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Xtandi During AS Reduced Progression Risk in Early Prostate Cancer

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Xtandi During AS Reduced Progression Risk in Early Prostate Cancer

Patients with low- or intermediate-risk localized prostate cancer who received enzalutamide (Xtandi) monotherapy saw a reduced risk of cancer progression, according to a randomized phase II trial.

Among 227 patients on active surveillance (AS), treatment with enzalutamide reduced the risk of pathological or therapeutic prostate cancer progression by 46% compared with AS alone (HR 0.54, 95% CI 0.33-0.89, P=0.02), reported Neal Shore, MD, of Carolina Urologic Research Center in Myrtle Beach, South Carolina.

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Enzalutamide monotherapy also delayed prostate-specific antigen (PSA) progression by 6 months versus AS alone (HR 0.71, 95% CI 0.53-0.97, P=0.03), they noted in JAMA Oncology.

This study “represents the first trial to compare the effects of a novel androgen receptor antagonist as monotherapy versus AS in patients with low-risk or intermediate-risk localized prostate cancer,” Shore and team wrote. “Results suggest that enzalutamide may offer an alternative short-term treatment option for this patient population, potentially reducing the need for more aggressive treatment approaches.”

In other findings, the odds of a negative biopsy were significantly higher at 1 year for enzalutamide patients (OR 3.5, 95% CI 1.76-6.92, P<0.001), and while there were more patients with a negative biopsy at 2 years, the difference was not statistically significant (OR 1.6, 95% 0.66-4.00, P=0.29).

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Likewise, the odds of a secondary rise in serum PSA levels were significantly reduced at 1 year (OR 0.1, 95% CI 0.08-0.26, P<0.001), but not 2 years (OR 1.1, 95% CI 0.37-3.53, P=0.81).

In an accompanying commentary, Susan Halabi, PhD, of Duke University Medical Center in Durham, North Carolina, and colleagues pointed out that outcomes between the two groups were similar at 2 years after cessation of enzalutamide, “suggesting that the natural history of the tumor may not have been altered but patients in the enzalutamide arm had different growth kinetics while receiving active enzalutamide treatment.”

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“Whether this will translate into substantially delaying or abrogating the need for definitive therapy for a cohort of patients will require longer follow-up,” they added.

Patient-reported outcomes were not significantly worse with enzalutamide, with the exception of sexual and physical function, which resolved at 24 months after treatment cessation.

While the data are “encouraging,” this study does not identify which patients will benefit from early intervention with enzalutamide, the commentators noted. “It is critical that patients with low-risk or intermediate-risk prostate cancer be followed for at least a decade with studies that are sufficiently powered to detect those differences in outcomes in various subsets of patients.”

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For this open-label study, 227 patients on AS from 66 U.S. and Canadian sites were randomized 1:1 to enzalutamide 160 mg or continued AS alone. From June 2016 to August 2020, patients were monitored for 1 year of treatment and up to 2 years of follow-up. Mean age was 66, 90% were white, and 9.3% were Black.

The primary endpoint was time to pathological or therapeutic prostate cancer progression. Secondary endpoints included incidence of a negative biopsy, incidence of a secondary rise in serum PSA levels at 1 and 2 years, and time to PSA progression.

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Just 74.6% of the men treated with enzalutamide and 70.8% of those in the AS-alone arm completed 1 year of AS, “highlighting one of the challenges of AS protocols,” Halabi and colleagues noted.

As for safety, patients treated with enzalutamide had a higher incidence of adverse events (AEs) than patients on AS alone (92.0% vs 54.9%) during the 1-year treatment period, most grade 1 or 2.

The most commonly reported AEs during treatment with enzalutamide were fatigue (55.4%), gynecomastia (36.6%), nipple pain (30.4%), breast tenderness (25.9%), and erectile dysfunction (17.9%), while the only AE that occurred in 5% or more of patients in the AS arm was hypertension (7.1%).

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Drug-related AEs were reported in 99 men (88.4%), with 2.7% considered serious and 7.1% leading to study drug discontinuation.

Three patients in the enzalutamide arm died, none of whom were receiving the drug at the time of death, and none considered treatment-related.

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  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

This study was funded by Astellas Pharma and Pfizer, the co-developers of enzalutamide.

Shore reported personal fees from Astellas and Pfizer during the conduct of the study, as well as personal fees from Bayer, AstraZeneca, Janssen, Dendreon, Sanofi, Myovant, and Merck outside the submitted work.

Co-authors reported multiple relationships with industry.

