Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal.

Genome sequencing is increasingly used in research and integrated into clinical care. In the research domain, large-scale analyses, including whole genome sequencing with variant interpretation and curation, virtually guarantee identification of variants that are pathogenic or likely pathogenic and actionable. Multiple guidelines recommend that findings associated with actionable conditions be offered to research participants in order to demonstrate respect for autonomy, reciprocity, and participant interests in health and privacy. Some recommendations go further and support offering a wider range of findings, including those that are not immediately actionable. In addition, entities covered by the US Health Insurance Portability and Accountability Act (HIPAA) may be required to provide a participant's raw genomic data on request. Despite these widely endorsed guidelines and requirements, the implementation of return of genomic results and data by researchers remains uneven. This article analyzes the ethical and legal foundations for researcher duties to offer adult participants their interpreted results and raw data as the new normal in genomic research.

Studying the impact of translational genomic research: Lessons from eMERGE.

Two major goals of the Electronic Medical Record and Genomics (eMERGE) Network are to learn how best to return research results to patient/participants and the clinicians who care for them and also to assess the impact of placing these results in clinical care. Yet since its inception, the Network has confronted a host of challenges in achieving these goals, many of which had ethical, legal, or social implications (ELSIs) that required consideration. Here, we share impediments we encountered in recruiting participants, returning results, and assessing their impact, all of which affected our ability to achieve the goals of eMERGE, as well as the steps we took to attempt to address these obstacles. We divide the domains in which we experienced challenges into four broad categories: (1) study design, including recruitment of more diverse groups; (2) consent; (3) returning results to participants and their health care providers (HCPs); and (4) assessment of follow-up care of participants and measuring the impact of research on participants and their families. Since most phases of eMERGE have included children as well as adults, we also address the particular ELSI posed by including pediatric populations in this research. We make specific suggestions for improving translational genomic research to ensure that future projects can effectively return results and assess their impact on patient/participants and providers if the goals of genomic-informed medicine are to be achieved.

Prospective, multi-site study of healthcare utilization after actionable monogenic findings from clinical sequencing.

As large-scale genomic screening becomes increasingly prevalent, understanding the influence of actionable results on healthcare utilization is key to estimating the potential long-term clinical impact. The eMERGE network sequenced individuals for actionable genes in multiple genetic conditions and returned results to individuals, providers, and the electronic health record. Differences in recommended health services (laboratory, imaging, and procedural testing) delivered within 12 months of return were compared among individuals with pathogenic or likely pathogenic (P/LP) findings to matched individuals with negative findings before and after return of results. Of 16,218 adults, 477 unselected individuals were found to have a monogenic risk for arrhythmia (n = 95), breast cancer (n = 96), cardiomyopathy (n = 95), colorectal cancer (n = 105), or familial hypercholesterolemia (n = 86). Individuals with P/LP results more frequently received services after return (43.8%) compared to before return (25.6%) of results and compared to individuals with negative findings (24.9%; p < 0.0001). The annual cost of qualifying healthcare services increased from an average of $162 before return to $343 after return of results among the P/LP group (p < 0.0001); differences in the negative group were non-significant. The mean difference-in-differences was $149 (p < 0.0001), which describes the increased cost within the P/LP group corrected for cost changes in the negative group. When stratified by individual conditions, significant cost differences were observed for arrhythmia, breast cancer, and cardiomyopathy. In conclusion, less than half of individuals received billed health services after monogenic return, which modestly increased healthcare costs for payors in the year following return.

Principles and Practices of Returning Individual Research Results to Participants in Large Studies of Pregnancy and Childhood.

