• Gastric Cancer Risk from PPI Use After Eradication of Helicobacter pylori
• Gut Microbiome Affects Response to Checkpoint Inhibitors
• Preserving Ovarian Function in Young Women with Breast Cancer
• Cord Clamping for Preterm Infants: Is the Wait Over?
• Allergic Disease and Sleep-Disordered Breathing are Associated with
Childhood Nocturnal Enuresis
• Preteen and Teenage Suicide Attempts: Characteristics and Sequelae
• Treatment to Lower BP Is Associated with Lower Mortality and Cardiovascular Risk
When Systolic BP Is ≥140 mm Hg
• Supplemental Oxygen is Associated with Excess Risk for Recurrent Myocardial Infarction
• Can Daily Skin Patches Help People with Peanut Allergies?
• Vaginal Seeding — Unproven Benefits, Potential Risks
• Dietary Pesticide Exposure may Hinder Women's Reproductive Potential
Gut 2017 Oct 31
Gastric Cancer Risk from PPI Use After Eradication of Helicobacter pylori
A positive association is observed between regular proton-pump inhibitor use and gastric cancer in a retrospective study in Hong Kong.
Helicobacter pylori infection is associated with atrophic gastritis, which can progress to gastric cancer in some patients. Proton-pump inhibitor (PPI) use has also been associated with atrophic gastritis in some studies. In the current retrospective cohort study, investigators evaluated the association between PPI use and gastric cancer in over 60,000 patients treated with clarithromycin-based triple therapy for H. pylori infection in Hong Kong. Approximately 5% of patients were prescribed PPIs after H. pylori therapy (median duration of PPI use, 3 years). Results were as follows:
- During a median follow-up of 8 years, gastric cancer incidence was 0.2%.
- A higher percentage of patients on chronic PPI therapy (weekly use or more) developed gastric cancer compared with non–PPI users (adjusted hazard ratio, 2.4).
- Increasing dose and duration of therapy were associated with greater risks for gastric cancer (adjusted HR, 4.6 for daily use and 8.3 for daily use for ≥3 years).
- Histamine-2 receptor antagonist use was not associated with gastric cancer.
COMMENT: The potential for a causal relationship between PPIs and gastric cancer is supported in this study by multiple sensitivity analyses and the observed dose-response relationship. However, the results should still be interpreted with caution because of the potential for residual confounding inherent in database studies. Also, despite the study's exclusion of patients with PPI use within 6 months of cancer diagnosis, PPI use could still possibly represent treatment of early gastric cancer symptoms more than 6 months prior to diagnosis. Undetected H. pylori treatment failure could also cause symptoms that might be treated with PPIs in patients predisposed to cancer. Finally, these results may not be generalizable beyond the population of China, where risk for gastric cancer is high.
CITATION(S): Cheung KS et al. Long-term proton pump inhibitors and risk of gastric cancer development after treatment for Helicobacter pylori: A population-based study. Gut 2017 Oct 31; [e-pub].
(http://dx.doi.org/10.1136/gutjnl-2017-314605)
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Science 2017 Nov 2
Gut Microbiome Affects Response to Checkpoint Inhibitors
Patients with certain types of cancers are more likely to respond to therapy if their gut microbiomes are diverse.
Immune checkpoint–inhibitor (ICI) drugs (such as pembrolizumab [Keytruda] and nivolumab [Opdivo]) help as many as 40% of patients with melanoma, non–small cell lung cancer (NSCLC), or renal cell carcinoma that is unresponsive to more traditional therapies. During the past 2 years, studies of mice with malignancies have suggested that the composition of the gut microbiome might affect which cancer patients will respond to ICI drugs.
Two multicenter groups now report results from hundreds of human cancer patients (with melanoma and several epithelial tumors) who are being treated with ICI drugs. Having a less-diverse gut bacterial population (i.e., fewer bacterial genes) correlated with poorer response to ICI drugs, after adjustment for confounding factors. Often, this reduced diversity was caused by antibiotic treatments that had been given to patients for routine intercurrent illnesses during ICI therapy. An abundance of particular bacterial families and genera was associated with a good response.
