The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
ObjectiveGut microbiota influence metabolic pathways related to the pathogenesis of obesity, insulin-resistance and diabetes. Antibiotic therapy can alter the microbiota, and is commonly used in ...western countries. We sought to evaluate whether past antibiotic exposure increases diabetes risk.Research design and methodsWe conducted a nested case–control study using a large population-based database from the UK. The cases were defined as those with incident diagnosis of diabetes. For every case, four eligible controls matched on age, sex, practice-site, and duration of follow-up before index-date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy >1 year before index-date. Odds ratios (ORs) and 95% CIs were estimated using conditional logistic regression. The risk was adjusted for BMI, smoking, last glucose level, and number of infections before index-date, as well as past medical history of coronary artery disease and hyperlipidaemia.ResultsThe study included 208 002 diabetic cases and 815 576 matched controls. Exposure to a single antibiotic prescription was not associated with higher adjusted diabetes risk. Treatment with two to five antibiotic courses was associated with increase in diabetic risk for penicillin, cephalosporins, macrolides and quinolones with adjusted OR ranging from 1.08 (95% CI 1.05–1.11) for penicillin to 1.15 (95% CI 1.08–1.23) for quinolones. The risk increased with the number of antibiotic courses and reached 1.37 (95% CI 1.19–1.58) for more than 5 courses of quinolones. There was no association between exposure to anti-virals and anti-fungals and diabetes risk.ConclusionsExposure to certain antibiotic groups increases diabetes risk.
Background
Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are an essential therapeutic option in the management of various solid tumors, particularly renal cell ...carcinoma (RCC). However, post-marketing data regarding their potential cardiovascular toxicities are scant.
Objective
To identify and characterize cardiovascular adverse events (CVAEs) of VEGFR-TKIs indicated for RCC.
Patients and Methods
Disproportionality analysis of the US Food and Drug Administration adverse event reporting system (July 2014–December 2019) using the reporting odds ratio (ROR) and the lower bound of the Information component (IC) 95% credibility interval (IC
025
> 0 is significant).
Results
We identified 51,836 adverse event reports of sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib in the full database 36% women; median age 65 years (range 57–73). CVAEs accounted for 11,784 (23%) of the reports, with hypertension
n
= 5548 (11%), ROR = 6.55 (95% CI 6.37–6.74), IC
025
= 2.48 and hemorrhages
n
= 3710 (7.2%), ROR = 1.28 (1.24–1.32), IC
025
= 0.28 being the most frequent types. Additional CVAEs were over-reported with VEGFR-TKIs treatment, including aortic dissection
n
= 61 (0.1%), ROR = 3.50 (2.71–4.51), pericardial diseases
n
= 173 (0.3%), ROR = 1.98 (1.70–2.30), cardiomyopathy
n
= 61 (0.1%), ROR = 1.89 (1.47–2.43), heart failure
n
= 868 (1.7%), ROR = 1.35 (1.26–1.44), and venous thromboembolism
n
= 604 (1.2%), ROR = 1.33 (1.23–1.45), all IC
025
> 0. The major pericardial disorder was non-malignant pericardial effusion
n
= 134 (77%). Aortic dissections were also over-reported in patients without concomitant elevated blood pressure ROR = 2.68 (1.97–3.63), IC
025
= 0.91. Finally, CVAEs were reported more often following lenvatinib and sunitinib treatment compared to other VEGFR-TKIs.
Conclusions
In post-marketing surveillance data, VEGFR-TKIs are associated with increased reporting of various CVAEs, including pericardial diseases, particularly non-malignant pericardial effusion, and aortic dissections. Moreover, VEGFR-TKIs differ in their CVAE reporting patterns. Clinicians should be conscious of these findings in the care of VEGFR-TKIs recipients.
