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Purpose Several professional organizations recommend universal genetic assessment for people with ovarian cancer as identifying pathogenic variants can affect treatment, prognosis, and all-cause mortality for patients and relatives. We sought to evaluate the literature on genetic assessment for women with ovarian cancer and determine if any interventions or patient characteristics drive utilization of services. Methods We searched key electronic databases to identify trials that evaluated genetic assessment for people with ovarian cancer. Trials with the primary aim to evaluate utilization of genetic assessment with or without interventions were included. Eligible trials were subjected to meta-analysis and the moderating influence of health interventions on rates of genetic assessment were examined. Results A total of 35 studies were included (19 report on utilization of genetic services without an intervention, 7 with an intervention, and 9 with both scenarios). Without an intervention, pooled estimates for referral to genetic counseling and completion of genetic testing were 39% [CI 27–53%] and 30% [CI 19–44%]. Clinician-facilitated interventions included: mainstreaming of genetic services (99% [CI 86–100%]), telemedicine (75% [CI 43–93%]), clinic-embedded genetic counselor (76% [CI 32–95%]), reflex tumor somatic genetic assessment (64% [CI 17–94%]), universal testing (57% [28–82%]), and referral forms (26% [CI 10–53%]). Random-effects pooled proportions demonstrated that Black vs. White race was associated with a lower rate of genetic testing (26%[CI 17–38%] vs. 40% [CI 25–57%]) as was being un-insured vs. insured (23% [CI 18–28%] vs. 38% [CI 26–53%]). Conclusions Reported rates of genetic testing for people with ovarian cancer remain well below the goal of universal testing. Interventions such as mainstreaming can improve testing uptake. Strategies aimed at improving utilization of genetic services should consider existing disparities in race and insurance status.

PURPOSEDespite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information.METHODSUsing a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size.RESULTSThe time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations.CONCLUSIONPeridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

The literature demonstrates that the quality of cancer family history (CFH) as currently collected in the outpatient setting is inadequate to assess disease risk. Prior to implementation of a web-based application for cancer family history collection, we aimed to review the quality of collected CFH in a gynecologic oncology outpatient clinic and determine contributing patient factors. Medical records were reviewed for 200 new patients presenting between 4/2019-7/2019. CFH was collected during the patient interview and evaluated for inclusion of eight elements based on standards set by the genetics community. Univariate and multivariable linear regression analyses were utilized to evaluate the effect of patient characteristics on the number of relatives included in the CFH. Among our cohort of 200 patients, CFH was documented for 185 patients (92.5%). On univariate analysis, patients with a family history of cancer and prior genetic testing had significantly greater median number of relatives included in the CFH. On multivariable analysis, patients with family members with cancer had significantly more relatives included. Our data are consistent with the literature, suggesting that the current collection methods may not adequately capture all measures of a high quality CFH. Patients reporting no family history of cancer and those without prior genetic testing were least likely to have CFH that included key quality elements and these patients might benefit from health information technology CFH collection tools.

We conducted an updated economic evaluation, from a healthcare system perspective, to compare the relative effectiveness and efficiency of eight Lynch syndrome (LS) screening protocols among newly diagnosed colorectal cancer (CRC) patients. We developed decision analytic models for a hypothetical cohort of 1000 patients. Model assumptions and parameter values were based on literature and expert opinion. All costs were in 2018 USD. For identifying LS cases, the direct germline sequencing (DGS) protocol provided the best performance (sensitivity 99.90%, 99.57–99.93%; specificity 99.50%, 97.28–99.85%), followed by the tumor sequencing to germline sequencing (TSGS) protocol (sensitivity, 99.42%, 96.55–99.63%; specificity, 96.58%, 96.46–96.60%). The immunohistochemistry (IHC) protocol was most efficient at $20,082 per LS case identified, compared to microsatellite instability (MSI) ($22,988), DGS ($31,365), and TSGS ($104,394) protocols. Adding double-somatic testing to IHC and MSI protocols did not change sensitivity and specificity, increased costs by 6% and 3.5%, respectively, but reduced unexplained cases by 70% and 50%, respectively. DGS would be as efficient as the IHC protocol when the cost of germline sequencing declines under $368 indicating DGS could be an efficient option in the near future. Until then, IHC and MSI protocols with double-somatic testing would be the optimal choices.

