Unselected Population Research Articles

Defining the normative cut-off for hirsutism in unselected populations: cluster analysis

Defining the normative cut-off for hirsutism in unselected populations: cluster analysis

Abstract PO2-09-03: Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants

Abstract Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 (BRCA1/2) pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline PALB2 PV have not previously been described. This is of particular relevance as PALB2 BC has demonstrated biologic features similar to BRCA1/2 BC such as poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) sensitivity. Methods: Patients with early-stage, HR+, HER2-, invasive breast cancer and a germline PALB2 PV were ascertained from academic cancer center databases and the Prospective Registry of MultiPlex Testing (PROMPT), an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. Study participants (pts) were categorized by age < 50 and ≥50. Oncotype DX RS were retrospectively reviewed and categorized as those that would and would not warrant consideration of chemotherapy (≥16 and < 16, respectively, for pts < 50; ≥26 and < 26, respectively, for pts ≥50). Yates corrected Chi-square tests were used to compare RS distributions between carriers and a previously published genetically unselected reference population. Results: Oncotype DX reports were reviewed for 20 pts with BC and germline PALB2 PV. Median RS was 19 (range 6-41) overall. Four patients were diagnosed under the age of 50 (range 33-48); median RS for these individuals was 19 (range 12-41). Sixteen patients were diagnosed at age 50 or greater (median 59, range 50-70); median RS for these individuals was also 19 (range 6-31). Compared to the genetically unselected reference population, Oncotype DX RS in pts with PALB2-associated BC demonstrated a numerical but not statistically significant shift in distribution towards categories in which chemotherapy would be considered. Among pts under the age of 50, 75% had Oncotype DX RS for which chemotherapy would be considered and 25% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.726 compared to reference). Among pts aged 50 and older, 25% had Oncotype DX RS for which chemotherapy would be considered and 75% had Oncotype DX RS for which endocrine therapy alone would likely be recommended (p=0.579 compared to reference). Conclusions: Compared to data from the published genetically unselected commercial database, BC associated with PALB2 PV may have higher Oncotype DX RS reflective of intrinsically less favorable biology and greater therapeutic sensitivity. Larger datasets are forthcoming to confirm presence of significant differences in Oncotype DX RS distributions between BC with and without PALB2 PV. Table 1. Oncotype DX RS distribution by age among pts with gPALB2 PV and genetically unselected reference *Jakubowski et al., J Surg Oncol 2020. PMID 3249731 Citation Format: Payal Shah, Siddhartha Yadav, Jamie Brower, Jada Hamilton, Erica Simmons, Judy Garber, Kenneth Offit, Mark Robson, Fergus Couch, Susan Domchek. Twenty-one gene recurrence scores in individuals with breast cancer associated with PALB2 germline pathogenic variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-09-03.

