• Pancreatic Cancer Organoids Successfully Created Ex Vivo
• Rise in Marijuana-Associated Emergency Care Visits for Adolescents in Colorado
• E-Cigarette Use Leads to Traditional Cigarette Use in Adolescents
• Gabapentinoid Use Has More Than Tripled in the U.S. Since 2002
• What Effect Does Diet Have on Disability in MS?
• Are Spinal Cord Lesions a Poor Prognostic Indicator in Multiple Sclerosis?
• Siponimod for Secondary Progressive Multiple Sclerosis
• Does High Red and Processed Meat Consumption Contribute to Nonalcoholic
Fatty Liver Disease?
• High Diet Quality Matters for Fatty Liver Disease
Gastrointest Endosc 2018 Jan 8
Pancreatic Cancer Organoids Successfully Created Ex Vivo
Tissue acquired with endoscopic ultrasound–guided fine-needle biopsy was used to grow organoids successfully in two thirds of pancreatic tumors sampled.
Blood and tissue samples are now being used to identify specific treatment regimens to treat various cancers. One approach is growing organoids, macroscopic organ-like structures, from a microscopic sample of a tumor. Organoids can be used to study a patient's tumor, including parenchymal and stromal elements, then be used as a “test bed” to help identify tumor- and patient-specific treatments via ex vivo testing. Growing organoids from pancreatic cancers sampled via endoscopic ultrasound (EUS) has been shown to be feasible.
In the current prospective pilot study, researchers evaluated the rate of successful isolation of organoids within 2 weeks of acquiring pancreatic ductal adenocarcinoma tumor tissue. Among 37 patients, 38 pancreatic adenocarcinoma tumors were diagnosed as malignant via fine-needle aspiration, and tissue collection for organoid development was performed via fine-needle biopsy (FNB). Organoid isolation was confirmed by organoid morphology and positive genotyping.
Successful isolation of organoids was achieved in 87% of tumors and creation of pancreatic ductal adenocarcinoma organoid lines in 66%.
COMMENT: These findings illustrate several important points. First, although only 66% of samples developed into organoids, this is still a remarkable percentage when one considers the high degree of desmoplasia and necrosis contained in many pancreatic cancers. Second, this is a very good example of a true translational research project in endoscopy, as it uses EUS to obtain tissue that is rapidly processed in a laboratory to create organoids. Finally, because EUS FNB can reach structures in the chest, abdomen, and pelvis, the techniques demonstrated here could potentially be used to create organoids from a wide range of tumors and treat a broad array of cancer patients.
CITATION(S): Tiriac H et al. Successful creation of pancreatic cancer organoids by means of EUS-guided fine-needle biopsy for personalized cancer treatment. Gastrointest Endosc 2018 Jan 8; [e-pub].
(http://dx.doi.org/10.1016/j.gie.2017.12.032)
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J Adolesc Health 2018 Mar 30
Rise in Marijuana-Associated Emergency Care Visits for Adolescents in Colorado
Between 2009 and 2015, rates for these types of visits increased significantly.
Nationally, marijuana-related emergency department (ED) visits among 15- to 17-year-olds increased between 2005 and 2011 (https://www.cdc.gov/nchs/data/nhcs/ED_Substance_Abuse_Factsheet.PDF). To determine if this trend was apparent in Colorado, which commercialized medical and recreational marijuana use in 2009 and 2014, respectively, investigators reviewed all marijuana-associated ED and urgent care (UC) visits to a Colorado children's hospital by patients aged 13 to 21. Marijuana-related visits were defined as those with an International Classification of Diseases 9/10 code for marijuana/cannabis use or a positive urine toxicology screen for tetrahydrocannabinol.
From 2005 to 2015, 4202 marijuana-related visits occurred (median patient age, 16; 54% male). The annual number of such visits increased from 161 in 2005 to 777 in 2015; from 2009 to 2015, the rate of such visits increased significantly from 1.8 to 4.9 per 1000 ED/UC visits. Marijuana-related behavioral health evaluations were obtained in 67% of visits overall; rates of these evaluations more than doubled from 2009 to 2015, from 1.2 to 3.2 per 1000 ED visits.
COMMENT: The authors state that there were no changes in their ED/UC protocols that would account for these increases, but it is possible that the increasing commercialization of marijuana use since 2009 has made adolescents feel more comfortable disclosing their marijuana use. Even so, the nationwide increase in marijuana-related ED visits coupled with the 2017 Monitoring the Future Survey data demonstrating a significant increase in marijuana use among adolescents argue for ongoing careful monitoring locally and nationally of the impact of marijuana decriminalization/legalization on adolescent health outcomes. Almost 70% of the adolescents in the study required a behavioral health consultation; it is critical that such youth be linked back to their primary care pediatricians for comprehensive follow-up care.