PURPOSE Collection of family cancer histories (FCHs) can identify individuals at risk for familial cancer syndromes. The aim of this study is to evaluate the literature on existing strategies whereby providers use information technology to assemble FCH. METHODS A systematic search of online databases (Ovid MEDLINE, Cochrane, and Embase) between 1980 and 2020 was performed. Statistical heterogeneity was assessed through the chi-square test (ie, Cochrane Q test) and the inconsistency statistic (I2). A random-effects analysis was used to calculate the pooled proportions and means. RESULTS The comprehensive search produced 4,005 publications. Twenty-eight studies met inclusion criteria. Twenty-seven information technology tools were evaluated. Eighteen out of 28 studies were electronic surveys administered before visits (18, 64.3%). Five studies administered tablet surveys in offices (5, 17.8%). Four studies collected electronic survey via kiosk before visits (4, 14.3%), and one study used animated virtual counselor during visits (1, 3.6%). Among the studies that use an FCH tool, the pooled estimate of the overall completion rate was 86% (CI, 72% to 96%), 84% (CI, 65% to 97%) for electronic surveys before visits, 89% (CI, 0.74 to 0.98) for tablet surveys, and 85% (CI, 0.66 to 0.98) for surveys via kiosk. Mean time required for completion was 31.0 minutes (CI, 26.1 to 35.9), and the pooled estimate of proportions of participants referred to genetic testing was 12% (CI, 4% to 23%). CONCLUSION Our review found that electronic FCH collection can be completed successfully by patients in a time-efficient manner with high rates of satisfaction.

PURPOSE OF REVIEW: Next-generation sequencing is becoming more accessible. This review focuses on the clinical application of somatic and germline sequencing to genitourinary oncology. RECENT FINDINGS: Germline variants have been increasingly recognized as contributing to the development of genitourinary malignancies, particularly in patients with advanced disease. A variety of commercial and institutional technologies are in use to detect variants, with newer tools focused on integrating these results into the clinical workflow. SUMMARY: DNA sequencing is becoming a valuable tool in caring for patients with genitourinary malignancies. Performing both somatic and germline sequencing will likely become standard practice. Interpretation and clinical application of these results can be challenging and often requires multidisciplinary expertise.

e17597 Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.

10592 Background: Evidence-based guidelines recommend that patients (probands) diagnosed with a hereditary cancer syndrome share the information with blood relatives as relatives can have 50% risk for harboring the same pathogenic mutation. This information offers the opportunity for relatives to undergo genetic counseling, genetic testing, early detection, and prevention of cancer. Limited literature on this topic suggests underutilization of recommended family member disclosure. We sought to evaluate rates of familial disclosure of hereditary cancer syndrome information in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines (PROSPERO no.: CRD42020134276). We searched key electronic databases to identify studies evaluating hereditary cancer cascade relative disclosure. Eligible trials were subjected to meta-analysis. Results: Thirty studies met inclusion criteria. This review included 3,779 probands and 12,751 at-risk relatives. Among 12,751 included relatives, 72% (CI 64-79%) received information about the hereditary cancer syndrome identified in their family and 28% (CI 19-37%) underwent genetic testing. On meta-analysis, there was a higher rate of disclosure among female vs male relatives (79% [73% - 84%] vs 67% [57% - 75%]) and a higher rate among first-degree vs. second degree relatives (83% [77% - 88%] vs 58% [45 – 69%]). The data regarding the contribution of race/ethnicity to disclosure were limited and inconsistent, with two studies demonstrating non-White vs. White relatives being less likely to have results disclosure and two studies finding no correlation; however, both studies finding no difference were limited by small sample sizes. Finally, one study found that higher proband annual income was associated with improved familial disclosure. Conclusions: Despite a growing understanding of the importance of cascade genetic counseling and testing, probands do not disclosure information on hereditary cancer syndromes to most at-risk relatives. Very few relatives complete genetic testing, representing a critical missed opportunity for precision cancer prevention. Future studies are needed to elucidate barriers to hereditary cancer syndrome disclosure and create innovative strategies to facilitate this essential process.

