Cystic Fibrosis

Healthy Omega-3 Fatty Acids Could Slow a Deadly Lung Disease

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News Picture: Healthy Omega-3 Fatty Acids Could Slow a Deadly Lung DiseaseBy Ernie Mundell HealthDay Reporter

WEDNESDAY, Jan. 3, 2024 (HealthDay News)

A diet laden with omega-3 fatty acids found in nuts and oily fish might help slow the progression of pulmonary fibrosis, researchers report.

Pulmonary fibrosis is a relentless, potentially fatal disease where lung tissue scars and hardens over time. Often tied to smoking, the illness impairs lung function so that patients become short of breath, weak and disabled.

The new study was led by Dr. John Kim, a pulmonary and critical care expert at the University of Virginia School of Medicine and UVA Health, in Charlottesville.

His team tracked the health of 300 patients with interstitial lung disease — the class of respiratory ailments that includes pulmonary fibrosis. Most had “idiopathic” pulmonary fibrosis (meaning the exact cause of the illness is unknown) and most were men (males are more prone to the disease).

Blood tests were taken to gauge each patient’s dietary intake of omega-3 fatty acids.

The team found that “higher levels of omega-3 fatty acids were predictive of better clinical outcomes in pulmonary fibrosis,” Kim said in a university news release.

Specifically, people with higher levels of the nutrient had lungs that were better able to exchange carbon dioxide and oxygen — a process necessary to life. They also were better able to survive without needing a lung transplant, the study found.

“These findings were consistent whether [or not] you had a history of cardiovascular disease, which suggests this may be specific to pulmonary fibrosis,” Kim added.

It’s not yet clear how omega-3s are providing this benefit, or whether taking in more of the nutrient in food or supplements would help patients.

However, it’s not the first time omega-3s have been linked to better health: Other studies have shown that the fatty acids can improve outcomes for folks battling heart disease, blood clots and even some cancers.

As for pulmonary fibrosis, “we need further research to determine if there are specific omega-3 fatty acids that may be beneficial and, if so, what are their underlying mechanisms,” Kim said.

“Similar to other chronic diseases, we hope to determine whether nutrition-related interventions can have a positive impact on pulmonary fibrosis,” he said.

The study was published recently in the journal Chest.

Higher BMI associated with favorable clinical outcomes in patients with cystic fibrosis

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In a systematic review and meta-analysis, researchers found higher BMI was associated with favorable clinical outcomes in patients with cystic fibrosis, urging reconsideration of the currently recommended target BMI.

“Currently, BMI is the generally accepted indicator for monitoring the nutritional status of patients with cystic fibrosis. In children older than 2 years, the target BMI is at least the 50th percentile; in adults, the target BMI is greater than or equal to 22 for women and greater than or equal to 23 for men,” Rita Nagy, MD, from the Institute for Translational Medicine at Szentágothai Research Centre Medical School at the University of Pécs, the Centre for Translational Medicine at Semmelweis University and the Heim Pál National Pediatric Institute, Budapest, Hungary, and colleagues wrote in JAMA Network Open. “However, BMI does not distinguish between the major components of the body, namely, fat mass, fat-free mass, total body water, bone mineral density and bone mineral content.”

Lungs
Source: Adobe Stock.

Researchers conducted a literature search of the MEDLINE, Embase and Cochrane Central Register of Controlled Trials databases in November 2020. Their search identified 17 studies that enrolled 9,114 patients aged 2 years and older with cystic fibrosis with altered BMI or body composition who were compared with patients with measured parameters in the reference ranges.

The primary outcomes were pulmonary function, exocrine pancreatic insufficiency and cystic fibrosis-related diabetes.

Compared with those with normal weight, researchers observed higher FEV1 among those who were overweight (–8.36%; 95% CI, –12.74 to –3.97) and obese (–12.06%; 95% CI, –23.91 to –0.22).

