Characteristics and clinical outcomes in young-onset cholangiocarcinoma.

BACKGROUND: While the incidence of cholangiocarcinoma is rising, little is known about young-onset disease. We compared clinical characteristics and outcomes between patients with young-onset cholangiocarcinoma, diagnosed between the ages of 18 and <50 years, and patients with typical-onset cholangiocarcinoma, diagnosed at age 50 years or greater. METHODS: We used the National Cancer Database to identify patients with young-onset cholangiocarcinoma (n = 2520) and typical-onset cholangiocarcinoma (n = 23,826). We compared the frequency of demographic and clinical characteristics between the two groups. We compared overall survival between the two groups using multivariable Cox regression analysis after adjusting for age, gender, race/ethnicity, comorbidity, facility type, tumor location, tumor stage, surgical status, and receipt of radiotherapy, chemotherapy and surgery. RESULTS: When compared to patients with typical-onset disease (median age 68 years), patients with young-onset cholangiocarcinoma (median age 44 years) were more likely to be non-White (35.0% vs. 27.4%, p < 0.01), and had lower overall comorbidity burden. Patients with young-onset disease had a greater proportion of intrahepatic cholangiocarcinoma (56.0% vs. 45.5%, p < 0.001) and stage IV disease (50.5% vs. 43.5%, p < 0.001). Younger patients were more likely than typical-onset patients to receive definitive surgery (30.9% vs. 25.0%, p < 0.001), radiation (27.7% vs. 19.6%, p < 0.001) and chemotherapy (73.1% vs. 50.1%, p < 0.001). In adjusted analyses, patients with young-onset disease had a 15% decreased risk of death, compared with patients with typical-onset disease (HR 0.85 [95% CI 0.80-0.89], p < 0.001). CONCLUSIONS: Patients with young-onset cholangiocarcinoma may represent a demographically and clinically distinct group from those with more typical-onset disease.

Immune Checkpoint Inhibitors in pMMR/MSS Colorectal Cancer.

BACKGROUND: Immune checkpoint inhibitors have recently replaced over chemotherapy as the first-line treatment for microsatellite instability-high or mismatch repair deficient (dMMR/MSI-H) stage 4 colorectal cancers. Considering this success, many studies have tried to replicate the use of immune checkpoint inhibitors, either as a single agent or in combination with other therapeutic agents, in the treatment of proficient mismatch repair (pMMR/MSS) stage 4 colorectal cancers. This review summarizes the seminal clinical data about the immune checkpoint inhibitors used in pMMR/MSS colorectal cancers and some future directions. RESULTS: Studies concerning the use of immune checkpoint inhibitors as a single agent or in combination with other immune checkpoint inhibitors, targeted therapy, chemotherapy, or radiotherapy have proven inefficient in the treatment of pMMR/MSS colorectal cancer. However, a small subset of patients with pMMR/MSS colorectal cancer who has a mutation in POLE and POLD1 enzymes may respond to immunotherapy. Moreover, patients without liver metastasis appear to have a better chance of response. New immune checkpoint targets are being identified, such as VISTA, TIGIT, LAG3, STING signal pathway, and BTLA, and studies are ongoing to determine their efficiency in this disease type. CONCLUSION: Immune checkpoint inhibitor-based regimens have not yet shown any meaningful positive outcomes for most pMMR/MSS colorectal cancers. A beneficial effect among a minority of these patients has been observed, but concrete biomarkers of response are lacking. Understanding the underlying mechanisms of immune resistance should guide further research for overcoming these obstacles.

Multicenter Randomized Clinical Trial of a Mailed Outreach Strategy for Hepatocellular Carcinoma Surveillance.

BACKGROUND: The effectiveness of hepatocellular carcinoma (HCC) surveillance is mitigated by underuse in clinical practice, highlighting a need for interventions. We evaluated the effectiveness of mailed HCC surveillance outreach to promote HCC surveillance in patients with cirrhosis. METHODS: We conducted a multicenter pragmatic randomized clinical trial comparing mailed outreach for surveillance ultrasound (n = 1436) and usual care with visit-based surveillance (n = 1436) among patients with cirrhosis at 3 health systems (tertiary care referral center, safety net health system, and Veterans Affairs medical center) from April 2018 to December 2019. The primary outcome of this interim analysis was guideline concordant semiannual HCC surveillance over a 12-month period and a secondary outcome was proportion time covered by surveillance. All patients were included in intention-to-screen analyses. RESULTS: Compared with usual care, the outreach arm had significantly higher semiannual surveillance (35.1% vs 21.9%) and lower no-surveillance (29.8% vs 43.5%) (P < .001), resulting in significant increases in the proportion of time covered by surveillance (41.3% vs 31.0%; P < .001). The intervention increased HCC surveillance across most predefined subgroups; however, there were site-level differences in the intervention effect, with significant increases in semiannual surveillance at the Veterans Affairs and safety net health systems but not at the tertiary care referral center. CONCLUSIONS: Mailed outreach significantly increased semiannual HCC surveillance vs usual care in patients with cirrhosis, with a consistent intervention effect across most examined subgroups. Continued follow-up is ongoing to determine if these increases in surveillance translate into improved downstream outcomes includi.ng early HCC detection and curative treatment receipt. (ClinicalTrials.gov, Numbers: NCT02582918 and NCT03756051).