Objectives: Despite clear consensus guidelines recommending universal germline genetic testing in ovarian cancer patients and a growing appreciation of the significant health implications for patients and their relatives, fewer than 50% of women with ovarian cancer undergo genetic testing. We aim to use systematic review and meta-analysis to assess the status of genetic testing in ovarian cancer and identify strategies that can improve uptake of genetic assessment in this high-risk population. Methods: A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for studies reporting on genetic testing in ovarian cancer without date restriction was performed. Random effects pooled proportions were calculated using the logit transformation and 95% confidence intervals for individual study proportions were calculated using the Clopper-Pearson exact method. Results: The comprehensive search produced 3026 studies, among which 38 met inclusion criteria. Among studies listing mean age of diagnosis, stage, and histology data, the median of the mean age of diagnoses across the studies was 60.5 years. The median proportion of patients with early stage (I/II) ovarian cancer was 22.8%, late stage (III/IV) 70%, and unknown stage 3.6%. The median proportion of patients with serous histology was 74.6%, endometrioid 8.6%, mucinous 6%, clear cell 7%, mixed 3.6%, carcinosarcoma 3.4%, adenocarcinoma 5.8%, and other/unknown histology 7.9%. Twenty-one papers described rates of referral to genetic counseling and found, among 9,629 women, a referral rate of 56% [CI 32-78%]. Twenty-three papers described genetic testing uptake without a specified intervention and found, among 16,412 women, 34% [CI 23-47%] underwent genetic testing (Figure 1). For patients completing genetic testing, 27% [CI 22-32%] had a pathogenic mutation and 7% [CI 3-16%] a variant of uncertain significance. The most successful strategy aimed at improving rates of genetic testing was ‘mainstreaming,’ the process of providing counseling and testing in the oncology clinic by trained non-genetics specialists. With mainstreaming, 99% [CI 86-100%] of patients completed genetic testing. Other strategies described in the literature included the use of telemedicine for genetic services (75% underwent genetic testing [CI 43-93%]), embedding a genetic counselor in the clinic (67% [CI 32-90%]), reflex somatic tumor BRCA1/2 testing to triage to germline testing (64% [17-94%]), practice recommendation for universal testing of all ovarian cancer patients (42% [CI 15-74%]), and incorporating dedicated referral forms into practice (26% [CI 10-53%]). Download : Download high-res image (203KB) Download : Download full-size image Conclusions: Identifying causative germline mutations in ovarian cancer can impact treatment decisions, inform risk of other malignancies and guide disease prevention and early detection in at-risk relatives. Rates of both referral to genetic counseling and testing remain low, 56% and 34% respectively, despite broad recommendations for universal testing. Mainstreaming, use of telemedicine, embedding genetic counselors in the clinic, and triage via reflex somatic BRCA1/2 assessment are all strategies demonstrating success in this patient population and should be considered for those providing care to women with ovarian cancer.

Objectives: Despite the recommendation for genetic assessment for all women with ovarian cancer, the limited available data suggest significant disparities in referral and uptake of genetic services in minority populations. Additionally, the COVID-19 pandemic has exacerbated many existing health care disparities, making it even more critical that inequalities be identified and addressed. We sought to evaluate differences in genetic counseling and genetic testing among women with ovarian cancer based on race and insurance status. Methods: A complete systematic search of online databases (PubMed, EMBASE, MEDLINE, and the Cochrane Library) for studies reporting on genetic testing in ovarian cancer without date restriction was performed. Random effects pooled proportions were calculated using the logit transformation and 95% confidence intervals for individual study proportions were calculated using the Clopper-Pearson exact method. Results: The comprehensive search produced 3026 studies, among which 38 met inclusion criteria. Eight studies included analysis by self-reported race/ethnicity and 6 included analysis by insurance status. Among studies listing mean age of diagnosis, stage, and histology data, the median of the mean age of diagnoses across the studies was 63.3 years. The median proportion of patients with early stage (I/II) ovarian cancer was 14.7%, late stage (III/IV) 68.6%, and unknown stage 9.3%. The median proportion of patients with serous histology was 81.8%, endometrioid 12.6%, mucinous 5%, clear cell 5.8%, mixed 3.7%, carcinosarcoma 3%, and other/unknown histology 81.8%. Among 7,862 patients, 6,469 reported being White, 599 Black, and 794 Asian. Random-effects pooled proportions by race/ethnicity to follow: Among White patients, 43% [CI 26-62%] were referred for genetic counseling and 40% [CI 25-57%] completed testing, and for Black patients, 24% [CI 13-42%] were referred for counseling and 26% [CI 17-38%] completed testing. For Asian patients, 23% [CI 2-83%] were referred for counseling and 14% [CI 2-51%] completed testing, although only two studies included referral and testing proportions in Asian patients, with the majority of patient data coming from one study with referral proportion of 39% and another study with testing proportion of 31%. Among 7,681 patients, 5,320 (69%) had private insurance, 2,078 (27%) had Medicare/Medicaid, and 283 (4%) were uninsured. Random-effects pooled proportions by insurance status to follow: Among patients with private insurance, 39% [CI 26-54%] were referred for genetic counseling and 47% [CI 30-64%] completed testing. Among patients with Medicare/Medicaid, 27% [CI 18-38%] were referred for counseling and 26% [CI 16-40%] completed testing, and among uninsured patients, 24% [CI 13-41%] were referred for counseling and 23% [CI 18-28%] completed testing. Small sample and high study heterogeneity observed in the race and insurance data resulted in large confidence intervals in the pooled proportions of interest. Conclusions: Rates of genetic counseling and genetic testing are below national guidelines for all women with ovarian cancer. Our systematic review of the existing literature on this topic suggests that minority women and patients without private insurance may be disproportionally affected by lower referral rates and more limited access to genetic testing. This disparity is concerning as it can have significant impact on the health of the affected patient and her at-risk relatives. Download : Download high-res image (212KB) Download : Download full-size image

