Prognostic imagination: Genetic counseling amidst therapeutic innovation and evolving futures.

Despite the moniker "precision medicine," genetic diagnoses are often imprecise with respect to prognosis. In a period when prognoses are evolving in lockstep with advances in genetic diagnostics and therapeutics, it is critical that clinicians and researchers consider how prognosis is communicated beyond the moment of diagnosis. Research has shown that genetic diagnoses are described differently in pre- and postnatal contexts, but we know relatively little about how patients and families make sense of prognostic information as affected children grow up. Here, I draw on research and personal narratives to describe how prognostic information impacts individuals' conceptions of the future. A deeper understanding of how patients and families view prognosis is important because parents may need support as prognostic conversations arise and because perceptions of prognosis may influence ideas about the future, psychological health, decisions, and planning. By exploring how specific ideas about an individuals' future take hold, clinicians and researchers may begin to identify the benefits, harms, and accuracy of varied sources of prognostic information, opening new areas of bioethical investigation. In closing, I propose prognostic imagination as a useful concept for considering how patients and families experience prognostic information amidst therapeutic innovations and evolving futures.

Summary of the experiences, knowledge, medical management, and family communication of monoallelic MUTYH carriers.

Germline genetic testing for inherited cancer risk is increasingly being performed with multigene panel testing with MUTYH often included on colorectal cancer- and polyposis-focused panels, as well as on broader pan-cancer panels. With up to 1%-2% of the general population being monoallelic MUTYH carriers, pathogenic/likely pathogenic (P/LP) variants in MUTYH are one of the most common findings on multigene cancer panels. However, little is known about patient experience and understanding of monoallelic MUTYH P/LP variants, nor whether such findings influence medical management recommendations and familial communication, which this study aims to better understand. Monoallelic P/LP MUTYH carriers were recruited from the Prospective Registry of Multiplex Testing (PROMPT) and completed a cross-sectional self-report survey on sociodemographic characteristics, medical and family history, experiences with MUTYH genetic testing, genetics and MUTYH knowledge, perceived cancer risk, and familial communication. Of 115 eligible PROMPT participants, 49 (43%) completed the survey who were primarily female (94%), white (96%), had a history of cancer (61%), and a median age of 51.4 years. Most participants (61%) reported satisfaction with how their healthcare provider managed their genetic test result and care, and 65% of survey participants reported their provider recommended colonoscopy based on their genetic test results. Participants' responses also reflected variable levels of knowledge regarding cancer risks and screening recommendations for MUTYH carriers. The majority (98%) of participants shared their genetic test results with at least some of their relatives; however, only 13% of eligible relatives reportedly underwent cascade testing. Taken together, this study provides needed insight into the overall experiences of monoallelic MUTYH carriers and highlights numerous areas for improvement in clinician education, communication, and management of these individuals.

The Impact of Transmissible Microbes: How the Cystic Fibrosis Community Mobilized Against Cepacia.

Long before COVID-19 made social distancing familiar, people with cystic fibrosis (CF) already practiced such behaviors. CF is held up as a classic example of genetic disease, yet people with CF are also susceptible to bacteria from the environment and from other CF patients. Starting in the 1980s, a bacterial epidemic in the CF population highlighted clashing priorities of connection, physical safety, and environmental protection. Policymakers ultimately called for the physical separation of people with CF from one another via recommendations that reconfigured the CF community. Simultaneously, medical researchers recognized that one highly transmissible CF pathogen called cepacia was being developed for environmental applications and got the EPA to limit cepacia's environmental deployment. Environmental regulations speak to the challenge of useful microbes that harm a minority, but CF cross-infection also involves legal implications for microbial and genetic discrimination, social consequences for CF communities, and ethical questions about balancing autonomy, harms, and benefits. As scientists increasingly study connections between host genetics, microbial genetics, and infectious risks, CF is a vital referent.

Uptake and acceptability of a mainstreaming model of hereditary cancer multigene panel testing among patients with ovarian, pancreatic, and prostate cancer.

PURPOSE: To address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone. METHODS: Among 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model. RESULTS: Only 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (pTime < 0.001; pTime2 < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty. CONCLUSION: This mainstreaming model may offer a feasible approach for extending access to germline genetic information.

Exploring Family Nurse Practitioners' Practices in Recommending mHealth Apps to Patients.

