"I just wanted more": Hereditary cancer syndromes patients' perspectives on the utility of circulating tumour DNA testing for cancer screening.

Hereditary cancer syndromes (HCS) predispose individuals to a higher risk of developing multiple cancers. However, current screening strategies have limited ability to screen for all cancer risks. Circulating tumour DNA (ctDNA) detects DNA fragments shed by tumour cells in the bloodstream and can potentially detect cancers early. This study aimed to explore patients' perspectives on ctDNA's utility to help inform its clinical adoption and implementation. We conducted a qualitative interpretive description study using semi-structured phone interviews. Participants were purposively sampled adult HCS patients recruited from a Canadian HCS research consortium. Thirty HCS patients were interviewed (n = 19 women, age range 20s-70s, n = 25 were white). Participants were highly concerned about developing cancers, particularly those without reliable screening options for early detection. They "just wanted more" than their current screening strategies. Participants were enthusiastic about ctDNA's potential to be comprehensive (detect multiple cancers), predictive (detect cancers early) and tailored (lead to personalized clinical management). Participants also acknowledged ctDNA's potential limitations, including false positives/negatives risks and experiencing additional anxiety. However, they saw ctDNA's potential benefits outweighing its limitations. In conclusion, participants' belief in ctDNA's potential to improve their care overshadowed its limitations, indicating patients' support for using ctDNA in HCS care.

"I don't need any more unknowns hanging over my head": Views of patients with cancer on variants of uncertain significance and low/moderate risk results from genomic sequencing.

PURPOSE: We sought to explore patient-reported utility of all types of cancer results from genomic sequencing (GS). METHODS: Qualitative study, using semi-structured interviews with patients who underwent GS within a trial. Thematic analysis employing constant comparison was used. Two coders coded transcripts, with use of a third coder to resolve conflicts. RESULTS: 25 patients participated: female (22), >50 years (18), European (12), Ashkenazi Jewish (5), Middle Eastern (3), or other ethnicity (5), with breast cancer history (20). Patients' perceptions of the utility of cancer GS results hinged on whether they triggered clinical action. For example, when patients were enrolled into high-risk breast cancer surveillance programs for low/moderate risk breast cancer genes, they perceived the results to be very "useful" and of moderate-high utility. In contrast, patients receiving low/moderate risk or primary variants of uncertain significance results without clinical action perceived results as "concerning," leading to harms, such as hypervigilance about cancer symptoms. Overall, having supportive relatives or providers enhanced perceptions of utility. CONCLUSION: Patients' perceptions of cancer GS results hinged on whether they triggered clinical management. Consequently, patients who received results without clinical action became hypervigilant, experiencing harms. Our findings call for a need to develop practice interventions to support patients with cancer undergoing GS.

A model for the return and referral of all clinically significant secondary findings of genomic sequencing.

Secondary findings (SFs) identified through genomic sequencing (GS) can offer a wide range of health benefits to patients. Resource and capacity constraints pose a challenge to their clinical management; therefore, clinical workflows are needed to optimise the health benefits of SFs. In this paper, we describe a model we created for the return and referral of all clinically significant SFs, beyond medically actionable results, from GS. As part of a randomised controlled trial evaluating the outcomes and costs of disclosing all clinically significant SFs from GS, we consulted genetics and primary care experts to determine a feasible workflow to manage SFs. Consensus was sought to determine appropriate clinical recommendations for each category of SF and which clinician specialist would provide follow-up care. We developed a communication and referral plan for each category of SFs. This involved referrals to specialised clinics, such as an Adult Genetics clinic, for highly penetrant medically actionable findings. Common and non-urgent SFs, such as pharmacogenomics and carrier status results for non-family planning participants, were directed back to the family physician (FP). SF results and recommendations were communicated directly to participants to respect autonomy and to their FPs to support follow-up of SFs. We describe a model for the return and referral of all clinically significant SFs to facilitate the utility of GS and promote the health benefits of SFs. This may serve as a model for others returning GS results transitioning participants from research to clinical settings.

Review of Opioid Sparing Interventional Pain Management Options and Techniques for Radiofrequency Ablations for Sacroiliac Joint Pain.

PURPOSE OF REVIEW: The goal of this clinical review was to provide an update about the existing treatment options and associated evidence for various radiofrequency ablation techniques for sacroiliac joint pain. An electronic literature search on radiofrequency for the treatment of sacroiliac joint pain was conducted using PubMed, NCBI and Google Scholar. The following search keywords were used: radiofrequency ablation (cooled, pulsed, conventional, bipolar, intra-articular), sacroiliac joint and sacroiliac pain. The search was limited to human subjects, English language and articles with available full text. The bibliographic sections of all manuscripts were further searched for additional relevant citations. The full text of the relevant articles was reviewed by all the authors. RECENT FINDINGS: Our study showed that radiofrequency ablation is a safe and effective treatment option that can be utilized to manage sacroiliac joint pain. It offers accessibility to the primary care physician, reduces office visits with "pain" as the primary complaint and provides the added benefit of acting as a non-opioid sparing means of analgesia.