Objectives: In a pilot study, we found that facilitated cascade genetic testing for cancer-associated pathogenic mutations with telephone counseling and mailed saliva kits resulted in testing of 58% of at-risk relatives (ARRs), significantly higher than prior reports. To ascertain the true value of cascade testing, we must determine whether ARRs act upon information gained to prevent cancer morbidity and mortality. We aim to evaluate whether detecting the familial pathogenic mutations in ARRs resulted in utilization of genetically targeted cancer prevention and assess long-term quality of life. Methods: ARRs found on cascade genetic testing to harbor a pathogenic mutation were contacted two years following testing for telephone interviews. Interviews focused on utilization of guideline-based cancer preventative medical services, additional testing of family members and quality of life (QOL), assessed via three validated survey instruments (Hospital Anxiety and Depression Scale (HADS), Satisfaction with Decision Scale (SDS) and The Multidimensional Impact of Cancer Risk Assessment Questionnaire (MICRA)). Results: Our pilot trial identified 28 ARRs with pathogenic mutations, among which 25 (89%) were contacted successfully for 2-year follow-up. A total of 4 ARRs (19%) had undergone a total of six risk-reducing surgeries as a result of testing results (hysterectomy with salpingo-oophorectomy-3, salpingo-oophorectomy-1, mastectomy-2). A total of 21 ARRs (75%) underwent 35 cancer surveillance interventions (Figure 1). A total of 5 patients (24%) reported that the genetic results affected their fertility planning and three were considering preimplantation genetic diagnosis. A total of 23 patients (92%) reported sharing their genetic testing results with relatives. A total of 12 patients (52%) reported that their testing resulted in additional testing of relatives. ARRs reported that 14 additional relatives underwent testing, 8 were found to carry the familial mutation, 6 of whom underwent cancer surveillance and one underwent risk-reducing surgery. At 2 years following cascade testing, surveys demonstrated low median levels of anxiety (HADS-A 3, IQR 6) and depression (HADS-D 0, IQR 1) and high levels of satisfaction with testing (MICRA 28, IQR 10, SDS 29, IQR 5). Download : Download high-res image (114KB) Download : Download full-size image Conclusions: Long-term follow-up of our pilot study of facilitated cascade testing for cancer-associated pathogenic mutations demonstrates that the majority of ARRs found to carry the familial mutation utilize recommended cancer surveillance interventions and many undergo risk-reducing surgery. Furthermore, we have detected a cascade of the cascade, whereby testing of ARRs leads to iterative rounds of testing of additional relatives who then also have the option for cancer risk reduction. A prospective randomized trial of cascade testing facilitated by the medical team versus standard of care proband-mediated tested is planned and will be critical to shaping the way that the oncology community approaches cascade testing.

Objectives: Despite a growing understanding of familial cancer, multiple studies demonstrate that the quality of family health history (FHH) as currently collected in a clinic setting is inadequate to assess disease risk. Proposed challenges in FHH collection include lack of patient preparation, lack of FHH standardization, and time requirement (especially during the COVID-19 pandemic with intentional minimization of office time). Prior to implementation of a web-based application for FHH collection, we aimed to review the quality of collected FHH in a gynecologic oncology clinic and to determine if any patient factors affect FHH collection. Methods: This was a single institution retrospective study of FHH collection for new patient appointments at a gynecologic oncology outpatient practice between 4/2019-7/2019. FHH was collected verbally during the patient face-to-face interview. FHH was evaluated for the following, previously published, quality measures on a point system: 1) Three generations, 2) Relative gender, 3) Relative lineage (maternal vs paternal), 4) Pertinent negatives (absence of hereditary cancers), 5) Age of relatives’ cancer diagnosis, and for deceased relatives, 6) Age of death and 7) Cause of death. Results: Among the 200 evaluable patients, 185 (92.5%) had FHH documented in the medical record. The median age was 52 years (range 23-93). Eighty-nine (44.5%) included three generations, 154 (77%) relatives’ gender, 109 (54.5%) relatives’ lineage, and 77 (38.5%) pertinent negatives (Figure 1). Among 147 patients reporting a history of cancer in their family, 23 (15.6%) included age of relatives’ cancer diagnosis. Among 75 patients listing deceased relatives, 13 (17.3%) included age of death and 48 (64%) cause of death. Age and personal cancer diagnosis were not associated with quality of FHH. Patients with family history of cancer scored higher in quality of FHH than those without family history (median=3.0 [IQR 3.0; 4.0] vs. 1.0 [0.0; 2.0], P Download : Download high-res image (82KB) Download : Download full-size image Conclusions: Our data are consistent with the literature suggesting that standard collection of family history may not adequately capture all measures of a high quality oncologic FHH. Patients without prior genetic testing and no family history of cancer had the lowest scores for FHH quality and might benefit from a web-based FHH collection tool, allowing them to contact relatives for more information prior to an office visit and permitting better patient preparation and efficiency. In light of the COVID-19 pandemic, tools that minimize inoffice time are increasingly important. A prospective evaluation of a web-based FHH collection tool to address these issues is ongoing.

