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.

The Effect of Self-Reported Race on Noninvasive Prenatal Screening Test Characteristics.

OBJECTIVE: Low fetal fraction (FF) on cell-free DNA (cfDNA)-based noninvasive prenatal screening (NIPS) is a common etiology for indeterminate results. As maternal Black race is implicated as a risk factor for low FF and more indeterminate results, we sought to evaluate this association. STUDY DESIGN: This was a single-institution, retrospective cohort study of cfDNA-based NIPS performed between May 2017 and May 2022 with complete clinical data abstraction. We compared FF, indeterminate rates, and total cfDNA concentration among self-reported Black, White, and Other groups from NIPS results from 2017 to 2022 with full clinical data abstraction. Using linear regression and interaction testing, we evaluated associations between self-reported race, FF, indeterminate rate, and total cfDNA concentration. RESULTS: In total, 1,591 participants met the inclusion criteria; 70.8% (n = 1,126) self-identified as White, 6.9% (n = 110) as Black, and 22.3% (n = 355) self-identified with another race. Mean FF was not different between the White, Black, or Other groups (11.8 vs. 11.2 vs. 11.7%, respectively, p = 0.52). This remained true after adjusting for body mass index (BMI), gestational age (GA) at draw, and fetal sex (all p > 0.17). Interaction testing for FF and total cfDNA by race with BMI, GA at draw, and fetal sex demonstrated no effect modification. CONCLUSION: In our population, maternal self-identified race, particularly Black race, does not affect FF. Biological plausibility for race-based differences on clinical tests requires ongoing thoughtful consideration. KEY POINTS: · NIPS is widely used to screen for fetal aneuploidy.. · FF is an important test metric, and low FF is associated with adverse outcomes, like aneuploidy.. · In existing studies, Black race is implicated as a risk factor for lower FF.. · Our study found no differences in FF between groups by self-reported race.. · Biological plausibility for race-based differences on clinical tests requires ongoing consideration..

European Groundshot-addressing Europe's cancer research challenges: a Lancet Oncology Commission.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

First evidence of long-term effects of transcranial pulse stimulation (TPS) on the human brain.

BACKGROUND: With the high spatial resolution and the potential to reach deep brain structures, ultrasound-based brain stimulation techniques offer new opportunities to non-invasively treat neurological and psychiatric disorders. However, little is known about long-term effects of ultrasound-based brain stimulation. Applying a longitudinal design, we comprehensively investigated neuromodulation induced by ultrasound brain stimulation to provide first sham-controlled evidence of long-term effects on the human brain and behavior. METHODS: Twelve healthy participants received three sham and three verum sessions with transcranial pulse stimulation (TPS) focused on the cortical somatosensory representation of the right hand. One week before and after the sham and verum TPS applications, comprehensive structural and functional resting state MRI investigations and behavioral tests targeting tactile spatial discrimination and sensorimotor dexterity were performed. RESULTS: Compared to sham, global efficiency significantly increased within the cortical sensorimotor network after verum TPS, indicating an upregulation of the stimulated functional brain network. Axial diffusivity in left sensorimotor areas decreased after verum TPS, demonstrating an improved axonal status in the stimulated area. CONCLUSIONS: TPS increased the functional and structural coupling within the stimulated left primary somatosensory cortex and adjacent sensorimotor areas up to one week after the last stimulation. These findings suggest that TPS induces neuroplastic changes that go beyond the spatial and temporal stimulation settings encouraging further clinical applications.

The Role of Patient Support Groups in Neuroendocrine Neoplasms.

PURPOSE OF REVIEW: The purpose of this review is to establish the role patient support groups play in NENs. RECENT FINDINGS: Published data on the role and work done by these groups is extremely sparse, so the review references publications in the wider cancer advocacy context. For the purposes of the review, a survey was carried out among the members of a global umbrella organization to ascertain the level of activities undertaken in support of the NEN patient community. The concept of "support groups" has changed significantly, as these groups have evolved from patient peer-to-peer support provision to a strategic focus on improving awareness and education among all stakeholders, generating patient evidence to influence policies for access to optimal diagnostics, treatment, and care, and setting the research agenda. Today, NEN patient organizations have an instrumental role of catalysts of change across the healthcare spectrum-especially relevant in a setting of less common and not well-understood diseases, where clear pathways and guidelines are still a challenge.