CITATION(S): Wang GS et al. Impact of marijuana legalization in Colorado on adolescent emergency and urgent care visits. J Adolesc Health 2018 Mar 30; [e-pub].
(https://doi.org/10.1016/j.jadohealth.2017.12.010)
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Pediatrics 2017 Dec 4
E-Cigarette Use Leads to Traditional Cigarette Use in Adolescents
Users of e-cigarettes were seven times more likely than nonusers to smoke conventional cigarettes in the future.
E-cigarettes have been heavily marketed to youth in the U.S., and there is concern that e-cigarette use is associated with future use of traditional cigarettes.
To examine this association, researchers repeatedly surveyed public high school students in Connecticut over a 3-year period (2013–2015) about their past-month use of e-cigarettes and conventional cigarettes. Using survey data from roughly 800 students (88% white), the investigators designed a model to analyze bidirectional relationships between e-cigarette and traditional cigarette use. They found that e-cigarette use in each of the survey years predicted traditional cigarette use in subsequent surveys. For example, compared with students who did not use e-cigarettes, students who reported e-cigarette use were seven times more likely to report use of traditional cigarettes in subsequent surveys. However, the reverse was not true: traditional cigarette use did not lead to e-cigarette use.
COMMENT: In the past, e-cigarettes were marketed as being safer than traditional cigarettes and a pathway to quitting smoking. As a result, many U.S. youth perceive e-cigarettes as less harmful and less addictive than traditional cigarettes. This well-designed longitudinal study proves that the perception of “safer” is false. Avoiding initial exposure to nicotine — one of the most addicting substances — in any form is the key message we should deliver to our adolescent patients. E-cigarettes should be closely regulated by the FDA and state and local governments to prevent their use by youth.
CITATION(S): Bold KW et al. Trajectories of e-cigarette and conventional cigarette use among youth. Pediatrics 2017 Dec 4; [e-pub].
(http://dx.doi.org/10.1542/peds.2017-1832)
Amrock SM et al. Perceptions of e-cigarettes and noncigarette tobacco products among US youth. Pediatrics 2016 Nov; 138:e20154306.
(http://dx.doi.org/10.1542/peds.2015-4306)
Klein JD. E-cigarettes: A 1-way street to traditional smoking and nicotine addiction for youth. Pediatrics 2017 Dec 4; [e-pub].
(http://dx.doi.org/10.1542/peds.2017-2850)
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JAMA Intern Med 2018 Jan 2
Gabapentinoid Use Has More Than Tripled in the U.S. Since 2002
Much of the increased use is in patients who also are using opioids and benzodiazepines for chronic conditions.
Gabapentin and pregabalin are approved for treating patients with several specific neurological and neuropathic conditions (e.g., gabapentin and pregabalin for partial seizures and postherpetic neuralgia; pregabalin for diabetic peripheral neuropathy and fibromyalgia). Off-label use of these gabapentinoids has risen markedly, with unclear benefit (N Engl J Med 2017; 377:411). In this study, a national health and medical care survey database was used to examine chronic conditions and prescription medication use in about 350,000 community-living adults from 2002 through 2015.
The proportion of participants who used gabapentinoids rose from 1.2% in 2002 to 3.9% in 2015. Increases in use occurred mostly after 2008 and were attributable mainly to gabapentin. Use increased among diabetics and older participants (age, ≥65), but it rose even more in patients with five or more chronic conditions and in those who reported more than two opioid prescriptions, particularly those who also reported at least one benzodiazepine prescription. In 2014 through 2015, 11% of participants reported more than two opioid prescriptions or at least one benzodiazepine prescription and accounted for 53% of gabapentinoid users.
COMMENT: These data suggest — although they don't prove — that much of the marked increase in gabapentinoid use is associated with chronic pain related to conditions for which these drugs are not FDA-approved. We have no evidence of benefits for gabapentinoid use in patients with most chronic pain conditions (e.g., back pain), and some potential exists for drug–drug interactions with opioids and benzodiazepines.
CITATION(S): Johansen ME. Gabapentinoid use in the United States 2002 through 2015. JAMA Intern Med 2018 Jan 2; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2017.7856)
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Neurology 2018 Jan 2; 90:e1
What Effect Does Diet Have on Disability in MS?
Poor diet is associated with worse outcomes in multiple sclerosis.
NARCOMS is an online, patient-generated registry with multiple questionnaires for patients self-reported as diagnosed with multiple sclerosis (MS). Investigators used the dietary screener questionnaire to understand associations between diet and MS symptoms and disability. Overall diets were scored based on consumption of fruits, vegetables, legumes, whole grains, sugars, and meats. Patients also reported whether they followed one of 19 diets advocated for use in MS. Lifestyle components included low body-mass index (BMI), routine physical exercise, and smoking status.