In addition, likelihood for cystic fibrosis-related diabetes and pancreatic insufficiency was higher among patients with normal weight (OR = 1.49; 95% CI, 1.1-2) compared with those with overweight (OR = 4.4; 95% CI, 3-6.45).

Researchers found high heterogeneity in the analysis of pulmonary function with a heterogeneity statistic I2 of 46.7% to 85.9%.

“Our findings suggest that nutritional status plays an important role in maintaining organ function in patients with cystic fibrosis. Because we noted that a higher BMI is associated with better clinical parameters, we advise clinicians to reconsider increasing the currently recommended target BMI. The use of a nutritional strategy that increases BMI, at least until the upper limit of normal BMI is reached, should be included in the daily protocol. Our results suggest that careful evaluation of body composition should be incorporated into everyday clinical practice,” the researchers wrote.

In an accompanying editorial, Christina S. Thornton, MD, PhD, postdoctoral research fellow at the University of Michigan Ann Arbor, said the association between improved lung function and higher BMI in this study “warrants careful consideration toward optimal targets of BMI” in patients with cystic fibrosis.

“Obesity is a major global health concern and is associated with increased morbidity and mortality due to higher rates of heart disease, hypertension and diabetes. Thus, emerging concern over patients with cystic fibrosis who are overweight or obese experiencing these detrimental health conditions is justified, particularly in the era of modulator therapies. … Further longitudinal studies to address the consequences associated with overweight status in patients with [cystic fibrosis] to optimize nutritional approaches and treatment plans will be required to help guide further clinical recommendations,” Thornton wrote.

Reference:

PERSPECTIVE

 Natalie E. West, MD, MHS)

Natalie E. West, MD, MHS

The systematic review and meta-analysis performed by Nagy and colleagues is a robust study with interesting findings. They analyzed a large pooled cohort of individuals with cystic fibrosis, and analyzed the association between BMI and clinical outcomes (lung function, pancreatic insufficiency and cystic fibrosis-related diabetes). The authors found that higher BMI, including overweight and obese categories, were associated with higher lung function and lower rates of pancreatic insufficiency and cystic fibrosis-related diabetes. Current cystic fibrosis guidelines recommend individuals with cystic fibrosis have a normal BMI, but the authors recommended that clinicians reconsider increasing this recommended target BMI.

While this study was done rigorously, I think caution is needed before changing BMI recommendations. Higher BMI in the overweight and obese categories are well known to be associated with higher morbidity and mortality due to cardiovascular disease (hypertension, stroke, heart attacks, diabetes) in the general population. Historically, individuals with cystic fibrosis have had a lower survival rate than the general population (individuals born with cystic fibrosis in the 1950s might not live past 5 years old; in the 1970s, mid-teens.) With the improvement in medications targeting infection as well as the underlying defect in cystic fibrosis, individuals with cystic fibrosis born between 2015 and 2019 have an average survival of 46 years old. Great news is that survival is improving in cystic fibrosis. However, not many individuals with cystic fibrosis have developed CVD given the shortened survival, yet we expect survival in individuals with cystic fibrosis to continue to increase over the next decade.

Therefore, many individuals with cystic fibrosis will come of age when CV complications may develop, and we will need further long-term studies to accurately assess the potential complications associated with a higher-than-normal BMI in individuals with cystic fibrosis. Furthermore, many individuals who are eligible for CFTR modulators — medications that correct the underlying defect in cystic fibrosis — have had large increases in their lung function to normal or near-normal levels, and it would be those individuals who would not benefit from any “extra” lung function that might be associated with a higher BMI. In fact, the risk of CV complications would not outweigh the lung function benefit they might receive.