Investigators conducting human subject research have typically conveyed only clinically actionable results back to individual participants. Shifting scientific culture around viewing participants as partners in research, however, is prompting investigators to consider returning as much data or results as the participant would like, even if they are not clearly actionable. Expanding return of individual results may add value for individual participants and their communities, refine future research questions and methods, build trust, and enhance retention of participants. Yet, gaps remain in understanding the implications of these changes for groups of 'vulnerable' participants, including pregnant and pediatric participants. We present the findings of a National Institutes of Health workshop on returning individual research results, particularly as applicable to pregnant and pediatric participants. Research participants who were panelists at the workshop agreed that they desire to receive their results. Workshop findings and current literature indicate that participants have differing preferences for what results they receive. One way to address the limits of current practice is to develop flexible digital platforms that convey individual results along with researchers' availability to answer questions, and to provide as much information as possible about actionable steps to control environmental exposures associated with disease risk.

Survival difference between secondary and de novo acute myeloid leukemia by age, antecedent cancer types, and chemotherapy receipt.

BACKGROUND: This study compared the survival of persons with secondary acute myeloid leukemia (sAML) to those with de novo AML (dnAML) by age at AML diagnosis, chemotherapy receipt, and cancer type preceding sAML diagnosis. METHODS: Data from Surveillance, Epidemiology, and End Results 17 Registries were used, which included 47,704 individuals diagnosed with AML between 2001 and 2018. Multivariable Cox proportional hazards regression was used to compare AML-specific survival between sAML and dnAML. Trends in 5-year age-standardized relative survival were examined via the Joinpoint survival model. RESULTS: Overall, individuals with sAML had an 8% higher risk of dying from AML (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.05-1.11) compared to those with dnAML. Disparities widened with younger age at diagnosis, particularly in those who received chemotherapy for AML (HR, 1.14; 95% CI, 1.10-1.19). In persons aged 20-64 years and who received chemotherapy, HRs were greatest for those with antecedent myelodysplastic syndrome (HR, 2.04; 95% CI, 1.83-2.28), ovarian cancer (HR, 1.91; 95% CI, 1.19-3.08), head and neck cancer (HR, 1.55; 95% CI, 1.02-2.36), leukemia (HR, 1.45; 95% CI, 1.12-1.89), and non-Hodgkin lymphoma (HR, 1.42; 95% CI, 1.20-1.69). Among those aged ≥65 years and who received chemotherapy, HRs were highest for those with antecedent cervical cancer (HR, 2.42; 95% CI, 1.15-5.10) and myelodysplastic syndrome (HR, 1.28; 95% CI, 1.19-1.38). The 5-year relative survival improved 0.3% per year for sAML slower than 0.86% per year for dnAML. Consequently, the survival gap widened from 7.2% (95% CI, 5.4%-9.0%) during the period 2001-2003 to 14.3% (95% CI, 12.8%-15.8%) during the period 2012-2014. CONCLUSIONS: Significant survival disparities exist between sAML and dnAML on the basis of age at diagnosis, chemotherapy receipt, and antecedent cancer, which highlights opportunities to improve outcomes among those diagnosed with sAML.

The changing landscape of small cell lung cancer.

BACKGROUND: Small-cell lung cancer (SCLC) is characterized by rapid proliferation and early dissemination. The objective of this study was to examine the demographic trends and outcomes in SCLC. METHODS: The authors queried the National Cancer Institute's Surveillance, Epidemiology, and End Results database to assess the trends in incidence, demographics, staging, and survival for SCLC from 1975 to 2019. Trends were determined using joinpoint analysis according to the year of diagnosis. RESULTS: Among the 530,198 patients with lung cancer, there were 73,362 (13.8%) with SCLC. The incidence per 100,000 population peaked at 15.3 in 1986 followed by a decline to 6.5 in 2019. The percentage of SCLC among all lung tumors increased from 13.3% in 1975 to a peak of 17.5% in 1986, declining to 11.1% by 2019. There was an increased median age at diagnosis from 63 to 69 years and an increased percentage of women from 31.4% to 51.2%. The percentage of stage IV increased from 58.6% in 1988 to 70.8% in 2010, without further increase. The most common sites of metastasis at diagnosis were mediastinal lymph nodes (75.3%) liver (31.6%), bone (23.7%), and brain (16.4%). The 1-year and 5-year overall survival rate increased from 23% and 3.6%, respectively, in 1975-1979 to 30.8% and 6.8%, respectively, in 2010-2019. CONCLUSIONS: The incidence of SCLC peaked in 1988 followed by a gradual decline. Other notable changes include increased median age at diagnosis, the percentage of women, and the percentage of stage IV at diagnosis. The improvement in 5-year overall survival has been statistically significant but clinically modest.