Could such associations indicate causality? Mice with malignancies that respond to ICI drugs were given fecal transplants either from human responders or from human nonresponders to ICI drugs. Mice treated with fecal transplants from human responders responded to ICI drugs, whereas mice treated with fecal transplants from human nonresponders did not. The investigators also identified the specific immune system changes that were provoked by such microbiome-altering treatments — changes that improved the immune attack on tumors.
COMMENT: These studies suggest that the human gut microbiome might affect the response to ICI drugs profoundly. That hypothesis can be proven only by controlled trials of therapies that alter the gut microbiome in patients undergoing ICI therapy.
CITATION(S): Gopalakrishnan V et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science 2017 Nov 2; [e-pub].
(http://dx.doi.org/10.1126/science.aan4236)
Routy B et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 2017 Nov 2; [e-pub].
(http://dx.doi.org/10.1126/science.aan3706)
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Ann Oncol 2017 Aug 1; 28:1811
Preserving Ovarian Function in Young Women with Breast Cancer
The gonadotropin-releasing hormone agonist goserelin reduced the risk for chemotherapy-induced ovarian insufficiency in premenopausal women with early-stage disease.
Balancing strategies to reduce the risk for disease recurrence while optimizing fertility preservation is a critical tension when caring for young women with early-stage breast cancer. To determine whether the use of the gonadotropin-releasing hormone agonist goserelin reduces the risk for chemotherapy-induced premature ovarian insufficiency (POI) in women with early breast cancer, investigators conducted a prospective, randomized study (OPTION) of 202 premenopausal patients (median age, 38 years) with stage I–III disease (about 44% estrogen receptor positive) receiving neoadjuvant or adjuvant chemotherapy.
Patients received six to eight cycles of cyclophosphamide, an anthracycline, or both, with or without a taxane. In addition, they were randomized to receive goserelin (starting 1–2 weeks prior to chemotherapy and continued every 3–4 weeks until chemotherapy was complete) or nothing (control group). Hormone levels were checked after cycle 3, after the final cycle, at 9 months, at 12 months, and annually thereafter. The primary endpoint was the rate of amenorrhea, defined as no menses between 12 and 24 months following randomization along with an elevated level of follicle stimulating hormone (FSH).
The rate of amenorrhea between 12 and 24 months was lower in the goserelin group than in the control group (22% vs. 38%; P=0.015), as were FSH levels at 12 months (P=0.027) and 24 months (P=0.001). The prevalence of POI was also lower with goserelin (18.5% vs. 34.8%; P=0.048), especially in women 40 or younger.
COMMENT: These results suggest that the rate of POI can be reduced in young women receiving adjuvant chemotherapy for breast cancer. Less clear is the effect of goserelin on follicle reserve and on the ability of women to get pregnant following chemotherapy. Nevertheless, this approach should be discussed with young breast cancer patients planning to receive adjuvant chemotherapy.
CITATION(S): Leonard RCF et al. GnRH agonist for protection against ovarian toxicity during chemotherapy for early breast cancer: The Anglo Celtic Group OPTION trial. Ann Oncol 2017 Aug 1; 28:1811.
(http://dx.doi.org/10.1093/annonc/mdx184)
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N Engl J Med 2017 Oct 29
Cord Clamping for Preterm Infants: Is the Wait Over?
Delayed umbilical cord clamping did not confer benefit for infants born at <30 weeks' gestation.
Throughout the modern era, recommendations about timing of umbilical cord clamping in both term and preterm infants have varied and evolved. Current professional recommendations advocate delayed cord clamping (variably defined) for infants born preterm, provided that immediate resuscitation is not required. Australian researchers evaluated the benefit of this practice in a randomized, controlled trial involving 1566 fetuses born before 30 weeks.