A limitation that the authors did not discuss is that the studies included in the meta-analysis were all conducted before Trikafta was approved in the U.S. (October 2019), which approximately 90% of people with cystic fibrosis are eligible for. Trikafta is associated with an average of 10% to 15% improvement in lung function and a drastic improvement in many other clinical outcomes. Some of our patients have seen their lung function improve by even 20% to 30%. Rates of hospitalizations are decreasing. Given the benefit we are seeing with Trikafta and other highly effective modulators, the lung function benefit associated with being overweight or obese may not be needed. For those individuals not eligible for modulators currently, there could be a benefit for a higher BMI in order to attain a higher lung function. However, that would need to be balanced by the risk of cardiovascular complications and considered on an individual patient basis.

Natalie E. West, MD, MHS

Assistant Professor of Medicine

Johns Hopkins University

Pulmonary and Critical Care Medicine

Cystic fibrosis therapies changing landscape of nutrition, cardiometabolic health

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The use of triple therapy and other highly effective modulator therapies will likely change the landscape of nutrition and that of cardiometabolic parameters in patients with cystic fibrosis, a speaker said.

At the North American Cystic Fibrosis Conference, Marina Litvin, MD, associate professor of medicine at the Washington University School of Medicine, St. Louis, discussed the “changing parameters” in nutritional status of patients with cystic fibrosis and the emergence of overnutrition and obesity, as well as the effects of highly effective modulator therapy on cardiovascular parameters.

Artistic lungs
Source: Adobe Stock.

Data from the Cystic Fibrosis Foundation Patient Registry Annual Data Report 2019 highlighted an increase in BMI and weight among children and adults with cystic fibrosis from 1999 to 2019. According to Litvin, “this is likely due to our effective multidisciplinary approach, better nutrition [and] earlier diagnosis, but it is also reflecting what is happening in the population as a whole … especially in areas of Western diets where overall the overweight and obesity incidence is increasing as well.” Litvin said this is important because among patients with a BMI of 25 kg/m2 or greater, there is a significant increase in the risk for adverse outcomes, with mortality increasing 30% every 5 BMI units above normal, and mortality due to chronic kidney disease and type 2 diabetes increasing 60% and 120%, respectively.

Highly effective modulator therapy with elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) was approved by the FDA for treatment of cystic fibrosis in October 2019. The triple therapy improves the processing and trafficking of the CFTR protein and was shown in clinical trials that, in addition to improving lung function, there was a decrease in sweat chloride and an increase in weight, Litvin said, which was also seen with other medications that target CFTR such as ivacaftor (Kalydeco, Vertex Pharmaceuticals) and lumacaftor.

This medication should be taken in conjunction with high fat foods, which may cause an increase in caloric intake. In addition, this therapy may cause decreases in energy expenditure and can improve a patient’s sense of taste, smell, absorption and appetite, which can all result in higher caloric intake and overall weight gain, according to Litvin.

Litvin and colleagues conducted a single-center, retrospective, observational analysis of the effect of elexacaftor/tezacaftor/ivacaftor on body weight and cardiometabolic parameters in 134 adults with cystic fibrosis from the Washington University Adult Cystic Fibrosis Center. They assessed body weight, BMI, lipid profiles and blood pressure in outpatients 1 year before they initiated elexacaftor/tezacaftor/ivacaftor and again at a median of 12.2 months after treatment. Researchers observed significant weight increases, with fewer patients who were underweight or normal weight and significantly more patients who were overweight or obese 1 year after elexacaftor/tezacaftor/ivacaftor initiation, Litvin said. The researchers also observed a decrease in the number of patients with normal BP prior to treatment compared with on treatment. This may be due to the effect of elexacaftor/tezacaftor/ivacaftor on sodium chloride secretion, therefore, causing more water retention, which can increase BP and weight, Litvin said.

Also, while on elexacaftor/tezacaftor/ivacaftor, patients without cystic fibrosis-related diabetes had significant improvement in their blood glucose levels, but patients with cystic fibrosis-related diabetes showed no change in blood glucose, but did have increases in cholesterol.

The potential mechanisms for changes in glycemic and lipid parameters include increased caloric intake, improved absorption, improved exocrine pancreatic function, enhanced insulin secretion, increased weight and decreased inflammation, Litvin said.

