Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in ...these genes are not well defined.
To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer.
Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123 136 individuals with exome sequence data in the public Genome Aggregation Database and 53 105 in the Exome Aggregation Consortium database.
Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer.
Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls.
Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 SD, 10.7 years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio OR, 12.33; 95% CI, 5.43-25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52-14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62-8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05).
In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.
Validation of a new coma scale: The FOUR score Wijdicks, Eelco F. M.; Bamlet, William R.; Maramattom, Boby V. ...
Annals of neurology,
October 2005, Letnik:
58, Številka:
4
Journal Article
Recenzirano
The Glasgow Coma Scale (GCS) has been widely adopted. Failure to assess the verbal score in intubated patients and the inability to test brainstem reflexes are shortcomings. We devised a new coma ...score, the FOUR (Full Outline of UnResponsiveness) score. It consists of four components (eye, motor, brainstem, and respiration), and each component has a maximal score of 4. We prospectively studied the FOUR score in 120 intensive care unit patients and compared it with the GCS score using neuroscience nurses, neurology residents, and neurointensivists. We found that the interrater reliability was excellent with the FOUR score (κw = 0.82) and good to excellent for physician rater pairs. The agreement among raters was similar with the GCS (κw = 0.82). Patients with the lowest GCS score could be further distinguished using the FOUR score. We conclude that the agreement among raters was good to excellent. The FOUR score provides greater neurological detail than the GCS, recognizes a locked‐in syndrome, and is superior to the GCS due to the availability of brainstem reflexes, breathing patterns, and the ability to recognize different stages of herniation. The probability of in‐hospital mortality was higher for the lowest total FOUR score when compared with the lowest total GCS score. Ann Neurol 2005;58:585–593
Background & Aims: Information on the clinical profile of pancreatic cancer (PaC) associated diabetes (DM) is limited. We compared the prevalence and clinical characteristics of DM in subjects with ...and without PaC. Methods: We prospectively recruited 512 newly diagnosed PaC cases and 933 controls of similar age, who completed demographic and clinical questionnaires and had fasting blood glucose (FBG) levels measured at recruitment and after pancreaticoduodenectomy (n = 105). Subjects with a FBG level >126 mg/dL or who were on antidiabetic treatment were classified as having DM. Results: DM was more prevalent (47% vs 7%; P < .001) and predominantly of new onset (<2-year duration) (74% vs 53%; P = .002) among cases compared with controls. Among PaC cases, those with DM (n = 243) were older (68 ± 10 vs 64 ± 12 years; P < .001), reported higher usual adult body mass index (30 ± 6 vs 27 ± 5 kg/m2 ; P < .001), and had a greater frequency of family history of DM (47% vs 31%; P < .001) compared with those without DM (n = 269). After pancreaticoduodenectomy, while DM resolved in 17 of 30 patients (57%) with new-onset DM, its prevalence was unchanged in patients with long-standing DM (n = 11) ( P = .009). Conclusions: PaC is a powerful diabetogenic state; DM associated with PaC is often new-onset, resolves following cancer resection, and appears to be associated with conventional risk factors for DM. New-onset DM in patients with PaC is likely induced by the tumor.
Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks ...that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-autonomous basal pre-inflammatory state in the pancreas of Nr5a2
mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2
mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.
Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model ...that recapitulated the progression of human PDAC, we identified secreted proteins and tested a subset as potential markers of PDAC. We optimized an enzyme-linked immunosorbent assay (ELISA) using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. A phase 1 discovery study (
= 20), a phase 2a validation study (
= 189), and a second phase 2b validation study (
= 537) revealed that concentrations of plasma thrombospondin-2 (THBS2) discriminated among all stages of PDAC consistently. The receiver operating characteristic (ROC) c-statistic was 0.76 in the phase 1 study, 0.84 in the phase 2a study, and 0.87 in the phase 2b study. The plasma concentration of THBS2 was able to discriminate resectable stage I cancer as readily as stage III/IV PDAC tumors. THBS2 plasma concentrations combined with those for CA19-9, a previously identified PDAC marker, yielded a c-statistic of 0.96 in the phase 2a study and 0.97 in the phase 2b study. THBS2 data improved the ability of CA19-9 to distinguish PDAC from pancreatitis. With a specificity of 98%, the combination of THBS2 and CA19-9 yielded a sensitivity of 87% for PDAC in the phase 2b study. A THBS2 and CA19-9 blood marker panel measured with a conventional ELISA may improve the detection of patients at high risk for PDAC.