Included were 6989 patients who completed the requisite surveys. Patients in the lowest (worst) quintile for diet quality were more likely to be smokers, have lower income, and have higher BMI. Patients in the highest (best) quintile for diet score were at 20% lower odds of higher disability score compared with those in the lowest quintile. Special diets, like Wahls or gluten-free, were associated with higher disability, likely owing to confounding by preferential use in progressive MS. Those with better diet scores were less likely than those with the worst scores to have severe depression (hazard ratio, 0.82). Those with an overall healthy lifestyle had less depression, fatigue, and cognitive symptoms. Diet quality was not associated with recent relapses.
COMMENT: Patients with MS should follow a healthy lifestyle, defined by eating fruits and vegetables, whole grains, and dairy; limiting sugar and red and processed meats; not smoking; exercising regularly; and avoiding obesity. Diet quality scores in quintiles 2 through 5 appeared generally similarly beneficial compared with the lowest quintile. Because the study was not randomized, we can say there is an association but not causation (e.g., more-disabled patients might eat poorly because of lack of access to good grocery stores). This article supports eating healthy foods and using moderation in consuming less-healthy options. Patients typically want recommendations on diet and MS; this study provides evidence that diet is associated with disability, but extreme diets may not be warranted.
CITATION(S): Fitzgerald KC et al. Diet quality is associated with disability and symptom severity in multiple sclerosis. Neurology 2018 Jan 2; 90:e1.
(http://dx.doi.org/10.1212/WNL.0000000000004768)
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Mult Scler 2018 Apr; 24:481
Are Spinal Cord Lesions a Poor Prognostic Indicator in Multiple Sclerosis?
Results suggesting no relationship contrast with prior literature.
Several studies have demonstrated greater disability at follow-up for patients with clinically isolated syndromes suggestive of increased multiple sclerosis (MS) risk who present with asymptomatic spinal cord lesions during their first demyelinating event (NEJM JW Neurol Oct 2016 and Mult Scler 2016; 23:665). In the present study, investigators recruited 178 patients within 12 months after first MS symptoms — 84 patients with symptomatic spinal cord lesions, 42 patients with asymptomatic spinal cord lesions, and 52 without spinal cord lesions.
Follow-up lasted at least 24 months (median, 6 years). Overall, 39.3% reached Expanded Disability Status Scale (EDSS) score 3 (moderate disability), 6.2% reached EDSS 6.0 (needing a cane to ambulate), 22% had worsening on the 25-foot timed walk, and 13% had worsening on the 9-hole peg test. Patients with asymptomatic spinal cord lesions did not differ from those with no spinal cord lesions in time to each of the disability measures but showed a trend toward shorter time to a second event. Also, no difference in any disability outcome at follow-up was observed between those with or without spinal cord lesions, regardless of whether the lesions were symptomatic or not.
COMMENT: The presence of spinal cord lesions is often regarded as a poor prognostic marker. However, this study did not find such as association. The precise reasons for the discrepancy remain unclear. Perhaps this cohort had a more favorable overall prognosis, follow-up was not long enough, or treatment altered the natural history. On balance, the presence of spinal cord lesions may be a mild prognostic indicator with much heterogeneity. Symptomatic or asymptomatic spinal cord lesions should not be an absolute indicator of a concerning prognosis, but one factor to consider among many.
CITATION(S): Dekker I et al. Asymptomatic spinal cord lesions do not predict the time to disability in patients with early multiple sclerosis. Mult Scler 2018 Apr; 24:481.
(https://doi.org/10.1177/1352458517736147)
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Lancet 2018 Mar 31; 391:1263
Siponimod for Secondary Progressive Multiple Sclerosis
Is siponimod an effective and safe drug for the treatment of patients with secondary progressive multiple sclerosis?
Secondary progressive multiple sclerosis (SPMS) is an MS subtype characterized by worsening of disability that begins insidiously in patients with preceding relapsing-remitting (RR) course, which is the most common mode of onset. The risk for and timing of transition from RRMS to SPMS is unpredictable; however, up to 90% of RRMS may evolve to SPMS over a 25-year time interval. Several disease-modifying therapies have shown efficacy in reducing relapses and disease activity in RRMS, but most of these have failed to prevent disease worsening in progressive MS.
This multicenter, randomized, double-blind, placebo-controlled, manufacturer-funded phase 3 study was done at almost 300 hospital clinics and specialized MS centers in 31 countries. Researchers randomized 1651 patients with a diagnosis of SPMS to the investigational drug siponimod (1105 patients) or placebo (546 patients). Of these, 1327 (80%) completed the study (82% on siponimod vs. 78% on placebo). Median time on study was 21 months and median exposure to the drug was 18 months. Three-month confirmed disability progression, the primary outcome, occurred in 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo, a significant difference (hazard ratio, 0.79; relative risk reduction, 21%). Adverse events were reported in more siponimod than placebo recipients (89% of 1099 patients vs. 82% of 546 patients), including adverse events described previously with other sphingosine-1-phophate receptor modulators (e.g., bradycardia, hypertension, varicella zoster reactivation) and more serious adverse events (18% vs. 15%). Frequencies of infections, malignancies, and mortality were the same in both treatment groups.