Abstract GS02-13: Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study

Abstract Background: Oncofertility counseling in BRCA carriers has unique challenges due to a possible negative impact of germline pathogenic/likely pathogenic variants (PVs) on reproductive potential and the indication to undergo risk-reducing bilateral salpingo-oophorectomy. While previous studies demonstrated the safety of pregnancy in women with prior breast cancer (BC) history, limited evidence exists in BRCA carriers specifically. We report the results of the largest study to date investigating likelihood of pregnancy after BC, reproductive and disease outcomes specifically in BRCA carriers. Methods: This was an international, multicenter, hospital-based, retrospective cohort study including young BRCA carriers with history of BC (NCT03673306). Eligible patients were women harboring germline PVs in BRCA1 and/or BRCA2 and diagnosed with stage I-III invasive BC at the age of ≤ 40 years between January 2000 and December 2020. BRCA healthy carriers or patients with BRCA variants of unknown significance, non-invasive BC, lack of follow-up, prior ovarian cancer or other malignancies without history of BC were excluded. Primary endpoints were pregnancy rate and disease-free survival (DFS). Overall survival (OS), BC specific survival (BCSS), pregnancy, fetal and obstetric outcomes were secondary endpoints. To mitigate the impact of guaranteed time bias, two survival analyses were performed: 1) Extended Cox model with occurrence of pregnancy as a time-varying covariate; 2) Case-control analysis by matching 1:3 patients with and without a pregnancy for type of BRCA PV, hormone receptor status, nodal status and year at diagnosis; moreover, each control had to have a disease-free interval longer than the time occurring between BC diagnosis and conception of the matched case. Results: From 78 centers worldwide, 4,732 patients were included, of whom 659 had at least one pregnancy after BC (pregnancy cohort) and 4,073 did not (non-pregnancy cohort). Patients in the pregnancy cohort were significantly more likely to carry BRCA1 PVs, to be younger at BC diagnosis, to have node-negative and hormone receptor-negative (HR-) BC (all p< 0.01). Pregnancy rate at 10 years was 22% (95% CI 21%-24%) overall, 18% (95% CI 16%-21%) and 26% (95% CI 24%-26%) in patients with HR+ and HR- BC, respectively (p< 0.01). Median time from BC diagnosis to conception was 3.5 years (IQR 2.2-5.3 years), significantly longer in patients with HR+ than HR- BC (4.3 vs 3.2 years, p< 0.01). Among 659 patients with a pregnancy after BC, 45 (6.8%) and 63 (9.6%) experienced an induced abortion or a miscarriage, respectively. Of the 517 (78.5%) patients with completed pregnancy, 54 (10.4%) had twins and 406 (78.5%) delivered at term (delivery ≥37 weeks). Among the 571 babies born, 5 (0.9%) had congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in DFS was observed between the pregnancy and non-pregnancy cohorts (unadjusted HR 0.97, 95% CI 0.82-1.15, p=0.74; adjusted HR [aHR] 0.99, 95% CI 0.81-1.20, p=0.90). Patients in the pregnancy cohort showed significantly better BCSS (HR 0.53, 95% CI 0.38-0.74, p< 0.01; aHR 0.59, 95% CI 0.41-0.86, p< 0.01) and OS (HR 0.52, 95% CI 0.38-0.72, p< 0.01; aHR 0.58, 95% CI 0.40-0.85, p< 0.01). Similar results were obtained in the case-control analysis. Subgroup analyses of survival endpoints according to patient, tumor and treatment characteristics will be presented at the conference. Conclusions: In this global study, 1 out of 5 young BRCA carriers conceived within 10 years after a BC diagnosis, higher than rates previously reported in unselected young BC populations. Pregnancy following BC in BRCA carriers did not appear to adversely impact maternal prognosis or fetal outcomes. These findings should be incorporated into oncofertility counseling of young BRCA carriers with BC. Citation Format: Matteo Lambertini, Eva Blondeaux, Elisa Agostinetto, Anne-Sophie Hamy-Petit, Hee Jeong Kim, Camila Chiodi, Rinat Bernstein-Molho, Florentine Hilbers, Katarzyna Pogoda, Estela Carrasco Lopez, Kevin Punie, Jyoti Bajpai, Michail Ignatiadis, Halle Moore, Kelly-Anne Phillips, Angela Toss, Christine Rousset-Jablonski, Fedro Alessandro Peccatori, Tiphaine Renaud, Alberta Ferrari, Shani Paluch-Shimon, Robert Fruscio, Wanda Cui, Stephanie Wong, Claudio Vernieri, Kathryn Ruddy, Maria Vittoria Dieci, Alexios Matikas, Mariya Rozenblit, Cynthia Villareal Garza, Laura De Marchis, Lucia Del Mastro, Fabio Puglisi, Maria Del Pilar Estevez-Diz, Kenny A. Rodriguez-Wallberg, Bela Mrinakova, Sarah Meister, Luca Livraghi, Florian Clatot, Rinat Yerushalmi, Carmine De Angelis, Rodrigo Sánchez-Bayona, Icro Meattini, Natalia Cichowska-Cwalińska, Martine Berlière, Mahmoud Salama, Ugo De Giorgi, Amir Sonnenblick, Hatem Azim, Ann Partridge. Pregnancy after breast cancer in young women with germline BRCA pathogenic variants: results from an international cohort study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-13.

