Uncertain Result Research Articles

Detection and quantification by molecular techniques of early infection by Lawsonia intracellularis in suckling piglets.

Lawsonia intracellularis is the causative agent of Porcine Proliferative Enteropathy (PPE), one of the most prevalent pig enteric diseases worldwide, but with sparse information about early infections in suckling piglets in the epidemiology of PPE. With that aim, this study evaluates the prevalence of L. intracellularis in 3-week-old piglets by analysing ileal digesta content and mucosal scrapings from 383 pigs from 16 farms (aprox., 25 pigs/batch) by real-time qPCR and droplet digital PCR (ddPCR). Forty-nine samples yielded a qPCR positive result. Eleven samples from eight farms were confirmed as positive with concentrations of L. intracellularis from 3.5 log10 to 4.5 log10 bacteria/g of sample. Another 16 samples, eight farms, were classified as low positive (2.07-2.38 log10 bacteria/g) and 22 provided an uncertain result. Finally, 334 samples tested negative for L. intracellularis. At batch level, half of the farms included in the study had at least one positive sample and in 10 farms (62.5%) there was at least one low positive sample. The ddPCR was run in 50 of the 383 samples based on their PCR output (including low positive, uncertain and negative samples). Correlation analyses revealed a strong association between qPCR and the ddPCR results (ρ = 0.75; p < 0.001). The ddPCR allowed us to detect and confirm a positive result in the 19 samples classified as uncertain by the qPCR and detect L. intracellularis in 8 of 15 negatives by qPCR. The results of the study demonstrate that a number of piglets are already infected with L. intracellularis during the suckling period evidencing early infection in certain animals, adding information of PPE epidemiology and opening new research topics such as sow-piglet transmission. Study results also evidence the usefulness of a combination of qPCR and ddPCR to improve qPCR sensitivity but assuring high specificity.

Errors in genome sequencing result disclosures: A randomized controlled trial comparing neonatology non-genetics healthcare professionals and genetic counselors

PurposeWe compared the rate of errors in genome sequencing (GS) result disclosures by genetic counselors (GC) and trained non-genetics healthcare professionals (NGHPs) in SouthSeq, a randomized trial utilizing GS in critically ill infants. MethodsOver 400 recorded GS result disclosures were analyzed for major and minor errors. We used Fisher’s exact test to compare error rates between GCs and NGHPs and performed a qualitative content analysis to characterize error themes. ResultsMajor errors were identified in 7.5% of disclosures by NGHPs and in no disclosures by GCs. Minor errors were identified in 32.1% of disclosures by NGHPs and in 11.4% of disclosures by GCs. Although most disclosures lacked errors, NGHPs were significantly more likely to make any error than GCs for all result types (positive, negative, or uncertain). Common major error themes include omission of critical information, overstating a negative result, and overinterpreting an uncertain result. The most common minor error was failing to disclose negative secondary findings. ConclusionTrained NGHPs made clinically significant errors in GS result disclosures. Characterizing common errors in result disclosure can illuminate gaps in education to inform the development of future genomics training and alternative service delivery models.

High accuracy epidermal growth factor receptor mutation prediction via histopathological deep learning

BackgroundThe detection of epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer is critical for tyrosine kinase inhibitor therapy. EGFR detection requires tissue samples, which are difficult to obtain in some patients, costing them the opportunity for further treatment. To realize EGFR mutation prediction without molecular detection, we aimed to build a high-accuracy deep learning model with only haematoxylin and eosin (H&E)-stained slides.MethodsWe collected 326 H&E-stained non-small cell lung cancer slides from Beijing Chest Hospital, China, and used 226 slides (88 with EGFR mutations) for model training. The remaining 100 images (50 with EGFR mutations) were used for testing. We trained a convolutional neural network based on ResNet-50 to classify EGFR mutation status on the slide level.ResultsThe sensitivity and specificity of the model were 76% and 74%, respectively, with an area under the curve of 0.82. When applying the double-threshold approach, 33% of the patients could be predicted by the deep learning model as EGFR positive or negative with a sensitivity and specificity of 100.0% and 87.5%. The remaining 67% of the patients got an uncertain result and will be recommenced to perform further examination. By incorporating adenocarcinoma subtype information, we achieved 100% sensitivity in predicting EGFR mutations in 37.3% of adenocarcinoma patients.ConclusionsOur study demonstrates the potential of a deep learning-based EGFR mutation prediction model for rapid and cost-effective pre-screening. It could serve as a high-accuracy complement to current molecular detection methods and provide treatment opportunities for non-small cell lung cancer patients from whom limited samples are available.

Assessing the necessity of intravenous contrast for computed tomography in the acute undifferentiated abdomen.

