bluuebunny/crossref_metadata_2025 huggingface dataset:
IMA Genome – F19
Authors: Aylward Janneke , Wilson Andi M. , Visagie Cobus M. , Spraker Joseph , Barnes Irene , Buitendag Carla , Ceriani Callin , Del Mar Angel Lina , du Plessis Deanné , Fuchs Taygen , Gasser Katharina , Krämer Daniella , Li WenWen , Munsamy Kiara , Piso Anja , Price Jenna-Lee , Sonnekus Byron , Thomas Chanel , van der Nest Ariska , van Dijk Alida , van Heerden Alishia , van Vuuren Nicole , Yilmaz Neriman , Duong Tuan A. , van der Merwe Nicolaas A. , Wingfield Michael J. , Wingfield Brenda D.
Published: June 2024

The pace at which Next Generation Sequence data is being produced continues to accelerate as technology improves. As a result, such data are increasingly becoming accessible to biologists outside of the field of bioinformatics. In contrast, access to training in the methods of genome assembly and annotation are not growing at a similar rate. In this issue, we report on a Genome Assembly Workshop for Mycologists that was held at the Forestry and Agricultural Biotechnology Institute (FABI) at the University of Pretoria, South Africa and make available the 12 draft genome sequences emanating from the event. With the aim of making the process of genome assembly and annotation more accessible to biologists, we provide a step-by-step guide to both genome assembly and annotation, intended to encourage and empower mycologists to use genome data in their research.
Validation of Methotrexate Intolerance Severity Score (MISS) questionnaire to measure methotrexate intolerance among rheumatoid arthritis Egyptian patients
Authors: Kabil Hagar Ahmed Tawfik , Sherif Nahed Mounir , Elhusseiny Mona Gamal Eldin , Nassif Mary Atef
Published: June 2024

Background

Rheumatoid arthritis (RA) is a systemic autoimmune chronic inflammatory disease, causing progressive disability. Methotrexate (MTX) is the gold standard drug treatment for RA. Long-term use of MTX is associated with intolerance including gastrointestinal effects. In addition, anticipatory, associative, and behavioral symptoms such as anxiety and irritability are also observed which are often inadequately managed, leading to discontinuation of treatment. Methotrexate Intolerance Severity Score (MISS) questionnaire designed to measure MTX intolerance. The work aims to validate the MISS questionnaire Arabic version for the detection of MTX intolerance among Egyptian RA patients to halt the progression of the disease.

Results

A total of 80 patients were involved in this study. Of those, 67 (83.8%) were females with a mean disease duration of 6.9 ± 6.1 years. Forty-eight patients (60%) were intolerant to MTX and 32 patients (40%) were tolerant. Comparison between the tolerant group (n = 32) to MTX and the intolerant group (n = 48) revealed a statistically significant difference between them regarding the DAS28 score and HAQ score. Behavioral intolerance is the predominant factor that directs MTX intolerance.

Conclusion

The MISS questionnaire has a good predictive ability to detect MTX intolerance among Egyptian RA patients. Due to its good reliability, serves as an invaluable tool as it detects anticipatory and associative symptoms.
Evaluation of left ventricular filling pressure by echocardiography in patients with atrial fibrillation
Authors: Khan Faraz H. , Zhao Debbie , Ha Jong-Won , Nagueh Sherif F. , Voigt Jens-Uwe , Klein Allan L. , Gude Einar , Broch Kaspar , Chan Nicholas , Quill Gina M. , Doughty Robert N. , Young Alistair , Seo Ji-Won , García-Izquierdo Eusebio , Moñivas-Palomero Vanessa , Mingo-Santos Susana , Wang Tom Kai Ming , Bezy Stephanie , Ohte Nobuyuki , Skulstad Helge , Beladan Carmen C. , Popescu Bogdan A. , Kikuchi Shohei , Panis Vasileios , Donal Erwan , Remme Espen W. , Nash Martyn P. , Smiseth Otto A.
Published: June 2024

Background

Echocardiography is widely used to evaluate left ventricular (LV) diastolic function in patients suspected of heart failure. For patients in sinus rhythm, a combination of several echocardiographic parameters can differentiate between normal and elevated LV filling pressure with good accuracy. However, there is no established echocardiographic approach for the evaluation of LV filling pressure in patients with atrial fibrillation. The objective of the present study was to determine if a combination of several echocardiographic and clinical parameters may be used to evaluate LV filling pressure in patients with atrial fibrillation.