Patients frequently download mHealth apps, which can be used to support health promotion. It remains unclear, however, if family nurse practitioners are recommending apps to patients. This study identified family nurse practitioners' current practices of recommending apps to patients and described their use and intent to use mHealth apps for health promotion with their patients. Nearly 70% of the 303 participants surveyed recommended mHealth apps to their patients, with the most common types comprising patient portal, diet and nutrition, and fitness apps. However, the frequency with which apps were recommended was low. Participants reported that apps complement patient care, enable health promotion behaviors, are easy to use, and improve clarity of patient data. These factors facilitated their intent to recommend mHealth apps to patients. Healthcare organizational support influenced participants' intent to recommend apps, and access to trustworthy apps and electronic health records compatibility increased usage. Barriers to recommending involved patient-specific characteristics and provider concerns about reliability, privacy, and efficacy of apps. Family nurse practitioners must be supported in guiding patients to use reliable, safe, and HIPAA-compliant apps. To help engage patients, clinicians should be educated on methods to evaluate mHealth apps and how to incorporate them into patient care.

Genetic counseling and oncology: proposed approaches for collaborative care delivery.

Demand for cancer genetic counseling has grown rapidly in recent years as germline genomic information has integrated into cancer care. There are currently an insufficient number of genetic counselors (GC) to address genetic testing need through traditional pre- and post-test counseling. Alternative genetic counseling frameworks, discussed here, are under study to increase access to genetic testing while optimizing the skillsets of existent master's-trained GCs.

Catalysts towards cancer risk management action: A longitudinal study of reproductive-aged women with BRCA1/2 mutations.

Deleterious mutations in BRCA1 or BRCA2 genes increase a woman's lifetime risk of breast and ovarian cancer. Risk management guidelines endorse early detection and prevention behaviors. Despite expressed intent, uptake of these measures remains low. This longitudinal, qualitative study integrated retrospective and prospective data to distinguish factors shaping intent to act from those that are catalysts to taking action to reduce cancer risk. Twelve BRCA1/2 mutation-positive women participating in the National Cancer Institute's Breast Imaging Study aged 18-35 completed two semi-structured interviews three years apart. Researchers completed focused coding to identify points of behavioral intent and action and contextual factors acting as catalysts upon participant narratives. All women shared only two action steps: seeking information about cancer risk and completing genetic testing. The constellation of action steps created a unique action trajectory that was defined, with precise ideas about risk perception and clear behavioral response, or iterative, in which unanticipated life events shifted the speed, accessibility, or order in which risk management and family planning goals were prioritized, planned, or executed. Factors shifting action steps included salient, unanticipated life events, such as infertility, insurance/financial constraints, birth of the last child, or a relative's cancer diagnosis. Focus on cancer morbidity may obfuscate how women prioritize actions, and ignore varied pragmatic, relational, and social factors affecting how intended actions are completed, particularly during the reproductive years. We recommend providers update patients' risk management plans at each visit to assess readiness for next steps and reduce reluctance to discuss, or guilt associated with, change.

Longitudinal cancer risk management trajectories of BRCA1/2 mutation-positive reproductive-age women.

Young women with BRCA1/2 mutations face difficult health-care decisions regarding family formation, fertility, breastfeeding, and whether/when to undergo cancer risk-reducing surgery. This longitudinal qualitative study investigated these life choices during the reproductive years. We conducted two semistructured interviews over three years with 12 reproductive-age BRCA1/2-positive women. Researchers coded transcripts to examine the evolution of risk perceptions, risk management, and family planning decisions. To cope with the conflict between cancer risk reduction versus plans for pregnancy, breastfeeding, and child rearing, participants deliberately prioritized either risk reducing surgery or family formation goals. Implications for mutation carriers and health-care providers are outlined.

Utilizing Remote Real-Time Videoconferencing to Expand Access to Cancer Genetic Services in Community Practices: A Multicenter Feasibility Study.