Undifferentiated abdominal pain in the emergency setting is frequently investigated with an intravenous contrast enhanced CT as a first line diagnostic test. However, global contrast shortages restricted the use of contrast for a period in 2022, altering standard practice with many scans performed without intravenous contrast. Whilst IV contrast can be useful to assist with interpretation, its necessity in the setting of acute undifferentiated abdominal pain is not well described, and its use comes with its own risks. This study aimed to assess the shortcomings of omitting IV contrast in an emergency setting, by comparing the rate of CT scans with "indeterminate" findings with and without the use of IV contrast. Data from presentations to a single centre emergency department for undifferentiated abdominal pain prior to and during contrast shortages in June 2022 were retrospectively compared. The primary outcome was the rate of diagnostic uncertainty, where the presence or absence of intra-abdominal pathology could not be ascertained. 12/85 (14.1%) of the unenhanced abdominal CT scans provided an uncertain result, compared with 14/101 (13.9%) of control cases performed with intravenous contrast (P = 0.96). There were also similar rates of positive and negative findings between the groups. Omitting intravenous contrast for abdominal CT in the setting of undifferentiated abdominal pain demonstrated no significant difference in the rate of diagnostic uncertainty. There are significant potential patient, fiscal and societal benefits as well as potential improvements to emergency department efficiency with the reduction of unnecessary intravenous contrast administration.

Information-seeking preferences in diverse patients receiving a genetic testing result in the Clinical Sequencing Evidence-Generating Research (CSER) study

PurposeAccurate and understandable information after genetic testing is critical for patients, family members, and professionals alike. MethodsAs part of a cross-site study from the Clinical Sequencing Evidence-Generating Research consortium, we investigated the information-seeking practices among patients and family members at 5 to 7 months after genetic testing results disclosure, assessing the perceived utility of a variety of information sources, such as family and friends, health care providers, support groups, and the internet. ResultsWe found that individuals placed a high value on information obtained from genetics professionals and health care workers, independent of genetic testing result case classifications as positive, inconclusive, or negative. The internet was also highly utilized and ranked. Study participants rated some information sources as more useful for positive results compared with inconclusive or negative outcomes, emphasizing that it may be difficult to identify helpful information for individuals receiving an uncertain or negative result. There were few data from non-English speakers, highlighting the need to develop strategies to reach this population. ConclusionOur study emphasizes the need for clinicians to provide accurate and comprehensible information to individuals from diverse populations after genetic testing.

Exploring the impact of the reclassification of a hereditary cancer syndrome gene variant: emerging themes from a qualitative study

The complexity of genetic variant interpretation means that a proportion of individuals who undergo genetic testing for a hereditary cancer syndrome will have their test result reclassified over time. Such a reclassification may involve a clinically significant upgrade or downgrade in pathogenicity, which may have significant implications for medical management. To date, few studies have examined the psychosocial impact of a reclassification in a hereditary cancer syndrome context. To address this gap, semi-structured telephone interviews were performed with eighteen individuals who had a BRCA1, BRCA2 or Lynch syndrome-related (MLH1, MSH2, MSH6 or PMS2) gene variant reclassified. The interviews were analysed utilising an inductive, qualitative approach and emergent themes were identified by thematic analysis. Variable levels of recall amongst participants were found. Common motivations for initial testing included a significant personal and/or family history of cancer and a desire to “find an answer”. No individual whose uncertain result was upgraded reported negative psychosocial outcomes; most reported adapting to their reclassified result and appraised their genetic testing experience positively. However, individuals whose likely pathogenic/pathogenic results were downgraded reported feelings of anger, shock and sadness post reclassification, highlighting that additional psychosocial support may be required for some. Genetic counselling issues and recommendations for clinical practice are outlined.