Objectives: In the US there are approximately 4 million individuals with a genetic cancer predisposition syndrome, however, the majority are not aware and cannot benefit from genetically-targeted cancer prevention. Family cancer history (FCH) can identify high risk patients and triage them to genetic assessment, however there is wide variability in accuracy, breadth and strategies for FCH collection. We aim to evaluate whether a web-based tool (WBT) can result in improved quality of FCH versus standard FCH collection via face-to-face interview. Methods: All patients scheduled for a gynecologic oncology new patient visit between 9/2019-9/2020 were offered enrollment in an institutional review board-approved prospective trial. Patients were randomized to one of three arms: 1) standard of care FCH collection during the interview, 2) WBT administered at home prior to the visit, 3) WBT administered in the office prior to the visit. The primary endpoint was evaluation of FCH quality based on established quality measures. Chi-square test was used to compare FCH quality between intervention arms and ANOVA test for the number of relatives/generations in the pedigree. A Bonferroni correction was used to account for multiple comparison testing. Results: A total of 100 patients were enrolled. The mean age was 56.2 years (SD 15.2). The WBT was completed successfully by 67% (22) of patients randomized to home administration vs 94% (31) randomized to office administration (P=0.01). Patients cited the following reasons for failure to complete the WBT at home: difficulty with technology, concern about privacy and forgetting about the WBT invitation. In the intention-to-treat analysis, office WBT collection resulted in significantly higher quality FCH vs the control and home arms (Table 1). The WBT resulted in significantly greater mean number of relatives included in the pedigree (Arm 1 - 3.9 [SD 3.0], Arm 2 - 32.4 [SD 16.8], Arm 3 - 29.0 [SD 18.3], P Download : Download high-res image (102KB) Download : Download full-size image Conclusions: FCH collection is an exciting application of information technology in the current healthcare setting with a growing emphasis on cancer genetics, disease prevention and thoughtful use of WBTs. In our cohort of gynecologic-oncology patients, a WBT resulted in significantly higher quality and more comprehensive family cancer pedigrees. With the COVID-19 pandemic inspired drive to minimize in-office time, future studies must assess strategies to improve patient engagement with WBT at home prior to the visit.

BACKGROUND Coronavirus disease (COVID-19) is a novel viral illness that has rapidly spread worldwide. While the disease primarily presents as a respiratory illness, gastrointestinal symptoms such as diarrhea have been reported in up to one-third of confirmed cases, and patients may have mild symptoms that do not prompt them to seek medical attention. Internet-based infodemiology offers an approach to studying symptoms at a population level, even in individuals who do not seek medical care. OBJECTIVE This study aimed to determine if a correlation exists between internet searches for gastrointestinal symptoms and the confirmed case count of COVID-19 in the United States. METHODS The search terms chosen for analysis in this study included common gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain. Furthermore, the search terms fever and cough were used as positive controls, and constipation was used as a negative control. Daily query shares for the selected symptoms were obtained from Google Trends between October 1, 2019 and June 15, 2020 for all US states. These shares were divided into two time periods: pre–COVID-19 (prior to March 1) and post–COVID-19 (March 1-June 15). Confirmed COVID-19 case numbers were obtained from the Johns Hopkins University Center for Systems Science and Engineering data repository. Moving averages of the daily query shares (normalized to baseline pre–COVID-19) were then analyzed against the confirmed disease case count and daily new cases to establish a temporal relationship. RESULTS The relative search query shares of many symptoms, including nausea, vomiting, abdominal pain, and constipation, remained near or below baseline throughout the time period studied; however, there were notable increases in searches for the positive control symptoms of fever and cough as well as for diarrhea. These increases in daily search queries for fever, cough, and diarrhea preceded the rapid rise in number of cases by approximately 10 to 14 days. The search volumes for these terms began declining after mid-March despite the continued rises in cumulative cases and daily new case counts. CONCLUSIONS Google searches for symptoms may precede the actual rises in cases and hospitalizations during pandemics. During the current COVID-19 pandemic, this study demonstrates that internet search queries for fever, cough, and diarrhea increased prior to the increased confirmed case count by available testing during the early weeks of the pandemic in the United States. While the search volumes eventually decreased significantly as the number of cases continued to rise, internet query search data may still be a useful tool at a population level to identify areas of active disease transmission at the cusp of new outbreaks.