Results

In a multicentre study of 148 atrial fibrillation patients, several echocardiographic parameters were tested against invasively measured LV filling pressure as the reference method. No single parameter had sufficiently strong association with LV filling pressure to be recommended for clinical use. Based on univariate regression analysis in the present study, and evidence from existing literature, we developed a two-step algorithm for differentiation between normal and elevated LV filling pressure, defining values ≥ 15 mmHg as elevated. The parameters in the first step included the ratio between mitral early flow velocity and septal mitral annular velocity (septal E/e’), mitral E velocity, deceleration time of E, and peak tricuspid regurgitation velocity. Patients who could not be classified in the first step were tested in a second step by applying supplementary parameters, which included left atrial reservoir strain, pulmonary venous systolic/diastolic velocity ratio, and body mass index. This two-step algorithm classified patients as having either normal or elevated LV filling pressure with 75% accuracy and with 85% feasibility. Accuracy in EF ≥ 50% and EF < 50% was similar (75% and 76%).

Conclusions

In patients with atrial fibrillation, no single echocardiographic parameter was sufficiently reliable to be used clinically to identify elevated LV filling pressure. An algorithm that combined several echocardiographic parameters and body mass index, however, was able to classify patients as having normal or elevated LV filling pressure with moderate accuracy and high feasibility.
Inversion of gas hydrate saturation and solid frame permeability in a gas hydrate-bearing sediment by Stoneley wave attenuation
Authors: Liu Lin , Zhang Xiumei , Wang Xiuming
Published: June 2024

Natural gas hydrate is a potential novel energy resource that is widely distributed globally. Acoustic logging can effectively provide information on the surrounding reservoir and plays an important guiding role in gas hydrate exploration and development. Natural gas hydrate-bearing sediments are composed of a solid frame with natural gas hydrates and water-filled pores. The borehole mode wave characteristics of two-phase porous media cannot be used to evaluate the parameters of such a multiphase porous medium. We explore factors that influence the monopole Stoneley wave in a borehole embedded in a multiphase porous medium containing two solids and one fluid and analyze the influence of each factor on monopole Stoneley wave attenuation systematically. The sensitivity analysis results indicate that the Stoneley wave attenuation is highly sensitive to solid frame permeability and gas hydrate saturation. Building upon this foundation, a method to invert for gas hydrate saturation and solid frame permeability is first developed using Stoneley wave attenuation. Synthetic logging data are used to demonstrate the feasibility of this method for inverting for gas hydrate-bearing sediment properties. Even in the presence of considerable noise added to the receiver signal arrays, the inversion method is stable, and reliably evaluates gas hydrate saturation and solid frame permeability.
Separating harmonics in the ground-force signal of a seismic vibratory source
Authors: Sun Yimin , Almubarak Mohammed S. , Marzooq Hussain
Published: June 2024

The ground-force signal of a Vibroseis truck is unavoidably contaminated by harmonics. To better characterize the subsurface, the fundamental mode in the ground-force signal is the preferred choice for crosscorrelation with the raw seismic data measured in the field. We develop a novel, efficient, and effective harmonics decomposition method to separate the different orders of harmonics in the ground-force signal. Our method first builds a mathematical model to describe the different orders of harmonics in the ground-force signal by honoring the physical mechanism behind the harmonics generation and then retrieves the different orders of harmonics by solving overdetermined linear problems in the analytic signal domain. The success of our method is demonstrated using synthetic and field data examples.
Optimized rejection sampling for estimating facies probabilities from seismic data
Authors: Connolly Patrick , Dutton Ben
Published: June 2024