Abstract P6-02-11: Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial

Abstract Kahler Ribeiro Fontana S1, Bonetti E2, Bernard L3, Calvello M4, Bonanni B4, Bonizzi G 5, Veronesi P1,6, Mazzarella L 2, Galimberti V1 Introduction Triple-negative breast cancer (TNBC) is frequently associated with germline genetic variants associated with cancer predisposition. Approximately 20% of TNBC carry a germline BRCA1 or BRCA2 mutation. Germline mutations in other genes involved in DNA repair, specifically Homologous Recombination (HRR), including ATM, BARD1, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD51D may be associated with TNBC however remain imprecise in several populations as in Italy. In recent years, there has been an increase in multigenic panel testing thanks to better technology and the fact that genetic testing is no longer done just for prevention but they have become relevant in the clinical setting and this is especially true for triple negative disease. At the European Institute of Oncology, we conducted a prospective clinical trial, the PERSONA Breast trial, aimed at providing a more comprehensive picture of the mutational landscape and cancer risk in patients with TNBC by multigene germline genetic testing. Methods PERSONA is a prospective observational trial conducted between June 2018 and January 2022 on 313 patients with a diagnosis of TNBC ≤ 60 years and able to undergo surgery (primary or post-neoadjuvant). Peripheral blood DNA was sequenced with the Illumina TruSight Cancer panel (94 cancer predisposition genes). Genes were classified as germline actionable (n. 15) or non-actionable (n. 79) according to their associated relative risk of cancer. Genetic variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and the databases of genetic variants (ClinVar, LOVD, BRCA-Exchange,). All enrolled patients were followed up six-monthly for 10 years from informed consent or to death or withdrawal of consent. Results We present preliminary germline results from a 94-gene panel testing performed on a cohort of 313 TNBC patients. The clinical data of these patients was considered for a descriptive analysis of the cohort. Data on outcome such as overall survival and disease-free survival were not yet available. Germline multigene testing detected 62 unique (i.e., n. 49 in actionable, n. 13 in non-actionable genes) pathogenic (C5) and likely pathogenic (C4) variants in 25.2% of TNBC patients (79/313). As expected, 53.2% (42/79) of TNBC patients were carriers of a C5/C4 in BRCA1. C4/C5 were identified also in other actionable genes: 13.9% (11/79) in BRCA2, 8.9% (7/79) in MUTYH, 3.8% (3/79) in PALB2, 2.5% (2/79) in MSH2, 1.3% (1/79) in PMS2, and 1.3% (1/79) in TP53. In addition, 12 TNBC patients had C4/C5 variants in non-actionable genes, and 4 were carriers of both C4/C5 variants in actionable and non-actionable genes. Multigene testing resulted in the identification of 655 (i.e., n.82 in actionable, n. 573 in non-actionable genes) variants of uncertain significance (C3 or VUS) in 89.8% (281/313) of patients. Of the 281 C3 carriers, 60 had other variants (C4 and/or C5), of an uncertain result (in whom C3 was the highest class of variant) only in 70.6% (221/313) of TNBC patients. In 13 patients (13/313; 4.1%) only benign (C1) or likely benign (C2) variants were identified. Regarding family history, 67% of BRCA1 carriers versus 30% of BRCA2 carriers were familial. Conclusion Germline multigene testing in TNBC can identify C4/C5 in actionable genes providing information for a more tailored management of TNBC. Our study showed that the rate of VUS remains high using multigene testing. Of note, VUS were mainly identified in non-actionable genes supporting the rationale of the use in the clinical setting of phenotype-specific multigene panels, including a minor, but more appropriate, number of genes. Citation Format: sabrina K. kahler ribeiro fontana, emanuele bonetti, loris bernard, mariarosaria calvello, Bernardo Bonanni, ppina Bonizzi, Paolo Veronesi, Luca Mazzarella, Viviana Galimberti, claudia sangalli. Implementation of multigene panel testing in triple-negative breast cancer. The PERSONA-breast trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-02-11.

Quality of Life in Patients After Stroke

Abstract The goal of all medical treatments is a better quality of life for patients. Post-stroke rehabilitation is a long process with uncertain result. The aim of this study was to explore the factors which affect the quality of life of patients recovering from a cerebrovascular disease. This is a prospective study evaluating the quality of life of one hundred patients one month and six months after a stroke, and patients also answered questions retrospectively, of how they felt before the stroke. As assessment tools we used a questionnaire on general and clinical data and Medical Outcomes Study Short Form (SF-36) questionnaire. Physical functioning and Physical role domains of SF-36 show significant differences in both measured periods (p&lt;0.001). Emotional role, Social functioning, Mental health, Vitality and General health domains show a statistically significant change during first six months, while Bodily pain domain did not change (p&gt;0.05). Physical summary score has changed significantly during 6 months (p &lt;0.001). Mental summary score showed no significant difference in both periods (p &lt;0.687; p &lt;0.958). The brain localization is important factor (p&lt;0.0002). Gender, age, education, employment status and previous strokes did not have a statistically significant influence (p&gt; 0.05). Post-stroke physical impairment is not always accompanied by emotional impairment. Emotional functioning impairments generally return to the premorbid level during the period of six months, while physical impairments continue to occur. Further research is needed for better understanding of these relationships.

Vacuum-assisted excision biopsy for definitive diagnosis of breast lesions of uncertain malignant potential (B3 lesions) on core biopsy - A single centre Western Australian experience.

In Australia, the usual approach to breast lesions where core biopsy returns an uncertain result ("B3" breast lesion) is to perform surgical diagnostic open biopsy (DOB). This is associated with patient time off work, costs of hospital admission, risks of general anaesthesia and surgical complications. The majority of B3 lesions return benign results following surgery. Vacuum assisted excision biopsy (VAEB) is a less invasive, lower cost alternative, and is standard of care for selected B3 lesions in the United Kingdom. Similar use of VAEB in Australia, could save many women unnecessary surgery. The aim of this study was to document our experience during the introduction of VAEB as an alternative to DOB for diagnosis of selected B3 lesions. The multidisciplinary team developed an agreed VAEB pathway for selected B3 lesions. Technically accessible papillary lesions, mucocele-like lesions and radial scars without atypia measuring ≤ 15mm were selected. Over a 7 month period, 18 women with 20 B3 lesions were offered VAEB. 16 women (18 lesions) chose VAEB over DOB. Papillomas were the commonest lesion type. All lesions were successfully sampled: 17/18 were benign. One lesion (6%) was upgraded to malignancy (ductal carcinoma insitu on VAEB, invasive ductal carcinoma at surgery). No major complications occurred. Patient satisfaction was high: 15/16 respondents would again choose VAEB over surgery. VAEB is a patient-preferred, safe, well-tolerated, lower-cost alternative to DOB for definitive diagnosis of selected B3 breast lesions.