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Halabi reported no disclosures. One of the commentary co-authors reported clinical trial support from Novartis outside the submitted work.

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Childhood Melatonin Poisonings Skyrocket in the Past 10 Years

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Childhood Melatonin Poisonings Skyrocket in the Past 10 Years

The number of children in the United States who unintentionally ingested melatonin supplements over the past 10 years has skyrocketed to the point where, as of 2021, melatonin ingestions by children accounted for almost 5% of all poisonings reported to poison control centers in the United States, data from the National Poison Data System (NPDS) indicate.

This compared with only 0.6% of melatonin ingestions reported to poison control centers in 2012, the authors added.

“Basically the number of pediatric melatonin ingestions increased 530% from 8,337 in 2012 to 52,563 in 2021 so it’s a 6.3-fold increase from the beginning of the study until the end,” Michael Toce, MD, one of the study authors and attending, pediatric emergency medicine/medical toxicology, Boston Children’s Hospital, said in an interview.

“And I think the biggest driver of this increase is simply that sales of melatonin have increased astronomically so there is just more melatonin at home and studies have shown there is a correlation between the amount of an individual medication in the home and the risk of pediatric exposure — so simply put: The more of a single substance in a home, the greater the chance that a child is going to get into it,” he underscored.

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The study was published in the Morbidity and Mortality Weekly Report.

Melatonin Ingestions

All cases of single substance melatonin ingestions involving children and adolescents between Jan. 1, 2012, and Dec. 31, 2021, were included in the analysis. During the 10-year study interval, 260,435 pediatric melatonin ingestions were reported to the NPDS. Over 94% of the reported ingestions were unintentional and 99% occurred in the home.

Over 88% of them were managed on-site; most involved young male children aged 5 years and under, and almost 83% of children who ingested melatonin supplements remained asymptomatic. On the other hand, 27,795 patients sought care at a health care facility and close to 15% of them were hospitalized. Among all melatonin ingestions, 1.6% resulted in more serious outcomes; more serious outcomes being defined as a moderate or major effects or death. Five children required mechanical ventilation in order to treat their symptoms and 2 patients died.

The largest number of patients who were hospitalized were adolescents who took melatonin intentionally but the largest increase in the rate of exposure was in young, unintentional patients, as Toce observed. Interestingly, the largest yearly increase in pediatric melatonin ingestions — almost 38% — coincided with the onset of the COVID-19 pandemic.

“This might be related to increased accessibility of melatonin during the pandemic, as children spent more time at home because of stay-at-home orders and school closures,” the authors speculate. Moreover, sleep disturbances were common during the pandemic, leading to a greater likelihood that parents were buying melatonin and thus exposing children to more melatonin at home.

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Taken appropriately and at normal does, melatonin in itself is quite safe, as Toce stressed. However, “for any substance, the dose makes the poison, so taken in any significant quantity, anything is going to be dangerous.” Moreover, it’s important to appreciate that melatonin, at least in the United States, is regulated as a dietary supplement, not as a pharmaceutical.

“Thus, it doesn’t get the same rigorous testing that something like acetaminophen does by the FDA and that means two things,” Toce noted. First, if the product says that each gummy contains 3 mg of melatonin, no independent body is verifying whether or not that statement is true so there could be 3 mg of melatonin in each gummy or there could be 10 mg.

Secondly, because there is no impartial oversight for dietary supplements, there may in fact be no melatonin at all in the product or something else may be added to it that might be harmful. “Just because something is sold over-the-counter does not necessarily mean that it’s safe,” Toce stressed. To keep children safe from pharmaceuticals and supplements, he recommended several generic poison prevention tips. This advice could be passed on to patients who are parents.

  • Keep all pharmaceuticals and supplements preferably locked away so there is less risk of children and adolescents taking products either unintentionally or intentionally

  • If parents have no place to lock their products up, put them out of reach, high-up so children cannot easily access them

  • Keep the product in the original child-resistant packaging as opposed to taking the pills out of the packaging and putting it in a plastic bag. “Certainly we’ve seen that when medications are moved into a non-child-resistant container, ingestions go up,” Toce warned

  • Don’t refer to any medicine or supplement a child might take as “candy.” “A lot of children have difficulty taking medications so some families will say: ‘It’s time for your candy,’ ” Toce explained. Then, if a child does discover the “candy” on a table where they have access to it, they will not recognize it as medication and they’re likely to pop it into their mouth, thinking it is candy

Lastly, and most importantly, parents who are considering trying a melatonin supplement to help a child sleep better should first establish a stable sleep routine for their child. “They also need to limit caffeinated beverages before bed as well as screen time,” Toce added.