Clinical Radiofrequency Ablation Outcomes of Combined Sensory Nerve Branch and Dorsal Entry Root Zone Complex Lesions for Sacroiliac Joint Complex Pain.

BACKGROUND: Chronic lower back pain (LBP) with or without leg pain (LP) is the most commonly reported anatomical site of pain among Canadian adults with chronic pain. A common cause for LBP and LP arises from dysfunction of the sacroiliac joint (SIJ) complex. When conventional medical management or rehabilitative efforts for SIJ-related LBP and LP fail to provide analgesia, pulsed radiofrequency (PRF) and/or radiofrequency ablation (RFA) of the dorsal entry root zone complex lesions (DREZC) and/or their more peripheral branches can also be a suitable means for treatment. Both PRF and RFA are interventional techniques that utilize heat to attenuate or ablate transmission of painful signals, respectively. The purpose of this chart review is to explore the clinical outcomes of patients experiencing SIJ-related pain who have undergone procedures with combined sensory nerve branch RFA and DREZC PRF lesions targeting the SIJ complex. METHODS: Following institutional review board approval, a retrospective chart review was performed from June 2018 to February 2021 for patients with LBP and/or LP refractory to physical rehabilitative efforts and medical management that underwent combined PRF and RF treatments for a diagnosis of SIJ complex pain. RF and PRF procedures were anatomically guided with the addition of sensory stimulation to ensure appropriate needle placement. Charts were reviewed for percentage of analgesia at final follow-up, duration of effect, degree of analgesia, patients' functional improvements, and changes in medication use patterns. RESULTS: Data was reviewed from 180 patients with LBP or LP who underwent combined PRF and RF treatments for a diagnosis of SIJ complex pain. The group consisted of 69 men and 111 women with a mean age of 59 years. All patients had lesions to their dorsal roots and/or branches (lumbar medial and sacral lateral), as determined using their pain profile as well as sensory stimulation. In the sample of 180 patients a total of 276 SIJs were treated over the period of data collection. Overall, 85.0% (n = 234) of procedures were considered successful with more than 50% analgesic relief at final follow-up. Of 234 successful outcomes, 110 reported ongoing analgesia (mean = 80.3% pain relief, SD ± 18.0) on the last date of follow up (mean = 53.2 days, SD ± 41.8) prior to being lost to follow-up. For patients not lost to follow-up, the mean amount of analgesia was reported to be 83.9% with an average duration of 86.3 days. Among all treatments, 6.9% (n = 19) provided no analgesic effect. Among the successful procedure outcomes, 54.4% (n = 150) reported increased activity/mobility, 24.3% (n = 67) reported improved sleep, 49.3% (n = 136) reported improved mood, and 11.6% (n = 32) reported decreased medication usage. Nine patients reported complications following the procedure. Complications included transient soreness, bruising, tenderness, myofascial pain, and two mild vagal responses without lasting sequelae. CONCLUSION: This review suggests that combined sensory nerve branch RFA and DREZC PRF lesions targeting the SIJ complex is a suitable intervention to treat SIJ-related LBP and/or LP refractory to physical rehabilitative efforts and medical management. Approximately 85% of these cases were successfully treated with the majority of patients report lasting analgesic effects with minimal complications, supporting the use of sensory stimulation-guided combined RF and PRF lesions for treatment of refractory SIJ complex pain.

A comprehensive genomic reporting structure for communicating all clinically significant primary and secondary findings.

Genomic sequencing (GS) can reveal secondary findings (SFs), findings unrelated to the reason for testing, that can be overwhelming to both patients and providers. An effective approach for communicating all clinically significant primary and secondary GS results is needed to effectively manage this large volume of results. The aim of this study was to develop a comprehensive approach to communicate all clinically significant primary and SF results. A genomic test report with accompanying patient and provider letters were developed in three phases: review of current clinical reporting practices, consulting with genetic and non-genetics experts, and iterative refinement through circulation to key stakeholders. The genomic test report and consultation letters present a myriad of clinically relevant GS results in distinct, tabulated sections, including primary (cancer) and secondary findings, with in-depth details of each finding generated from exome sequencing. They provide detailed variant and disease information, personal and familial risk assessments, clinical management details, and additional resources to help support providers and patients with implementing healthcare recommendations related to their GS results. The report and consultation letters represent a comprehensive approach to communicate all clinically significant SFs to patients and providers, facilitating clinical management of GS results.

"Doctors shouldn't have to cheat the system": Clinicians' real-world experiences of the utility of genomic sequencing.

