrease of efficacy of immune check point inhibitors (microbiome modifications). Absoption and efficacy of capecitabine seem also poorer with negative prognosis effect on treatment of gastric and colon cancer. Their long term use, particularly in cancer patients, should probably be avoided.

[Status of non-steroidal anti-inflammatory drugs use in areas with a high incidence of upper gastrointestinal cancer in China: a multi-center cross-sectional survey].

Objective: To describe the status of non-steroidal anti-inflammatory drugs (NSAIDs) use in areas with a high incidence of upper gastrointestinal cancer in China. Methods: This study was based on the National Key Research and Development Program of "National Precision Medicine Cohort of Esophageal Cancer" and "Study on Identification and Prevention of High-risk Populations of Gastrointestinal Malignancies (Esophageal cancer, Gastric cancer and Colorectal cancer)" . From January 2017 to August 2018, 212 villages or communities with a high incidence of esophageal cancer or gastric cancer were selected from 12 regions in 6 provinces. A total of 35 910 residents aged between 40 and 69 years old who met the inclusion criteria and signed the informed consent were investigated and enrolled in this study. The use of NSAIDs, demographic characteristics, health-related habits, height, weight, and blood pressure were collected by the questionnaire and physical examination. The status of main NSAIDs (aspirin, acetaminophen and ibuprofen) use with the difference varying in genders, age groups and regions were analyzed by using χ(2) test and Cochran-Armitage trend analysis method. Results: Of 35 910 subjects, the mean age was (54.6±7.1) years old and males accounted for 43.42% (15 591). The overall prevalence of NSAIDs intake was 4.56% (1 638), but it significantly varied in different provinces (P<0.001). The overall prevalence of NSAIDs intake was 4.87% (1 750) in females, which was significantly higher than that in males 4.24% (1 524) (P<0.001). The prevalence of NSAIDs intake increased with age (P for trend <0.001). As the frequency of NSAIDs intake increased, the incidence of gastrointestinal symptoms, gastrointestinal ulcers and black stools increased (P for trend <0.05 for all). Conclusion: The use of NSAIDs is prevalent in some areas with a high incidence of upper gastrointestinal cancer in China. The increased use of NSAIDs may lead to more adverse effects related to the gastrointestinal tract.

The Comparison of the Plasma Levels of the Lead Element in Patients with Gastrointestinal Cancers and Healthy Individuals.

Back ground and Aim: Heavy metals are considered as risk factors in the development of some types of cancers. In this context, the lead (Pb) along with its biological impacts on the human body has raised significant concerns in public health. The aim of this study was to compare the plasma levels of the lead element in patients with gastrointestinal (GI) cancer and healthy subjects to examine whether this element has a role in the susceptibility of cancer. Methods: In a case-control study conducted between March 2016 to February 2017, the plasma levels of the lead were assessed. One-hundred patients with upper and lower GI cancers, as well as one-hundered healthy subjects who were age- and sex-matched participated in our study. A classic flame atomic absorption spectroscopy (FAAS) method was employed for the determination of the lead element in plasma levels of all subjects. Results: The mean age of patients was 53.8±10.6 years old. The patient group consisted of 51 male and 49 female patients. The results showed that the concentrations of Pb were lower than the defined toxic levels. The comparison of the mean levels of Pb between the case and control groups revealed that there was no statistically significant difference even when the gender, age, and history of smoking were included in the statistical analysis. Our findings showed that the concentration of Pb is significantly associated with the type of cancer (p<0.003) and the location of the tumor (whether upper or lower tract was affected) (p<0.003). Conclusion: Lead may contributes to the pathology and progression of GI cancers but we can not conclude that it involved in the causation or susceptibility of healthy individuals to develop GI cancer.

Bruton tyrosine kinase inhibitors for the treatment of mantle cell lymphoma: review of current evidence and future directions.