Abstract PS16-01: Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial

Abstract Background: Improvement of systemic therapy of TNBC still is a medical need. Exploratory data from the neoadjuvant GeparNuevo trial suggested a benefit from an immune checkpoint inhibitor (ICI) monotherapy window in TNBC. The neoMono trial prospectively analyzed whether the addition of a preceding Atezolizumab monotherapy window prior to Atezolizumab and chemotherapy (CTX) improves pCR rates among patients (pts) with early TNBC. In an interim analysis after 100 pCR events, patients with unselected TNBC did not show a significant benefit from an Atezolizumab monotherapy window, while an exploratory analysis suggested a highly clinically relevant benefit among pts with PD-L1 positive TNBC. Here we present the final primary endpoint analysis. Methods: NeoMono is a phase 2 randomized multicenter trial that was planned to recruit a maximum of 458 female and male pts with primary TNBC (defined as ER/PR < 10% and HER2 negative) with tumor stages cT1c – cT4d (cN0 and cN+). As the protocol mandated termination of trial recruitment based on the results of the interim analysis, the final ITT population was limited to 359 pts. PD-L1 status had to be identifiable by central pathology by means of the VENTANA PD-L1 (SP142) assay and was defined by PD-L1 expression on immune cells (IC). Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w). Combination therapy in arm A was preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy, while patients in arm B received no immune monotherapy window. Study goals are to compare the efficacy of neoadjuvant CTX + Atezolizumab with versus without a two-week atezolizumab monotherapy window preceding CTX + ICI (primary endpoint: pCR) and to identify biomarkers for response and resistance through analysis of sequential tissue and liquid biopsies. The neoMono statistical design uses Bayesian posterior probabilities (uniform prior distribution) and logistic regression to analyze the primary endpoint. Results: 180 pts in arm A and 179 in arm B from 34 study sites were included in the final primary endpoint analysis. Demographics and baseline characteristics as well as drug exposure were well-balanced in both arms. Posterior mean pCR rates in the ITT population in study arms A and B were 65.7% (95% high posterior density interval (HPDI): 58.5%, 72.5%) and 69% (62.2%, 75.9%), respectively. In an exploratory analysis stratified by PD-L1 IC status (negative: < 1% versus positive: ≥ 1%), pCR rates in arm A were 91.5% in the PD-L1 IC-positive group and 56.1% in the PD-L1 IC-negative group, the corresponding pCR rates in arm B were 82.2% and 64.5%, respectively. In a multivariate analysis of the ITT population including tumor size, nodal status, tumor grade, age and PD-L1 status, the odds ratio for achieving a pCR was 4.77 (p < 0.001) for PD-L1-positive and 2.36 (p=0.023) for grade 3 tumors. In an exploratory analysis including HER2 status, odds for achieving a pCR were significantly higher for patients with HER2-negative (IHC 0) vs. HER2-low tumors (OR 1.73, p=0.036). No new safety signals were observed. Conclusion: The final primary endpoint analysis of the neoMono trial demonstrated the highest pCR rates ever reported in a phase II/III trial in TNBC. While a significant impact of an ICI monotherapy window on the pCR rate after combination of CTX + ICI in an unselected ITT population could not be demonstrated, neoMono indicates for the first time in a randomized prospective setting that patients with immune active TNBC might derive particular benefit from a preceding ICI monotherapy window. The results of the neoMono trial are mainly justifying the conduction of a confirmative trial in immune active TNBC. However, our results underscore the potential role of pre-therapeutic ICI monotherapy window as part of future therapeutic concepts in TNBC. Citation Format: Hans-Christian Kolberg, Johannes Schumacher, Ramona Erber, Michael Braun, Peter A. Fasching, Eva-Maria Grischke, Christian Schem, Michael P. Lux, Mustafa Deryal, Oliver Hoffmann, Bernhard Heinrich, Georg Kunz, Kristina Lübbe, Petra Krabisch, Arndt Hartmann, Philip Raeth, Sabine Kasimir-Bauer, Cornelia Kolberg-Liedtke. Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-01.