Chronic pain in post-COVID syndrome

Our body senses two types of pain, acute and chronic. Acute pain lasts for a short time. It occurs when our body wants to protect us from a dangerous situation. This way, our nerves are telling us that something is wrong. But if some time passes since our injury, treatment or surgery and the pain or discomfort persists, we are speaking of chronic pain. It is often difficult to determine its intensity or even prove its existence. The discomfort and pain are not relieved and physical pain may be accompanied by mental issues. At present, during the COVID-19 pandemic, chronic pain is becoming more prominent, and it is also associated with the post-COVID syndrome. In their efforts to help patients suffering from COVID-19, many new treatment protocols have been prepared and various antiviral drugs and other potentially useful drugs have been used (often without prior approval or testing). Basically, it was a kind of 'experimental' treatment. At present, thanks to quick therapy decisions and as part of COVID-19 prevention, we have succeeded in stabilising the situation all over the world. A relatively fast development of vaccines against SARS-CoV-2 with a view to achieve collective immunity has greatly contributed to this. On the other hand, 'quick decisions' have contributed to other significant issues which we are beginning to deal with now, i.e, in the effort to defeat the virus, many experts regarded the adverse effects of the medications used to be of secondary importance. In the article we would like to point out the other side of the 'successful' treatment of COVID-19, namely the possible iatrogenic conditions which significantly contribute to the post-COVID‑19 syndrome and chronic pain. The importance of preventive measures over uncertain result of COVID-19 treatment is emphasised (Tab. 4, Fig. 1, Ref. 50). Text in PDF www.elis.sk Keywords: iatrogenic conditions; chronic pain; co-morbidity; pain syndrome; pandemic; post-COVID‑19 syndrome.

Impact of returning unsolicited genomic results to nongenetic health care providers in the eMERGE III Network

PurposeAs genomic sequencing becomes more common, medically actionable secondary findings will increasingly be returned to health care providers (HCPs), who will be faced with managing the resulting patient care. These findings are generally unsolicited, ie, unrelated to the sequencing indication and/or ordered by another clinician. MethodsTo understand the impact of receiving unsolicited results, we interviewed HCPs who received genomic results for patients enrolled in the Electronic Medical Records and Genomics (eMERGE) Phase III Network, which returned results on >100 actionable genes to eMERGE participants and HCPs. ResultsIn total, 16 HCPs across 3 eMERGE sites were interviewed about their experience of receiving a positive (likely pathogenic or pathogenic), negative, or variant of uncertain significance result for a patient enrolled in eMERGE Phase III and about managing their patient on the basis of the result. Although unsolicited, HCPs felt responsible for managing the patient’s resulting medical care. HCPs indicated that clinical utility depended on the actionability of results, and whereas comfort levels varied, confidence was improved by the availability of subspecialist consults. HCPs were concerned about patient anxiety, insurability, and missing an actionable result in the electronic health record. ConclusionOur findings help inform best practices for return of unsolicited genomic screening findings in the future.

Abstract P3-14-20: Racial and ethnic groups have different clustering of variants of uncertain significance

Abstract Background:Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods:Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS), likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results:Hispanic and African American patients had approximately twice as many uncertain results (VUS) compared to Caucasian patients for all cancer genes examined. Conclusions:Variant adjudication has disproportionately sorted out more uncertain results in Caucasians than Hispanics and African Americans. This leads to greater uncertainty in post-test counseling for these groups and should be a focus for lab testing companies going forward. Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of variants of uncertain significance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-20.

Abstract P3-14-19: Racial and ethnic groups have different clustering of common cancer genes