PURPOSE: Emerging genetic tests such as genomic sequencing (GS) can generate a broad range of benefits, but funding criteria only prioritize diagnosis and clinical management. There is limited evidence on all types of benefits obtained from GS in practice. We aimed to explore real-world experiences of Canadian clinicians across specialties on the full range of benefits obtained from the results from GS. METHODS: We conducted a qualitative study using semistructured interviews with Canadian clinicians. Transcripts were thematically analyzed using constant comparison. RESULTS: In total, 25 clinicians participated, including 12 geneticists, 7 genetic counselors, 4 oncologists, 1 neurologist, and 1 family physician. Although diagnoses and management were the most valued benefits of GS, clinicians also prioritized nontraditional utility, such as access to community supports. However, clinicians felt "restricted" by funding bodies, which only approved funding when GS would inform diagnoses and management. Consequently, clinicians sought ways to "cheat the system" to access GS (eg, research testing) but acknowledged workarounds were burdensome, drove inequity, and undermined patient care. CONCLUSION: Current governance structures undervalue real-world benefits of GS leading clinicians to adopt workarounds, which jeopardize patient care. These results support calls for the expansion of the definition of clinical utility and research to quantify the additional benefits.

Genetics Adviser: a protocol for a mixed-methods randomised controlled trial evaluating a digital platform for genetics service delivery.

INTRODUCTION: The high demand for genetic tests and limited supply of genetics professionals has created a need for alternative service delivery models. Digital tools are increasingly being used to support multiple points in the genetic testing journey; however, none are transferable across multiple clinical specialties and settings nor do they encompass the entire trajectory of the journey. We aim to evaluate the effectiveness of the Genetics Adviser, an interactive, patient-facing, online digital health tool that delivers pre-test counselling, provides support during the waiting period for results, and returns results with post-test counselling, encompassing the entire patient genetic testing journey. METHODS AND ANALYSIS: We will compare the Genetics Adviser paired with a brief genetic counselling session to genetic counselling alone in a randomised controlled trial. One hundred and forty patients who previously received uninformative genetic test results for their personal and family history of cancer will be recruited from familial cancer clinics in Toronto and offered all clinically significant results from genomic sequencing. Participants randomised into the intervention arm will use the Genetics Adviser to learn about genomic sequencing, receive pre-test counselling, support during the waiting period and results, supplemented with brief counselling from a genetic counsellor. Participants in the control arm will receive standard pre-test and post-test counselling for genomic sequencing from a genetic counsellor. Our primary outcome is decisional conflict following pre-test counselling from the Genetics Adviser+genetic counsellor or counsellor alone. Secondary outcomes include: knowledge, satisfaction with decision-making, anxiety, quality of life, psychological impact of results, empowerment, acceptability and economic impact for patients and the health system. A subset of patients will be interviewed to assess user experience. ETHICS AND DISSEMINATION: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System (REB#20-035). Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04725565.

Pulsed Radiofrequency in Interventional Pain Management: Cellular and Molecular Mechanisms of Action - An Update and Review.

BACKGROUND: Pulsed radiofrequency (PRF) treatment uses low energy, short pulsations to modulate tissue characteristics. PRF treatment has been effective as an interventional pain management technique to treat a variety of chronic neuropathic pain (neuralgia) disorders, but a comprehensive review of its biological mechanism has not been updated in a decade. OBJECTIVES: In this literature review, we performed a literature search in PubMed to identify publications describing the mechanisms of action of pulsed radiofrequency for pain indications. STUDY DESIGN: Narrative literature review. METHODS: A systematic search was performed through PubMed from database inception to December 31, 2019, to identify all articles addressing the cellular or molecular mechanisms of action of PRF on neuropathic pain. The search terms "pulsed radiofrequency" and "pulsed radiofrequency mechanisms" were used. Cellular and molecular mechanisms of PRF interventions were subdivided into 3 broad categories: nociceptive signalling, immune activity, and synaptic function. A total of 20 publications were identified for inclusion in this updated review. RESULTS: It was found that pulsed radiofrequency impacts many different biological pathways involved in the modulation of chronic neuropathic pain (neuralgia). With regards to nociceptive signalling, PRF treatment modulates ion channels (Na/K ATPase, HCN, P2X3), CGRP, neurotransmitters (aspartate, citrulline, M-ENK, glutamate), postsynaptic receptors (AMPA-R, GABA-B), and synaptic function (KCC2). PRF treatment also modulates immune activity, including microglial markers (CD3, CD56, Iba1), inflammatory cytokines (IL-6, IL-17, IRF8, IFN-g, TNFa), and intracellular proteins implicated in immune mediated neuropathic pain (BDNF, b-catenin, JNK, p38, ERK1/2). LIMITATIONS: This review is primarily limited by the diverse data sets that needed to be collated and correlated, as no study was comprehensive in addressing all markers, cytokines, pathways, neurotransmitters, ion channels, proteins, genes, and gene expression changes, along with their clinical outcomes concurrently. As such, the interplay of these individual pathways and mechanisms and their isolated effects on efficacy of PRF cannot be concluded. Rather, the large majority of findings can be seen as associations instead of definitive causal relationships to clinical outcomes. CONCLUSIONS: Herein describes a clinically relevant collated update describing the cellular and molecular mechanisms of action of PRF for pain management.