Abstract GS01-05: Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) showed statistically significant improvements in PFS and OS vs placebo + chemo in patients (pts) with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) whose tumors expressed PD-L1 with a combined positive score (CPS) ≥10 in the phase 3 KEYNOTE-355 study. Tolerable and effective maintenance regimens after induction therapy are needed to sustain clinical benefit. The PARP inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumor types and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect. KEYLYNK-009 (NCT04191135) is a randomized open-label phase 2 study to evaluate the efficacy and safety of maintenance pembro + olaparib vs pembro + chemo in pts with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with 1L pembro + platinum-based chemo. Methods: Eligible pts with measurable, locally recurrent inoperable or metastatic TNBC that had not been previously treated with chemo in the metastatic setting received induction therapy for up to 6 cycles of pembro 200 mg + chemo (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8) every 3 wk (Q3W). Pts with complete response (CR), partial response (PR), or stable disease (SD) after 4-6 treatment cycles were randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or pembro + chemo (continued induction regimen). Olaparib or chemo was continued until progression or unacceptable toxicity; pembro was continued for up to 35 cycles (including induction treatment), progression, or unacceptable toxicity. Pts were stratified by induction response (CR or PR vs SD, by RECIST v1.1), tumor PD-L1 status (CPS ≥1 vs CPS < 1), and tumor genomic status (tBRCAm vs tBRCAwt). Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS from randomization in all pts. Secondary endpoints included PFS and OS from randomization in pts with PD-L1 CPS ≥10 tumors and in pts with tBRCAm, and safety. Results: Of the 460 pts who received induction therapy, 271 were randomly assigned to pembro + olaparib (n=135) or pembro + chemo (n=136). At the Dec 15, 2022 data cutoff, median follow-up was 17.2 mo. Maintenance pembro + olaparib did not significantly improve PFS or OS vs pembro + chemo after induction therapy (Table). Median PFS was longer with pembro + olaparib vs pembro + chemo in pts with tBRCAm, but not in pts with PD-L1 CPS ≥10 tumors; a similar trend was observed for OS (Table). In 268 treated pts, treatment-related AEs (TRAEs) occurred in 114 of 135 pts (84.4%) for pembro + olaparib and in 128 of 133 pts (96.2%) for pembro + chemo. Grade ≥3 TRAEs occurred in 44 pts (32.6%) for pembro + olaparib (0 deaths) and in 91 pts (68.4%) for pembro + chemo (2 [1.5%] deaths), with 12 (8.9%) vs 26 (19.5%) discontinuations for TRAEs, respectively. Conclusions: The primary endpoints of PFS and OS were not met in an unselected population of pts with advanced TNBC. However, directionally favorable improvements in PFS and OS were observed in pts with tBRCAm with pembro + olaparib vs pembro + chemo, representing a potential maintenance strategy. Further data are required to confirm this effect. No new safety signals were observed, and there were fewer TRAEs in the pembro + olaparib group vs the pembro + chemo group. PFS and OS were evaluated from the time of randomization. *Based on stratified Cox regression model with Efron’s method of tie-handling with treatment as a covariate. NR = not reached. Citation Format: Hope Rugo, Mark Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Nadia Harbeck, Li Fan, Jaime Mejia, Vassiliki Karantza, David Cescon. Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-05.

Haemorrhoidal disease in pregnancy: results from a self-assessment questionnaire administered by means of a social network

BackgroundThe anal symptoms occurring during pregnancy and post-partum, mainly related to Haemorrhoidal Disease (HD), have been reported with in a wide range of incidence in the literature. Although in many cases the course of the disease is mild and self-limiting, sometimes it is severe enough to affect quality of life.MethodsOur study has been conducted through a questionnaire administered via social media with the aim of obtaining epidemiologic data on the incidence of the symptoms of HD in an unselected population of pregnant women. In addition, we looked for the presence of those factors notoriously predisposing or associated to HD (constipation, straining on the toilet, low dietary fibres and fluid intake).ResultsOut of 133 patients 51% reported symptoms of HD during pregnancy, mainly in the second and third trimester. Constipation, straining on the toilet, low dietary fibres and fluid intake were not significantly related to incidence of HD. Only a previous history of HD was correlated to onset of symptoms of HD in pregnancy and reached a statistical significance (odds ratio = 5.2, p < 0.001).ConclusionAlthough with the limitations posed by the nature of our retrospective study via a self-assessment interview, our results suggest that the occurrence of HD in pregnancy seems not sustained by the classical risk factors observed in the general population. At the moment, specific therapeutic measures are lacking and treatment relies on empiric suggestions concerning diet, fluid intake, bowel care, local ointment. Further studies are needed in order to identify a targeted etiologic treatment.

Post Percutaneous Transluminal Coronary Angioplasty (PTCA) Coronary Aneurysm- A Case Report

Introduction Coronary aneurysm defined angiographically as luminal dilation 50% larger than that of the adjacent reference segment. (1) Drug-eluting stents (DES), which locally elute antiproliferative drugs, can dramatically inhibit neointimal growth. However, several pathological studies have indicated that DES may delay healing after vascular injury, and DES implantation may be theoretically associated with a risk of coronary artery aneurysm formation. Coronary aneurysms have been reported from 3 days to up to 4 years after DES implantation procedures, with varying clinical presentations. The incidence of coronary artery aneurysms after DES implantation is low within the first 9 months, with a reported incidence of 0.2% to 2.3%, a rate similar to that reported after bare-metal stent (BMS) implantation (0.3% to 3.9%) in the DES versus BMS randomized trials.(2) However, the true incidence of coronary aneurysms in an unselected patient population is still largely unknown. It can be congenital, or secondary to vasculitis (Kawasaki disease) or after percutaneous coronary intervention. Drug-eluting stents (DES), which locally elute antiproliferative drugs, can dramatically inhibit neointimal growth has become standard of care for routine coronary angioplasty. However, several pathological studies have indicated that DES may delay endothelial healing after vascular injury, and DES implantation may be theoretically associated with a risk of coronary artery aneurysm formation (3)

Polyclonally Derived Alloantigen-Specific T Regulatory Cells Exhibit Target-Specific Suppression and Capture MHC Class II from Dendritic Cells.