Cost-of-care discussions for individuals with advanced non-small cell lung cancer and melanoma: Findings from a large, population-based pilot study.

BACKGROUND: Costs of cancer care can result in patient financial hardship; many professional organizations recommend provider discussions about treatment costs as part of high-quality care. In this pilot study, the authors examined patient-provider cost discussions documented in the medical records of individuals who were diagnosed with advanced non-small cell lung cancer (NSCLC) and melanoma-cancers with recently approved, high-cost treatment options. METHODS: Individuals who were newly diagnosed in 2017-2018 with stage III/IV NSCLC (n = 1767) and in 2018 with stage III/IV melanoma (n = 689) from 12 Surveillance, Epidemiology, and End Results regions were randomly selected for the National Cancer Institute Patterns of Care Study. Documentation of cost discussions was abstracted from the medical record. The authors examined patient, treatment, and hospital factors associated with cost discussions in multivariable logistic regression analyses. RESULTS: Cost discussions were documented in the medical records of 20.3% of patients with NSCLC and in 24.0% of those with melanoma. In adjusted analyses, privately insured (vs. publicly insured) patients were less likely to have documented cost discussions (odds ratio [OR], 0.54; 95% confidence interval [CI], 0.37-0.80). Patients who did not receive systemic therapy or did not receive any cancer-directed treatment were less likely to have documented cost discussions than those who did receive systemic therapy (OR, 0.39 [95% CI, 0.19-0.81] and 0.46 [95% CI, 0.30-0.70], respectively), as were patients who were treated at hospitals without residency programs (OR, 0.64; 95% CI, 0.42-0.98). CONCLUSIONS: Cost discussions were infrequently documented in the medical records of patients who were diagnosed with advanced NSCLC and melanoma, which may hinder identifying patient needs and tracking outcomes of associated referrals. Efforts to increase cost-of-care discussions and relevant referrals, as well as their documentation, are warranted.

INDUCE-2: A Phase I/II, open-label, two-part study of feladilimab in combination with tremelimumab in patients with advanced solid tumors.

Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.

Manipulating 2D Materials through Strain Engineering.

This review explores the growing interest in 2D layered materials, such as graphene, h-BN, transition metal dichalcogenides (TMDs), and black phosphorus (BP), with a specific focus on recent advances in strain engineering. Both experimental and theoretical results are delved into, highlighting the potential of strain to modulate physical properties, thereby enhancing device performance. Various strain engineering methods are summarized, and the impact of strain on the electrical, optical, magnetic, thermal, and valleytronic properties of 2D materials is thoroughly examined. Finally, the review concludes by addressing potential applications and challenges in utilizing strain engineering for functional devices, offering valuable insights for further research and applications in optoelectronics, thermionics, and spintronics.

Preparing for the unexpected: Recommendations for returning secondary findings in late-stage cancer care.