Low fetal fraction in obese women at first trimester cell-free DNA based prenatal screening is not accompanied by differences in total cell-free DNA.

OBJECTIVE: Reasons for first trimester noninvasive prenatal screening (NIPS) test failure in obese women remain elusive. As dilution from maternal sources may be explanatory, we determined the relationship between obesity, fetal fraction (FF), and total cell-free DNA (cfDNA) using our NIPS platform. METHODS: We assessed differences in first trimester (≤14 weeks) FF, indeterminate rate, and total cfDNA between obese (n = 518) and normal-weight women (n = 237) after exclusion of confounders (anticoagulation, autoimmunity, aneuploidy) and controlling for covariates. RESULTS: Fetal fraction was lower, and the indeterminate rate higher, in obese compared to controls (9.2% ± 4.4 vs. 12.5% ± 4.5, p < 0.001 and 8.4 vs. 1.7%, p < 0.001, respectively), but total cfDNA was not different (92.0 vs. 82.1 pg/µl, p = 0.10). For each week, the FF remained lower in obese women (all p < 0.01) but did not increase across the first trimester for either group. Obesity increased the likelihood of indeterminate result (OR 6.1, 95% CI 2.5, 14.8; p < 0.001) and maternal body mass index correlated with FF (ß -0.27, 95% CI -0.3, -0.22; p < 0.001), but not with total cfDNA (ß 0.49, 95% CI -0.55, 1.53; p = 0.3). CONCLUSIONS: First trimester obese women have persistently low FF and higher indeterminate rates, without differences in total cfDNA, suggesting placental-specific mechanisms versus dilution from maternal sources as a potential etiology.

Unmet needs in the international neuroendocrine tumor (NET) community: Assessment of major gaps from the perspective of patients, patient advocates and NET health care professionals.

Due to the increasing incidence and prevalence of neuroendocrine tumors (NETs), there is a need to assess any gaps in awareness and care. A survey was undertaken in 2017 to identify perceived unmet needs from the perspectives of patients/families, patient advocates and health care professionals (HCPs). The survey consisted of 33-37 questions (depending on type of respondent) across four areas: information, care, treatments and research. In total, 443 participants from 26 countries responded: 338 patients/families, 35 advocates and 70 HCPs. Perceived unmet needs regarding provision of information at diagnosis differed between groups. While 59% of HCPs believed they provided sufficient information, informational needs were mostly/fully met for only 30% of patients and 18% of advocates. Additionally, 91% of patients and 97% of advocates felt that patients had to search for information themselves. Availability of Gallium-68-Dotatate PET/CT scan was limited for the majority of patients (patients: 73%; advocates: 85%; HCP: 86%), as was access to treatments, particularly peptide receptor radionuclide therapy (patients: 42%; advocates: 95%; HCPs: 77%). All groups felt that standards of care, including psychological needs and diagnosis of mental health, were not fully met. Although about two-thirds of patients were managed by a multidisciplinary team, 14% of patients reportedly did not have enough contact. All groups supported more patient involvement in research; patients and advocates prioritized improvement in diagnosis and HCPs focused on clinical trials. This survey revealed significant unmet needs but differing perceptions regarding these among the groups. There is a need for investigation and collaboration to improve standards of care for NET patients.

In vitro activity of the mTOR inhibitor everolimus, in a large panel of breast cancer cell lines and analysis for predictors of response.