“In addition to increase in overnutrition, and likely increase in incidence of hyperlipidemia and hypertension, our patients are living longer, and that fact within itself may place them at higher risk for cardiometabolic conditions, as well as coronary artery disease and stroke,” Litvin said.

Litvin offered the following recommendations for clinicians caring for patients with cystic fibrosis who are on highly effective modulator therapy:

  • Assess weight, BMI and BP at each visit.
  • Provide individualized counseling for each patient on caloric goals, fitness goals and nutritional status to aim for normal BMI.
  • If a patient has abnormal BP, have the patient monitor BP at home in case this becomes a pattern wherein medical therapy may be considered.
  • Continue annual oral glucose tolerance testing.
  • Screen patients for hyperlipidemia development once a year.

“Patients would benefit from nutritional support services to identify and treat patients whose weight is not in a reasonable range,” Litvin said.

Future research is needed to establish how these factors contribute to increased risk for cardiovascular and cerebrovascular disease as well as mortality, Litvin said.

Cystic fibrosis, sickle-cell anemia could be corrected in embryos with new CRISPR variant.

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Since the discovery of the genome-editing tool CRISPR/Cas9, scientists have been looking to utilize the technology to make a significant impact on correcting genetic diseases. Technical challenges have made it difficult to use this method to correct disorders that are caused by single-nucleotide mutations, such as cystic fibrosis, sickle-cell anemia, Huntington’s disease, and phenylketonuria. … [Researchers] have just used a variation of CRISPR/Cas9 to produce mice with single-nucleotide differences. The findings from this new study were published recently in Nature Biotechnology in an article entitled “Highly Efficient RNA-Guided Base Editing in Mouse Embryos.

The most frequently used CRISPR/Cas9 technique works by cutting around the faulty nucleotide in both strands of the DNA and cuts out a small part of DNA. In the current study, the investigators used a variation of the Cas9 protein (nickase Cas9, or nCas9) fused with an enzyme called cytidine deaminase, which can substitute one nucleotide into another—generating single-nucleotide substitutions without DNA deletions

“The next goal is to correct a genetic defect in animals. Ultimately, this technique may allow gene correction in human embryos,” [remarked senior study investigator Jin-Soo Kim].

Cystic Fibrosis: New Hope for Gene Therapy?

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Gene therapy to treat cystic fibrosis patients was associated with stabilization — but not improvement — in lung function, according to the results of a randomized, double-blinded phase IIb trial of the therapy in the U.K.

In a per protocol analysis, Professor Eric W.F.W. Alton, of Imperial College in London, and colleagues found a significant, but modest, treatment effect in cystic fibrosis patients treated with the nonviral, chemically designed gene-liposome pGM169/GL67A compared with those treated with a placebo of 0.9% saline (3.7%, 95% CI 0.1-7.3, P=0.046).

While a significant ANCOVA-adjusted effect was observed after 12 months’ follow-up, relative differences in FEV1 after 12 months of treatment were -0.4% (95% CI -2.8 to 2.1) for the treatment group compared to -4.0% (CI -6.6 to -1.4) for the placebo, they reported in The Lancet Respiratory Medicine.

The primary endpoint of the study was defined as relative percent change in forced expiratory volume (FEV1) after 12 months. The authors achieved that because while treatment with pGM169/GL67A did not improve lung function, it did not worsen it either.

Modest Benefit

“This study proves for the first time that copies of the normal CF gene delivered by aerosol inhalation can have a measurable beneficial effect on lung function, compared with placebo, in patients with cystic fibrosis,” senior co-author Dr. Alastair Innes, of Western General Hospital in Edinburgh, Scotland, told MedPage Today. He added that while the effect was statistically significant, he also described it as “modest.”