PURPOSE: We conducted qualitative interviews with patients with cancer and providers to identify gaps in clinical care and highlight care delivery solutions for the return of secondary germline findings. METHODS: Twelve patients and 19 cancer providers from the United States were interviewed between January 2019 and May 2021. Interviews elicited feedback about patient information needs, emotional responses to secondary findings, and recommendations for improving pre-test education. RESULTS: Patients' responses ranged from gratitude to regret, depending on how much pre-test counseling they received before tumor testing. Providers cited insufficient clinic time as a major barrier to pretest education, favoring online support tools and standardized pre-test education models. Providers had differing perspectives on how pre-test education should be integrated into clinical workflows but agreed that it should include the differences between somatic and germline testing, the likelihood of medically actionable findings, and the possibility of being referred to a genetics provider. CONCLUSION: The spectrum of participants' responses to their secondary findings underscores the importance of adequate pre-test discussions before somatic sequencing. Although educational interventions could address patients' information needs and augment traditional pre-test counseling, health care systems, labs, and genetic providers may be called on to play greater roles in pre-test education.

Views of adults living with sickle cell disease on the theoretical return of secondary genomic findings.

PURPOSE: Although the body of research investigating research participants' opinions on the return of actionable secondary genomic findings grows, there has been limited study of individuals with genetic conditions, such as sickle cell disease (SCD). It is imperative that the views of diverse research participants on return of results (RoR) be investigated and rooted in the context of advancing health equity in genomics research. METHODS: We conducted qualitative, semi-structured interviews with 30 adults living with SCD with differing insurance coverages and utilized a directed content analysis to derive themes. RESULTS: Study findings show that living with SCD is a key influence on views of RoR. Participants were in favor of RoR while expressing concern regarding the burden RoR would place on their SCD management. Respondents also expressed an expectation for researchers to devote resources toward seeking ancillary care downstream and discussed how barriers faced when navigating SCD would inform their access to ancillary care. CONCLUSION: Research participants living with chronic genetic conditions such as SCD are generally in favor of RoR but anticipate experiencing barriers to care similar to those faced navigating their SCD. Understanding the views of diverse cohorts on RoR will help researchers better understand downstream barriers participants may face.

Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group.

About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.

MR Elastography of the Pancreas: Bowel Preparation and Repeatability Assessment in Pancreatic Cancer Patients and Healthy Controls.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) stromal viscoelasticity can be measured using MR elastography (MRE). Bowel preparation regimens could affect MRE quality and knowledge on repeatability is crucial for clinical implementation. PURPOSE: To assess effects of four bowel preparation regimens on MRE quality and to evaluate repeatability and differentiate patients from healthy controls. STUDY TYPE: Prospective. POPULATION: 15 controls (41 ± 16 years; 47% female), 16 PDAC patients (one excluded, 66 ± 12 years; 40% female) with 15 age-/sex-matched controls (65 ± 11 years; 40% female). Final sample size was 25 controls and 15 PDAC. FIELD STRENGTH/SEQUENCE: 3-T, spin-echo echo-planar-imaging, turbo spin-echo, and fast field echo gradient-echo. ASSESSMENT: Four different regimens were used: fasting; scopolaminebutyl; drinking 0.5 L water; combination of 0.5 L water and scopolaminebutyl. MRE signal-to-noise ratio (SNR) was compared between all regimens. MRE repeatability (test-retest) and differences in shear wave speed (SWS) and phase angle (ϕ) were assessed in PDAC and controls. Regions-of-interest were defined for tumor, nontumorous (n = 8) tissue in PDAC, and whole pancreas in controls. Two radiologists delineated tumors twice for evaluation of intraobserver and interobserver variability. STATISTICAL TESTS: Repeated measures analysis of variance, coefficients of variation (CoVs), Bland-Altman analysis, (un)paired t-test, Mann-Whitney U-test, and Wilcoxon signed-rank test. P-value<0.05 was considered statistically significant. RESULTS: Preparation regimens did not significantly influence MRE-SNR. Therefore, the least burdensome preparation (fasting only) was continued. CoVs for tumor SWS were: intrasession (12.8%) and intersession (21.7%), and intraobserver (7.9%) and interobserver (10.3%) comparisons. For controls, CoVs were intrasession (4.6%) and intersession (6.4%). Average SWS for tumor, nontumor, and healthy tissue were: 1.74 ± 0.58, 1.38 ± 0.27, and 1.18 ± 0.16 m/sec (ϕ: 1.02 ± 0.17, 0.91 ± 0.07, and 0.85 ± 0.08 rad), respectively. Significant differences were found between all groups, except for ϕ between healthy-nontumor (P = 0.094). DATA CONCLUSION: The proposed bowel preparation regimens may not influence MRE quality. MRE may be able to differentiate between healthy tissue-tumor and tumor-nontumor. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

The influence of hematological profiles on the transfusion management and mortality risk of mothers presenting to the obstetric unit of a South African tertiary medical facility.