In all, 782 infants were assigned to immediate cord clamping (≤10 seconds) and 784 to delayed clamping (≥60 seconds). The primary outcome of infant death or major morbidity at 36 weeks did not differ between groups (37% in each group). While fewer babies in the delayed clamping group died by 36 weeks, the between-group difference was not significant after multiple comparisons were taken into account. Notably, 26% of infants assigned to delayed clamping actually had their cords clamped before 60 seconds.
COMMENT: Despite recent recommendations, these results suggest that delayed cord clamping is neither harmful nor beneficial for preventing major morbidities or death in preterm infants. The finding of fewer deaths among fetuses assigned to the delayed group warrants further study; although no single investigation will be large enough to demonstrate a difference in this outcome, I agree with the authors that meta-analysis is advisable. For now, I will continue to offer and inform parents of the recommendation of groups such as the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics to delay cord clamping for 30 to 60 seconds in term and preterm fetuses alike when feasible, in addition to advocating for interventions such as skin-to-skin contact and breast-feeding.
CITATION(S): Tarnow-Mordi W et al. Delayed versus immediate cord clamping in preterm infants. N Engl J Med 2017 Oct 29; [e-pub].
(http://dx.doi.org/10.1056/NEJMoa1711281)
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Pediatr Nephrol 2017 Dec; 32:2293
Allergic Disease and Sleep-Disordered Breathing are Associated with Childhood Nocturnal Enuresis
In Taiwanese children aged 5 to 12 years, allergic disorders and obstructive sleep apnea were associated with higher likelihood of having nocturnal enuresis.
Nocturnal enuresis is a common pediatric condition that is likely multifactorial in etiology. Allergic disorders and asthma, as well as sleep disorders, have been purported to be among the etiologies.
To investigate these possible causes further, researchers in Taiwan retrospectively analyzed nationwide health insurance data to compare the prevalences of these conditions between 4300 children aged 5 to 18 years with nocturnal enuresis (cases) and 4300 age- and sex-matched children without nocturnal enuresis (controls). Allergic diseases included asthma, allergic rhinitis, atopic dermatitis, and allergic conjunctivitis. Sleep-disordered breathing included snoring and obstructive sleep apnea (OSA). Results were as follows:
- The prevalences of allergic disorders and sleep-disordered breathing were significantly higher among children with nocturnal enuresis compared with controls.
- Asthma was the only allergic disorder not associated with increased odds of nocturnal enuresis.
- OSA but not snoring was associated with nocturnal enuresis.
- The odds of nocturnal enuresis were highest in children with both allergic disorders and sleep-disordered breathing.
- The positive associations of allergic disorders and sleep-disordered breathing with enuresis were limited to children aged 5 to 12 years old.
- Among boys, conditions positively associated with nocturnal enuresis were limited to allergic rhinitis and OSA.
- The odds of nocturnal enuresis increased with the number of allergic disorders present.
COMMENT: Though intriguing, these observed associations do not establish causation. The retrospective and limited investigation into the diagnoses is a weakness of the study. It would be interesting to see if treatment for allergic disorders and OSA might ameliorate nocturnal enuresis, but that will require prospective evaluation.
CITATION(S): Tsai J-D et al. Association between allergic disease, sleep-disordered breathing, and childhood nocturnal enuresis: A population-based case-control study. Pediatr Nephrol 2017 Dec; 32:2293.
(http://dx.doi.org/10.1007/s00467-017-3750-0)
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BMJ 2017 Oct 18; 359:j4351
Preteen and Teenage Suicide Attempts: Characteristics and Sequelae
During long-term follow-up, having a self-harm history increased the risk 18-fold for dying by suicide and 34-fold for having fatal alcohol or drug overdoses.
Suicide attempts have been increasing in adults (NEJM JW Psychiatry Dec 2017 and JAMA Psychiatry 2017; 74:1095), and rates of completed suicide after self-harm are markedly high (NEJM JW Psychiatry May 2017 and Am J Psychiatry 2017; 174:765). Less is known about self-harm in preteen and teenage populations. Using a national, demographically representative database of 647 U.K. practices, investigators examined self-harm episodes in 16,912 patients aged 10 to 19 (73% girls) from 2001 to 2014.