Development and Validation of HSCAPS-1: A Clinical Decision Support Tool for Diagnosis of Hidradenitis Suppurativa over Cutaneous Abscess.

BACKGROUND: A clinical decision support tool may improve recognition of hidradenitis suppurativa (HS) and reduce diagnosis delay. OBJECTIVE: To develop and initially validate a clinical decision support to predict diagnosis of HS and distinguish it from cutaneous abscess of the axilla, groin, perineum, and buttock. METHODS: This was a retrospective, cross-sectional analysis between January 2012 and June 2017 (development set) and July 2017 and March 2019 (validation set). We used an electronic records sample of 56 million patients from the Explorys database to identify patients with an ambulatory visit associated with either HS or cutaneous of the axilla, groin, perineum, and buttock. The outcome was predicted probability of HS diagnosis. RESULTS: Development set included 7,974 patients with mean age of 41.4 years, who were predominantly female (66%) and white (62%). Validation set included 1,560 patients with similar demographic composition. Factors which were stronger independent predictors of HS included female sex (OR 2.17 [95% CI 1.96-2.40]); African American race (1.28 [95% CI 1.15-1.44]); increasing BMI (OR 1.05 [95% CI 1.05-1.06)]; history of acne (OR 3.46 [95% CI 2.83-4.23]); Down syndrome (OR 5.35 [95% CI 2.03-14.12]); and prescription for at least 7 opioid medications in the past year (OR 1.05 [95% CI 0.83-1.33]). Up to age 45 years, increasing age was a stronger predictor of HS diagnosis. The simplified model showed good discrimination (c-statistic 0.746 [SE 0.013]) and moderate calibration (calibration intercept -0.260 [SE 0.055]; calibration slope 1.142 [SE 0.076]). CONCLUSION: This clinical decision support tool shows good performance in predicting diagnosis of HS and distinguishing it from cutaneous abscess that involves the axilla, groin, perineum, and buttock.

Women's higher brain metabolic rate compensates for early Alzheimer's pathology.

INTRODUCTION: The female advantage in brain metabolic function may confer cognitive resilience against Alzheimer's disease (AD). METHODS: A total of 1259 participants (44% women; 52% mild cognitive impairment; 18% AD) aged 55 to 90 from the Alzheimer's Disease Neuroimaging Initiative (ANDI) completed tests of global cognition, verbal memory, and executive function, and neuroimaging assessments of regional glucose metabolism, hippocampal volume (HV), and amyloid beta (Aß). We examined sex differences in brain metabolism and cognition by AD biomarker quartiles (Aß, HV). We then examined if metabolism mediates sex differences in cognition. RESULTS: Metabolism was higher in women versus men when pathology was mild-to-moderate (quartiles 2 to 3). Women outperformed men on all cognitive outcomes at ≥1 biomarker quartile, reflecting minimal-to-moderate pathology; however, these differences were eliminated/attenuated after adjusting for metabolism. The female advantage in verbal memory was also observed at minimal pathology quartiles but was unchanged after metabolism adjustment. DISCUSSION: Women's greater brain metabolism may confer cognitive resilience against early AD.

Incidence of Myocardial Infarction and Cerebrovascular Accident in Patients With Hidradenitis Suppurativa.