PURPOSE A powerful consequence of detecting cancer-associated pathogenic variants is the ability to test at-risk relatives (ARRs), termed cascade testing. However, historical studies suggest cascade testing uptake of 30% or less. Here, we tested the feasibility of a novel, streamlined method of cascade testing using telephone genetic counseling and mailed saliva-based genetic testing. PATIENTS AND METHODS Probands with newly diagnosed cancer-associated pathogenic variants were offered facilitated cascade testing whereby the genetics team identified and contacted ARRs by telephone to disclose the familial pathogenic variant and offer telephone counseling and mailed saliva testing. Results and guideline-based recommendations were reviewed by telephone and shared with the primary care physician. RESULTS Thirty probands were enrolled, and 114 ARRs were identified. Twelve ARRs were excluded (lived outside of the United States, n = 5; proband did not approve of contact, n = 7). Among 102 ARRs telephoned, contact was established with 95 (93%). Among 114 identified ARRs, 66 (58%) completed genetic testing. Among those completing testing, 27 (41%) carried the familial pathogenic variant. Surveys of ARRs at the time of genetic testing and 6 months later demonstrated low levels of anxiety, depression, distress, and uncertainty and high levels of satisfaction with testing. At 6 months, 7 ARRs with pathogenic variants had undergone cancer surveillance interventions and 4 had undergone cancer risk-reducing surgery. CONCLUSION Facilitated cascade testing with telephone genetic counseling and mailed saliva kits resulted in high testing uptake among ARRs. Positive genetic testing resulted in utilization of genetically targeted primary disease prevention at short-term follow-up. Facilitated cascade testing is a straightforward, low-cost, easily implemented strategy with significant potential to promote early detection for affected ARRs and reduce cancer mortality and should be evaluated in larger scale clinical trials.

TO THE EDITOR: Inherited bone marrow failure syndromes (IBMFSs), characterized by bone marrow failure and developmental anomalies, are among a group of rare cancer predisposition syndromes. As illustrated by Fanconi anemia (FA),[1][1] the unique biology of this IBMFS has provided important insights

Background This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults. Methods We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and focused on interventions aimed at prophylactic management and abortive treatment of adults with CVS. Specifically, this evidence review addresses the following clinical questions: (a) Should the following pharmacologic agents be used for prophylaxis of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, or mitochondrial supplements? (b) Should the following pharmacologic agents be used for abortive treatment: triptans or aprepitant? Results We found very low‐quality evidence to support the use of the following agents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, and mitochondrial supplements. We have moderate certainty of evidence for the use of triptans as abortive therapy. We found limited evidence to support the use of ondansetron and the treatment of co‐morbid conditions and complementary therapies. Conclusions This evidence review helps inform the accompanying guideline for the management of adults with CVS which is aimed at helping clinicians, patients, and policymakers, and should improve patient outcomes.

Cyclic vomiting syndrome (CVS) is characterized by severe episodic emesis in adults and children. Cannabinoid hyperemesis syndrome is an increasingly recognized CVS‐like illness that has been associated with chronic cannabis use. There are significant gaps in our understanding of the pathophysiology, clinical features, comorbidities, and effective management options of CVS. Recommendations for treating CVS are based on limited clinical data, as no placebo‐controlled, randomized trials have yet been conducted. Diseases associated with CVS, including migraine, mitochondrial disorders, autonomic dysfunction, and psychiatric comorbidities, provide clues about pathophysiologic mechanisms and suggest potential therapies. We review our current understanding of CVS and propose future research directions with the aim of developing effective therapy. Establishing a multicenter, standardized registry of CVS patients could drive research on multiple fronts including developing CVS‐specific outcome measures to broaden our understanding of clinical profiles, to serve as treatment end points in clinical trials, and to provide a platform for patient recruitment for randomized clinical trials. Such a robust database would also facilitate conduct of research that aims to determine the underlying pathophysiological mechanisms and genetic basis for CVS, as well as identifying potential biomarkers for the disorder. Soliciting government and industry support is crucial to establishing the necessary infrastructure and achieving these goals. Patient advocacy groups such as the Cyclic Vomiting Syndrome Association (CVSA), which partner with clinicians and researchers to disseminate new information, to promote ongoing interactions between patients, their families, clinicians, investigators, to support ongoing CVS research and education, must be an integral part of this endeavor.

Cannabis is commonly used in cyclic vomiting syndrome (CVS) due to its antiemetic and anxiolytic properties. Paradoxically, chronic cannabis use in the context of cyclic vomiting has led to the recognition of a putative new disorder called cannabinoid hyperemesis syndrome (CHS). Since its first description in 2004, numerous case series and case reports have emerged describing this phenomenon. Although not pathognomonic, a patient behavior called “compulsive hot water bathing” has been associated with CHS. There is considerable controversy about how CHS is defined. Most of the data remain heterogenous with limited follow-up, making it difficult to ascertain whether chronic cannabis use is causal, merely a clinical association with CVS, or unmasks or triggers symptoms in patients inherently predisposed to develop CVS. This article will discuss the role of cannabis in the regulation of nausea and vomiting, specifically focusing on both CVS and CHS, in order to address controversies in this context. To this objective, we have collated and analyzed published case series and case reports on CHS in order to determine the number of reported cases that meet current Rome IV criteria for CHS. We have also identified limitations in the existing diagnostic framework and propose revised criteria to diagnose CHS. Future research in this area should improve our understanding of the role of cannabis use in cyclic vomiting and help us better understand and manage this disorder.