Graphic Abstract
Cardiovascular toxicities of VEGFR-TKIs in the FDA adverse events reporting system (FAERS) database. Post-marketing data of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-associated cardiovascular toxicities are scant. We identified 51,836 safety reports of VEGFR-TKIs (sunitinib, pazopanib, axitinib, cabozantinib, and lenvatinib) in the FAERS database, including 11,784 (23%) cardiovascular adverse events (CVAEs). Hypertension, aortic dissections, and pericardial diseases had the highest reporting odds ratios. While the association of VEGFR-TKIs with hypertension is well established, pericardial diseases were not observed to date, and aortic dissection was reported in a small case series.
Abstract
In the Tinea Capitis Study (Israel, 1966–2011), we assessed the association between childhood exposure to low to moderate doses of ionizing radiation (IR) to the head and neck and the ...development of vascular diseases (ischemic heart disease, carotid artery stenosis, and stroke) in adulthood. The study included 17,734 individuals from the Tinea Capitis cohort (7,408 irradiated in childhood and 10,326 nonirradiated), insured by Israel’s largest health provider. Individual dosimetry was estimated based on measurements made on a head phantom and original treatment records. The mean doses were 1.5, 0.09, 0.78, and 0.017 Gy to brain, thyroid, salivary gland, and breast, respectively. Data on vascular diseases was abstracted from computerized medical records. Using Poisson regressions, we examined the association of radiation with morbidity. Any vascular disease was reported for 2,221 individuals. Adjusted for age, sex, socioeconomic status, smoking, hypertension, and diabetes, exposure to IR increased the risk of developing any vascular diseases (relative risk (RR) = 1.19, 95% confidence interval (CI): 1.09, 1.29), stroke (RR = 1.35, 1.20, 1.53), carotid artery stenosis (RR = 1.32, 1.06, 1.64), and ischemic heart disease (RR = 1.12, 1.01, 1.26). The risk of developing vascular diseases was positively associated with dose and inversely associated with age at exposure. In conclusion, the results indicate that early exposure to low to moderate doses of IR increases the risk of cerebro- and cardiovascular impairments.
Current screening guidelines for colorectal cancer (CRC) do not consider thyroid dysfunction as a risk factor for disease development. We sought to determine the risk of developing CRC in patients ...with thyroid dysfunction, with and without thyroid hormone replacement (THR).
We conducted a nested case-control study using a large population-based medical records database from the United Kingdom. Study case patients were defined as those with any medical code of CRC. Subjects with familial colorectal cancer syndromes or inflammatory bowel disease (IBD) were excluded. For every case patient, four eligible control patients matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence density sampling. Exposure was THR therapy before index date. We further divided the THR unexposed group into patients with hypothyroidism (TSH > 4 mg/dl), patients with hyperthyroidism (TSH < 0.4 mg/dl), and subjects without documented thyroid abnormality. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for CRC were estimated using conditional logistic regression. All statistical tests were two-sided.
We identified 20990 CRC patients and 82054 control patients. The adjusted odds ratio for CRC associated with THR was 0.88 (95% CI = 0.79 to 0.99, P = .03) and 0.68 (95% CI = 0.55 to 0.83, P < .001) for treatment initiated five to 10 years and more than 10 years before index date, respectively. This protective association increased with cumulative duration of therapy. In contrast, hyperthyroidism (adjusted OR = 1.21, 95% CI = 1.08 to 1.36, P = .001) or untreated hypothyroidism (adjusted OR = 1.16, 95% CI = 1.08 to 1.24, P < .001) were associated with increased risk of CRC.
Long-term THR is associated with a decreased risk of CRC. Hyperthyroidism and untreated hypothyroidism are associated with modestly elevated risk of CRC.
Current guidelines recommend that clinically staged T1N0 esophageal cancers are to be referred to surgery or endoscopic resection. Using the National Cancer Database, we identified 733 individuals ...with clinically staged T1N0 esophageal carcinoma, who underwent upfront surgery and did not receive any prior treatment. We assessed upstaging, which was defined as ≥ T2 disease or positive lymph nodes. Poorly differentiated adenocarcinomas were associated with upstaging, whereas squamous cell carcinomas were not. Specifically, the percentage of upstaging among individuals with clinically staged T1b and poorly differentiated tumor was 33.8%. Therefore, clinically staged T1bN0 poorly differentiated esophageal adenocarcinomas are at high risk for upstaging following surgery.