Everolimus (RAD001, Afinitor(®)) is an oral, selective mTOR inhibitor recently approved by the US-FDA in combination with exemestane for treatment of hormone receptor positive advanced breast cancer. To date, no molecular predictors of response to everolimus in breast cancer have been identified. We hypothesized predictive markers could be identified using preclinical models. Using a molecularly characterized panel of human breast cancer and immortalized breast epithelial cell lines, we determined sensitivity to everolimus alone or in combination with ER- or HER2- targeted therapy. Gene expression microarrays and comparative genomic hybridization were performed on the cell lines to identify predictors of response to everolimus. Among 13 everolimus-sensitive cell lines, 10/13(77 %) were luminal, while in 26 resistant cell lines, 16/26(62 %) were non-luminal, and 10/26(38 %) were luminal. Only 3/24 non-luminal lines were sensitive, two of which were HER2+. Everolimus enhanced the anti-proliferative effect of both tamoxifen (TAM) and fulvestrant (FUL) in ER+ breast cancer cell lines, as well as trastuzumab in HER2+ cell lines. Everolimus + FUL but not everolimus + TAM reversed acquired resistance to TAM. Everolimus inhibited mTOR in tested cell lines by decreasing S6 phosphorylation, mediating its anti-proliferative effect by G0/G1 cell cycle arrest and induction of apoptosis. Chromosomal amplifications of AURKA (p value = 0.04) and HER2 (p value = 0.03) were each associated with increased sensitivity to everolimus. Transcript expression microarrays identified GSK3A, PIK3R3, KLF8, and MAPK10 among the genes overexpressed in sensitive luminal lines, while PGP, RPL38, GPT, and GFAP were among the genes overexpressed in resistant luminal cell lines. These preclinical in vitro data provide further support for continued clinical development of everolimus in luminal (ER+ or HER2+) breast cancer in combination with targeted therapies. We identified several potential molecular markers associated with response to everolimus that will require validation in clinical material.

Effect of Uterine Leiomyomas on Noninvasive Prenatal Testing Parameters in the First Trimester.

Uterine leiomyomas may affect the performance of cell-free DNA (cfDNA)-based noninvasive prenatal testing (NIPT). We conducted a retrospective cohort study of pregnant individuals with and without leiomyomas undergoing first-trimester cfDNA-based NIPT. Characteristics of NIPT in patients with leiomyomas (n=122) were compared with those in patients without leiomyomas (n=937). Mean fetal fraction was lower in patients with leiomyomas compared with patients without (10.0% vs 11.5%; P =.001); however, the rate of indeterminate results was different only in patients without obesity (body mass index [BMI] lower than 30) (5.3% vs 1.5%; P =0.03). Total cfDNA concentration was higher in patients with leiomyomas ( P =.002), suggesting possible dilution of the fetal fraction. Leiomyoma size did not affect NIPT metrics. In conclusion, uterine leiomyomas are associated with lower fetal fraction and, in patients without obesity, with a higher rate of indeterminate results independent of leiomyoma size.

AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53.

Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 >10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 <10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between AURKA amplification and response to AMG 900 (response ratio = 2.53, p = 0.09). mRNA expression levels of AURKA, AURKB, and AURKC and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with TP53 loss of function mutations (RR = 1.86, p = 0.004) and low baseline p21 protein levels (RR = 2.28, p = 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt TP53. AMG 900 caused the accumulation of cells with >4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that TP53 loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.

Reconsidering Race Adjustment in Prenatal Alpha-Fetoprotein Screening.

OBJECTIVE: Black racial designation is the only race for which adjustment is recommended for maternal prenatal serum alpha-fetoprotein (AFP) screening. The objective of this study is to reevaluate the relationship between maternal race and maternal serum AFP values in prenatal analyte screening. METHODS: This was a single-center retrospective analysis of patients who underwent prenatal analyte screening between January 2007 and December 2020. Nomograms for raw maternal serum AFP values by gestational age were created and compared between patients identified as "Black" and "non-Black" on the laboratory requisition. Multivariable linear regression models were created to evaluate the relationship among gestational age, maternal weight, and maternal race on maternal serum AFP levels. The new models were compared with the laboratory-derived calculations, which used historically determined race adjustments. RESULTS: A total of 43,997 patients underwent analyte screening, and 27,710 patients had complete data for analysis. Of these, 6% were identified as Black. Black patients had laboratory blood draws at a mean gestational age of 123 days, compared with 120 days in non-Black patients ( P <.001), and had higher maternal weight (mean 170 vs 161 lbs, P <.001). Nomograms for raw maternal serum AFP values did not differ between Black and non-Black patients ( P =.065). When adjusted for gestational age and maternal weight, no difference in maternal serum AFP values was identified between Black and non-Black individuals ( P =.81). CONCLUSION: No difference in maternal serum AFP values was identified between Black and non-Black pregnant individuals when adjusted by maternal weight and gestational age at blood draw. These findings suggest that routine race-based adjustment of maternal serum AFP screening should be discontinued.