Foxp3+ T regulatory (Treg) cells prevent allograft rejection and graft-versus-host disease. Although polyclonal Tregs have been used both in animal models and in humans, the fine specificity of their suppressive function is poorly defined. We have generated mouse recipient-derived alloantigen-specific Tregs invitro and explored the fine specificity of their suppressive function and their mechanism of action invitro and invivo. In vitro, when alloantigen and peptide Ag were both presented on the same dendritic cell, both responses were suppressed by iTregs specific either for the alloantigen or for the peptide Ag. In vivo, iTreg suppression was limited to the cognate Ag, and no bystander suppression was observed when both allo-antigen and peptide Ag were present on the same dendritic cell. In vitro, alloantigen-specific Tregs captured cognate MHC but failed to capture noncognate MHC. Our results demonstrate that a polyclonal population of iTregs generated from naive T cells can mediate highly specific function invivo and support the view that Treg therapy, even with unselected polyclonal populations, is likely to be target antigen-specific and that bystander responses to self-antigens or to infectious agents are unlikely.

External validation of the colorectal cancer risk score LiFeCRC using food frequency questions in the HUNT study

PurposeTo mitigate the increasing colorectal cancer (CRC) incidence globally and prevent CRC at the individual level, individual lifestyle information needs to be easily translated into CRC risk assessment. Several CRC risk prediction models exist and their clinical usefulness depends on their ease of use. Our objectives were to assess and externally validate the LiFeCRC score in our independent, unselected population and to investigate the use of simpler food frequency measurements in the score.MethodsIncidental colon and rectal cancer cases were compared to the general population among 78,580 individuals participating in a longitudinal health study in Norway (HUNT). Vegetable, dairy product, processed meat and sugar/confectionary consumption was scored based on food frequency. The LiFeCRC risk score was calculated for each individual.ResultsOver a median of 10 years following participation in HUNT, colon cancer was diagnosed in 1355 patients and rectal cancer was diagnosed in 473 patients. The LiFeCRC score using food frequencies demonstrated good discrimination in CRC overall (AUC 0.77) and in sex-specific models (AUC men 0.76 and women 0.77) in this population also including individuals ≥ 70 years and patients with diabetes. It performed somewhat better in colon (AUC 0.80) than in rectal cancer (AUC 0.72) and worked best for female colon cancer (AUC 0.81).ConclusionReadily available clinical variables and food frequency questions in a modified LiFeCRC score can identify patients at risk of CRC and may improve primary prevention by motivating to lifestyle change or participation in the CRC screening programme.

Diagnostic Accuracy of Abdominal Point of Care Ultrasound in Primary Care: Study Design and Protocol.

The aim of this study is to estimate the diagnostic accuracy of abdominal point of care ultrasound (POCUS) performed by family physicians (FPs) in primary care (PC), in comparison with the findings in the medical record (MR) at 12 months of follow-up. This study is conducted entirely in PC healthcare centers in Spain. Abdominal ultrasound scans performed by FPs (selected on the basis of their ultrasound knowledge and experience) are compared with the findings, or not, in the patient's MR after a 12-month follow-up period. The study will involve 100 FPs in Spain and an estimated sample size of 1334 patients who are to undergo abdominal POCUS at the indication of their physician. The results of the abdominal POCUS will be collected and compared with the findings of the MR. This comparison will be performed by another physician of the research team, different from their FP after one year of follow-up.The diagnostic accuracy of abdominal POCUS has been addressed in the hospital setting but not in PC. This lack of evidence can begin to be resolved with studies such as the one we present, designed for unselected populations such as those treated in PC and taking the patient's MR as the gold standard, which will allow us to make comparisons with the patient's clinical course.

Incorporation of vasa previa screening into a routine anomaly scan: A single center cohort study.