Highlights • Hypergastrinemia is mechanistically linked to pancreatic cancer risk. • Proton pump inhibitors (PPIs) cause hypergastrinemia. • PPIs may be associated with an increased risk of ...pancreatic cancer. • PPI use is not associated with survival in pancreatic cancer patients. • PPIs should be prescribed judiciously but not withheld in patients with pancreatic cancer.
Purpose
Digoxin affects several cellular pathways involved in tumorigenesis. We sought to determine the association between digoxin use and pancreatic cancer risk and survival.
Methods
A nested ...case–control study using The Health Improvement Network (THIN), a population-representative database from the United Kingdom (UK). Cases included all individuals with incident diagnosis of pancreatic cancer. Each case was matched to up to four controls using incidence density sampling based on age, sex, practice site, calendar time, and duration of follow-up. Exposure of interest was digoxin therapy before cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between digoxin use and pancreatic cancer risk were estimated using conditional logistic regression. We further conducted a retrospective cohort study among pancreatic cancer cases using Cox regression model in order to evaluate the association between digoxin use and overall survival.
Results
We identified 4,113 cases with incident pancreatic cancer and 16,072 matched controls. The adjusted OR for diagnosis of pancreatic cancer among active digoxin users was 1.41 (95% CI 1.16–1.72). The risk did not change among active users with duration of therapy of more than 1 year (adjusted OR of 1.39, 95% CI 1.11–1.76). Digoxin was not associated with change in overall survival with an adjusted hazard ratio of 0.97 (95% CI 0.81–1.18).
Conclusions
Digoxin use was associated with modestly increased pancreatic cancer risk but did not affect overall survival.
Several prior studies have found an association between statin use and reduced risk of colorectal cancer. We hypothesized that these findings may be due to systematic bias and examined the ...independent association of colorectal cancer risk with statin use, serum cholesterol, and change in cholesterol concentration.
22,163 colorectal cancer cases and 86,538 matched controls between 1995 and 2013 were identified within The Health Improvement Network (THIN) a population-representative database. Conditional logistic regression models estimated colorectal cancer risk with statin use, serum total cholesterol (mmol/L), and change in total cholesterol level. We confirmed a decreased risk of colorectal cancer with statin use (long-term: odds ratio OR, 0.95; 95% confidence interval CI, 0.91-0.99; short-term: OR, 0.92; 95% CI, 0.85-0.99). However, to assess whether the observed association may result from indication bias, a subgroup analysis was conducted among patients prescribed a statin. In this subgroup (n = 5,102 cases, n = 19,032 controls), 3.1% of case subjects and 3.1% of controls discontinued therapy. The risk of colorectal cancer was not significantly different among those who continued statin therapy and those who discontinued (OR, 0.98; 95% CI, 0.79-1.22). Increased serum cholesterol was independently associated with decreased risk of colorectal cancer (OR, 0.89 per mmol/L increase; 95% CI, 0.87-0.91); the association was only present if serum cholesterol was measured near the cancer diagnosis (<6 mo: OR, 0.76; 95% CI, 0.47-0.61; >24 mo: OR, 0.98; 95% CI, 0.93-1.03). Decreases in serum total cholesterol >1 mmol/L ≥1 year prior to cancer diagnosis were associated with subsequent colorectal cancer (statin users: OR, 1.25; 95 CI%, 1.03-1.53; nonusers: OR, 2.36; 95 CI%, 1.78-3.12). As an observational study, limitations included incomplete data and residual confounding.
Although the risk of colorectal cancer was lower in statin users versus nonusers, no difference was observed among those who continued versus discontinued statin therapy, suggesting the potential for indication bias. The association between decreased serum cholesterol and colorectal cancer risk suggests a cholesterol-lowering effect of undiagnosed malignancy. Clinical judgment should be used when considering causes of cholesterol reduction in patients, including those on statin therapy.
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