Satisfaction with injection experience of patients with neuroendocrine tumors enrolled on lanreotide autogel patient support programs: Results from the international HomeLAN survey.

Lanreotide autogel/depot (LAN) is a somatostatin analog used in first-line treatment for neuroendocrine tumors (NETs). The aim of HomeLAN was to evaluate the satisfaction with injection experience among patients with NETs receiving at-home LAN injection via patient support programs (PSPs). This was an international, non-interventional, cross-sectional, online survey in adults with NETs enrolled in PSPs, receiving LAN injections at home, administered by a healthcare professional (HCP) or administered independently (self or caregiver administering injection). The primary endpoint was satisfaction with the most recent LAN injection. Secondary endpoints included the level of anxiety prior to injection, impact on daily life, and the extents to which participants felt in control of their life and agreed that home administration met their medical needs. In total, 111 participants from Belgium, Greece, the Netherlands, and Spain completed the survey (50.5% male; mean age, 63.6 years; most common primary tumor site was intestine [47.7%]). For 99 participants, their most recent injection was administered by an HCP. Overall, 95.5% of all participants were satisfied with their most recent injection experience (95% confidence interval: 89.89%-98.06%); 67% reported experiencing no anxiety prior to injection, 91.0% reported that home injection had a "great deal" or "quite a bit" of positive impact on their daily life, and 85.6% strongly agreed that the PSP met their medical needs. In the HCP injection subgroup, 71.7% reported that this mode of administration helped them to feel in control of their lives. In this patient survey, satisfaction levels were high among patients with NETs receiving LAN injections at home via a LAN PSP. Most patients did not experience anxiety prior to their most recent injection and acknowledged that thanks to their treatment they had a good quality of life despite their disease. Most strongly agreed that the PSP met their medical needs, which highlights the valuable service that LAN PSPs provide for patients with NETs.

Key Device Attributes for Injectable Somatostatin Receptor Ligand Therapy in Acromegaly and Neuroendocrine Tumours.

INTRODUCTION: People living with acromegaly and neuroendocrine tumours (NETs) may be treated with injectable somatostatin receptor ligands (SRLs), administered by either a caregiver or as self-injection via a proprietary or generic device. Injection device attributes that contribute to ease of use and storage, minimise preparation requirements, and reduce injection pain are associated with improved adherence and more favourable therapeutic outcomes. The aim of this study was to assess current opinion surrounding favourable SRL device attributes for people living with acromegaly and NETs as well as that of their caregivers. METHODS: Participants (healthcare professionals [HCPs] and patients/non-HCP caregivers) from 11 countries were invited to answer survey questions related to their demographic, experience, and preferences as they relate to the real-world use of injectable SRL devices. Questions were developed based on review of available literature and meetings with a Scientific Committee. RESULTS: Device attributes preferred by the patient/non-HCP caregiver group (n = 211) included confidence that the correct drug amount is delivered (76%), quick administration with minimal pain/discomfort (68%), and device safety (needle-safety and low risk of contamination; 53%). Device attributes preferred by HCPs (n = 52) were quick administration with minimal pain/discomfort (69%), correct use is easy to learn, confidence in handling the device (63%), and confidence that the correct drug amount is delivered (62%). CONCLUSION: The results identified key features of injection devices for SRL therapy which merit consideration for optimal management and underscore the importance of patient partnership in treatment decisions.

Increased fetal microchimerism in immune and stem cell subsets in preeclampsia.