Abstract Background: Racial/ethnic disparities in minority access to genetic testing have perpetuated a higher likelihood of identifying an uncertain result in minority populations. Methods :Patient data was obtained from the Informed Genetics Annotated Patient Registry (iGAP), an IRB-approved multi-center longitudinal, observational study designed to capture genetic and genomic test results and their utilization and impact on treatment practices and outcomes. Patients self-declare race/ethnicity. Genetic panels contained between 1 and 148 genes and variant classification was determined by the performing genetic testing companies and reported as negative, variant of uncertain significance (VUS),likely-pathogenic, or pathogenic. Descriptive statistics were used to assess and compare data of these populations and germline genetic testing results indicating variant of uncertain significance. Results: The three racial/ethnic groups have similar percentages of BRCA1 and BRCA2pathogenic variants. However, Caucasians have considerably more pathogenic variants in lesser penetrant genes [see Table 1]. Conclusions: Racial/ethnic groups vary by volume of lesser penetrant genes with Caucasians having the highest numbers. Correlation by SNP heritage assignment may lead to a better understanding of these differences. Gene NameAshkenazi PV% Askenazi PVs% of PV subjects AshkenaziAshkenazi VUS%VUS Ashkenazi VUS% of subjects VUS AshkenaziAsian% Asian PVs% of PV subjects AsianAsian VUS%VUS Asian mutations% of subjects VUS AsianBlack/African% Black/African PVs% of PV subjectsBlack/AfricanBlack/African VUS%VUS Black/Africanmutations% of subjects VUSBlack/AfricanCaucasian% Caucasian PVs% of PV subjects CaucasianCaucasian VUS% Caucasian Mutations% of subjects VUS CaucasianHispanic% Hispanic PVs% of PV subjects HispanicHispanic VUS% Hispanic Mutations% of subjects VUS HispanicOther% Other PVs% of PV subjects OtherOther RE VUS% Other RE Mutations% of subjects VUS Other#PV Total% Total PV#VUS TotalBRCA20.00%0.00%0.00%0.00%125.00%25.00%24.17%4.26%531.25%31.25%34.62%4.76%3414.47%16.50%122.42%2.44%815.69%18.18%45.26%5.48%211.11%12.50%36.67%6.82%5014.97%24BRCA1327.27%30.00%0.00%0.00%0.00%0.00%36.25%6.38%318.75%18.75%23.08%3.17%177.23%8.25%91.81%1.83%1631.37%36.36%11.32%1.37%211.11%12.50%24.44%4.55%4112.28%17CHEK20.00%0.00%112.50%12.50%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%2711.49%13.11%51.01%1.02%11.96%2.27%0.00%0.00%15.56%6.25%12.22%2.27%298.68%8ATM19.09%10.00%0.00%0.00%0.00%0.00%510.42%10.64%0.00%0.00%812.31%12.70%218.94%10.19%346.85%6.92%35.88%6.82%911.84%12.33%0.00%0.00%36.67%6.82%257.49%59CHEK2/1100delC19.09%10.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%104.26%4.85%30.60%0.61%23.92%4.55%22.63%2.74%0.00%0.00%0.00%0.00%133.89%6MUTYH0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%114.68%5.34%51.01%1.02%11.96%2.27%22.63%2.74%15.56%6.25%12.22%2.27%133.89%8PALB20.00%0.00%0.00%0.00%0.00%0.00%12.08%2.13%0.00%0.00%0.00%0.00%72.98%3.40%71.41%1.43%35.88%6.82%11.32%1.37%15.56%6.25%12.22%2.27%113.29%10BLM19.09%10.00%0.00%0.00%0.00%0.00%48.33%8.51%0.00%0.00%34.62%4.76%93.83%4.37%112.22%2.24%0.00%0.00%22.63%2.74%0.00%0.00%0.00%0.00%102.99%20MITF0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%83.40%3.88%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%0NBN0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%11.54%1.59%83.40%3.88%40.81%0.81%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%82.40%5FH327.27%30.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%41.70%1.94%40.81%0.81%0.00%0.00%11.32%1.37%0.00%0.00%0.00%0.00%72.10%5MSH619.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%0.00%0.00%4.62%4.76%31.28%1.46%132.62%2.65%23.92%4.55%22.63%2.74%15.56%6.25%0.00%0.00%72.10%19MUTYH-Biallelic/Compound Heterozygous0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%52.13%2.43%10.20%0.20%11.96%2.27%0.00%0.00%15.56%6.25%0.00%0.00%72.10%1MUTYH-Monoallelic0.00%0.00%0.00%0.00%0.00%0.00%0.00%0.00%16.25%6.25%0.00%0.00%52.13%2.43%0.00%0.00%11.96%2.27%0.00%0.00%0.00%0.00%0.00%0.00%72.10%0PMS219.09%10.00%112.50%12.50%0.00%0.00%0.00%0.00%16.25%6.25%11.54%1.59%52.13%2.43%51.01%1.02%0.00%0.00%33.95%4.11%0.00%0.00%0.00%0.00%72.10%10Other00.00%0.00%562.50%62.50%375.00%75.00%3164.58%65.96%531.25%31.25%4467.69%69.84%6125.96%29.61%38377.22%78.00%1325.49%29.55%4964.47%67.12%950.00%56.25%3475.56%77.27%9127.25%546Grand Total11PV Ash108VUS Ash84PV Asi448Asi VUS4716PV Bla1665VUS Bla63235PV Cau206496VUS Cau49151PV His4476VUS His7318PV Oth1645VUS Oth44334334 PV Mutations Found738 Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Maureen Graham, Pat Whitworth, Rakesh Patel. Racial and ethnic groups have different clustering of common cancer genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-14-19.