Context: In existence for nearly 25 years, the Healthcare Systems Research Network (HCSRN) is an established and sustainable network of health care systems that serves as a “real world” laboratory to enable the integration of research findings into practice. The objective of this paper is to demonstrate how the HCSRN serves as an ideal environment for studying dissemination and implementation of evidence-based practices into health care systems through the example of developing a multi-site study on the implementation of evidence-based precision medicine practices.Case description: The “Implementing Universal Lynch Syndrome Screening (IMPULSS)” study (NIH R01CA211723) involves seven HCSRN health care systems and two external health care systems. The IMPULSS study will describe and explain organizational variability around Lynch syndrome (LS) screening to identify which factors in different organizational contexts are important for successful implementation of LS screening programs and will create a toolkit to facilitate organizational decision making around implementation and improvement of precision medicine programs in health care systems.Major Themes: The strengths of the HCSRN that facilitate D&I research include: 1) a culture of collaboration, 2) standardization of data and processes across systems, and 3) researchers embedded in diverse health care systems. We describe how these strengths contributed to developing the IMPULSS study.Conclusion: Given the importance of conducting research in real world settings to improve patient outcomes, the unique strengths of the HCSRN are of vital importance. The IMPULSS study is one case example of how the strengths of the HCSRN make it an excellent environment for research on implementing evidence-based precision medicine practices in health care systems.

The increasing recognition of cyclic vomiting syndrome (CVS) in adults prompted the development of these evidence‐based guidelines on the management of CVS in adults, which was sponsored by the American Neurogastroenterology and Motility Society (ANMS) and the Cyclic Vomiting Syndrome Association (CVSA). GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework was used and a professional librarian performed the literature search. The expert committee included the President of the CVSA who brought a patient perspective into the deliberations. The committee makes recommendations for the prophylaxis of CVS, treatment of acute attacks, diagnosis, and overall management of CVS. The committee strongly recommends that adults with moderate‐to‐severe CVS receive a tricyclic antidepressant (TCA), such as amitriptyline, as a first‐line prophylactic medication and receive topiramate or aprepitant as alternate prophylactic medications. Zonisamide or levetiracetam and mitochondrial supplements (Coenzyme Q10, L‐carnitine, and riboflavin) are conditionally recommended as alternate prophylactic medications, either alone or concurrently with other prophylactic medications. For acute attacks, the committee conditionally recommends using serotonin antagonists, such as ondansetron, and/or triptans, such as sumatriptan or aprepitant to abort symptoms. Emergency department treatment is best achieved with the use of an individualized treatment protocol and shared with the care team (example provided). The committee recommended screening and treatment for comorbid conditions such as anxiety, depression, migraine headache, autonomic dysfunction, sleep disorders, and substance use with referral to appropriate allied health services as indicated. Techniques like meditation, relaxation, and biofeedback may be offered as complementary therapy to improve overall well‐being and patient care outcomes.

These practice recommendations for the management of mild-to-moderate UC were developed using the GRADE framework and in adherence to the standards set forth by the Institute of Medicine for creation of trustworthy guidelines 9, 10. They are intended to reduce practice variation and promote high quality, high value care for patients with mild-to-moderate UC. The current evidence supports use of standard-dose mesalamine or diazo-bonded 5-ASAs for induction and maintenance of remission in patients with extensive mild-moderate UC. Use of combined oral and rectal 5-ASA in patients with extensive disease may improve rates of induction of remission, as may escalation to high-dose oral with rectal 5-ASA in patients with suboptimal response to standard-dose therapy. Those with moderate symptoms may benefit from early use of combined oral and rectal 5-ASA. Patients with proctosigmoiditis or proctitis can be treated with topical mesalamines rather than oral 5-ASA. Those patients with suboptimal response or intolerance to rectal mesalamine may opt to use rectal corticosteroids enemas or foams. Patients with inadequate response to optimized 5-ASA require escalation of therapy to oral prednisone or budesonide MMX. We identified several knowledge gaps and areas for future research in this patient population. Due to evidence gaps, the AGA makes no recommendation for use of probiotics, curcumin, or FMT in patients with mild-moderate UC. Although these modalities appear to be safe, their use risks delaying proven effective therapy with the potential for worsening symptoms or complications. Thus, further studies of their efficacy and safety as compared to the therapies recommended here are urgently needed. Development and validation of risk stratification tools to identify patients who have mild-to-moderate symptoms but who are at high risk of progression to moderate-severe disease and/or colectomy are needed. Better understanding of optimal dosing regimens, in particular which patients might benefit from initial use of high-dose mesalamine or topical mesalamine, is also required. We also identified a need to better understand the relative effectiveness and side effects of budesonide and systemic corticosteroids in patients who do not respond adequately to 5-ASAs. Finally, studies to identify the appropriate patient and timing for escalation to immunomodulators and/or biologics would help with targeting therapy appropriately.