Seismic inversion for facies has nonunique solutions. There are invariably many vertical facies arrays that are consistent with both a data trace and the prior information. Stochastic sampling algorithms set within a Bayesian framework can provide an estimate of the posterior probability distribution of facies arrays by finding the arrays with relatively high posterior probabilities for each data trace. Sample-by-sample facies probabilities can be estimated by measuring the proportions of each facies type at each sample location from the set of posterior facies arrays. To enable the estimation of probabilities of facies mixtures and to obtain high-quality images of facies probability curves, facies must be modeled at high resolution. The facies arrays, or vectors, on which the sampling algorithm operates, must also be long enough to allow for vertical coupling caused by the wavelet. This results in very large sample spaces. The posterior probability distribution is highly nonconvex, which, combined with the large sample space, severely challenges conventional stochastic sampling methods in obtaining convergence of the estimated posterior distribution. The posterior sets of vectors from conventional methods tend to be either correlated or have low predictabilities, resulting in biased or noisy facies probability estimates, respectively. However, accurate estimates of facies probabilities can be obtained from a relatively small number of posterior facies vectors (about 100), provided that they are uncorrelated and have high predictabilities. Full convergence of the posterior distribution is not required. A hybrid algorithm optimized rejection sampling can be designed specifically for the seismic facies probability inversion problem by combining independent sampling of the prior, which ensures posterior vectors are uncorrelated, with an optimization step to obtain high predictabilities. Tests on both real and synthetic data demonstrate better results than conventional rejection sampling and Markov chain Monte Carlo methods.
Testicular germ cell tumor survival among children, adolescents, and young adults: A population-based retrospective cohort study.
Authors: Ajaj Rand , Lau Cindy , Gupta Sumit , Baxter Nancy N. , Sutradhar Rinku , Pole Jason D. , Malkiel Sarah , Shaikh Furqan , Nathan Paul C.
Published: June 2024

10035

Background: While testicular germ cell tumor (TGCT) overall survival (OS) exceeds 90%, some patient groups, such as adolescents, have inferior event free survival (EFS) outcomes. There is a paucity of granular, population-derived data about outcomes in children, adolescents, and young adults (CAYA) with TGCT, limiting a deeper understanding of the factors that impact their survival. Methods: All male CAYA (ages 11-21 years) in Ontario, Canada diagnosed with TGCT between 1992-2021 were identified using provincial cancer registries. Detailed disease and treatment characteristics were chart abstracted for ~2/3 of the cohort and determined through health administrative databases for the remainder. We assessed 5-year OS and EFS (first of death, recurrence/progression, or subsequent malignant neoplasm [SMN]) using Kaplan-Meier analysis and the log rank test. Follow-up started at TGCT diagnosis, except for survival after SMN or recurrence, where follow-up started at event date. Results: 748 TGCT patients were identified; 521 were chart abstracted and thus had EFS data available. Median age at diagnosis was 19 years (interquartile range:18-21) and 83.6% had non-seminoma histology. OS and EFS ± standard error (SE) were (94.7 ± 0.8 %, n=748) and (76.4 ± 1.9%, n=521), respectively. Among patients with chart abstracted data, OS and EFS differed by cancer extent at diagnosis and were lowest among CAYA with non-lung organ metastases (Table). Patients who underwent retroperitoneal lymph node dissection (RPLND) for initial treatment (91/521) had higher survival than those who did not (OS 96.6 ± 1.9% vs 93.7 ± 1.2%, p=0.04; EFS 87.6 ± 3.5 % vs 74.1 ± 2.1 %, p=0.0008), particularly CAYA with lung-only organ metastases. OS post SMN (n=28) was 77.3 ± 8.2%, with lower OS after non-TGCT SMN (50.8 ± 14.4%, n=13) than second primary TGCT (100 ± 0%, n=15), p=0.002. OS after recurrence/progression (n=116) was superior in the 59 who did not receive chemotherapy at initial diagnosis (89.7 ± 4%) compared to the 57 who had initial chemotherapy (65.9 ± 6.4%; p=0.0001). Conclusions: CAYA with TGCT have low EFS, consistent with previous studies. The extent of metastasis is a significant predictor. Efforts are needed to improve the survival outcomes of young TGCT patients with organ metastasis at diagnosis, and those who recur or develop a non-TGCT SMN. [Table: see text]
The role of immune checkpoint blockade in children, adolescents, and young adults: A systematic review and meta-analysis.
Authors: Reis Pedro Cotta Abrahão , Ponte Conrado João Evangelista , Noronha Mariana , Leite da Silva Luis Felipe , Saldanha Erick Figueiredo , Metts Jonathan
Published: June 2024