And they should talk with their primary care provider as to whether or not initiation of a melatonin supplement is appropriate for their child — “and not just jump right into giving them melatonin without first discussing whether it is appropriate to do so,” Toce stressed.

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Remarkable Rise

In a comment on his own experience with melatonin poisoning over recent years, toxicology expert Kevin Osterhoudt, MD, of the University of Pennsylvania, Philadelphia, and the Children’s Hospital of Philadelphia, noted that it has been their experience that there has been a remarkable rise in poison center reports of children ingesting melatonin in the recent past. For example, the Poison Control Center at CHOP received nearly 4,000 calls involving melatonin ingestion by children 5 years old or younger in the 5 years between 2017 and 2021 with increasing numbers every year.

“The [current study] supports our regional observation that this has been a national trend,” Osterhoudt said. Osterhoudt agreed with Toce that good sleep is healthy, and it is very important to develop good sleep habits and a regular bedtime routine. “In some situations, melatonin may be useful as a short-term sleep aid and that’s a good discussion to have with your child’s health care provider.”

If parents do decide to give their child a melatonin supplement, they need to keep in mind that melatonin may alter how the body handles other drugs such as those used to treat epilepsy or blood clotting. They also need to know experts are still uncertain about how melatonin affects the body over the long term and whether it is safe for mothers to take during pregnancy.

Osterhoudt offered his own recommendations for safe melatonin use in the home:

  • Discuss planned melatonin use with your health care provider

  • Buy only high-quality supplements by looking for the “USP Verified” mark

  • Insist that manufacturers sell products in child-resistant bottles

  • Periodically inspect the medications in your home and dispose of medications that are no longer being used

  • Program the phone number of your regional poison control center into your phone; poison center experts are available 24/7 to answer questions and concerns about ingestions of melatonin (in the United States the number is 1-800-222-1222)

The study authors and neither Toce nor Osterhoudt had any relevant conflicts of interest to declare.

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This story originally appeared on MDedge.com, part of the Medscape Professional Network.

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CDC Releases New Details on Mysterious Hepatitis in Children

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CDC Releases New Details on Mysterious Hepatitis in Children

A new analysis from the Centers for Disease Control and Prevention (CDC) provides further details on mysterious cases of pediatric hepatitis identified across the United States. While 45% percent of patients have tested positive for adenovirus infection, it is likely that these children “represent a heterogenous group of hepatitis etiologies,” the CDC authors write.

Of the 296 children diagnosed between October 1, 2021, and June 15, 2022, in the United States, 18 have required liver transplants and 11 have died.

On April 21, 2022, the CDC issued an alert to providers to report pediatric hepatitis cases of unknown etiology in children under 10 after similar cases had been identified in Europe and the United States. While the United Kingdom has found an uptick in cases over the past year, researchers from the CDC published data on June 14 that suggested pediatric hepatitis cases had not increased from 2017 to 2021.

This newest analysis, published Friday, June 24, in the CDC’s Morbidity and Mortality Weekly Report, provides additional demographic data on affected patients and explores possible causes, including previous infection with COVID-19. Investigators had earlier ruled out COVID-19 vaccination as a potential factor in these cases, as most children were unvaccinated or not yet eligible to receive the vaccine. According to the analysis, only five patients had received at least one dose of a COVID-19 vaccine.

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The 296 cases included in the analysis occurred in 42 US states and territories, and the median age for patients was 2 years and 2 months. Nearly 60% of patients were male (58.1%) and 40.9% were female. The largest percentage of cases occurred in Hispanic or Latino children (37.8%), followed by non-Hispanic White (32.4%) children. Black patients made up 9.8% of all cases, and 3.7% of affected children were of Asian descent. Vomiting, fatigue, and jaundice were all common symptoms, and about 90% (89.9%) of children required hospitalization..

Of 224 children tested for adenovirus, 44.6% were positive. The analysis also included information on 123 of these hepatitis patients tested for other various pathogens. Nearly 80% (98/123) received a COVID-19 test and just 10.2% were positive. Twenty-six percent of patients had previously had COVID-19, and hepatitis onset occurred, on average, 133 days after the reported SARS-CoV-2 infection.

Other viruses detected included:

  • rhinovirus/enterovirus (24.5%)

  • rotavirus (14.0%)

  • acute Epstein-Barr virus (11.4%)

Simultaneous infection with SARS-CoV-2 and adenovirus occurred in three patients.

There was no evidence of viral inclusions in the 36 patients who had pathologic evaluation liver biopsies, explants, or autopsied tissue.