Pancreatic adenocarcinoma (PaC) is one of most difficult tumors to treat. Much of this is attributed to the late diagnosis. To identify biomarkers for early detection, we examined DNA methylation ...differences in leukocyte DNA between PaC cases and controls in a two-phase study. In phase I, we measured methylation levels at 1,505 CpG sites in treatment-naïve leukocyte DNA from 132 never-smoker PaC patients and 60 never-smoker healthy controls. We found significant differences in 110 CpG sites (false discovery rate <0.05). In phase II, we tested and validated 88 of 96 phase I selected CpG sites in 240 PaC cases and 240 matched controls (p≤0.05). Using penalized logistic regression, we built a prediction model consisting of five CpG sites (IL10_P348, LCN2_P86, ZAP70_P220, AIM2_P624, TAL1_P817) that discriminated PaC patients from controls (C-statistic = 0.85 in phase I; 0.76 in phase II). Interestingly, one CpG site (LCN2_P86) alone could discriminate resectable patients from controls (C-statistic= 0.78 in phase I; 0.74 in phase II). We also performed methylation quantitative trait loci (methQTL) analysis and identified three CpG sites (AGXT_P180_F, ALOX12_E85_R, JAK3_P1075_R) where the methylation levels were significantly associated with single nucleotide polymorphisms (SNPs) (false discovery rate <0.05). Our results demonstrate that epigenetic variation in easily obtainable leukocyte DNA, manifested by reproducible methylation differences, may be used to detect PaC patients. The methylation differences at certain CpG sites are partially attributable to genetic variation. This study strongly supports future epigenome-wide association study using leukocyte DNA for biomarker discovery in human diseases.
Epidemiologic studies show strong associations between pancreatic cancer (PC) and inflammatory stimuli or conditions such as cigarette smoking and diabetes, suggesting that inflammation may play a ...key role in PC. Studies of dietary patterns and cancer outcomes also suggest that diet might influence an individual's risk of PC by modulating inflammation. We therefore examined independent and joint associations between inflammatory potential of diet, cigarette smoking and long-standing (≥5 years) type II diabetes in relation to risk of PC. Analyses included data from 817 cases and 1756 controls. Inflammatory potential of diet was measured using the dietary inflammatory index (DII), calculated from dietary intake assessed via a 144-item food frequency questionnaire, and adjusted for energy intake. Information on smoking and diabetes were obtained via risk factor questionnaires. Associations were examined using multivariable-adjusted logistic regression. Higher DII scores, reflecting a more proinflammatory diet, were associated with increased risk of PC odds ratio (OR)Quintile 5 versus 1 = 2.54, 95% confidence interval (CI) = 1.87-3.46, P trend < 0.0001. Excess risk of PC also was observed among former (OR = 1.29, 95% CI = 1.07-1.54) and current (OR = 3.40, 95% CI = 2.28-5.07) smokers compared with never smokers, and among participants with long-standing diabetes (OR = 3.09, 95% CI = 2.02-4.72) compared with nondiabetics. Joint associations were observed for the combined effects of having greater than median DII score, and being a current smoker (OR = 4.79, 95% CI = 3.00-7.65) or having long-standing diabetes (OR = 6.03, 95% CI = 3.41-10.85). These findings suggest that a proinflammatory diet may act as cofactor with cigarette smoking and diabetes to increase risk of PC beyond the risk of any of these factors alone.