Importance: Although hidradenitis suppurativa (HS) is associated with several cardiovascular risk mediators, information on the risk of myocardial infarction (MI) and cerebrovascular accident (CVA) in this population is sparse. Objective: To compare risk of MI, CVA, and composite disease (MI or CVA) in patients with HS, stratified by use of biologic agents, with controls without HS. Design, Setting, and Participants: A retrospective cohort analysis was conducted between January 1, 1999, and April 1, 2019, using a demographically heterogeneous population-based sample of over 56 million unique patients. Individuals with HS (n = 49 862) and without HS (n = 1 421 223) were identified using electronic health records data. Main Outcomes and Measures: The primary outcome was incidence of composite MI or CVA. Results: Of the 49 862 patients with HS, 37 981 were women (76.2%), 29 711 were white (59.6%), and mean (SD) age was 38.3 (13.3) years. Crude incidence rate of composite disease was 6.6 (95% CI, 6.3-7.0) per 1000 person-years in patients with HS compared with 6.8 (95% CI, 6.7-6.8) per 1000 person-years in controls. In patients with HS, crude incidence rates were 2.9 (95% CI, 2.6-3.1) per 1000 person-years for MI alone and 4.1 (95% CI, 3.9-4.4) per 1000 person-years for CVA alone compared with 3.2 (95% CI, 3.18-3.25) per 1000 person-years for MI alone in control patients and 4.1 (95% CI, 4.0-4.1) per 1000 person-years for CVA alone in control patients. In adjusted analysis, patients with HS had a 23% increased risk of composite disease (hazard ratio [HR], 1.23; 95% CI, 1.17-1.30; P < .001) and a similar increase in the risk of MI alone (HR, 1.21; 95% CI, 1.12-1.32; P < .001) and CVA alone (HR, 1.22; 95% CI, 1.14-1.31; P < .001) compared with control patients. The relative difference in composite MI or CVA risk between patients with HS and controls was highest among younger patients HR in subgroup aged 18-29 years: 1.67; 95% CI, 1.37-2.03). Conclusions and Relevance: Patients with HS appear to have an increased risk of MI and CVA. Early management of modifiable cardiovascular risk mediators may be warranted in patients with HS.

Incidence of Long-term Opioid Use Among Opioid-Naive Patients With Hidradenitis Suppurativa in the United States.

IMPORTANCE: Risk of long-term opioid use among patients with hidradenitis suppurativa (HS), who experience pain that substantially impairs quality of life, is unknown to date. OBJECTIVE: To compare overall and subgroup incidence of long-term opioid use in a population of opioid-naive patients with HS and control patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was based on a demographically heterogeneous population-based sample of more than 56 million unique patients from January 1, 2008, through December 10, 2018. Patients with HS (n = 22 277) and controls (n = 828 832) were identified using electronic health records data. Data were analyzed from December 13, 2018, through January 28, 2019. MAIN OUTCOMES AND MEASURES: The primary outcome was incident long-term opioid use. RESULTS: Among the 22 277 patients with HS, mean (SD) age was 40.8 (14.6) years, 16 912 (75.9%) were women, and 13 190 (59.2%) were white. Crude 1-year incidence of long-term opioid use among opioid-naive patients with HS was 0.33% (74 of 22 277), compared with 0.14% (1168 of 828 832) among controls (P < .001). In adjusted analysis, patients with HS had 1.53 (95% CI, 1.20-1.95; P < .001) times the odds of new long-term opioid use compared with controls. Among patients with HS, advancing age (odds ratio [OR], 1.02 per 1-year increase; 95% CI, 1.00-1.03; P = .05), ever smoking (OR, 3.64; 95% CI, 2.06-6.41; P < .001), history of depression (OR, 1.97; 95% CI, 1.21-3.19; P = .006), and baseline Charlson comorbidity index score (OR, 1.15 per 1-point increase; 95% CI, 1.03-1.29; P = .01) were associated with higher odds of long-term opioid use. Among patients with HS and long-term opioid use, 4 of 74 (5.4%) were diagnosed with opioid use disorder during the study period. The most frequent schedule II opioid prescriptions included oxycodone hydrochloride (55 of 74 patients [74.3%]), hydrocodone bitartrate (44 [59.5%]), hydromorphone hydrochloride (16 [21.6%]), morphine sulfate (13 [17.6%]), and fentanyl citrate (6 [8.1%]). Tramadol hydrochloride (32 [43.2%]) represented the most frequent non-schedule II prescription. Disciplines prescribing the most opioids to patients with HS included primary care (398 [72.8%]), anesthesiology/pain management (48 [8.8%]), gastroenterology (25 [4.6%]), surgery (23 [4.2%]), and emergency medicine (10 [1.8%]). CONCLUSIONS AND RELEVANCE: In this study, patients with HS were at higher risk for long-term opioid use. These results suggest that periodic assessment of pain and screening for long-term opioid use may be warranted, particularly among patients who are older, who smoke tobacco, or who have depression and other medical comorbidities.

All-cause mortality among patients with hidradenitis suppurativa: A population-based cohort study in the United States.

BACKGROUND: The mortality risk for patients with hidradenitis suppurativa (HS) is largely unknown. OBJECTIVE: To compare mortality risk among individuals with and without HS in the United States. METHODS: Retrospective cohort study in a population sample identified by using electronic health records data between January 1, 2012, and December 31, 2016. Primary outcome was incidence of 5-year all-cause mortality. RESULTS: The crude 5-year mortality rate among patients with HS was 2.4% (321/13 289), compared with 2.7% (18 508/685 573) among control individuals. In the fully adjusted model, the increase in HS mortality risk was 14% (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.01-1.28). Overall, excess risk of death attributable to HS was 3.1 deaths per 1000 patients (95% CI, 0.2-6.0) during the study period. Characteristics associated with mortality among patients with HS included age (OR, 1.05; 95% CI, 1.04-1.06), male sex (OR, 1.40; 95% CI, 1.09-1.79), ever-smoking status (OR, 1.48; 95% CI, 1.16-1.92), and Charlson Comorbidity Index score (OR, 1.25; 95% CI, 1.21-1.29). LIMITATIONS: The follow-up period may not have been long enough to assess the influence of disease severity or duration on mortality. CONCLUSION: HS appears to confer an independent risk of all-cause mortality. This risk is also influenced by tobacco smoking and comorbidities, which may be modifiable.