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The findings suggest that there may be many different causes behind these severe hepatitis cases, the authors write, and it is estimated that about one third of hepatitis cases in children do not have a known cause. However, the identification of adenovirus infection in many cases “raises the question whether a new pattern of disease is emerging in this population or if adenovirus might be an underrecognized cause or cofactor in previously indeterminate cases of pediatric hepatitis,” the authors write. As the investigation continues, they added, “further clinical data are needed to understand the cause of these cases and to assess the potential association with adenovirus.”

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Risk of premature death in patients with childhood immune-mediated inflammatory disease over three times greater

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Risk of premature death in patients with childhood immune-mediated inflammatory disease over three times greater

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Credit: CC0 Public Domain

Patients with a pediatric onset immune-mediated inflammatory disease (pIMID) have a significantly higher risk of premature death, according to new research being presented today at the 54th Annual Meeting of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN).

Whilst higher mortality was found in patients across all included pediatric onset immune-mediated inflammatory conditions compared to controls, pediatric autoimmune liver disease (pAILD) and pediatric vasculitis patients had the highest risk of mortality with a fourteen times (aHR* 14.3) and fifteen times (aHR 15.8) greater chance of death respectively.

For pAILD patients specifically, the study reveals for the very first time that the high death rate was driven by the risk of cancer, which was thirty times greater in pAILD patients. Coupled with the 6-times increased risk of death from cancer in pediatric onset inflammatory bowel disease (pIBD) patients, the researchers believe the findings show a definitive need to establish early cancer screening in pAILD and pIBD patients to prevent unnecessary premature deaths.

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The study also revealed a significantly higher suicide risk (almost two-and-a-half times greater [aHR 2.4]) amongst pIMID patients compared to controls. Primarily driven by pIBD and juvenile idiopathic arthritis (JIA) patients, the median age of suicide was just 25 years.

These findings show a possible impact on the mental health of patients, spotlighting the true burden of these conditions. As the majority of suicides occurred in patients after transfer into adult care, an increased focus is warranted on systematic transitioning programs in pediatric departments. This focus must be continued into the period after the transfer of the patient to an adult department, due to this critical life period.

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The survey also showed that being diagnosed with more than one IMID appears to be a risk factor, with significantly higher mortality risk found in these patients (aHR 9.2). This is important as previous studies have found that patients diagnosed with one IMID are at an increased risk of subsequently being diagnosed with an additional IMID.

The Danish population-based study recorded data from 12,036 pIMID patients between 1980—2018, consisting of 5,671 (47%) pIBD, 396 (3%) pAILD, 6,018 (50%) JIA, and 300 (2%) individuals with pediatric onset vasculitis. Of these, 342 (3%) individuals were diagnosed with more than one pIMID.

Commenting on the findings, lead author, Dr. Mikkel Malham from the Department of Paediatrics and Adolescent Medicine at the Copenhagen University Hospital Hvidovre in Copenhagen, Denmark, stated: “This is the first study to report an increased mortality in pIMID. While for pIBD this risk is quite well known, for the rest of the included pIMIDs the presented risk estimates should raise considerable concern.”

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“The increased risk of dying from several different causes should warrant a multidisciplinary approach which includes caring for a child’s mental health. It is of utmost importance that this multidisciplinary approach is continued into early adulthood, as this is when suicide typically occurs.”

“Additionally, cancer screening in IMID patients diagnosed in childhood, particularly with IBD and AILD, should probably be initiated early to prevent premature death,” adds Dr. Malham.

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Referencing the higher mortality rate, particularly amongst pAILD patients, and the prominent role of suicide as a cause, Chair of the ESPGHAN Hepatology Committee, Professor Giuseppe Indolfi elaborates on the broader implications: “The clinical and therapeutic management of children and adolescents with autoimmune liver and gastrointestinal diseases remains a significant challenge for pediatric hepatologists and gastroenterologists. This study reinforces that every effort should be made to further improve our knowledge and ultimately the quality of care for children with immune-mediated inflammatory diseases.”



More information:
Conference abstracts: journals.lww.com/jpgn/Documents/54th%20Annual%20Meeting%20of%20ESPGHAN_Abstract_Book.pdf

Provided by
The European Society for Paediatric Gastroenterology Hepatology and Nutrition

Citation:
Risk of premature death in patients with childhood immune-mediated inflammatory disease over three times greater (2022, June 24)
retrieved 24 June 2022
from https://medicalxpress.com/news/2022-06-premature-death-patients-childhood-immune-mediated.html

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