Vasa previa (VP), defined as unprotected fetal vessels traversing the membranes over the cervix, is associated with a high perinatal mortality when undiagnosed prenatally. Conversely, prenatal diagnosis with ultrasound and cesarean delivery before the membranes rupture is associated with excellent outcomes. However, controversy exists regarding screening for VP. In the UK, routine screening for VP is not recommended. The objective of this study was to report the incidence of VP and our experience in the detection of VP with a universal screening protocol at the time of the second-trimester fetal anomaly scan with third-trimester confirmation in an unselected population of pregnancies. We performed a single-center historical cohort study of all pregnant women who underwent routine second-trimester anomaly screening scans at West Middlesex University Hospital, London, UK, between 2012 and 2016. Over 5 years, every patient undergoing routine anomaly screening was evaluated for VP using a systematic protocol during their 20-week anomaly scan. Suspected cases of VP were rescanned in the third trimester by specialist sonographers with an interest in VP. The primary outcomes were the incidence and detection of VP. During the study period, 24 690 anatomy scans were performed. A total of 64 patients were identified as having potential VP at the second-trimester anomaly screening scan, of which 19 were confirmed by the specialist sonographer in the third trimester and at delivery. The screen positive rate was 0.26% (95% confidence interval [CI] 0.20%-0.32%). VP at birth was found in 19/24690 births (1:1299 [95% CI: 1:832-1:2030] births). Universal screening for VP using our protocol had a sensitivity of 100% and a specificity of 99.78% (95% CI: 99.72%-99.84%). The false-positive rate of the second-trimester screen was 0.18% (95% CI: 0.13-0.24). There were no false positives or false negatives at delivery. Of the 19 patients with confirmed VP, 17 had scheduled cesarean deliveries, and two required emergency deliveries due to antepartum hemorrhage. One baby died, giving a perinatal mortality of 5%. VP complicates approximately 1:1300 pregnancies. Routine screening for VP yielded a 100% detection rate. We suggest the inclusion of structured VP assessment in standard fetal anomaly screening programs.

Can serum progesterone concentration direct a fresh or freeze-all transfer strategy in the first in vitro fertilisation cycle?

PurposeTo examine the interaction between serum progesterone concentration on the trigger day and choice of freeze-all and fresh transfer strategies on live birth in an unselected population as well as in patients over 35 years old.MethodsWe performed a retrospective cohort study of 26,661 patients commencing their first IVF cycle in a large fertility centre between 2015 and 2019, including 4687 patients over 35 years old. We performed a multivariable fractional polynomial interaction analysis within a logistic regression model to investigate the interaction between serum progesterone concentration and the choice of freeze-all or fresh transfer strategy following the first transfer.Results15,539 patients underwent a fresh embryo transfer and 11,122 underwent a freeze-all strategy in their first IVF cycle. The freeze-all group had a higher live birth rate compared to the fresh group (43.9% vs 40.3%). After adjusting for confounding factors, there was a positive interaction between serum progesterone concentrations and the choice of a freeze-all versus fresh embryo transfer on live birth (p for interaction 0.0001), with a larger magnitude of effect when progesterone concentration was higher. Such an interaction was also observed in patients over 35 years old (p for interaction 0.01), but the treatment effect curve over progesterone concentrations was almost flat.ConclusionsIn an unselected population, frozen transfer is associated with greater chances of live birth, especially in patients with higher serum progesterone concentration. In patients over 35 years old, the benefit of a freeze-all policy appears small across all serum progesterone concentrations.

Obesity Treatment Ladder: Medical Nutrition Therapy and Physical Activity in Clinical Practice

Algorithms for treating obesity largely focus on pharmacological and surgical treatment options. Despite vast literature on different dietary approaches, focus has remained on comparing these approaches amongst themselves. The different dietary strategies result in similar weight loss in the unselected population over the long term. However, at an individual level, there should be an algorithm that will allow every individual a chance to be able to select a diet that works on a long term basis. A comprehensive and practical approach to the application of medical nutrition therapy (MNT), that amalgamates all different dietary strategies is currently lacking. An algorithm placing these diets in an ascending order of their complexity and restrictiveness is proposed to fill this gap in literature. Physical activity is an integral part of MNT for weight loss treatment. However, application of adequately intense and meaningful physical activity is often difficult in clinical practice. A step by step approach to build stamina gradually and achieve long term goal of weight loss and maintenance is discussed.

Family history as a major prerequisite for microsatellite instability screening in colorectal cancer is a poor selection tool.

