The U.S. Preventive Services Task Force (USPSTF) in an updated guidance has expanded its recommendations for testing women for BRCA mutations associated with increased risk of cancer (JAMA 2019;322:652-65). USPSTF now recommends that primary care providers screen asymptomatic women for their risk of BRCA1/2 mutations when they have either a personal or family history of breast, ovarian, tubal, or peritoneal cancers or Ashkenazi Jewish heritage.

In this “B” rating signifying moderate to substantial net benefit of screening, the panel outlined a three-step process for determining a woman’s risk: a brief risk assessment with one of six tools deemed “accurate” for identifying women with increased risk of BRCA1/2 mutations; referral to a genetic counselor if the assessment proves positive; and finally BRCA1/2 testing, if warranted.

The panel’s recommendation in comparison to its 2013 update includes women who have been treated successfully for the cancers in question and makes more explicit the connection to ancestry as a screening criterion.

USPSTF recommended against screening women who do not have a personal or family history or ancestry associated with pathogenic BRCA1/2 mutations, as the benefits of doing so would be “small to none.”  

The panel did not recommend multigene panel testing, and instead focused only on BRCA1/2 mutations, based on the available evidence about and prevalence of these variants, as well as their clinical actionability. USPSTF noted that “the clinical significance of identifying pathogenic variants in multigene panels requires further investigation.” Evidence is “limited on moderate penetrance genes, given their relatively low incidence in the population,” wrote the panel.

One of a series of editorials issued in conjunction with the updated statement called it a “missed opportunity” that the document does not recommend BRCA-associated cancer risk assessment in men (JAMA Oncol 2019; doi: 10.1001/jamaoncol.2019.3431). “It is increasingly being recognized that additional cancers, including prostate cancer, pancreatic cancer, and possibly melanoma, are part of the spectrum of disease associated with BRCA mutations,” wrote the editorialists.

USPSTF cited the need for more information about mutation prevalence and effects on the general population as well as on ancestries and ethnicities associated with BRCA1/2 mutations. The panel also called for a registry of patients counseled about or tested for BRCA1/2 mutations “to provide useful information about predictors of cancer and response to interventions.”

Elevated Markers of Inflammation, Immunosuppression Tied to Poor Long-term Outcomes in Sepsis Survivors

Persistently elevated markers of inflammation and immunosuppression signal increased risk of poor long-term outcomes, including death, after surviving hospitalization for sepsis (JAMA Network Open 2018;2:e198686).

In this prospective study of 483 patients hospitalized for sepsis at 12 institutions, the researchers tracked values of nine biomarkers during patients’ index hospitalization for sepsis and at 3, 6, and 12-month follow-ups, but they found the trajectories of two tests—high-sensitivity C-reactive protein (hs-CRP) and soluble programmed death ligand 1 (sPD-L1)—particularly informative in identifying those most at risk.

Patients with high levels of both hs-CRP and sPD-L1—dubbed the hyperinflammation or immunosuppression phenotype—had an 8.26 adjusted odds ratio of 1-year mortality in comparison to those with a normal phenotype, who had normal hs-CRP and sPD-L1 levels. More than two-thirds of patients fit the hyperinflammation or immunosuppression phenotype, while nearly 30% were in the normal phenotype. Just a few patients had only hyperinflammation or only immunosuppression.

The authors also analyzed markers of hemostasis (D-dimer, plasminogen activator inhibitor 1), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress (nitrate). Elevated hs-CRP levels persisted 1 year after hospitalization in about a quarter of patients, while nearly half had high sPD-L1 levels after 1 year. 

New Reference Reagent Promises Reduced Variability Among anti-ds DNA Test Methods

 Avalidation study of the new World Health Organization reference reagent for anti-double-stranded DNA (anti-dsDNA) shows that this standard, 15/174, can be used to align and improve the many test methods for quantifying anti-dsDNA (Ann Rheum Dis 2019;0:1-4).

The first international standard for anti-dsDNA was established in 1985 to assign international units (IU) to diagnostic tests, but this standard, Wo/80, was exhausted more than 10 years ago and needs a replacement.

In all, 42 laboratories in the European League Against Rheumatism Autoantibody Study Group blindly evaluated 15/174, a plasmapheresis specimen obtained from a female patient diagnosed with systemic lupus erythematosus according to 1997 classification criteria that had been transferred to 4,300 ampoules and lyophilized. The British National Institute for Biological Standards and Control subsequently prepared 15/174 as a candidate reference material. In a second study, 36 laboratories from 17 countries analyzed 15/174 in comparison to local standards and the three patient samples to evaluate commutability.

The labs used 26 different methods, including Crithidia luciliae immunofluorescence test (CLIFT), enzyme-linked immunosorbent assays, chemiluminescence immunoassays, fluoroenzyme immunoassays, addressable laser bead immunoassays, and Farr immunoassays, and found high variability in their analyses. For example, estimates of 15/174 against kit standards ranged from 56 IU/mL to 847 IU/mL. The end-point titers for CLIFT were even more variable, ranging from 50 to 1,000 for 15/174. Similar variability occurred in their analyses of the patient samples, according to the authors.

Comparing estimates reported in terms of kit standards versus those calculated against 15/174 showed reductions in the percentage of geometric coefficients of variation for two of the three patient samples.

“This international evaluation showed that although the performance of 15/174 was not perfect, the current situation with large differences between different anti-dsDNA assays would be improved by use of 15/174 as a reference reagent,” said senior author Johan Rönnelid, MD, a professor at Uppsala University in Sweden, in a separate statement.