COMMENT: In this study, siponimod reduced the risk for disability progression in a large population of patients, many of whom entered the study having already reached the nonrelapsing stage of SPMS with a high level of established disability. Although siponimod also had a good safety profile, other studies must be carried out to confirm that this drug could be an option in the treatment of SPMS.
CITATION(S): Kappos L et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomised, phase 3 study. Lancet 2018 Mar 31; 391:1263.
(https://doi.org/10.1016/S0140-6736(18)30475-6)
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J Hepatol 2018 Mar 19;
Does High Red and Processed Meat Consumption Contribute to Nonalcoholic Fatty Liver Disease?
A positive dose–response relationship was evident in a cross-sectional study.
Obesity, insulin resistance, and genetic factors are implicated in the development of nonalcoholic fatty liver disease (NAFLD). Studies have observed an association between eating red and processed meats and risk for type 2 diabetes. To evaluate whether consumption of these meats is also linked with developing NAFLD, as well as insulin resistance, researchers in Israel conducted a cross-sectional study among nearly 800 patients undergoing screening colonoscopy.
Participants underwent fasting blood tests and liver ultrasound and completed a detailed dietary history using a food frequency questionnaire during a single-day visit. Insulin resistance was calculated using the homeostasis model assessment.
After adjusting for physical activity, body-mass index, smoking, alcohol, and fat and cholesterol intake, high intake of red meat, processed meat, or both was significantly associated with higher odds of NAFLD and insulin resistance (odds ratio, 1.47; 95% confidence interval, 1.04–2.09 and OR, 1.55; 95% CI, 1.07–2.23, respectively). Dose–response associations were observed in multivariate analyses.
COMMENT: Although a causal relationship cannot be established in this cross-sectional study, the observed dose–response relationship strengthens its likelihood. The findings are also consistent with a recent publication noting the association between eating a higher-quality diet and lower incidence of fatty liver disease (NEJM JW Gastroenterol Apr 11 2018; [e-pub] and Gastroenterology 2018 Mar 28; [e-pub].). Eliciting a detailed dietary intake history and subsequent counseling should be a key part of NAFLD management in clinical practice.
CITATION(S): Zelber-Sagi S et al. High red and processed meat consumption is associated with non-alcoholic fatty liver disease and insulin resistance. J Hepatol 2018 Mar 19; [e-pub].
(https://doi.org/10.1016/j.jhep.2018.01.015)
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Gastroenterology 2018 Mar 28
High Diet Quality Matters for Fatty Liver Disease
Longitudinal data suggest that clinicians should advise their patients with NAFLD not just to lose weight but to eat healthier foods.
Several studies show that weight loss through dietary changes improves nonalcoholic fatty liver disease (NAFLD). However, it is unknown if improving the quality of dietary intake improves fatty liver. To investigate this issue, researchers analyzed data from over 1500 middle-aged and older participants of an ongoing, long-term cohort study.
Responses to a validated food frequency questionnaire were used to determine dietary intake during the year before liver fat measurements. Liver fat was assessed using computed tomography and represented by the liver phantom ratio (LPR), which is inversely related to liver fat content. The two diet scores used were Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI). The primary outcome was the change in LPR score between baseline and follow-up assessments.
During a median follow-up of 6 years, mean body-mass index increased by 0.7 kg/m2, mean waist circumference increased by 3.1 cm, and mean LPR decreased by 1.1. Increasing MDS and AHEI scores (indicating a healthier diet) from baseline to follow-up were each significantly associated with reduced fat accumulation after adjusting for covariates. The odds for incident fatty liver decreased by 26% and 21% with each 1-standard-deviation increase in MDS and AHEI scores, respectively.
COMMENT: In this longitudinal cohort study, improved diet quality was associated with reduced fat accumulation in the liver in middle-aged to older adults. Diets scoring high on the MDS and AHEI are marked by higher consumption of fruits and vegetables and lower consumption of red meats and trans fats. As clinicians, we should not only be advising our patients with NAFLD to lose weight, but also to eat higher-quality diets.
Note to readers: At the time we reviewed this paper, its publisher noted that it was not in final form and that subsequent changes might be made.
CITATION(S): Ma J et al. Improved diet quality associates with reduction in liver fat — particularly in individuals with high genetic risk scores for nonalcoholic fatty liver disease. Gastroenterology 2018 Mar 28; [e-pub].
(https://doi.org/10.1053/j.gastro.2018.03.038)
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