Deficient mismatch repair (MMR) leading to microsatellite instability (MSI) in tumors is thought to be present in over 15% of colorectal cancer (CRC) cases. Testing CRC for MSI has traditionally been recommended following the fulfillment of clinical criteria. However, the performance of clinical criteria, especially the family history, as a selection tool for MSI screening in CRC is questionable. We retrospectively investigated the incidence of high degree MSI (MSI-H) tumors in an unselected population of CRC patients and compared its prevalence between individuals with and without family history of cancers within the spectrum of MSI-H tumors as defined in the revised Bethesda criteria. The study population included 274 patients, 70 with positive and 204 without family history of MSI-H tumors with complete data including findings from MSI analysis. The overall incidence of MSI-H CRC was 18.98%. There was no statistically significant difference in the incidence of MSI-H CRC amongst both groups. The sensitivity and specificity of family history with regard to the presence of an MSI-H tumor in this collective was 36.5% and 77.5%, respectively. A relevant number of cases with high MSI-H CRC may be missed secondary to screening based on clinical criteria like family history alone. Thus, systematic screening independent of clinical characteristics, especially family history of cancer should be recommended in all cases with CRC.

Microsatellite instability is highly prevalent in older patients with colorectal cancer.

Clinical guidelines suggest screening of colorectal cancer (CRC) for microsatellite instability (MSI). However, microsatellite instability-high (MSI-H) CRC is not rare in older patients. This study aimed to investigate the prevalence of MSI-H CRC in an unselected population in an age-based manner. A retrospective analysis of data from patients undergoing radical surgery for CRC was performed. Only cases with results from MSI testing using immunochemistry (IHC) were analyzed. Age-based analyses were performed using two cut-off ages: 50 years. as stated in Amsterdam II guidelines, and 60 years. as outlined in the revised Bethesda criteria. The study population included 343 (146 female and 197 male) patients with a median age of 70 years (range 21-90 years). The prevalence of MSI-H tumors in the entire cohort was 18.7%. The prevalence of MSI-H CRC was 22.5% in the group ≤50 years vs. 18.2% in the group >50 years using the age limit in the Amsterdam II guidelines. MSI-H CRC was present in 12.6% of the group aged ≤60 years compared to 20.6% in the control group >60 years. MSI screening of CRC based on age alone is associated with negative selection of a relevant number of cases. MSI-H CRC is also common in elderly patients, who may be negatively selected secondary to an age-based screening algorithm. Following the results of this study, screening based on clinical criteria should be omitted in favor of systematic screening as is already internationally practiced.

Detection of cardiac amyloidosis on routine bone scintigraphy: an important gatekeeper role for the nuclear medicine physician

Cardiac amyloidosis (CA)—mostly transthyretin-related (ATTR-CA)—has recently gained interest in cardiology. Bone scintigraphy (BS) is one of the main screening tools for ATTR-CA but also used for various other reasons. The objective was to evaluate whether all CA cases are detected and what happens during follow-up. All routine BS performed at the Maastricht University Medical Center (May 2012–August 2020) were screened for the presence of CA. Scans performed for suspected CA were excluded. A Perugini stage ≥1 was classified as positive necessitating further examination. The electronic medical record system was evaluated for any contact with cardiology or other specialists until 2021. Of the 2738 BS evaluated, 40 scans (1.46%; median age 73.5 [IQR: 65.8–79.5], 82.5% male) were positive (Perugini grade 1: 31/77.5%, grade 2: 6/15%, grade 3: 3/7.5%); the potential diagnosis ATTR-CA was not seen in 38 patients (95%) by the nuclear medicine specialist. During follow-up, 19 out of those 40 patients (47.5%) underwent cardiac evaluation without diagnosing CA. Available echocardiograms of patients with a positive BS showed left ventricular hypertrophy, a preserved ejection fraction, and diastolic dysfunction ≥2 in 9/47%, 10/53%, and 4/21% of patients, respectively. Additionally, 20 (50%) patients presented to at least one specialty with symptoms indicative of cardiac amyloidosis. The prevalence of a positive BS indicating potential CA in an unselected population is low but substantial. The majority was not detected which asks for better awareness for CA of all involved specialists to ensure appropriate treatment and follow-up.Graphical abstract

Ovarian Morphology in Non-Hirsute, Normo-Androgenic, Eumenorrheic Premenopausal Women from a Multi-Ethnic Unselected Siberian Population.