BACKGROUND: Videoconferencing has been used to expand medical services to low-access populations and could increase access to genetic services at community sites where in-person visits with genetic providers are not available. OBJECTIVE: To evaluate the feasibility of, patient feedback of, and cognitive and affective responses to remote two-way videoconferencing (RVC) telegenetic services at multiple sociodemographically diverse community practices without access to genetic providers. METHODS: Patients at 3 community sites in 2 US states outside the host center completed RVC pretest (visit 1, V1) and post-test (visit 2, V2) genetic counseling for cancer susceptibility. Surveys evaluated patient experiences, knowledge, satisfaction with telegenetic and cancer genetics services, anxiety, depression, and cancer worry. RESULTS: A total of 82 out of 100 (82.0%) approached patients consented to RVC services. A total of 61 out of 82 patients (74%) completed pretest counseling and 41 out of 61 (67%) proceeded with testing and post-test counseling. A total of 4 out of 41 (10%) mutation carriers were identified: BRCA2, MSH2, and PMS2. Patients reported many advantages (eg, lower travel burden and convenience) and few disadvantages to RVC telegenetic services. Most patients reported feeling comfortable with the video camera--post-V1: 52/57 (91%); post-V2: 39/41 (95%)--and that their privacy was respected--post-V1: 56/57 (98%); post-V2: 40/41 (98%); however, some reported concerns that RVC might increase the risk of a confidentiality breach of their health information--post-V1: 14/57 (25%); post-V2: 12/41 (29%). While the majority of patients reported having no trouble seeing or hearing the genetic counselor--post-V1: 47/57 (82%); post-V2: 39/41 (95%)--51 out of 98 (52%) patients reported technical difficulties. Nonetheless, all patients reported being satisfied with genetic services. Compared to baseline, knowledge increased significantly after pretest counseling (+1.11 mean score, P=.005); satisfaction with telegenetic (+1.74 mean score, P=.02) and genetic services (+2.22 mean score, P=.001) increased after post-test counseling. General anxiety and depression decreased after pretest (-0.97 mean anxiety score, P=.003; -0.37 mean depression score, P=.046) and post-test counseling (-1.13 mean anxiety score, P=.003; -0.75 mean depression score, P=.01); state anxiety and cancer-specific worry did not significantly increase. CONCLUSIONS: Remote videoconferencing telegenetic services are feasible, identify genetic carriers in community practices, and are associated with high patient satisfaction and favorable cognitive and affective outcomes, suggesting an innovative delivery model for further study to improve access to genetic providers and services. Potential barriers to dissemination include technology costs, unclear billing and reimbursement, and state requirements for provider licensure.

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.

PURPOSE: Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. METHODS: Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing. RESULTS: In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing. CONCLUSION: A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.

Langerhans cell histiocytosis of the auditory canal detected by 18F-FDG PET/CT.

A 24-year-old woman presented with recurrent bilateral ear infections since childhood and a more recent history of partial hearing loss, discharge, and ear pain. Biopsy of the left external auditory canal revealed Langerhans cell histiocytosis. An F-FDG PET/CT was done to look for additional sites of disease. Increased metabolic activity was seen within both external ear canals.

Accumulation of intrahepatic islet amyloid in a nonhuman primate transplant model.

Islet amyloid is hypothesized to play a role in nonimmunologic transplanted islet graft loss. We performed a quantitative histologic analysis of liver biopsies from intrahepatic islet grafts transplanted in streptozotocin-induced diabetic cynomolgus macaques. Seven animals treated with antithymocyte globulin (ATG) and rapamycin or ATG and rituximab experienced islet graft rejection with lymphocytic infiltrates present on islet graft biopsies. Except for one case involving the oldest and largest donor where amyloid was present on initial biopsy 1 month after transplant, none of the six other cases with rejection contained amyloid, including one case biopsied serially to 25 months. In contrast, four out of six animals treated with ATG and rituximab and rapamycin had no evidence of rejection at the time of biopsy (two animals that discontinued rapamycin had mild periislet lymphocytes), and all four cases followed more than 4 months demonstrated amyloid deposition at subsequent time points. Amyloid severity increased with time after transplant (r = 0.68; P < 0.05) and with decreasing islet ß-cell area (r = -0.68; P < 0.05). In two islet recipients with no evidence of rejection and still normoglycemic and insulin independent at the first detection of amyloid, ß-cell secretory capacity declined over time coincident with increasing amyloid severity and decreasing ß-cell area, with both animals eventually becoming hyperglycemic and insulin dependent. Transplanted islet amyloid also developed in autologous islets placed sc. These results indicate that in cynomolgus macaques, transplanted islets may accumulate amyloid over time associated with subsequent decline in ß-cell mass and function and support the development of intrahepatic islet amyloid as a potential mechanism for nonimmunologic islet graft loss.

Is cystic fibrosis genetic medicine's canary?

In 1989 the gene that causes cystic fibrosis (CF) was identified in a search accompanied by intense anticipation that the gene, once discovered, would lead rapidly to gene therapy. Many hoped that the disease would effectively disappear. Those affected were going to inhale vectors packed with functioning genes, which would go immediately to work in the lungs. It was a bewitching image, repeatedly invoked in both scientific and popular texts. Gene therapy clinical trials were carried out with a range of strategies and occasionally success seemed close, but by 1996 the idea that gene therapy for CF would quickly provide a cure was being abandoned by the communities engaged with treatment and research. While conventional wisdom holds that the death of Jesse Gelsinger in an unrelated gene therapy trial in 1999 produced new skepticism about gene therapy, the CF story suggests a different trajectory, and some different lessons. This article considers the rise and fall of gene therapy for CF and suggests that CF may provide a particularly compelling case study of a failed genomic technology, perhaps even of a medical "canary." The story of CF might be a kind of warning to us that genetic medicine may create as many problems as it solves, and that moving forward constructively with these techniques and practices requires many kinds of right information, not just about biology, but also about values, priorities, market forces, uncertainty, and consumer choice.

Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes.

Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.