A small number of patients in both groups did experience improvements in lung function. The authors note that a post-hoc analysis showed 18% of patients (15 in the treatment group and six in the control group) showed an improvement in percent predicted FEV1 of 5% or more of their initial baseline values. By contrast, overall treatment effect in the 65 patients in the treatment group and 56 in the control group was 3.6% (95% CI 0.2-7.0,P=0.039). Of the 20 patients who did not complete the full treatment of one dose per 28 days for 12 months, they received a mean 3.7 doses (SD 1-9).

Patients were randomized into a number of stratified subgroups, but the authors attributed any treatment effect to a greater decline in FEV1 from the placebo group as opposed to greater improvement from pGM169/GL67A. Stratifying by baseline predicted FEV1 (<70% versus ≥70%) found that patients with a more severe disease (FEV1 49.6%-69.2% predicted) had a treatment effect of 6.4% (95% CI 0.8-12.1). By contrast, those with less severe disease (FEV1 69.6%-89.9% predicted) had a 0.2% treatment effect (CI -4.6 to 4.9, P interaction=0.065).

The authors also cited the post-trial and pre-trial changes in the placebo group (-4.9%) compared with the treatment group (1.5%) as contributing to the treatment effect. There were no differences observed by age, sex, or CTFR mutation.

The study also had a number of secondary outcomes, which achieved mixed results. Patients in the treatment group experienced greater improvements in forced vital capacity (FVC) and CT gas trapping, or the inability to exhale completely (P=0.031 andP=0.048, respectively) than the control group. But authors observed no treatment effect for other measures of lung function, imaging, and quality of life. Similar to the primary analysis, they did note that secondary outcomes tended to be more favorable for those with more severe disease.

The authors commented that patients with more severe disease seemed to experience an enhanced treatment effect, and saw this as an opportunity for further research.

“A larger trial with a stratified trial entry design, powered to assess subgroups, and that addresses the mechanisms of response heterogeneity will be important to verify or refute these data,” they wrote.

A total of six serious adverse events were recorded from the pGM169/GL67A group. The committee judged that they were unrelated to the treatment, though one may have been related to a trial procedure (bronchoscopy), the authors said. Two patients total discontinued treatment; one in the placebo group due to fatigue and one in the treatment group due to flu-like symptoms. There were no deaths during the study, and the authors saw no clinically relevant changes in patients throughout the study.

This randomized, double-blinded, placebo-controlled trial consisted of two cystic fibrosis centers in London and Edinburgh at 18 sites in the U.K. from June 12, 2012, to June 24, 2013. Participants were eligible if they were ages ≥12 years, had a FEV1 of 50%-90% predicted and had any combination of CFTR gene mutations. Of the 140 patients, 78 received pGM169/GL67A and 62 received a placebo. There were 116 patients (83%) completing the treatment and included in the per protocol analysis.

Limitations

The most important limitation the authors cite is that the mean difference is at the lower end of clinical trials for gene therapy in patients with cystic fibrosis, mainly due to the reduction in FEV1 volume in the placebo group. They suggest several reasons for this, such as optimal respiratory health for patients at time of trial entry, enthusiasm for the trial leading to improvements in lung function during the recruitment period, and that the trial included all available data, even if the patients were unstable, while registry data only contains measurements from an annual review. They also note the trial’s heterogeneous response and that the fact that changes may be the result of a “non-specific response” to the pGM169/GL67A treatment.

The authors describe their conclusions as a “proof of concept” for nonviral CFTR gene therapy, calling it “another step along the path of translational cystic fibrosis gene therapy.”

Innes said that the efficiency of the gene uptake needs to be improved before the therapy is applicable to clinical practice, adding that the UK Gene Therapy Consortium is engaged in pursuing several lines of research.

“We are exploring whether increased or more frequent dosing would increase benefit, the possible additional benefit of combining gene therapy with other basic treatments which help the CF ion channel to remain open, and novel viral gene therapy vectors which may increase the efficiency of gene transfer,” he said.