Coronary atherosclerosis progression in patients after coronary stenting, depending on a cardiology follow-up strategy

Aim. To compare the prevalence of coronary atherosclerosis in patients after coronary stenting (CS) receiving outpatient and remote cardiology follow-up during a one-year study.Material and methods. We enrolled 279 patients aged 61,5±9,5 years with class ≥II stable angina or silent ischemia after CS. Three groups were formed: group 1 (n=96) — outpatient visits before CS, 1, 3, 6 and 12 months after CS. Group 2 (n=95) — remote monitoring: patients were followed up by a primary care physician with the involvement of a cardiologist via remote communication (e-mail, telephone, Skype) 1, 3, 6 and 12 months after CS. Group 3 (n=88) were followed up by a primary care physician and contacted with the study coordinator before and 12 months after CS. After 12 months, all patients underwent stress-induced myocardial ischemia testing. In case of a positive or uncertain test result, coronary angiography (CA) was performed.Results. Stress-induced myocardial ischemia 12 months after CS was verified in 58 patients (21%): 19 patients (19,8%) — group 1; 9 patients (9,5%) — group 2; 30 patients (34,1%) — group 3 (p&lt;0,05). Repeat CA was performed in 96 patients (34,4% of the total number of patients). Restenosis was detected in 8 (2,9%) patients, coronary atherosclerosis progression — in 38 (13,6%), combination of restenosis and atherosclerosis progression — in 4 (1,4%) patients. Coronary atherosclerosis progression was significantly more frequent in group 3: 10,4%, 9,5% and 21,6% in groups 1, 2 and 3, respectively (p&lt;0,05). The incidence of stent restenosis was comparable: 2,1%, 3,2% and 3,5% in groups 1, 2, and 3, respectively.Conclusion. Coronary atherosclerosis progression was the main reason for repeated revascularizations 12 months after the CS. Outpatient and remote cardiology follow-up is associated with a lower incidence of coronary atherosclerosis progression and repeated CA during 12-month follow-up after CS.

Genome sequencing as a first-line diagnostic test for hospitalized infants

PurposeSouthSeq is a translational research study that undertook genome sequencing (GS) for infants with symptoms suggestive of a genetic disorder. Recruitment targeted racial/ethnic minorities and rural, medically underserved areas in the Southeastern United States, which are historically underrepresented in genomic medicine research. MethodsGS and analysis were performed for 367 infants to detect disease-causal variation concurrent with standard of care evaluation and testing. ResultsDefinitive diagnostic (DD) or likely diagnostic (LD) genetic findings were identified in 30% of infants, and 14% of infants harbored an uncertain result. Only 43% of DD/LD findings were identified via concurrent clinical genetic testing, suggesting that GS testing is better for obtaining early genetic diagnosis. We also identified phenotypes that correlate with the likelihood of receiving a DD/LD finding, such as craniofacial, ophthalmologic, auditory, skin, and hair abnormalities. We did not observe any differences in diagnostic rates between racial/ethnic groups. ConclusionWe describe one of the largest-to-date GS cohorts of ill infants, enriched for African American and rural patients. Our results show the utility of GS because it provides early-in-life detection of clinically relevant genetic variations not detected by current clinical genetic testing, particularly for infants exhibiting certain phenotypic features.

Radiological Follow-up After the Bony Obliteration Tympanoplasty in Detecting Residual Cholesteatoma: Towards an Optimal Postoperative MR Imaging Protocol.

There is no consensus in literature on the most optimal follow-up imaging protocol for non-echoplanar diffusion-weighted magnetic resonance imaging (non-EP DW MRI) after the canal wall-up bony obliteration tympanoplasty. Clearly, no residual cholesteatoma should be missed but on the other hand, unnecessary MR controls should be avoided. The aim of this study is to evaluate the postoperative results of non-EP DW MRI after canal wall-up bony obliteration tympanoplasty surgery at our Institute and to propose an optimal postoperative MR imaging scheme based on our data. Retrospective cohort study; all 271 patients who underwent the bony obliteration tympanoplasty between January 2010 and January 2016 with follow-up at our Institute were included. A postoperative MR imaging was systematically performed at 1 year after surgery and repeated at either 5 or both 3 and 5 years after surgery, based on the preferences of the surgeon. Variables of interest were retrieved from electronic patient records. The median follow-up time was 60 months (inter-quartile range 56-62 mo). Two hundred seventy-one patients (100%) received a 1-year MRI, 107 (39%) a 3-year MRI, and 216 (79.7%%) a 5-year MRI. Residual cholesteatoma was found in nine cases (3.3%), corresponding with an estimated residual rate at 5 years follow-up of 3.7% when using Kaplan-Meier analysis. Of these nine cases, six cases of residual cholesteatoma (66.7%) were detected at the 1-year MRI (12-14 mo postsurgery), two cases (22.2%) at the 3-year MRI (35-39 mo postsurgery), and one case (11.1%) at the 5-year MRI (51 mo postsurgery, in this patient no 3-year MRI was performed). An uncertain MRI result was found in 15 cases, presenting as relatively hyperintense lesions. However, subsequent follow-up scans did not show persistent evidence for residual disease in 14 of these 15 cases. A postoperative MRI scan after 1 and 5 years is essential to detect early and late residual cholesteatoma. In our cohort, 22.2% of residual cases were detected at the 3-year MRI. However, this percentage could potentially have been higher when all patients would have received a 3-year MRI. Therefore, in order to detect residual disease as soon as possible, we propose to perform an MRI scan at 1, 3, and 5 years after the bony obliteration tympanoplasty. In cases with an unclear MR result, we suggest a repeat MRI after 12 months.

