IMPORTANCE: Patients with germline mutations in BAP1 may develop several flesh-colored melanocytic BAP1–mutated atypical intradermal tumors (MBAITs). These tumors generally develop earlier than other ...BAP1–associated tumors, highlighting an important role for dermatologists in identifying and screening patients with a history suggestive of a germline mutation. OBJECTIVE: To describe 8 new families with germline mutations in BAP1 and provide a comprehensive review of reported cases. DESIGN, SETTINGS AND PARTICIPANTS: Patients were identified in an outpatient dermatology clinical setting over a 6-month period (10 mutation carriers from 8 families) and through a literature review using PubMed (205 patients). EXPOSURES: Mutations were identified through next-generation sequencing of saliva or blood samples, and RNA was extracted from fibroblasts cultured from a patient with an intronic variant to determine the impact of the mutation on the coding sequence. MAIN OUTCOMES AND MEASURES: All 215 patients were assessed for personal and/or family history and genotype. These findings were compiled and assessed for any association between genotype and phenotype. RESULTS: Overall, this study included 215 patients (108 women, 91 men, and 16 gender unspecified; median range age, 46.5 10.0-79.0 years). Nine of the 10 patients who were identified in the outpatient dermatology setting were found to have MBAITs on clinical examination. Forty of 53 patients (75%) identified in the literature review who underwent total-body skin examinations (TBSE) were found to have MBAITs, suggesting a high penetrance in patients who have undergone TBSE. The most prevalent malignancies among BAP1 mutation carriers were uveal melanoma (n = 60 28%), mesothelioma (n = 48 22%), cutaneous melanoma (n = 38 18%), and renal cell carcinoma (n = 20 9%). A total of 71 unique mutations in BAP1 have been reported. CONCLUSIONS AND RELEVANCE: Our results indicate that germline mutations in both coding and noncoding regions throughout the BAP1 gene can impair protein function, leading to an increased risk for several associated malignancies. Four of the 8 probands we present had no history of BAP1-associated malignancies and were assessed for germline mutations when found to have MBAITs on dermatologic examination. Dermatologists can identify patients with a high likelihood of the BAP1 cancer syndrome through personal and family history and TBSE for the presence of possible MBAITs.
Although guidelines recommend in-person counseling before BRCA1/BRCA2 gene testing, genetic counseling is increasingly offered by telephone. As genomic testing becomes more common, evaluating ...alternative delivery approaches becomes increasingly salient. We tested whether telephone delivery of BRCA1/2 genetic counseling was noninferior to in-person delivery.
Participants (women age 21 to 85 years who did not have newly diagnosed or metastatic cancer and lived within a study site catchment area) were randomly assigned to usual care (UC; n = 334) or telephone counseling (TC; n = 335). UC participants received in-person pre- and post-test counseling; TC participants completed all counseling by telephone. Primary outcomes were knowledge, satisfaction, decision conflict, distress, and quality of life; secondary outcomes were equivalence of BRCA1/2 test uptake and costs of delivering TC versus UC.
TC was noninferior to UC on all primary outcomes. At 2 weeks after pretest counseling, knowledge (d = 0.03; lower bound of 97.5% CI, -0.61), perceived stress (d = -0.12; upper bound of 97.5% CI, 0.21), and satisfaction (d = -0.16; lower bound of 97.5% CI, -0.70) had group differences and confidence intervals that did not cross their 1-point noninferiority limits. Decision conflict (d = 1.1; upper bound of 97.5% CI, 3.3) and cancer distress (d = -1.6; upper bound of 97.5% CI, 0.27) did not cross their 4-point noninferiority limit. Results were comparable at 3 months. TC was not equivalent to UC on BRCA1/2 test uptake (UC, 90.1%; TC, 84.2%). TC yielded cost savings of $114 per patient.
Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs.
As genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for ...hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling.
Methods include multivariable logistic regression and interaction analyses.