Types of self-harm included overdose (84%), other poisoning (3%), hanging or suffocating (1%), and self-cutting (12%). It is unknown whether the self-cutting cases were potentially lethal. At 1 year after the incident, 22% of self-harmers had a repeat episode.
Records of about 50% of these patients were matched to hospitalization and mortality records. Over follow-up, self-harmers compared with 170,274 patients without self-harm were 9 times more likely to die from unnatural causes, 18 times more likely to die by suicide and 34 times more likely to die from alcohol or drug intoxication. Annual rates of self-harm were 37.4/10,000 in girls versus 12.3/100,000 in boys. From 2011 to 2014, the rate increased by 68% among girls aged 13 to 16.
COMMENT: These data, and those on young children (NEJM JW Psychiatry Dec 2016 and Pediatrics 2016; 138:e20160436), debunk the myth that childhood is an age of innocence. Rather, these dire outcomes are similar to those seen in adults. Because of the widespread shortage of child psychiatrists, other physicians typically see teenage suicidal patients. All caretakers of preteens and teenagers need to inquire about suicidal ideation and attempts. A self-harm incident should be treated as a potentially lethal illness requiring intensive intervention, and not as an en passant teenage “phase.”
CITATION(S): Morgan C et al. Incidence, clinical management, and mortality risk following self harm among children and adolescents: Cohort study in primary care. BMJ 2017 Oct 18; 359:j4351.
(http://dx.doi.org/10.1136/bmj.j4351)
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JAMA Intern Med 2017 Nov 13
Treatment to Lower BP Is Associated with Lower Mortality and Cardiovascular Risk When Systolic BP Is ≥140 mm Hg
Initiating treatment at lower systolic blood pressure levels might be justified in patients with known CV disease.
High blood pressure (BP), particularly high systolic BP, is the strongest predictor of cardiovascular (CV)-related mortality, but the systolic BP level at which BP-lowering treatment should be initiated is somewhat controversial. In this meta-analysis, researchers examined data from 74 mostly industry-funded randomized trials in which pharmacologic treatment was compared with placebo, or different BP goals were compared with each other. Analysis involved about 306,000 participants and 1.2 million person-years of follow-up. Two thirds of the trials were classified as primary prevention (i.e., <50% of participants had known CV disease).
For primary prevention in patients with baseline systolic BPs of 140 to 159 mm Hg, treatment was associated with relative risk reductions of 13% for all-cause death and 12% for adverse CV events (i.e., CV-related mortality, major CV events, coronary heart disease, stroke, heart failure, and end-stage renal disease). Corresponding relative risk reductions in patients with baseline systolic BPs of ≥160 mm Hg were 7% and 22%. Treatment did not lower risk for either all-cause death or adverse CV events when baseline systolic BPs were <140 mm Hg. For secondary prevention, treatment in those with baseline systolic BPs <140 mm Hg was associated with lower risk for major adverse CV events but not all-cause or CV-related death.
COMMENT: The new hypertension guideline from the American College of Cardiology, the American Heart Association, and other societies recommends drug therapy for selected patients with no history of CV disease whose baseline systolic BPs are 130 to 139 mm Hg — lower than the traditional threshold of 140 mm Hg (NEJM JW Gen Med Dec 15 2017 and J Am Coll Cardiol 2017 Nov 13; [e-pub]). However, this meta-analysis does not support that recommendation: In primary prevention populations, treating patients whose systolic BPs were <140 mm Hg did not improve their CV outcomes.
CITATION(S): Brunström M and Carlberg B.Association of blood pressure lowering with mortality and cardiovascular disease across blood pressure levels: A systematic review and meta-analysis. JAMA Intern Med 2017 Nov 13; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2017.6015)
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Int J Nurs Stud 2017 Sep; 74:8
Supplemental Oxygen Is Associated with Excess Risk for
Recurrent Myocardial Infarction
A meta-analysis suggests we limit supplemental oxygen for nonhypoxemic patients with MI.