Parliamentary Elections in Bulgaria and Moldova. Take 2

The subject of the article is repeat parliamentary elections in two countries by mere chance run on the same date. The external parallels of both election campaigns, such as the low turnout and the importance of voters from abroad, the continuing relevance of the agenda of toplevel corruption, the electoral failure of the socialists in both rounds are striking, and are scrutinized in the article. However, the outcomes of the campaigns are very different. In Bulgaria, even the second attempt to renew the government and the political class ended with an uncertain intermediate result, and its main triumphant Slavi Trifonov’s standing is far from looking encouraging. The success of the new counter-elite force and its leader is not promising to end the political crisis and is remindful of the previous scenarios already seen twice in Bulgaria: the unexpected rise of political psychics and the subsequent shift of sympathies to the next idol of the masses. In Moldova, the renovators succeeded in consolidating their grip on power and securing impressive credit of popular trust thus making a credible step towards implementation of their promises. It remains to keep track of who will be more successful.

How are uncertain prenatal genetic results perceived and managed twoyears after they were received? A qualitative interview study.

Chromosomal microarray has considerably improved our ability to identify or dismiss genetic conditions in the unborn child. However, this detailed analysis also reveals copy number variants (CNVs) of unknown or uncertain significance, in which the specific child's prognosis can be difficult to predict. Little is known about the longer-term impacts of receiving an uncertain prenatal CNV result. Our qualitative study explored how such a result was perceived and managed in everyday life, 2years after it was received. From an original sample of 16 couples, nine women participated in a semi-structured follow-up phone interview. Transcripts were analyzed using thematic analysis. The results show that these women did not perceive the CNV result to be a part of their everyday lives. They managed the CNV result by focusing on the child's positive development, by not sharing the CNV information in wider social networks, and by emphasizing parental values such as taking life as it comes, welcoming human variation, and accepting that dealing with a child's struggles is an inherent part of parenthood. Overall, the women expressed a positive attitude toward prenatal genetic information about serious disorders but considered 'their' CNV to be close to normal; several women suggested that such findings should not be reported. However, they also recognized the difficulties in making such decisions, given variable penetrance and that couples' definitions of 'serious' could vary significantly. The diagnostic process during pregnancy was remembered as being highly stressful, and many expressed a need for more control in a future pregnancy. Our study provides insight into how mothers reconfigure CNV results to fit their values and everyday lives. When delivering uncertain CNV results in a prenatal setting, genetics healthcare providers should present and discuss long-term coping strategies with expecting parents.