A pilot study was conducted to longitudinally quantify effect of onabotulinum toxin A (BoNT-A) on passive muscle properties in children with cerebral palsy using ultrasound shear wave elastography.
...This was a prospective longitudinal cohort study.
Between 1 and 3 mos post-BoNT-A, a significant improvement in the shear modulus of the lateral gastrocnemius was found at 10-degrees plantar flexion (PF) (-7.57 -10.98, -5.07, P = 0.02) and 0-degrees PF (-14.74 -18.21, -9.38, P = 0.03). There was a notable, but nonsignificant, difference in shear modulus at 20-degrees PF, 10-degrees PF, and 0-degrees PF between pre-BoNT-A and 1 mo post-BoNT-A. Pre-BoNT-A shear modulus was not significantly different from 3 mos post-BoNT-A at all foot positions. No significant differences in ankle passive range of motion or spasticity were found.
Despite no significant change in ankle range of motion or spasticity, shear wave elastography was able to detect a difference in lateral gastrocnemius passive muscle properties in children with cerebral palsy after BoNT-A injections. The difference in passive muscle properties resolved by 3 mos post-BoNT-A.
Background and Aims Among the greatest hurdles to pancreatic cancer (PC) therapy is the limited tissue penetration of systemic chemotherapy because of tumor desmoplasia. The primary study aim was to ...determine the toxicity profile of EUS-guided fine-needle injection (EUS-FNI) with gemcitabine. Secondary endpoints included the ability to disease downstage leading to an R0 resection and overall survival (OS) at 6 months, 12 months, and 5 years after therapy. Methods In a prospective study from a tertiary referral center, gemcitabine (38 mg/mL) EUS-FNI was performed in patients with PC before conventional therapy. Initial and delayed adverse events (AEs) were assessed within 72 hours and 4 to 14 days after EUS-FNI, respectively. Patients were followed for ≥5 years or until death. Results Thirty-six patients with stage II (n = 3), stage III (n = 20), or stage IV (n = 13) disease underwent gemcitabine EUS-FNI with 2.5 mL (.7-7.0 mg) total volume of injectate per patient. There were no initial or delayed AEs reported. Thirty-five patients (97.2%) were deceased at the time of analysis with a median 10.3 months of follow-up (range, 3.1-63.9). OS at 6 months and 12 months was 78% and 44%, respectively. The median OS was 10.4 months (range, 2.7-68). Among patients with stage III unresectable disease, 4 (20%) were downstaged and underwent an R0 resection. Conclusions Our study suggests the feasibility, safety, and potential efficacy of gemcitabine EUS-FNI for PC. Additional data are needed to verify these observations and to determine the potential role relative to conventional multimodality therapy.
The prevalence of germline pathogenic mutations in a comprehensive panel of cancer predisposition genes is not well-defined for patients with pancreatic ductal adenocarcinoma (PDAC). To estimate the ...frequency of mutations in a panel of 22 cancer predisposition genes, 96 patients unselected for a family history of cancer who were recruited to the Mayo Clinic Pancreatic Cancer patient registry over a 12-month period were screened by next-generation sequencing. Fourteen pathogenic mutations in 13 patients (13.5%) were identified in eight genes: four in ATM, two in BRCA2, CHEK2, and MSH6, and one in BARD1, BRCA1, FANCM, and NBN. These included nine mutations (9.4%) in established pancreatic cancer genes. Three mutations were found in patients with a first-degree relative with PDAC, and 10 mutations were found in patients with first- or second-degree relatives with breast, pancreas, colorectal, ovarian, or endometrial cancers. These results suggest that a substantial proportion of patients with PDAC carry germline mutations in predisposition genes associated with other cancers and that a better understanding of pancreatic cancer risk will depend on evaluation of families with broad constellations of tumors. These findings highlight the need for recommendations governing germline gene-panel testing of patients with pancreatic cancer.
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