BACKGROUND: Laboratory results are frequently abnormal in pregnant mothers. Abnormalities usually relate to pregnancy or associated complications. Hematological abnormalities and age in pregnancy may increase the likelihood for transfusion and mortality. STUDY DESIGN AND METHODS: Hematological profiles and transfusion history of pregnant mothers presenting to a tertiary hospital, were evaluated over 2 years. Age, anemia, leukocytosis and thrombocytopenia were assessed for transfusion likelihood. Iron deficiency and coagulation were assessed in transfused patients. Anemia, leukocytosis, thrombocytopenia, human immunodeficiency virus (HIV) and transfusion were assessed for mortality likelihood. RESULTS: There were 12,889 pregnant mothers included. Mothers <19-years-old had the highest prevalence of anemia (31.5%) and proportion of transfusions (19%). The transfusion likelihood was increased in mothers with anemia (odds ratios [OR] = 6.41; confidence intervals at 95% [95% CI] 5.46-7.71), leukocytosis (OR = 2.35; 95% CI 2.00-2.76) or thrombocytopenia (OR = 2.71; 95% CI 2.21-3.33). Mothers with prolonged prothrombin times received twice as many blood products as their normal counterparts (p = .03) and those with iron deficiency anemia five times more blood products (p < .001). Increased likelihood for mortality was seen in patients with anemia (OR = 4.15, 95% CI 2.03-8.49), leukocytosis (OR = 2.68; 95% CI 1.19-6.04) and those receiving blood transfusion (OR = 3.6, 95% CI 1.75-7.47). DISCUSSION: Adolescence, anemia, leukocytosis and thrombocytopenia expose mothers to a high risk for transfusion and/or mortality. These risk factors should promptly trigger management and referral of patients. Presenting hematological profiles are strong predictors of maternal outcome and transfusion risk.

Phase II study of SOXIRI (S-1/oxaliplatin/irinotecan) chemotherapy in patients with unresectable pancreatic ductal adenocarcinoma.

BACKGROUND: To provide data on the safety and efficacy of a combination chemotherapy regimen consisting of S-1, oxaliplatin, and irinotecan (SOXIRI) as a first-line therapy in unresectable pancreatic ductal adenocarcinoma (UPDA) patients. METHODS: Patients with UPDA and no prior treatment chemotherapy in the UPDA setting were enrolled. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival (PFS) and adverse events. Patients received 80 mg/m2 S-1 twice a day for 2 weeks in an alternate-day administration cycle, 85 mg/m2 oxaliplatin on Day 1, and 150 mg/m2 irinotecan on Day 1 of a 2-week cycle. RESULTS: In these 62 enrolled patients, the ORR was 27.4 %, median OS was 12.1 months, and median PFS was 6.5 months. Major grade 3 or 4 toxicity included neutropenia (22.3 %), leucopenia (16.1 %), nausea (9.7 %), vomiting (9.7 %), thrombocytopenia (6.5 %), anorexia (8.5 %), anemia (4.8 %), and diarrhea (1.6 %). No treatment-related deaths occurred. In addition, the analysis of 32 patients suffering pain revealed that the rate of pain relief was 34.4 %. CONCLUSION: SOXIRI might be a standard regimen with an acceptable toxicity profile and favorable efficacy for use as chemotherapy in patients with UPDA.

Variation in cervical cancer screening test utilization and results in a United States-based program.