PROBLEM: Preeclampsia (PE) is associated with an increased risk of maternal cardiovascular disease (CVD), however, it is unclear whether this is due to shared underlying physiology or changes which occur during the disease process. Fetal microchimerism (FMc) within the maternal circulation can durably persist decades after pregnancy, is known to occur at greater frequency in PE, and can potentially affect local and systemic immune programming, thus changes in cellular FMc may provide a mechanism for long-term health outcomes associated with PE. METHOD OF STUDY: We investigated whether PE is associated with alterations in FMc immune and stem cell populations. We analyzed maternal peripheral blood mononuclear cells (PBMC) from PE cases (n = 16) and matched controls from normal pregnancies (n = 16), from which immune and stem cell subsets were isolated by flow cytometry. Genomic DNA was extracted from total PMBC and individual cell subsets, and FMc frequency was quantified by quantitative polymerase chain reaction assays targeting a fetal-specific non-shared polymorphism identified from family genotyping. RESULTS: There was a significant increase in FMc concentration in immune cell subsets in PE cases compared to controls, predominantly in B cell, and NK cell lymphocyte populations. There was no significant difference in FMc frequency or concentration within the stem cell population between PE and controls. CONCLUSIONS: The altered concentrations of immune cells within FMc in the maternal blood provides a potential mechanism for the inflammation which occurs during PE to induce long-lasting changes to the maternal immune system and may potentially promote chronic maternal disease.

Global challenges in access to diagnostics and treatment for neuroendocrine tumor (NET) patients.

SCAN, an online survey, measured access to diagnosis, treatments and monitoring of neuroendocrine tumor (NET) patients globally. Between September and November 2019, NET patients and healthcare professionals (HCPs) completed an online, semi-standardized survey with 54 patient questions and 33 HCP questions. A total of 2359 patients with NETs and 436 HCPs responded. Misdiagnosis was common (44% [1043/2359]). Mean time to diagnosis was 4.8 years (standard deviation [SD], 6.2). Compared with global figures (60% [1407/2359]), the availability of 68 Ga-DOTA positron emission tomography (PET)/computed tomography (CT) was significantly lower in Asia (45% [126/280]) and higher in Oceania (86% [171/200]). HCPs reported that 68 Ga-DOTA PET/CT was free/affordable to fewer patients in Emerging and Developing Economies (EDE) than Advanced Economies (AE; 17% [26/150] and 59% [84/142], respectively). Compared with global data (52% [1234/2359]), patient-reported availability of peptide receptor radionuclide therapy (PRRT) was significantly lower in Asia (31% [88/280]) and higher in Oceania (61% [122/200]). Significant differences were observed in average annual NET specialist costs between AE and EDE ($1081 and $2915, respectively). Compared with AE, patients in EDE traveled further for NET specialists (1032 [SD, 1578] and 181 [SD, 496] km, respectively). Patients and HCPs both recommended referral to HCPs that were more knowledgeable in the field of NETs and had better access to NET experts/specialist centers. National care pathways, enhancing HCP NET knowledge and ensuring effective diagnostics and access to appropriate treatments are crucial to improving patient survival and NET care worldwide.

Association of fetal fraction with hypertensive disorders of pregnancy incidence and disease severity.