Although oxygen has been used for more than a century to treat patients with myocardial infarction (MI), its benefits and risks have come into question recently. For this systematic review and meta-analysis, investigators culled relevant medical literature through 2016 to identify five randomized controlled trials (RCTs) in which the safety and efficacy of oxygen therapy, compared with no oxygen therapy, was evaluated in 921 adults with MI.
Rate of recurrent MI was significantly higher in patients who received oxygen therapy than in those who did not (5.6% vs. 0.7%; number needed to harm, 20). No differences were found between groups in short-term mortality (3.5% vs. 3.4%) or rates of arrhythmia (36% vs. 31%) or chest pain (83% vs. 86%). The follow-up interval for these endpoints was 6 months.
COMMENT: Although this meta-analysis did not include recent data from a large RCT in which oxygen therapy showed no benefit over ambient air in 6000 patients with suspected MI (NEJM JW Hosp Med Oct 2017 and N Engl J Med 2017; 377:1240), adding up all of the trial data still leaves oxygen therapy with, at best, providing no benefit in nonhypoxemic patients with MI and, at worst, conferring excess risk for adverse outcomes in this patient population. It's time that we stop the free flow of oxygen to our patients when it's not absolutely needed.
CITATION(S): Fu S et al. Oxygen therapy for acute myocardial infarction: A systematic review and meta-analysis. Int J Nurs Stud 2017 Sep; 74:8. (http://dx.doi.org/10.1016/j.ijnurstu.2017.04.005)
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JAMA 2017 Nov 14; 318:1798
Can Daily Skin Patches Help People with Peanut Allergies?
They appear to increase peanut tolerance, but only in children.
Peanut allergy is the most common cause of severe food-induced anaphylaxis in the U.S. Currently approved treatment consists of avoidance and self-injectable epinephrine, but studies of oral, sublingual, and epicutaneous peanut immunotherapy are promising.
In an industry-sponsored phase IIb trial, 221 peanut-allergic patients (age range, 6−55) were randomized to one of three doses of an epicutaneous peanut-protein patch or placebo applied daily. At 12 months, 50% of patients who received the highest-dose patch (250 µg) were treatment responders (defined as a ≥10-fold increase in tolerated oral peanut challenge dose or ability to tolerate ≥1000 mg of peanuts [roughly 4−5 peanuts]), compared with 25% of placebo recipients. When results were analyzed by age group, difference in response between patients who received active treatment or placebo was significant only in children (age, 6−11 years). Adverse events were limited to frequent but mild skin irritation.
COMMENT: Epicutaneous peanut immunotherapy is an attractive concept, because it confers fewer side effects than oral immunotherapy. However, this study was disappointing in that the patch did not meet the 30% assumed response rate over placebo, and its benefit was limited to younger children. A phase III study of the 250-µg patch in children only is planned; if these results are duplicated, this patch might give parents peace of mind about accidental exposures that otherwise could cause life-threatening anaphylaxis.
CITATION(S): Sampson HA et al. Effect of varying doses of epicutaneous immunotherapy vs placebo on reaction to peanut protein exposure among patients with peanut sensitivity: A randomized clinical trial. JAMA 2017 Nov 14; 318:1798.
(http://dx.doi.org/10.1001/jama.2017.16591)
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Obstet Gynecol 2017 Nov; 130:e274
Vaginal Seeding — Unproven Benefits, Potential Risks
ACOG advises that vaginal seeding should be done only within a research protocol.
Some data suggest cesarean delivery is associated with increased risk for asthma and other allergic disorders, possibly because the infant's gastrointestinal tract is initially colonized with microflora from maternal skin and the environment rather than from the maternal gut as occurs in infants delivered vaginally. While these discrepancies in neonatal gut microbiome are present soon after birth, they disappear within 6 months. In one study, vaginal seeding was performed in 4 infants within 2 minutes of cesarean birth: A swab inoculated with maternal vaginal secretions was wiped across the infant's mouth, face, and skin. The gut microbiome resembled that of infants delivered vaginally. Notably, mothers were negative for group B streptococci and had vaginal pH <4.5, consistent with optimal vaginal flora.