10057

Background: Immune checkpoint blockade (ICB) has changed the treatment landscape for many types of adult cancer. However, while certain subsets of cancer in children, adolescents, and young adults (CAYA) are ICB-responsive, ICBs are less routinely used in clinical practice, thus clinical experience lags behind that of adults. Therefore, we performed a systematic review and meta-analysis to evaluate the safety and efficacy of ICB in the CAYA population. Methods: PubMed, Cochrane and Embase libraries were systematically searched for clinical trials evaluating ICB therapies for cancer in CAYA patients. We excluded reviews, case reports, observational studies, retrospective studies, studies with overlapping populations, trials with no outcomes of interest, and studies enrolling the adult populations (>40 years). We pooled the prevalence of treatment-related adverse events (TRAE), objective response rate (ORR), stable disease (SD), and their corresponding 95% confidence intervals (95% CI). For ORR and TRAE endpoints, we performed a subgroup analysis of each drug (PD-1, PD-L1 and CTLA-4) and each tumor type. A comparative analysis of the reported median overall survival (OS) and progression-free survival (PFS) was also completed. Statistical analysis was performed using R software version 4.3.1 and heterogeneity was evaluated through I2 statistics. Results: From 3,753 initial studies, 15 clinical trials were included, comprising 797 patients with median age ranging from 6.5 to 16.0 years (1-30 years) and multiple types of hematologic and solid malignancies. An all-grade TRAE rate of 66% was found (95% CI 60-71), while the proportion of grade 3/4 TRAE was 19% (95% CI 13-27). In the tumor type subgroup analysis for all-grade TRAE and grade 3/4 TRAE, solid tumors had the highest rates; 92% (95% CI 41-99) and 50% (95% CI 14-42), respectively. Central nervous system tumors had all-grade and grade 3/4 TRAE rates of 61% (95% CI 53-68) and 21% (95% CI 12-33), respectively. Fatigue, anemia, and nausea were the most frequently reported TRAE. The ORR was 13% (95% CI 5-27) (82 of 531 patients). For drug class and tumor type subgroup analysis, PD-1 inhibitors and lymphoma presented the highest proportion of ORR, with 25% (95% CI 8-56) and 59% (95% CI 23-87), respectively. SD was noted in 21% (95% CI 14-30) of patients (97 of 467 patients). Median OS, available for 300 patients, ranged from 4.4 to 23.7 months, while median PFS, available for 299 patients, ranged from 1.2 to 6.2 months. Conclusions: This study suggests that ICB is well tolerated in CAYA patients with different cancer types. As previously reported in the literature, certain subsets of CAYA cancer are ICB-responsive. This pooled safety data supports the continued investigation of ICB in CAYA patients most likely to benefit from ICB therapy, including advancing ICB into combination strategies.
Survival outcomes in patients with high-risk neuroblastoma (HRNB) in remission after relapsed or refractory treatment receiving eflornithine (DFMO) maintenance.
Authors: Saulnier Sholler Giselle Linda , Ferguson William , Bergendahl Genevieve , Clinch Thomas , Kraveka Jacqueline M.
Published: June 2024