Comparative Overall Comorbidity Burden Among Patients With Hidradenitis Suppurativa.

Importance: The overall comorbidity burden among patients with hidradenitis suppurativa (HS) has not been systematically evaluated. Objectives: To investigate the standardized overall comorbidity burden among patients with HS and to compare it with the comorbidity burden in patients with psoriasis and a control group. Design, Setting, and Participants: A cross-sectional analysis was conducted of 5306 patients with HS, 14 037 patients with psoriasis, and 1 733 810 controls identified using electronic health records data from October 1, 2013, through October 1, 2018. Main Outcome and Measure: The primary outcome was the mean Charlson Comorbidity Index (CCI) score. Results: Each matched cohort had 3818 patients (2789 women and 1029 men; mean [SD] age, 45.7 [15.0]). Before matching, the overall mean (SD) CCI score was highest among the psoriasis cohort (2.33 [3.13]), followed by the HS cohort (1.80 [2.79]) and control cohort (1.26 [2.35]). In matched analyses, the overall mean (SD) CCI score was highest among the HS cohort (1.95 [2.96]), followed by the psoriasis cohort (1.47 [2.43]; P < .001) and control cohort (0.95 [1.99]; P < .001) patients. A total of 516 patients with HS (13.5%) had an overall mean CCI score of 5 or greater. Mean CCI score was highest for patients with HS across all sex, race, and age groups. The most common comorbidities among patients with HS were chronic pulmonary disease (1540 [40.3%]), diabetes with chronic complications (365 [9.6%]), diabetes without chronic complications (927 [24.3%]), and mild liver disease (455 [11.9%]). Patients with HS with a CCI score of 5 or greater had 4.97 (95% CI, 1.49-16.63) times the adjusted risk of 5-year mortality compared with patients with HS with a CCI score of zero. Conclusions and Relevance: Patients with HS have a higher overall comorbidity burden compared with patients with psoriasis and a control group. A significant proportion of patients with HS have CCI scores of 5 or greater, which are associated with increased mortality. This degree of comorbidity burden may warrant multidisciplinary implementation of routine screening measures.

Proposal to characterise legacy Sellafield ponds using SONAR and RadLine™.

Sellafield Nuclear Reprocessing Plant in Cumbria contains storage ponds built in the 1950s which was originally intended to hold spent nuclear fuel for reprocessing, and eventual production of weapons grade plutonium. Parts of the spent fuel have corroded; some are buried under a layer of sediment or intertwined with other debris and removal and destruction of this nuclear waste is not a trivial task due to elevated radiation levels. We propose a system in collaboration with the National Nuclear Laboratory (NNL) to characterise the ponds using a system containing three main parts; an ultrasonic SONAR system used to physically map the pond, scintillator based radiation detector (known as RadLine™) used to map the pond from a radiation point of view, and bespoke software intended to combine the physical and radiation plots of this environment to create an overall 3D source map.

Serum concentration of an inflammatory glycotoxin, methylglyoxal, is associated with increased cognitive decline in elderly individuals.

BACKGROUND: Advanced glycations end products increase oxidant stress, inflammation, and neurotoxicity. Serum levels are increased in diabetes and aging. We examined the relationship between serum methylglyoxal derivatives (sMG), and cognitive decline, in 267 non-demented elderly. METHODS: Tobit mixed regression models assessed the association of baseline sMG with cognitive decline in the Mini Mental State Exam (MMSE) over time, controlling for sociodemographic factors (age, sex, and years of education), cardiovascular risk factors (diabetes and presence of an ApoE4 allele), and kidney function. sMG was assessed by ELISA. RESULTS: The fully adjusted model showed an annual decline of 0.26 MMSE points per unit increase in baseline sMG (p = 0.03). Significance was unchanged as additional risk factors were added to the model. The interactions of sMG with diabetes, sex, age, kidney function, and ApoE4 genotype were not significant. CONCLUSIONS: Higher levels of baseline sMG were associated with a faster rate of cognitive decline, after adjusting for several sociodemographic and clinical characteristics. This relationship did not differ by sex, ApoE4 genotype, or diabetes status suggesting its generality. Since subjects were cognitively normal at the beginning of the study, elevated sMG may be indicative of brain cell injury initiated before clinically evident cognitive compromise.