In 2012, the US Preventive Services Task Force (USPSTF) discouraged prostate-specific antigen (PSA) -based prostate cancer screening. Previous USPSTF recommendations did not appreciably alter ...prostate cancer screening. Therefore, we designed a trend analysis to determine the population-based impact of the 2012 recommendation.
The nationally representative National Health Interview Survey was used to estimate the proportion of men age 40 years and older who saw a physician and were screened for prostate cancer in 2013. An externally validated 9-year mortality index was used to analyze screening rates based on remaining life expectancy. Screening rates from 2005, 2010, and 2013 were compared using logistic regression.
PSA-based screening did not significantly change from 2010 to 2013 among 40- to 49-year-old men (from 12.5% to 11.2%; P = .4). Screening rates significantly declined in men age 50 to 59 years (from 33.2% to 24.8%; P < .01), age 60 to 74 years (from 51.2% to 43.6%; P < .01), and age 75 years or older (from 43.9% to 37.1%; P = .03). A large percentage of men were screened for prostate cancer despite a high risk (> 52%) of 9-year mortality, including approximately one third of men older than age 75 years. Approximately 1.4 million men age 65 years or older with a high risk (> 52%) of 9-year mortality were screened in 2013.
Prostate cancer screening significantly declined among men older than age 50 years after the 2012 USPSTF guideline discouraging PSA-based screening. A significant proportion of men continue to be screened despite a high risk of 9-year mortality, including one third of men age 75 years and older.
Expansion of cDC cells via FLT3 agonism has promising therapeutic potential in the treatment of advanced solid tumors. Here, we discuss the results of a clinical trial using GS-3583, an FLT3 agonist, ...that was stopped after a patient in the study developed acute myeloid leukemia.
Comprehensive genomic profiling of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cases have enabled the detection and differentiation of driver and subclonal mutations, informed ...risk prognostication, and defined targeted therapies. These insights into disease biology, and management have made multigene-acquired mutation testing a critical part of the diagnostic assessment of patients with sporadic MDS and AML. More recently, our understanding of the role of an increasing number of inherited genetic factors on MDS/AML risk and management has rapidly progressed. In recognition of the growing impact of this field, clinical guidelines and disease classification systems for both MDS and AML have recently incorporated familial MDS/AML predisposition syndromes into their diagnostic algorithms. In this perspective piece, we contemplate the advantages, disadvantages, and barriers that would need to be overcome to incorporate inherited MDS/AML genetic testing into the upfront molecular diagnostic work-up of every MDS/AML patient. For centers already performing panel-based tumor-only testing, including genes associated with familial forms of MDS/AML (e.g., RUNX1, CEBPA, GATA2, TP53), we advocate optimizing these tests to detect all types of germline variants in these genes and moving toward upfront paired tumor/germline testing to maximize detection and streamline patient care.
In this review, we provide an overview of familial myelodysplastic syndromes (MDS)/acute leukemia (AL) and bone marrow failure syndromes, as well as insights into familial myeloproliferative ...neoplasms (MPNs), familial multiple myeloma (MM), familial Waldenström macroglobulinemia (WM), familial lymphoma, and cancer predisposition syndromes with increased risk of MDS/AL. This field will continue to accelerate as next-generation sequencing (NGS) techniques identify novel predisposition alleles in families with a genetic predisposition to hematologic malignancies. Newly identified predisposition genes continue to inform the field of inherited leukemia and other hematologic malignancies. Current developments in clinical translation include techniques detailing the acquisition of appropriate germline material for patient work-ups, methods for genetic testing, and nuances essential for the treatment and clinical management of patients with a genetic predisposition to hematologic malignancies.
To determine the degree of testing consistency among commercially available diagnostic assays for hereditary hematopoietic malignancies (HHMs).
Next-generation sequencing assays designed for the ...diagnosis of HHMs were studied to determine which genes were sequenced, their ability to detect variant types relevant for HHMs, and clinical-grade characteristics such as price, turnaround time, and tissue types accepted.
Commercial assays varied in price (USD 250–4702), number of genes sequenced (12–73), and average turnaround time (14–42 days). A number of nongermline tissue types were accepted despite the tests being designed for germline diagnostic purposes. Multiple genes with well-characterized roles in HHM pathogenesis were omitted from more than one-third of panels intended for the evaluation of HHMs. Only 4 of 82 genes were consistently covered across all HHM diagnostic panels. The assays were highly variable in their sensitivity for structural alterations relevant to HHMs, such as copy-number variants.
A high degree of diagnostic heterogeneity exists among commercially available HHM diagnostic assays. Many of these assays are incapable of detecting the full spectrum of HHM-associated variants, leaving patients vulnerable to the consequences of underdiagnosis, missed opportunities for screening, and the potential for donor-derived malignancies.
Background
This study aimed to investigate if peritoneal mesothelioma (PM) patients with germline mutations (GM) have distinct surgical characteristics when compared to those without GM.
Methods
PM ...patients were selected from an ongoing prospective study that conducts germline testing of 82 susceptibility genes. Germline status was correlated with surgical data obtained from a prospectively collected database using univariate, multivariate, and receiver operating characteristic (ROC) analyses.