Polycystic ovary syndrome (PCOS) is a highly prevalent disorder in women, and its diagnosis rests on three principal features: ovulatory/menstrual dysfunction, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology (PCOM). Currently, data on age- and ethnicity-dependent features of PCOM remain insufficient. We aimed to estimate ethnicity- and age-dependent differences in ovarian volume (OV) and follicle number per ovary (FNPO) in a healthy, medically unbiased population of Caucasian and Asian premenopausal women, who participated in the cross-sectional Eastern Siberia PCOS epidemiology and phenotype (ESPEP) study (ClinicalTrials.gov ID: NCT05194384) in 2016-2019. The study population consisted of 408 non-hirsute, normo-androgenic, eumenorrheic premenopausal women aged 18-44 years. All participants underwent a uniform evaluation including a review of their medical history and a physical examination, blood sampling, and pelvic ultrasonography. The statistical analysis included non-parametric tests and the estimation of the upper normal limits (UNLs) by 98th percentiles for OV and FNPO. In the total study population, the upper OV percentiles did not differ by ethnicity or age group. By contrast, the UNL of FNPO was higher in Caucasian women than in Asian women, and women aged <35 years demonstrated a higher UNL of FNPO compared to older women. In summary, these data suggest that the estimation of FNPO, but not OV, should take into account the ethnicity and age of the individual in estimating the presence of PCOM.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies

Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Skin biopsy for detection of phosphorylated α-synuclein. Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

Efficacy of NSCLC Rechallenge with Immune Checkpoint Inhibitors following Disease Progression or Relapse.

Immune checkpoint inhibitors (ICIs) are at the forefront of advanced non-small-cell lung cancer (NSCLC) treatment. Still, only 27-46% of patients respond to initial therapy with ICIs, and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6-3.1 months and a Disease Control Rate (DCR) of 21.4-41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75-81%, according to post hoc analyses of several clinical trials. Future research on ICI rechallenge for NSCLC should focus on better patient stratification to reflect the underlying biology of immunotherapy resistance more accurately. In this review, we summarize evidence regarding rechallenge immunotherapy efficacy following NSCLC disease progression or relapse, as well as ongoing trials on immunotherapy rechallenge.

Genetics Visit Uptake Among Individuals Receiving Clinically Actionable Genomic Screening Results

Screening unselected populations for clinically actionable genetic disease risk can improve ascertainment and facilitate risk management. Genetics visits may encourage at-risk individuals to perform recommended management, but little has been reported on genetics visit completion or factors associated with completion in genomic screening programs. To identify factors associated with postdisclosure genetics visits in a genomic screening cohort. This was a cohort study of biobank data in a health care system in central Pennsylvania. Participants' exome sequence data were reviewed for pathogenic or likely pathogenic (P/LP) results in all genes on the American College of Medical Genetics and Genomics Secondary Findings list. Clinically confirmed results were disclosed by phone and letter. Participants included adult MyCode biobank participants who received P/LP results between July 2015 and November 2019. Data were analyzed from May 2021 to March 2022. Clinically confirmed P/LP result disclosed by phone or letter. Completion of genetics visit in which the result was discussed and variables associated with completion were assessed by electronic health record (EHR) review. Among a total of 1160 participants (703 [60.6%] female; median [IQR] age, 57.0 [42.1-68.5] years), fewer than half of participants (551 of 1160 [47.5%]) completed a genetics visit. Younger age (odds ratio [OR] for age 18-40 years, 2.98; 95% CI, 1.40-6.53; OR for age 41-65 years, 2.36; 95% CI, 1.22-4.74; OR for age 66-80 years, 2.60; 95% CI, 1.41-4.98 vs age ≥81 years); female sex (OR, 1.49; 95% CI, 1.14-1.96); being married (OR, 1.74; 95% CI, 1.23-2.47) or divorced (OR, 1.80; 95% CI, 1.11-2.91); lower Charlson comorbidity index (OR for score of 0-2, 1.76; 95% CI, 1.16-2.68; OR for score of 3-4, 1.73; 95% CI, 1.18-2.54 vs score of ≥5); EHR patient portal use (OR, 1.42; 95% CI, 1.06-1.89); living closer to a genetics clinic (OR, 1.64; 95% CI, 1.14-2.36 for <8.9 miles vs >20.1 miles); successful results disclosure (OR for disclosure by genetic counselor, 16.32; 95% CI, 8.16-37.45; OR for disclosure by research assistant, 20.30; 95% CI, 10.25-46.31 vs unsuccessful phone disclosure); and having a hereditary cancer result (OR, 2.13; 95% CI, 1.28-3.58 vs other disease risk) were significantly associated with higher rates of genetics visit completion. Preference to follow up with primary care was the most common reported reason for declining a genetics visit (68 of 152 patients [44.7%]). This cohort study of a biobank-based population genomic screening program suggests that targeted patient engagement, improving multidisciplinary coordination, and reducing barriers to follow-up care may be necessary for enhancing genetics visit uptake.