Abstract PD10-12: Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations

Abstract Background: Talazoparib, a PARP1 inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 less well understood. The Talazoparib Beyond BRCA clinical trial treated 20 patients with germline (g) or somatic (s) mutations in HR pathways genes other than BRCA1/2, which included PALB2, CHEK2, ATM, BRIP1, RAD50, ATR, PTEN, and FANCA. Talazoparib treatment was associated with a 31% overall response rate in patients with breast cancer, including tumor regression from baseline as best response in 6 out of 6 patients treated gPALB2 mutations. We now present the results of additional genomic studies to further characterize treatment responses and resistance mechanisms. Methods: Primary and metastatic tumor biopsies were assessed using the commercially-available next-generation sequencing HRD assay (Myriad). Panel gene sequencing of tumors was performed for 108 genes associated with genomic instability. Loss-of-heterozygosity (LOH) was assessed in tumors. Tumor/normal exome sequencing identified pre-treatment somatic variants. Circulating-tumor DNA at baseline and disease progression was assessed by targeted panel sequencing and plasma whole exome sequencing. Results: Of the 18 HRD assays performed, 3 failed and were thus excluded. Seven patients had HRD analysis performed on both primary and metastatic tumors. For these patients the HRD score was significantly higher in the metastasis versus the primary (means 46.2 versus 36.5, p = 0.018 by paired t-test). By panel sequencing of tumors (n=18) the most common alterations detected included mutations in PIK3CA (n=8), PALB2 (n=6), ATM (n=5), KRAS (n=4), PTEN (n=5) and TP53 (n=4). In all cases except one, the HR-associated mutation used as entry criteria were detected. LOH analysis showed that of tumors with gPALB2 mutations, 3 of the 6 had LOH for PALB2, and an additional two tumors had 2 independent PALB2 mutations suggesting bi-allelic inactivation. The one remaining tumor had an uncertain LOH result due to test failure. Thus, it is likely that most, if not all, of the tumors in our cohort with gPALB2 mutations had complete inactivation of PALB2 gene function. Other detected mutations that were associated with LOH included all sTP53 mutations (n=4), all gCHEK2 mutations (n=3), gFANCA (n=1), all sRB1 mutations (n=3) and NF1 (n=1). Of the three gATM mutations one had LOH, while the others had two independent mutations, suggestive of bi-allelic inactivation. sATM mutations were associated with LOH in a breast cancer and with 2 independent (possibly bi-allelic) mutations in a non-breast cancer. Additional results from ctDNA targeted sequencing and plasma whole exome sequencing of baseline and progression samples will be presented. Conclusions: In this proof-of-concept phase II study, talazoparib demonstrated activity in HER2-negative advanced breast cancer patients with a HR pathway mutation beyond BRCA1/2, especially in patients with gPALB2 mutations and high HRD scores. These additional genomic analyses provide evidence that HRD scores may be significantly higher in metastatic samples compared to primary tumors. Also, we detected either LOH or bi-allelic inactivation for most HR-associated mutations used to determine eligibility. These findings may inform selection of patients for PARP inhibitor monotherapy beyond BRCA1/2. Citation Format: Joshua J Gruber, Anosheh Afghahi, Alyssa Hatton, Wyatt Gross, Jessica Foran, Alex McMillan, James M Ford, Melinda L Telli. Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-12.

Vessel morphology depicted by three‐dimensional power Doppler ultrasound as second‐stage test in adnexal tumors that are difficult to classify: prospective diagnostic accuracy study

ABSTRACTObjectivesTo assess whether vessel morphology depicted by three‐dimensional (3D) power Doppler ultrasound improves discrimination between benignity and malignancy if used as a second‐stage test in adnexal masses that are difficult to classify.MethodsThis was a prospective observational international multicenter diagnostic accuracy study. Consecutive patients with an adnexal mass underwent standardized transvaginal two‐dimensional (2D) grayscale and color or power Doppler and 3D power Doppler ultrasound examination by an experienced examiner, and those with a ‘difficult’ tumor were included in the current analysis. A difficult tumor was defined as one in which the International Ovarian Tumor Analysis (IOTA) logistic regression model‐1 (LR‐1) yielded an ambiguous result (risk of malignancy, 8.3% to 25.5%), or as one in which the ultrasound examiner was uncertain regarding classification as benign or malignant when using subjective assessment. Even when the ultrasound examiner was uncertain, he/she was obliged to classify the tumor as most probably benign or most probably malignant. For each difficult tumor, one researcher created a 360° rotating 3D power Doppler image of the vessel tree in the whole tumor and another of the vessel tree in a 5‐cm3 spherical volume selected from the most vascularized part of the tumor. Two other researchers, blinded to the patient's history, 2D ultrasound findings and histological diagnosis, independently described the vessel tree using predetermined vessel features. Their agreed classification was used. The reference standard was the histological diagnosis of the mass. The sensitivity of each test for discriminating between benign and malignant difficult tumors was plotted against 1 – specificity on a receiver‐operating‐characteristics diagram, and the test with the point furthest from the reference line was considered to have the best diagnostic ability.ResultsOf 2403 women with an adnexal mass, 376 (16%) had a difficult mass. Ultrasound volumes were available for 138 of these cases. In 79/138 masses, the ultrasound examiner was uncertain about the diagnosis based on subjective assessment, in 87/138, IOTA LR‐1 yielded an ambiguous result and, in 28/138, both methods gave an uncertain result. Of the masses, 38/138 (28%) were malignant. Among tumors that were difficult to classify as benign or malignant by subjective assessment, the vessel feature ‘densely packed vessels’ had the best discriminative ability (sensitivity 67% (18/27), specificity 83% (43/52)) and was slightly superior to subjective assessment (sensitivity 74% (20/27), specificity 60% (31/52)). In tumors in which IOTA LR‐1 yielded an ambiguous result, subjective assessment (sensitivity 82% (14/17), specificity 79% (55/70)) was superior to the best vascular feature, i.e. changes in the diameter of vessels in the whole tumor volume (sensitivity 71% (12/17), specificity 69% (48/70)).ConclusionVessel morphology depicted by 3D power Doppler ultrasound may slightly improve discrimination between benign and malignant adnexal tumors that are difficult to classify by subjective ultrasound assessment. For tumors in which the IOTA LR‐1 model yields an ambiguous result, subjective assessment is superior to vessel morphology as a second‐stage test. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.