BACKGROUND: Little is known about cervical cancer screening strategy utilization (cytology alone, cytology plus high-risk human papillomavirus [HPV] testing [cotesting], primary HPV testing) and test results in the United States. METHODS: Data from the Centers for Disease Control and Prevention's National Breast and Cervical Cancer Early Detection Program were analyzed for 199,578 persons aged 21-65 years screened from 2019 to 2020. Screening test utilization and results were stratified by demographic characteristics and geographic region. Age-standardized pooled HPV test positivity and genotyping test positivity were estimated within cytology result categories. RESULTS: Primary HPV testing was performed in 592 persons (0.3%). Among the remaining 176,290 persons aged 30-65 years, cotesting was utilized in 72.1% (95% confidence interval [CI] 71.9-72.3%), and cytology alone was utilized in 27.9% (95% CI 27.7-28.1%). Utilization of cytology alone varied by geographic region, ranging from 18.3% (95% CI 17.4-19.1%) to 49.0% (95% CI 48.4-49.6%). HPV genotyping test utilization among those with positive pooled HPV test results was 33.9%. In persons aged ≥30 years, variations in age-adjusted test results by region were observed for pooled HPV-positive test results and for HPV genotyping-positive test results. CONCLUSIONS: Cervical cancer screening strategy utilization and test results vary substantially by geographic region within a national screening program. Variation in utilization may be due to regional differences in screening test availability or the preferences of healthcare systems, screened persons and/or clinicians. Test result variations may reflect differing risk factors for HPV infections by geographic region.

Anticoagulation use is associated with lower fetal fraction and more indeterminate results.

BACKGROUND: Maternal anticoagulation use may increase indeterminate result rates on cell-free DNA-based screening, but existing studies are confounded by inclusion of individuals with autoimmune disease, which alone is associated with indeterminate results. Changes in chromosome level Z-scores are proposed by others as a reason for indeterminate results, but the etiology of this is uncertain. OBJECTIVE: This study aimed to evaluate differences in fetal fraction, indeterminate result rate, and total cell-free DNA concentration in individuals on anticoagulation without autoimmune disease compared with controls undergoing noninvasive prenatal screening. Secondly, using a nested case-control design, we evaluated differences in fragment size, GC-content, and Z-scores to evaluate laboratory-level test characteristics. STUDY DESIGN: This was a retrospective single-institution study of pregnant individuals undergoing cell-free DNA-based noninvasive prenatal screening using low-pass whole-genome sequencing between 2017 and 2021. Individuals with autoimmune disease, suspected aneuploidy, and cases where fetal fraction was not reported were excluded. Anticoagulation included heparin-derived products (unfractionated heparin, low-molecular-weight heparin), clopidogrel, and fondaparinux, with a separate group for those on aspirin alone. An indeterminate result was defined as fetal fraction <4%. We evaluated the association between maternal anticoagulation or aspirin use, and fetal fraction, indeterminate results, and total cell-free DNA concentration using univariate and multivariate analyses, controlling for body mass index, gestational age at sample collection, and fetal sex. For the anticoagulation cohort, we compared laboratory-level test characteristics among cases (on anticoagulation) and a subset of controls. Lastly, we evaluated for differences in chromosome level Z-scores among those on anticoagulation with and without indeterminate results. RESULTS: A total of 1707 pregnant individuals met the inclusion criteria. Of those, 29 were on anticoagulation and 81 were on aspirin alone. For those on anticoagulation, the fetal fraction was significantly lower (9.3% vs 11.7%; P<.01), the indeterminate result rate was significantly higher (17.2% vs 2.7%; P<.001), and the total cell-free DNA concentration was significantly higher (218 pg/µL vs 83.7 pg/µL; P<.001). Among those on aspirin alone, the fetal fraction was lower (10.6% vs 11.8%; P=.04); however, there were no differences in the rate of indeterminate results (3.7% vs 2.7%; P=.57) or total cell-free DNA concentration (90.1 pg/µL vs 83.8 pg/µL; P=.31). After controlling for maternal body mass index, gestational age at sample collection, and fetal sex, anticoagulation was associated with an >8-fold increase in the likelihood of an indeterminate result (adjusted odds ratio, 8.7; 95% confidence interval, 3.1-24.9; P<.001), but not aspirin (adjusted odds ratio, 1.2; 95% confidence interval, 0.3-4.1; P=.8). Anticoagulation was not associated with appreciable differences in cell-free DNA fragment size or GC-content. Although differences in chromosome 13 Z-scores were observed, none were observed for chromosomes 18 or 21, and this difference did not contribute to the indeterminate result call. CONCLUSION: In the absence of autoimmune disease, anticoagulation use, but not aspirin, is associated with lower fetal fraction, higher total cell-free DNA concentration, and higher rates of indeterminate results. Anticoagulation use was not accompanied by differences in cell-free DNA fragment size or GC-content. Statistical differences in chromosome level Z-scores did not clinically affect aneuploidy detection. This suggests a likely dilutional effect by anticoagulation on cell-free DNA-based noninvasive prenatal screening assays contributing to low fetal fraction and indeterminate results, and not laboratory or sequencing-level changes.