BACKGROUND: Hypertensive disorders of pregnancy contribute to maternal and offspring morbidity and mortality. Studies suggest that a lower early pregnancy fetal fraction is associated with an increased risk of hypertensive disorders of pregnancy. However, maternal obesity significantly affects fetal fraction and is a risk factor for hypertensive disorders of pregnancy. OBJECTIVE: We determined the association between fetal fraction (using a standardized single-institution platform, including male and female fetuses) and hypertensive disorders of pregnancy, stratified by obesity status. Second, we evaluated differences in total cell-free DNA concentration and correlation of fetal fraction with clinical markers of hypertensive disorders of pregnancy severity. STUDY DESIGN: This was a retrospective, single-institution study of a previously validated cell-free DNA-based noninvasive prenatal screening assay of 1058 samples. Maternal body mass index at the time of noninvasive prenatal screening was assessed, and hypertensive disorders of pregnancy were confirmed by a detailed medical record review. Differences in fetal fraction and total cell-free DNA concentration between the groups were assessed with univariate analyses. Multivariable regression was used to evaluate the association between fetal fraction and hypertensive disorders of pregnancy, adjusted for body mass index, maternal age, gestational age at noninvasive prenatal screening, and fetal sex. The association between fetal fraction and hypertensive disorders of pregnancy among individuals with obesity (body mass index, ≥30 kg/m2) and individuals without obesity (body mass index, <30 kg/m2) was investigated while controlling for the aforementioned covariates. Lastly, multivariable linear regression was used to evaluate the association between fetal fraction and clinical markers of hypertensive disorders of pregnancy severity. RESULTS: We identified individuals with (n=117) and without (n=941) hypertensive disorders of pregnancy with noninvasive prenatal screening drawn before 20 weeks of gestation and with fetal fraction and body mass index data available. Those with hypertensive disorders of pregnancy had a lower fetal fraction (10.2%±4.2% vs 11.6%±4.7%; P<.01), without differences in total cell-free DNA concentration (P=.14). When groups were stratified by obesity status, this relationship was only valid for individuals without obesity (P=.02). Only when logistic regression analysis was restricted to individuals without obesity did the likelihood of hypertensive disorders of pregnancy rise with decreasing fetal fraction (odds ratio, 0.93; 95% confidence interval, 0.88-0.99; P=.02). In addition, fetal fraction was inversely associated with maximum systolic blood pressure at the time of hypertensive disorders of pregnancy only in the population without obesity (ß, -0.08; 95% confidence interval, -0.147 to -0.01; P=.02). CONCLUSION: Although a lower fetal fraction is associated with the development of hypertensive disorders of pregnancy, the use of this parameter for the prediction may be problematic in individuals with obesity, as obesity has such a profound effect on fetal fraction. However, we uniquely noted that among individuals without obesity, fetal fraction is lower for those that develop hypertensive disorders of pregnancy and lower fetal fraction increases the odds of hypertensive disorders of pregnancy development. Lastly, low fetal fraction in the population without obesity that developed hypertensive disorders of pregnancy was associated with higher systolic blood pressure at the time of hypertensive disorders of pregnancy, an important clinical marker of hypertensive disorders of pregnancy severity. As analytical approaches of cell-free DNA interrogation advance, the prediction of placental-mediated disorders with first-trimester sampling is likely to improve, although this may remain challenging in gravidas with obesity, a cohort at high risk of developing hypertensive disorders of pregnancy.

Co-creating with patients an impact framework across the medicine's life cycle: a qualitative study exploring patients' experiences of involvement in and perceptions of impact measures.

BACKGROUND: The biopharmaceutical industry is challenged with efficiently delivering medicines that patients truly value. This can be addressed by engaging patients and caregivers throughout a medicine's life cycle, ensuring that products meet the needs and expectations of those who take them. While isolated best practice examples of patient engagement exist, they remain relatively ad hoc and not fully embedded within Research & Development (R&D) practices. To encourage more patient engagement, the 'impact' of patient engagement projects (PEP) must be objectively measured and demonstrated. Some frameworks have been proposed; however, there is no evidence of widespread adoption, nor have patients' perspectives been robustly explored. The objective of this qualitative study was therefore to understand patients' perspectives of impact measurement that can be systematically applied within a biopharmaceutical company. METHODS: Semi-structured interviews were conducted with 13 patient organisation (PO) representatives exploring their experiences of engagement and reflections on 23 candidate patient engagement impact measures categorised into five groups: Medicines R&D Priorities; Clinical Trial Design; Regulatory & Market Access Submissions; Product Support & Information; and Disease Support & Information. Thematic analysis was undertaken and impact measures revised in line with interview participant feedback. Emerging themes and revisions to impact measures were validated at a joint workshop with 4 patient advisors representing 4 POs. RESULTS: The study revealed that PO representatives feel a deep sense of accomplishment and ownership when collaborating on PEPs with biopharmaceutical companies. They largely conceptualise 'impact' as positive, tangible and useful outcomes. The revisions made to the pre-defined patient engagement impact measures fell into three broad categories: (1) a requirement for greater context; (2) capturing the nature of patient influence; and (3) terminology changes. The greatest number of revisions concerned 'requiring greater context', for example, including additional descriptions, patient quotes, and satisfaction. CONCLUSIONS: This study sheds light on how patient advocates view 'impact'. Typically this means delivering 'value' important for them. Therefore, the authors of this paper created the term 'value-impact' to comprehensively characterise this conceptualisation, and propose a value-impact measurement plan, incorporating longitudinal data. Through this understanding and in light of other recently published work, wide-scale adoption and implementation of the measurement of value-impact across the biopharmaceutical industry can be realised.

