Preliminary data suggest that pooling bilateral collections may be a feasible way to achieve the required volume for sweat chloride testing in cystic fibrosis (CF) patients and that the minimum sweat rate for macroduct collectors may be overly stringent (J Appl Lab Med 2023; doi: 10.1093/jalm/jfad067).
Sweat chloride testing is the gold standard for CF diagnosis. Guidelines from the Clinical and Laboratory Standards Institute (CLSI) endorse a minimum sweat rate for reporting results and recommend bilateral sweat collection. If both sites fail to meet the minimum rate or quantity is insufficient, the test should be repeated.
The researchers examined the correlation between sweat rate and sweat chloride concentration, assessed the accuracy of specimens collected at suboptimal rates, and investigated use of pooled bilateral specimens for chloride measurement. They used a Pearson correlation to analyze the relationship between sweat rate and chloride concentration (CI-) in 674 macroduct collections. The researchers weighted kappa to CF diagnostic classification concordance for 18 tests with paired arms above versus below the minimum sweat rate. They also applied Deming regression to compare CI- from pooled bilateral specimens to neat specimens in 27 collections with residual volume available after clinical testing.
The Pearson correlation of sweat rate versus CI- was minimal across specimens with varying rate and CI-, the researchers found. They observed substantial agreement in CF diagnostic classification between arms for bilateral collections with discordant sweat rates. Regression analysis of CI- in pooled versus nonpooled specimens revealed a slope of 0.984 and an intercept of 0.796.
The researchers concluded that sweat rate does not influence sweat CI- when following the CLSI recommendations and using macroduct collectors, and that negligible correlation of sweat rate and CI- suggests the minimum sweat rate for macroduct collectors may be overly stringent. Reporting of CI- in specimens equal to or greater than 10 μL, or with a rate equal to or greater than 0.3 μL/minute, may reduce quantity not sufficient rates without compromising diagnostic accuracy, the researchers added.
NEW ALS GUIDELINES CALL FOR MORE TESTING, BETTER LAB PRACTICES
New evidence-based, consensus guidelines for amyotrophic lateral sclerosis (ALS) genetic testing and counseling call upon clinicians to offer them to all ALS patients in the United States, regardless of family history (Ann Clin Transl Neurol 2023; doi: 10.1002/acn3.51895).
Testing should cover mutations in the most common genes linked to the disease, the guidelines say. At a minimum, these include C9orf72, SOD1, FUS, and TARDBP because genetic mutations can occur in both the familial and sporadic forms of the disease. The guidelines describe patient education and genetic risk assessments to be provided.
Noting labs’ inconsistent methodology and clinical results reporting, the guidelines propose standards to harmonize methodologies. They suggest that testing DNA derived from tissues outside of the central nervous system is sufficient to establish the presence of a C9orf72 repeat expansion and that C9orf72 testing should use a method with high sensitivity and specificity for expanded alleles. The guidelines also recommend as acceptable repeat-primed PCR, performed bidirectionally for detecting expanded C9orf72 alleles with high sensitivity and specificity in some circumstances, as well as dual-mode for detecting expanded C9orf72 alleles with high sensitivity and specificity. Interrogation of non-C9orf72 ALS genes should use simultaneous sequencing methods instead of sequential gene sequencing.
The guidelines call on labs to harmonize reporting.. Those with C9orf72 findings should specify the sizes of non-expanded alleles, while those alleles classified as “intermediate” or “uncertain” should include a statement outlining up-to-date data regarding uncertainty of pathogenicity of these allele sizes. C9orf72 repeat expansion findings should include a statement clearly outlining the maximum number of repeats detectable by the assay employed. Additionally, gene panel reports should differentiate clearly between genes that are causal for ALS and those genes where the evidence is sparse, conflicting, or insufficient, based on National Human Genome Research Institute Clinical Genome Resource (ClinGen) classifications. The guidelines also state that if testing involved targeted-capture, exome, or whole-genome methods, reports should note inadequately assessed gene regions that should be interrogated further.
These guidelines are a first step toward a uniform and equitable approach to ALS and will require periodic revision based on genetic discoveries and new genetic therapies relevant to ALS, the authors said.
The researchers concluded that their results demonstrate how large exome sequencing studies, combined with efficient burden analyses, can identify additional breast cancer susceptibility genes. They called for further studies to replicate their findings in large datasets.
RISK STRATIFICATION BENEFITS YOUNGER MEN WITH EARLY PROSTATE CANCER
Prostate cancer (PC) patients younger than 70 with early PC and unfavorable PC risk profiles can be identified so they potentially may benefit from treatment escalation with androgen receptor signaling inhibitors or cytotoxic chemotherapy and participate in randomized treatment escalation studies, recent research suggests. (JAMA Network Open 2023; doi: 10.1001/jamanetworkopen.2023.36390).
Age under 70 years, comorbid diseases, and other likely indicators of fitness are important covariates when predicting risk of prostate-specific antigen (PSA) failure and survival, the study adds.
A shorter time interval to PSA failure is associated with worse clinical outcomes, but specific factors defining this state are unknown. The researchers reported on unplanned post-hoc analyses from a larger trial and identified factors associated with shorter time to PSA failure among 250 patients with nonmetastatic unfavorable-risk PC. The researchers sought to measure cumulative incidence rates curves of PSA failure, defined as PSA nadir plus 2 ng/mL or initiation of salvage therapies. The researchers used Fine and Gray competing risks regression to assess prognostic association between these factors and time to PSA failure.
After a median follow-up of 10.2 years, the researchers found that baseline PSA of 10 ng/mL or greater, a Gleason score of 8–10, and being younger than 70 were associated with shorter time to PSA failure. The researchers combined these three factors to create a high-risk category associated with almost 3-fold higher risk compared to men without the three factors and a 43.8% risk of PSA failure at 3 years.
An accompanying editorial calls for risk stratification for early PC that also includes pathologic and genomic features of the PC and detailed patient assessment of fitness and comorbid disease to decide on the optimal intensity, type, and duration of treatment.