Methodological rigour in preclinical urology: a systematic review reporting research quality over a 14-year period.

OBJECTIVE: To investigate the prevalence and trends of essential study design elements in preclinical urological studies, as well as key factors that may improve methodological rigour, as the demand for methodological rigour in preclinical studies is increasing since research reproducibility and transparency in the medico-scientific field are being questioned. METHODS AND RESULTS: PubMed was searched to include preclinical urological studies published between July 2007 to June 2021. A total of 3768 articles met the inclusion criteria. Data on study design elements and animal models used were collected. Citation density was also examined as a surrogate marker of study influence. We performed an analysis of the prevalence of seven critical study design elements and temporal patterns over 14 years. Randomisation was reported in 50.0%, blinding in 15.0%, sample size estimation in 1.0%, inclusion of both sexes in 6.3%, statistical analysis in 97.1%, housing and husbandry in 47.7%, and inclusion/exclusion criteria in 5.0%. Temporal analysis showed that the implementation of these study design elements has increased, except for inclusion of both sexes and inclusion/exclusion criteria. Reporting study design elements were associated with increased citation density in randomisation and statistical analysis. CONCLUSIONS: The risk of bias is prevalent in 14-year publications describing preclinical urological research, and the quality of methodological rigour is barely related to the citation density of the article. Yet five study design elements (randomisation, blinding, sample size estimation, statistical analysis, and housing and husbandry) proposed by both the National Institutes of Health and Animal Research: Reporting of In Vivo Experiments guidelines have been either well reported or are being well reported over time. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022233125.

Immunotherapy with autologous dendritic cells in the complex treatment of malignant gliomas - results.

ANNOTATION: Malignant gliomas are the most common primary brain tumor. Despite the variety of modern treatments, it is still a fatal disease with an extremely poor prognosis. The use of immunotherapy as a technique for the treatment of malignant tumors has great promise, retraining and exploiting the patient's immune response against tumors. OBJECTIVE: Evaluation of the effectiveness of dendritic cell vaccine in patients with malignant brain gliomas in the structure of complex treatment in comparison with the control group of patients without immunotherapy in the structure of treatment. MATERIALS AND METHODS: In a single-center, prospective, cohort study, taking place on the basis of the RNSI named after prof. A.L. Polenov, 91 patients with morphologically established malignant glial tumor (glioblastoma) took part. The main group of 41 patients who, in addition to standard treatment (surgical, radiation and chemotherapy), underwent specific antitumor immunotherapy. 50 patients received only standard treatment, without immunotherapy. RESULTS: Median survival was 21.7 months in the immunotherapy group (95% CI 4-37 months) and 15.8 months (95% CI 3-22 months) in the non-immunotherapy group (p = 0.002). The median relapse-free period in the group with immunotherapy was 13.8 months (95% CI 1-20 months), and in the group without immunotherapy 7.9 months (95% CI 1-12 months) (p = 0.003). CONCLUSION: In general, the use of immunotherapy in the structure of complex treatment of patients with malignant gliomas demonstrates a clear positive trend in terms of overall survival and median relapse-free period. But nevertheless, immunotherapy requires further development as a therapeutic tool, study and improvement, which will take into account immunosuppression in malignant gliomas and means of overcoming it, optimization in terms of target antigen selection, cell preparation and integration of dendritic vaccines into other treatment regimens.