Developing medicines involves multiple stages, all essential for pharmaceutical companies. However, this approach is becoming increasingly costly and patients are rarely involved in defining treatment outcomes. Patient insight is important for everyone involved in medicinal development and required by authorities reviewing new treatments. To identify best practices, the difference ('impact') made by engaging with patients must be measured continuously throughout the treatment development process. Possible impact measures have been proposed (for example, the PARADIGM initiative), but problems remain.This study aimed to work with patients and adapt standard measuring approaches that can be used to provide ongoing insight into the impact of patient engagement activities for companies and patients. Researchers interviewed 13 patient organisation (PO) representatives to explore their experiences of impact measures. Thematic analysis was conducted, and data used to adapt 23 potential impact measures in collaboration with patients.This study identified that PO representatives view impact as being positive, tangible, and useful outcomes, achieving a deep sense of accomplishment and ownership for those patients and representatives involved. The authors created the term 'value-impact' to describe how patients perceive such achievements. Furthermore, measures should be adapted to: 1) include greater context such as descriptions, patients quotes and satisfaction; 2) capture patient influence; and 3) use language that is understandable for all parties. Examples and suggestions for engagement at different stages and revised impact measures are presented in this report. It is our hope that this study will encourage more frequent and effective use of patient engagement strategies as medicines are developed.

At Preeclampsia Diagnosis, Total Cell-Free DNA Concentration is Elevated and Correlates With Disease Severity.

Background Placental derived cell-free DNA (cfDNA), widely utilized for prenatal screening, may serve as a biomarker for preeclampsia. To determine whether cfDNA parameters are altered in preeclampsia, we conducted a case-control study using prospectively collected maternal plasma (n=20 preeclampsia, n=22 normal) using our in-house validated prenatal screening assay. Methods and Results Isolated cfDNA was quantified, sequenced using Illumina NextSeq 500, and the placental-derived fraction was determined. Clinical and test characteristics were compared between preeclampsia and controls, followed by comparisons within the preeclampsia cohort dichotomized by cfDNA concentration. Lastly, cfDNA parameters in preeclampsia were correlated with markers of disease severity. Maternal age, body mass index, gestational age at delivery, cesarean rate, and neonatal birthweight were expectedly different between groups (P≤0.05). The placental-derived cfDNA fraction did not differ between groups (21.4% versus 16.9%, P=0.06); however, total cfDNA was more than 10 times higher in preeclampsia (1235 versus 106.5 pg/µL, P<0.001). This relationship persisted when controlling for important confounders (OR 1.22, 95% CI 1.04-1.43, P=0.01). The dichotomized preeclampsia group with the highest cfDNA concentration delivered earlier (33.2 versus 36.6 weeks, P=0.02) and had lower placental-derived fractions (9.1% versus 21.4%, P=0.04). Among preeclampsia cases, higher total cfDNA correlated with earlier gestational age at delivery (P=0.01) and higher maximum systolic blood pressure (P=0.04). Conclusions At diagnosis, total cfDNA is notably higher in preeclampsia, whereas the placental derived fraction remains similar to healthy pregnancies. In preeclampsia, higher total cfDNA correlates with earlier gestational age at delivery and higher systolic blood pressure. These findings may indicate increased release of cfDNA from maternal tissue injury.

The impact of maternal autoimmune disease on cell-free DNA test characteristics.