Background Coronavirus disease (COVID-19) is a novel viral illness that has rapidly spread worldwide. While the disease primarily presents as a respiratory illness, gastrointestinal symptoms such as diarrhea have been reported in up to one-third of confirmed cases, and patients may have mild symptoms that do not prompt them to seek medical attention. Internet-based infodemiology offers an approach to studying symptoms at a population level, even in individuals who do not seek medical care. Objective This study aimed to determine if a correlation exists between internet searches for gastrointestinal symptoms and the confirmed case count of COVID-19 in the United States. Methods The search terms chosen for analysis in this study included common gastrointestinal symptoms such as diarrhea, nausea, vomiting, and abdominal pain. Furthermore, the search terms fever and cough were used as positive controls, and constipation was used as a negative control. Daily query shares for the selected symptoms were obtained from Google Trends between October 1, 2019 and June 15, 2020 for all US states. These shares were divided into two time periods: pre–COVID-19 (prior to March 1) and post–COVID-19 (March 1-June 15). Confirmed COVID-19 case numbers were obtained from the Johns Hopkins University Center for Systems Science and Engineering data repository. Moving averages of the daily query shares (normalized to baseline pre–COVID-19) were then analyzed against the confirmed disease case count and daily new cases to establish a temporal relationship. Results The relative search query shares of many symptoms, including nausea, vomiting, abdominal pain, and constipation, remained near or below baseline throughout the time period studied; however, there were notable increases in searches for the positive control symptoms of fever and cough as well as for diarrhea. These increases in daily search queries for fever, cough, and diarrhea preceded the rapid rise in number of cases by approximately 10 to 14 days. The search volumes for these terms began declining after mid-March despite the continued rises in cumulative cases and daily new case counts. Conclusions Google searches for symptoms may precede the actual rises in cases and hospitalizations during pandemics. During the current COVID-19 pandemic, this study demonstrates that internet search queries for fever, cough, and diarrhea increased prior to the increased confirmed case count by available testing during the early weeks of the pandemic in the United States. While the search volumes eventually decreased significantly as the number of cases continued to rise, internet query search data may still be a useful tool at a population level to identify areas of active disease transmission at the cusp of new outbreaks.

Background Systematic screening of all colorectal tumors for Lynch Syndrome (LS) has been recommended since 2009. Currently, implementation of LS screening in healthcare systems remains variable, likely because LS screening involves the complex coordination of multiple departments and individuals across the healthcare system. Our specific aims are to (1) describe variation in LS screening implementation across multiple healthcare systems; (2) identify conditions associated with both practice variation and optimal implementation; (3) determine the relative effectiveness, efficiency, and costs of different LS screening protocols by healthcare system; and (4) develop and test in a real-world setting an organizational toolkit for LS screening program implementation and improvement. This toolkit will promote effective implementation of LS screening in various complex health systems. Methods This study includes eight healthcare systems with 22 clinical sites at varied stages of implementing LS screening programs. Guided by the Consolidated Framework for Implementation Research (CFIR), we will conduct in-depth semi-structured interviews with patients and organizational stakeholders and perform economic evaluation of site-specific implementation costs. These processes will result in a comprehensive cross-case analysis of different organizational contexts. We will utilize qualitative data analysis and configurational comparative methodology to identify facilitators and barriers at the organizational level that are minimally sufficient and necessary for optimal LS screening implementation. Discussion The overarching goal of this project is to combine our data with theories and tools from implementation science to create an organizational toolkit to facilitate implementation of LS screening in various real-world settings. Our organizational toolkit will account for issues of complex coordination of care involving multiple stakeholders to enhance implementation, sustainability, and ongoing improvement of evidence-based LS screening programs. Successful implementation of such programs will ultimately reduce suffering of patients and their family members from preventable cancers, decrease waste in healthcare system costs, and inform strategies to facilitate the promise of precision medicine. Trial registration N/A Electronic supplementary material The online version of this article (10.1186/s12913-018-3636-2) contains supplementary material, which is available to authorized users.

Objective: To provide guidance for guideline developers on how to consider health equity at key stages of the guideline development process. Study Design and Setting: Literature review followed by group discussions and consensus building. Results: The key stages at which guideline developers could consider equity include setting priorities, guideline group membership, identifying the target audience(s), generating the guideline questions, considering the importance of outcomes and interventions, deciding what evidence to include and searching for evidence, summarizing the evidence and considering additional information, wording of recommendations, and evaluation and use. We provide examples of how guidelines have actually considered equity at each of these stages. Conclusion: Guideline projects should consider the aforementioned suggestions for recommendation's, that are equity sensitive. (C) 2017 Elsevier Inc. All rights reserved.

Objectives: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. Study Design and Setting: Consensus-based guidance developed by the GRADE working group members and other methodologists. Results: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an 'outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. Conclusion: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society. (C) 2017 The Authors. Published by Elsevier Inc.

Objectives This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for development of clinical, public health, and health system guidelines. Study Design and Setting We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve. Results We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation. Conclusion Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development.