Results
Out of 88 PM patients enrolled between 2009 and 2019, 18 GMs (20.5%) were identified in BRCA1‐associated protein 1 (BAP1) (n = 11, 12.5% of all patients), SDHA (n = 2) and WT1, CDKN2A, CHEK2, ATM, and BRCA2 (n = 1 patient each). Surgical procedures were performed in 71 patients, the most common of which were cytoreductive surgeries with hyperthermic intraperitoneal chemotherapy (n = 61). Patients with GM presented with a higher prevalence of other prior cancers (61.1% vs. 31.4%, p = .02) and lower platelet count (251 160–413 vs. 367 196–780 K/µL, p = .005) compared to those without GM (n = 70). Survival outcomes did not differ significantly between the groups. Patients with BAP1 GMs were more likely to develop bicavitary disease and to present with lower platelet count and mitotic count score, and higher peritoneal cancer index (PCI, all p ≤ .04) compared with those without GM. On ROC analysis, the combination of PCI, platelet count and mitotic score yielded an area under the curve of 0.96 (95% CI, 0.91–1.0) for BAP1 GM detection among operated PM patients.
Conclusion
Higher intraoperative tumor burden and lower platelet count and mitotic score are suggestive of BAP1 GMs in surgical PM patients and should prompt germline testing.
Surgical peritoneal mesothelioma patients who carry a BRCA1‐associated protein 1 germline mutation were found to have a distinctive phenotype characterized by a higher incidence of bicavitary disease, lower platelet count at diagnosis, unique pathological features (including lower mitotic count), and a higher tumor burden found during their surgery.
A growing understanding of the complexities of hematopoietic malignancies necessitates the existence of clinical recommendations that are sufficiently comprehensive. Although hereditary hematopoietic ...malignancies (HHMs) are increasingly recognized for conferring risk of myeloid malignancy, frequently utilized clinical recommendations have never been appraised for the ability to reliably guide HHM evaluation. We assessed established society-level clinical guidelines for inclusion of critical HHM genes and graded the strength of testing recommendations. We uncovered a substantial lack of consistency of recommendations guiding HHM evaluation. Such heterogeneity in guidelines likely contributes to refusal by payers to support HHM testing, leading to underdiagnoses and lost opportunities for clinical surveillance.
For patients who elect to have prostate cancer screening, the optimal time to discontinue screening is unknown. Our objective was to describe rates and predictors of prostate-specific antigen (PSA) ...screening among older men in the United States.
Data were extracted from the population-based 2000 and 2005 National Health Interview Survey (NHIS). PSA screening was defined as a PSA test as part of a routine exam within the past year. Demographic, socioeconomic, and functional characteristics were collected, and a validated 5-year estimated life expectancy was calculated. Age-specific rates of PSA screening were determined, and sampling weight-adjusted multivariate regressions were fitted to determine predictors of screening among men age 70 years or older.
The PSA screening rate was 24.0% in men age 50 to 54 years, and it increased steadily with age until a peak of 45.5% among age 70 to 74 years. Screening rates then gradually declined by age, and 24.6% of men age 85 years or older reported being screened. Among men age 70 years or older, screening rates varied by estimated 5-year life expectancy: rates were 47.3% in men with high life expectancies (≤ 15% probability of 5-year mortality), 39.2% in men with intermediate life expectancies (16% to 48% probability), and 30.7% in men with low life expectancies (> 48% probability; P < .001). In multivariate analysis, estimated life expectancy and age remained independently associated with PSA screening (P < .001 for each).
Rates of PSA screening in the United States are associated with age and estimated life expectancy, but excessive PSA screening in elderly men with limited life expectancies remains a significant problem. The merits and limitations of PSA should be discussed with all patients considering prostate cancer screening.
•Deleterious germ line predisposition variants are shared in patients with MDS and their related donors and occur at all ages.•Based on the significant frequency of germ line variants in MDS, genetic ...testing is recommended for all patients.
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The frequency of pathogenic/likely pathogenic (P/LP) germ line variants in patients with myelodysplastic syndrome (MDS) diagnosed at age 40 years or less is 15% to 20%. However, there are no comprehensive studies assessing the frequency of such variants across the age spectrum. We performed augmented whole-exome sequencing of peripheral blood samples from 404 patients with MDS and their related donors before allogeneic hematopoietic stem cell transplantation. Single-nucleotide and copy number variants in 233 genes were analyzed and interpreted. Germ line status was established by the presence of a variant in the patient and related donor or for those seen previously only as germ line alleles. We identified P/LP germ line variants in 28 of 404 patients with MDS (7%), present within all age deciles. Patients with P/LP variants were more likely to develop higher-grade MDS than those without (43% vs 25%; P = .04). There was no statistically significant difference in outcome parameters between patients with and without a germ line variant, but the analysis was underpowered. P/LP variants in bone marrow failure syndrome genes were found in 5 patients aged less than 40 years, whereas variants in DDX41 (n = 4), telomere biology disorder genes (n = 2), and general tumor predisposition genes (n = 17) were found in patients aged more than 40 years. If presumed germ line variants were included, the yield of P/LP variants would increase to 11%, and by adding suspicious variants of unknown significance, it would rise further to 12%. The high frequency of P/LP germ line variants in our study supports comprehensive germ line genetic testing for all patients with MDS regardless of their age at diagnosis.
Widespread adoption of next-generation sequencing in myeloid malignancies is revealing the importance of inherited germ line predisposition disorders (GPDs). Feurstein and colleagues demonstrate that approximately 7% of patients with myelodysplastic dis-orders carry a pathogenic or likely pathogenic germ line variant associated with GPDs. This surprisingly high frequency has implications as to when germ line testing should be considered in this disease.
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