Of the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20-3.20), perceived stress (OR = 0.89, 95% CI: 0.81-0.98), knowledge (OR = 1.12, 95% CI: 1.02-1.23), and randomization group (OR = 1.48, 95% CI: 1.01-2.16). Further, race/ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing.
Evidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone.Genet Med 17 6, 467-475.
Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related ...malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes.
Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, and biochemical recurrence after treatment. Statistical analyses were conducted using the Kaplan-Meier method and Cox regression.
Among 855 evaluable patients, 300 (35.1%) patients had any family history of prostate cancer, and 95 (11.1%) had a family history of related malignancies suggestive of a hereditary cancer syndrome. Family history of prostate cancer alone was not associated with biopsy progression, whereas family history suggestive of a hereditary cancer syndrome was associated with a significantly increased risk of biopsy progression (HR 1.43, 95%CI 1.01-2.02), independent of other known clinicopathological risk factors in multivariable analysis. Similarly, family history suggestive of a hereditary cancer syndrome was associated with significantly lower treatment-free survival (HR 1.58, 95%CI 1.14-2.18) in multivariable analysis. No significant association was found between family history and adverse features on surgical pathology or biochemical recurrence.
An expanded family history suggestive of a hereditary cancer syndrome is an independent predictor of biopsy progression during active surveillance. Men with such a family history may still be offered active surveillance but should be counseled regarding the higher risk of disease progression.
Melanoma tumor syndromes (MTS) represent an important minority of familial melanoma cases. In these patients, the accumulation of sequence alterations in essential genes may prelude the risk of ...internal malignancies, in addition to melanoma. Although several host and environmental factors have been implicated in familial melanoma, the exact mechanisms of cancer predisposition—particularly in the context of mixed cancer syndromes—still remain unclear. In this paper, we review new insights into MTS and elucidate recent efforts that guide individualized prognostication and treatment for these diseases in the past quarter century.
Telephone genetic counseling (TC) for hereditary breast/ovarian cancer risk has been associated with positive outcomes in high risk women. However, little is known about how patients perceive TC. As ...part of a randomized trial of TC versus usual care (UC; in-person genetic counseling), we compared high risk women’s perceptions of: (1) overall satisfaction with genetic counseling; (2) convenience; (3) attentiveness during the session; (4) counselor effectiveness in providing support; and (5) counselor ability to recognize emotional responses during the session. Among the 554 participants (TC,
N
= 272; UC,
N
= 282), delivery mode was not associated with self-reported satisfaction. However, TC participants found counseling significantly more convenient than UC participants (OR = 4.78, 95 % CI = 3.32, 6.89) while also perceiving lower levels of support (OR = 0.56, 95 % CI = 0.40–0.80) and emotional recognition (OR = 0.53, 95 % CI = 0.37–0.76). In exploratory analyses, we found that non-Hispanic white participants reported higher counselor support in UC than in TC (69.4 % vs. 52.8 %; OR = 3.06, 95 % CI = 1.39–6.74), while minority women perceived less support in UC vs. TC (58.3 % vs. 38.7 %; OR = 0.80, 95 % CI = 0.39–1.65). We discuss potential research and practice implications of these findings which may further improve the effectiveness and utilization of TC.
This study presents the findings from the first 101 patients to complete the first round of screening in the PROGRESS trial. Interim results suggest that magnetic resonance imaging–alone screening ...strategies enhance early detection of prostate cancer in germline carriers of prostate cancer risk variants.
The risk of early-onset and clinically aggressive prostate cancer is elevated in carriers of certain rare pathogenic germline mutations. The utility of augmenting traditional prostate-specific antigen (PSA)-based screening measures with multiparametric magnetic resonance imaging (MRI) in this population is not yet known.
To evaluate MRI-based screening in comparison with traditional PSA-based screening among individuals at an elevated genetic risk for prostate cancer.