Yale scientists use gene editing to correct mutation in cystic fibrosis

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Left to right, cystic fibrosis cells treated with gene-correcting PNA/DNA show increasing levels of uptake, or use to correct the mutation. (Images by Rachel Fields)

Yale researchers successfully corrected the most common mutation in the gene that causes cystic fibrosis, a lethal genetic disorder.

The study was published April 27 in Nature Communications.

Cystic fibrosis is an inherited, life-threatening disorder that damages the lungs and digestive system. It is most commonly caused by a mutation in the cystic fibrosis gene known as F508del. The disorder has no cure, and treatment typically consists of symptom management. Previous attempts to treat the disease through gene therapy have been unsuccessful.

To correct the mutation, a multidisciplinary team of Yale researchers developed a novel approach. Led byDr. Peter Glazer, chair of therapeutic radiology, Mark Saltzman, chair of biomedical engineering, and Dr. Marie Egan, professor of pediatrics and of cellular and molecular physiology, the collaborative team used synthetic molecules similar to DNA — called peptide nucleic acids, or PNAs — as well as donor DNA, to edit the genetic defect.

“What the PNA does is clamp to the DNA close to the mutation, triggering DNA repair and recombination pathways in cells,” Egan explained.

The researchers also developed a method of delivering the PNA/DNA via microscopic nanoparticles. These tiny particles, which are billionths of a meter in diameter, are specifically designed to penetrate targeted cells.

In both human airway cells and mouse nasal cells, the researchers observed corrections in the targeted genes. “The percentage of cells in humans and in mice that we were able to edit was higher than has been previously reported in gene editing technology,” said Egan. They also observed that the therapy had minimal off target, or unintended, effects on treated cells.

While the study findings are significant, much more research is needed to refine the genetic engineering strategy, said Egan. “This is step one in a long process. The technology could be used as a way to fix the basic genetic defect in cystic fibrosis.”

Blood mRNA biomarkers for detection of treatment response in acute pulmonary exacerbations of cystic fibrosis.

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Abstract

Background Acute pulmonary exacerbations accelerate pulmonary decline in cystic fibrosis (CF). There is a critical need for better predictors of treatment response.

Objective To test whether expression of a panel of leucocyte genes directly measured from whole blood predicts reductions in sputum bacterial density.

Methods A previously validated 10-gene peripheral blood mononuclear cell (PBMC) signature was prospectively tested in PBMC and whole blood leucocyte RNA isolated from adult subjects with CF at the beginning and end of treatment for an acute pulmonary exacerbation. Gene expression was simultaneously quantified from PBMCs and whole blood RNA using real-time PCR amplification. Test characteristics including sensitivity, specificity, positive and negative predictive values were calculated and receiver operating characteristic curves determined the best cut-off to diagnose a microbiological response. The findings were then validated in a smaller independent sample.

Results Whole blood transcript measurements are more accurate than forced expiratory volume in 1 s (FEV1) or C reactive protein (CRP) alone in identifying reduction of airway infection. When added to FEV1, the whole blood gene panel improved diagnostic accuracy from 64% to 82%. The specificity of the test to detect reduced infection was 88% and the positive predictive value for the presence of persistent infection was 86%. The area under the curve for detecting treatment response was 0.81. Six genes were the most significant predictors for identifying reduction in airway bacterial load beyond FEV1 or CRP alone. The high specificity of the test was replicated in the validation cohort.

Conclusions The addition of blood leucocyte gene expression to FEV1 and CRP enhances specificity in predicting reduced pulmonary infection and may bolster the assessment of CF treatment outcomes.

Source: Thorax.

 

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.

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Background

Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis.

Methods

We did a multicentre trial in two phases. We enrolled patients aged 5—30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3—6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population.

Findings

We screened 540 patients and enrolled 171 (mean age 13·8 years, SD 5·9, range 5—30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16·3% in the alendronate group (n=65) versus 3·1% in the placebo group (n=63; p=0·0010). 19 of 57 young people (33·3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events.

Interpretation

Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density.