BACKGROUND: Maternal biologic factors can affect the fetal fraction in cell-free DNA-based prenatal screening assays, thereby limiting the effectiveness. Higher rates of indeterminate results because of a low fetal fraction have been described in cases of maternal autoimmune disease in pregnancy. Existing studies are confounded by the concomitant maternal use of anticoagulants, which may independently influence the test characteristics. OBJECTIVE: This study aimed to evaluate the differences in fetal fraction, indeterminate results, and total cell-free DNA concentration among women with an autoimmune disease in comparison with controls, using our in-house developed, noninvasive prenatal screening platform in the absence of maternal anticoagulation use. STUDY DESIGN: This was a retrospective, single institution cohort study of a previously validated, cell-free DNA-based, noninvasive prenatal screening assay using a low-pass whole-genome sequencing platform between 2017 and 2019. A diagnosis of an autoimmune disease included systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and others. Immunomodulator therapies included biologics, corticosteroids, hydroxychloroquine, azathioprine, and intravenous immunoglobulin. Women who were using anticoagulants were excluded. We evaluated the association between autoimmune disease and fetal cell-free DNA fraction, indeterminate results, and total cell-free DNA concentration using univariate and multivariate analyses, stratified according to immunomodulator therapy and adjusted for body mass index, fetal sex, and gestational age at sample collection. RESULTS: A total of 1445 patients met inclusion criteria. Of those, 43 women had a confirmed autoimmune disease, with 25 of those not on immunomodulator therapy and 18 on immunomodulator therapy. The mean fetal fraction for women with an autoimmune disease was significantly lower than for controls (9.7% vs 11.9%; P=.004). The rate of indeterminate results was significantly higher among women with an autoimmune disease than among controls (16.3% vs 3.5%; P<.001). The total cell-free DNA concentration was not statistically different between the groups (94.8 pg/µL for women with an autoimmune disease vs 83.9 pg/µL for controls; P=.06). In a logistic regression, women with an autoimmune disease had significantly higher odds of receiving an indeterminate result than controls, (adjusted odds ratio, 5.3; 95% confidence interval, 2.0-14.2). Linear regression analysis showed a significant negative association between having an autoimmune disease and the fetal cell-free DNA fraction (aß, -2.1; 95% confidence interval, -3.4 to -0.6). When stratifying by treatment status, the mean fetal fraction was 9.8%, 9.6%, and 11.9% for women with an autoimmune disease not on immunomodulator therapy, women with an autoimmune disease on immunomodulator therapy, and the controls, respectively (P=.02). The rate of indeterminate results increased in a stepwise fashion from 3.5% to 11.1% to 20.0% for controls, women with an autoimmune disease on immunomodulator therapy, and women with an autoimmune disease not on immunomodulator therapy, respectively (P<.001). Logistic regression analysis demonstrated higher odds of an indeterminate result for women with an autoimmune disease not on immunomodulator therapy than for controls, (adjusted odds ratio, 7.3; 95% confidence interval, 2.3-22.5). There was a negative association between women with an autoimmune disease not on immunomodulator therapy and the fetal fraction when compared with controls (aß, -2.2; 95% confidence interval, -4.2 to -0.3). CONCLUSION: Women with an autoimmune disease have lower fetal cell-free DNA fractions and higher rates of indeterminate results than women without an autoimmune disease. There was no difference in total cell-free DNA concentration. Treatment of maternal autoimmune diseases with immunomodulator therapy may decrease the indeterminate result rate.

Practical recommendations for the management of patients with gastroenteropancreatic and thoracic (carcinoid) neuroendocrine neoplasms in the COVID-19 era.

Neuroendocrine neoplasms (NENs) are a heterogeneous family of uncommon tumours with challenging diagnosis, clinical management and unique needs that almost always requires a multidisciplinary approach. In the absence of guidance from the scientific literature, along with the rapidly changing data available on the effect of COVID-19, we report how 12 high-volume NEN centres of expertise in 10 countries at different stages of the evolving COVID-19 global pandemic along with members of international neuroendocrine cancer patient societies have suggested to preserve high standards of care for patients with NENs. We review the multidisciplinary management of neuroendocrine neoplasms during the COVID-19 pandemic, and we suggest potential strategies to reduce risk and aid multidisciplinary treatment decision-making. By sharing our joint experiences, we aim to generate recommendations for proceeding to other institutions facing the same challenges.