Male germline carriers of pathogenic/likely pathogenic variants in any of 19 prostate cancer risk genes between the ages of 35 and 74 yr with no prior history of prostate cancer were recruited.
Intervention
Enrolled participants underwent screening with annual PSA, digital rectal examination (DRE), and triennial multiparametric MRI. Individuals with abnormal DRE, elevated age-adjusted PSA (>1.5 ng/ml for 35–49 yr, >2.0 ng/ml for 50–54 yr, and >3.0 ng/ml for 55–74 yr), or suspicious multiparametric MRI (Prostate Imaging Reporting and Data System PI-RADS ≥3 lesion) were offered prostate biopsy.
Outcome measurements and statistical analysis
Endpoints were diagnosis of any and clinically significant prostate cancer, and alternative screening strategies were compared by a decision curve analysis.
To date, 101 males have completed the first round of screening. The greatest proportion of participants are carriers of BRCA2 (n = 44), BRCA1 (n = 35), and ATM (n = 7) variants. Twenty-one have undergone biopsy, resulting in the detection of nine cases of cancer (seven clinically significant). For the detection of clinically significant prostate cancer, abnormal MRI (PI-RADS ≥3) demonstrated 100% sensitivity (7/7) with a negative predictive value (NPV) of 100%, whereas PSA-based screening alone had 57% (4/7) sensitivity with an NPV of 73%. Of six screening strategies evaluated in the decision curve analysis, MRI-based screening alone achieved superior net benefit at all threshold probabilities compared with PSA screening—detecting one additional cancer case per 7.5 patients, while avoiding more unnecessary biopsies at the same threshold probability.
Disease prevalence is high among carriers of prostate cancer–associated pathogenic germline mutations. Early results suggest that MRI-based screening enhances early detection of clinically significant disease beyond PSA screening alone.
In this study, we present the interim results from the PROGRESS prostate cancer screening trial. We found that in certain germline carriers of prostate cancer risk mutations, magnetic resonance imaging–based screening enhances detection of prostate cancer while reducing biopsies triggered, in comparison with traditional prostate-specific antigen screening strategies.
Animal studies have shown that large volumes of IV lactated Ringerʼs solution (LR) decrease serum osmolality, thereby increasing cerebral water.These studies have led to recommendations to limit LR ...to avoid cerebral edema in neurosurgical patients. Eighteen healthy human volunteers aged 20-48 yr received 50 mL/kg LR over 1 h on one occasion and 0.9% sodium chloride (NS) on another. Venous samples were taken at baseline (T1), at infusion end (T2), and 1 h after T2 (T3). Time until first urination was noted. With LR, serum osmolality decreased by 4 +/- 3 mOsm/kg from T1 to T2 and increased insignificantly with NS. At T3, osmolality returned almost to baseline in the LR group. Blood pH increased from T1 to T2 with LR by 0.04 +/- 0.04 and decreased with NS by 0.04 +/- 0.04. These pH changes persisted at T3. Subjective mental changes occurred only with NS. Abdominal discomfort was more common with NS. Time until first urination was longer with NS (106 +/- 11 min) than with LR (75 +/- 10 min) (P < 0.001). In healthy humans, an infusion of large volumes of LR, but not NS, transiently decreased serum osmolality, whereas acidosis associated with NS persisted and urinary output was slower with NS. ImplicationsLarge volumes of lactated Ringerʼs solution administered to healthy humans produced small transient changes in serum osmolality. Large volumes of sodium chloride did not change osmolality but resulted in lower pH.(Anesth Analg 1999;88:999-1003)
Telephone genetic counseling (TC) for high-risk women interested in
BRCA1/
2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, ...little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5-item genetic counselor process questionnaire (GCQ) assessing key elements of pre-test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision-making) with the 479 female participants (TC, N = 236; UC, N = 243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11,
p
= 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (β = 0.172,
p
< 0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21,
p
= 0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non-Hispanic Whites). We discuss other potential clinical and research implications of our findings.
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