Given the sparse evidence for the safety and efficacy of vaginal seeding — and no evidence for improved long-term outcomes — the American College of Obstetricians and Gynecologists' (ACOG's) view is to avoid this practice outside of a clinical research protocol. Women who insist on vaginal seeding should be free of chlamydial, gonococcal, and group B strep infection and should undergo serologic testing for herpes simplex virus (HSV); they should be informed of the risks, and the infant's healthcare provider should be alerted.
COMMENT: The impetus for vaginal seeding originated in assumptions (propagated by the lay press) that vaginal flora constitutes the normal colonizing microbiome and therefore must be healthy. I agree with ACOG that supporting data are insufficient; still, I am concerned that women may go ahead without informing their clinicians if they think the interest in vaginal seeding is being disregarded. Women who are interested in this practice are likely to be engaged in their prenatal care and to have been tested for sexually transmitted diseases and group B strep. I'm not sure that HSV serologies are informative, as most will be positive for HSV-1, HSV-2, or both, and the consequences are manifested only if genital HSV shedding during delivery occurs. As HSV infection occurs via mucosa or broken skin, limiting the seeding procedure to wiping the infant's skin (avoiding the mouth and other mucous membranes) might represent a reasonable compromise for women who insist on this practice.
CITATION(S): ACOG Committee on Obstetric Practice.Committee opinion no. 725: Vaginal seeding. Obstet Gynecol 2017 Nov; 130:e274.
(http://dx.doi.org/10.1097/AOG.0000000000002402)
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JAMA Intern Med 2017 Oct
Dietary Pesticide Exposure May Hinder Women's Reproductive Potential
Eating larger amounts of conventionally grown produce was associated with unfavorable reproductive outcomes in women receiving fertility treatment.
In the U.S., detectable concentrations of pesticides or their metabolites are present in most individuals, primarily through eating conventionally grown fruits and vegetables (FVs) — but the effects on reproductive outcomes remain unknown. Using a validated questionnaire to estimate dietary exposure to pesticide residues, researchers investigated the associations between preconception intake of high- and low-pesticide residue FVs and reproductive outcomes in a prospective cohort of 325 women undergoing 541 in vitro fertilization (IVF) cycles.
In all, 228 cycles (42%) resulted in live birth. High-pesticide FV intake was inversely associated with probability of clinical pregnancy and live birth per IVF cycle: Compared with women in the lowest quartile (<1.0 servings daily), those in the highest quartile (≥2.3 servings daily) had 18% lower probability of clinical pregnancy and 26% lower probability of live birth. Eating low-pesticide residue FVs was associated with a nonsignificant higher probability of clinical pregnancy and live birth and was inversely associated with early pregnancy loss. The authors estimated that replacing one daily serving of high-pesticide residue FVs with low-pesticide residue FVs was associated with a 79% greater probability of clinical pregnancy and an 88% greater chance of live birth.
COMMENT: These results indicate that pesticides at quantities present in many conventionally grown FVs can affect women's reproductive performance (hence, the data add to previous observations that pesticides in FVs may reduce sperm count [NEJM JW Womens Health May 2015 and Hum Reprod 2015; 30:1342]). Association does not prove causality, but these findings should remind clinicians to educate their patients about food safety and the hidden dangers of environmental pesticides while urging them to minimize exposure (for example, by avoiding high-pesticide residue FVs [the “dirty dozen”], properly washing FVs, and eating organically grown FVs whenever feasible).
CITATION(S): Chiu YH et al. Association between pesticide residue intake from consumption of fruits and vegetables and pregnancy outcomes among women undergoing infertility treatment with assisted reproductive technology. JAMA Intern Med 2017 Oct 30; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2017.5038)
Landrigan PJ.Pesticides and human reproduction. JAMA Intern Med 2017 Oct 30; [e-pub].
(http://dx.doi.org/10.1001/jamainternmed.2017.5092)
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