Natural History and Prognostic Model of Untreated Papillary Thyroid Cancer: A SEER Database Analysis.

PURPOSE: This investigation leveraged the SEER database to delve into the progression patterns of PTC when left untreated. Furthermore, it aimed to devise and authenticate a nomogram for prognosis prediction for such patients. METHODS: We extracted data from the SEER database, focusing on PTC-diagnosed individuals from 2004-2020. To discern disease progression intervals, median survival times across stages were gauged, and the disease progression time was estimated by subtracting the median survival time of a more severe stage from its preceding stage. Prognostic determinants in the training set were pinpointed using both univariate and multivariate Cox regression. Using these determinants, a prognostic nomogram was crafted. RESULTS: In untreated PTC patients, those in stages I and II had a favorable prognosis, with 10-year overall survival rates of 86.34% and 66.03%, respectively. Patients in stages III and IV had a relatively poorer prognosis. The median survival time of stage III, stage IVA, stage IVB and stage IVC patients was 108months, 43 months, 20 months and 8 months, respectively. The deduced progression intervals from stages III-IVC were 65, 23, and 12 months. In the training set, age, tumor stage, gender, and marital status were identified as independent risk factors influencing the prognosis of untreated PTC, and a nomogram was constructed using these variables. CONCLUSION: In the absence of treatment intervention, early-stage PTC progressed slowly with an overall favorable prognosis. However, in mid to advanced-stage PTC, as tumor stage increased, disease progression accelerated, and prognosis gradually worsened. Age, tumor stage, marital status, and gender were independent risk factors influencing the prognosis of untreated PTC, and the nomogram based on these factors demonstrated good prognostic capability.

PurposeThis investigation leveraged the SEER database to delve into the progression patterns of PTC when left untreated. Furthermore, it aimed to devise and authenticate a nomogram for prognosis prediction for such patients.MethodsWe extracted data from the SEER database, focusing on PTC-diagnosed individuals from 2004-2020. To discern disease progression intervals, median survival times across stages were gauged, and the disease progression time was estimated by subtracting the median survival time of a more severe stage from its preceding stage. Prognostic determinants in the training set were pinpointed using both univariate and multivariate Cox regression. Using these determinants, a prognostic nomogram was crafted.ResultsIn untreated PTC patients, those in stages I and II had a favorable prognosis, with ten-year overall survival rates of 86.34% and 66.03%, respectively. Patients in stages III and IV had a relatively poorer prognosis. The median survival time of stage III, stage IVA, stage IVB and stage IVC patients was 108months, 43 months, 20 months and 8 months, respectively. The deduced progression intervals from stages III-IVC were 65, 23, and 12 months. In the training set, age, tumor stage, gender, and marital status were identified as independent risk factors influencing the prognosis of untreated PTC, and a nomogram was constructed using these variables.ConclusionIn the absence of treatment intervention, early-stage PTC progressed slowly with an overall favorable prognosis. However, in mid to advanced-stage PTC, as tumor stage increased, disease progression accelerated, and prognosis gradually worsened. Age, tumor stage, marital status, and gender were independent risk factors influencing the prognosis of untreated PTC, and the nomogram based on these factors demonstrated good prognostic capability.