Source: Lancet

 

 

 

Fluid-fluid level in cystic vestibular schwannoma: a predictor of peritumoral adhesion.

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Abstract

OBJECT

The aim of this study was to evaluate the clinical results and surgical outcomes of cystic vestibular schwannomas (VSs) with fluid-fluid levels.

METHODS

Forty-five patients with cystic VSs and 86 with solid VSs were enrolled in the study. The patients in the cystic VSs were further divided into those with and without fluid-fluid levels. The clinical and neuroimaging features, intraoperative findings, and surgical outcomes of the 3 groups were retrospectively compared.

RESULTS

Peritumoral adhesion was significantly greater in the fluid-level group (70.8%) than in the nonfluid-level group (28.6%) and the solid group (25.6%; p < 0.0001). Complete removal of the VS occurred significantly less in the fluid-level group (45.8%, 11/24) than in the nonfluid-level group (76.2%, 16/21) and the solid group (75.6%, 65/86; p = 0.015). Postoperative facial nerve function in the fluid-level group was less favorable than in the other 2 groups; good/satisfactory facial nerve function 1 year after surgery was noted in 50.0% cases in the fluid-level group compared with 83.3% cases in the nonfluid-level group (p = 0.038).

CONCLUSIONS

Cystic VSs with fluid-fluid levels more frequently adhered to surrounding neurovascular structures and had a less favorable surgical outcome. A possible mechanism of peritumoral adhesion is intratumoral hemorrhage and consequent inflammatory reactions that lead to destruction of the tumor-nerve barrier. These findings may be useful in predicting surgical outcome and planning surgical strategy preoperatively.

Source: http://thejns.org

Treatment of low bone density in young people with cystic fibrosis: a multicentre, prospective, open-label observational study of calcium and calcifediol followed by a randomised placebo-controlled trial of alendronate.

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Background
Long-term complications of cystic fibrosis include osteoporosis and fragility fractures, but few data are available about effective treatment strategies, especially in young patients. We investigated treatment of low bone mineral density in children, adolescents, and young adults with cystic fibrosis.
Methods
We did a multicentre trial in two phases. We enrolled patients aged 5—30 years with cystic fibrosis and low bone mineral density, from ten cystic fibrosis regional centres in Italy. The first phase was an open-label, 12-month observational study of the effect of adequate calcium intake plus calcifediol. The second phase was a 12-month, double-blind, randomised, placebo-controlled, parallel group study of the efficacy and safety of oral alendronate in patients whose bone mineral apparent density had not increased by 5% or more by the end of the observational phase. Patients were randomly assigned to either alendronate or placebo. Both patients and investigators were masked to treatment assignment. We used dual x-ray absorptiometry at baseline and every 6 months thereafter, corrected for body size, to assess lumbar spine bone mineral apparent density. We assessed bone turnover markers and other laboratory parameters every 3—6 months. The primary endpoint was mean increase of lumbar spine bone mineral apparent density, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01812551.
Findings
We screened 540 patients and enrolled 171 (mean age 13•8 years, SD 5•9, range 5—30). In the observational phase, treatment with calcium and calcifediol increased bone mineral apparent density by 5% or more in 43 patients (25%). 128 patients entered the randomised phase. Bone mineral apparent density increased by 16•3% in the alendronate group (n=65) versus 3•1% in the placebo group (n=63; p=0•0010). 19 of 57 young people (33•3%) receiving alendronate attained a normal-for-age bone mineral apparent density Z score. In the observational phase, five patients had moderate episodes of hypercalciuria, which resolved after short interruption of calcifediol treatment. During the randomised phase, one patient taking alendronate had mild fever versus none in the placebo group; treatment groups did not differ significantly for other adverse events.
Interpretation
Correct calcium intake plus calcifediol can improve bone mineral density in some young patients with cystic fibrosis. In those who do not respond to calcium and calcifediol alone, alendronate can safely and effectively increase bone mineral density.
Source: Lancet