Mantle cell lymphoma (MCL) is a heterogeneous and uncommon non-Hodgkin lymphoma that affects predominantly older patients and often is associated with an aggressive clinical course. MCL relies upon B-cell receptor signaling through Bruton tyrosine kinase (BTK); therefore, the development of the BTK inhibitors ibrutinib and acalabrutinib represents a therapeutic breakthrough. In this review, we provide a summary of the efficacy and safety data from the landmark trials of single-agent ibrutinib and acalabrutinib that led to US Food and Drug Administration approval of these agents for patients with relapsed or refractory MCL. Toxicities of interest observed with ibrutinib include bleeding, atrial fibrillation, and increased risk for infection. The selectivity of acalabrutinib for BTK is greater than that of ibrutinib, which mitigates the risk for certain off-target toxicities, including atrial fibrillation; however, these toxicities, along with frequent headaches, still occur. Ongoing clinical trials are investigating both alternate BTK inhibitors and BTK inhibitors in combination with chemo-immunotherapy or other targeted agents in an effort to enhance the depth and duration of response. Trials to evaluate the use of these agents in the frontline setting are emerging and are likely to build upon the success of BTK inhibitors in patients with MCL.

Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden.

OBJECTIVES: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are potential candidates for chemoprevention of gastrointestinal cancer. We aimed to assess the association between contemporary NSAID use (≥180 days) and gastrointestinal cancer. DESIGN: Nationwide Swedish population-based cohort study (2005-2012). SETTING: Sweden PARTICIPANTS: All adults exposed to maintenance NSAIDs use (aspirin, n=783 870; unselective NSAIDs, n=566 209, selective cyclo-oxygenase (COX)-2 inhibitors, n=17 948) compared with the Swedish background population of the same age, sex and calendar period. OUTCOME MEASURES: The risk of different gastrointestinal cancer types expressed as standardised incidence ratios (SIR) and 95% CIs, taking into account concurrent proton pump inhibitors (PPIs) and statins usage. RESULTS: The SIR for gastrointestinal cancer for aspirin use was 1.02 (95% CI 1.00 to 1.04), with clearly reduced risk for long-term users (SIR=0.31, 95% CI 0.30 to 0.33 for 5.5-7.7 years), but an increased risk for short-term users (SIR=2.77, 95% CI 2.69 to 2.85), and stronger protective effect for low-dose aspirin (SIR=0.86, 95% CI 0.85 to 0.88). Users of non-selective NSAIDs showed an overall decreased risk of gastrointestinal cancer (SIR=0.79, 95% CI 0.77 to 0.82), in particular for cancer of the stomach, colorectum and oesophagus, and the SIRs were further decreased among long-term users. Users of selective COX-2 inhibitors showed a SIR=0.89 (95% CI 0.73 to 1.09) for gastrointestinal cancers. Both aspirin and unselective NSAIDs users who also were using PPIs, had higher risks for all gastrointestinal cancer types; and lower risk if using statins. CONCLUSION: Long-term use of (low-dose) aspirin and non-selective NSAIDs was associated with a decreased risk of all gastrointestinal cancer types.

Identification of risk factors in epidemiologic study based on ROC curve and network.

This article proposes a new non-parametric approach for identification of risk factors and their correlations in epidemiologic study, in which investigation data may have high variations because of individual differences or correlated risk factors. First, based on classification information of high or low disease incidence, we estimate Receptor Operating Characteristic (ROC) curve of each risk factor. Then, through the difference between ROC curve of each factor and diagonal, we evaluate and screen for the important risk factors. In addition, based on the difference of ROC curves corresponding to any pair of factors, we define a new type of correlation matrix to measure their correlations with disease, and then use this matrix as adjacency matrix to construct a network as a visualization tool for exploring the structure among factors, which can be used to direct further studies. Finally, these methods are applied to analysis on water pollutants and gastrointestinal tumor, and analysis on gene expression data in tumor and normal colon tissue samples.