10060

Background: Five-year overall survival in newly diagnosed HRNB patients is around 50%, with relapse as the primary cause of mortality. While survival for newly diagnosed HRNB has improved with new treatment advances, relapsed or refractory (R/R) patients continue to have poor outcomes, with a high risk of subsequent relapse even among those who achieve remission, underscoring the need for treatments to improve EFS in this group. DFMO has been evaluated as a chemopreventative therapy in a single arm phase 2 study designed to compare Event Free Survival (EFS) and Overall Survival (OS) outcomes with published data for HRNB. The results of patients treated after standard therapy have been previously published. We now present an analysis of EFS/OS for patients with R/R disease, who historically have had a two-year EFS of approximately 10%. Methods: A total of 140 HRNB patients were enrolled, prospectively divided into two strata. S1 included patients in initial remission after upfront therapy, whereas S2 included patients who had either relapsed or had disease refractory to standard induction chemotherapy but achieved remission with additional therapy. Patients received 2 years of continuous treatment with oral DFMO 750 ±250 mg/m2 BID and were followed for up to 7 years. Results: A total of 35 patients withR/R disease who had achieved remission after additional therapy were enrolled onto S2, including 28 patients in remission after one or more prior relapses and 7 refractory patients in remission after subsequent therapies. Of the relapsed patients, 23 had one prior relapse, while 5 patients had two or more relapses prior to enrollment; only one previously relapsed patient had received chemoimmunotherapy prior to enrollment in the study. For the entireS2 cohort, two-year EFS was 46% (95% CI 29%, 61%) with the lower confidence interval above the 10% historical control estimate. Four-year EFS was 46% (95% CI 29%, 61%) and OS 62% (95% CI 44%, 76%), with no relapses occurring after 18 months. For patients enrolled with refractory disease only (n=7) the four-year EFS was 85.7%. In the 28 relapsed patients, the four-year EFS was 35.7%, with single relapse patients (n=23) having an EFS rate of 39.1% and multiple relapsed patients (n=5) 20.0%. Conclusions: Patients in remission after chemotherapy for relapsed or refractory HRNB and treated with DFMO had improved EFS compared to the best historical estimate available at the time of the study. Although the number of patients is too small to support clear conclusions, the subgroup of refractory patients had outcomes that trended better than the relapsed subgroup with an EFS rate that was unexpectedly similar to prior reports of DFMO-treated S1 patients in remission after standard upfront therapy. Clinical trial information: NCT02395666 , NCT00026312 .
Factors associated with fertility status assessment among female survivors of childhood cancer.
Authors: Cherven Brooke , Liu Katie , Gillespie Scott , Mertens Ann C. , Harris Ebonee , Burns Karen Cristly , Sopfe Jenna , Hoefgen Holly , Klosky James L.
Published: June 2024

10072

Background: Female survivors of childhood cancer with prior gonadotoxic treatment are at risk for infertility. As such, fertility status assessment (FSA) with ovarian reserve assessment and antral follicle count in consultation with a fertility specialist may be indicated to evaluate options for biological parenthood. FSA is underutilized in this population. This study explored psychosocial, developmental, and clinical factors associated with FSA. Methods: Female survivors (aged 18-29 years, diagnosis < 21 years, > 1 year from treatment completion, prior gonadotoxic treatment) were recruited from four cancer centers in the U.S. Participants reported sociodemographics (race, sexual orientation, gender identity, relationship status), developmental milestones (living and financial independence, full-time employment), reproductive concerns (modified Reproductive Concerns Scale), knowledge of reproductive health, decisional factors, and history of FSA. Clinical characteristics (cancer diagnosis, treatment-related risk for infertility, hormonal testing, clinical encounter with pediatric reproductive health subspecialist [gynecology, endocrinology]) were abstracted from the medical record. Multivariate logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for factors associated with FSA. Results: Of 325 participants, N = 260 completed all survey items of interest. Participants were an average of 23.7±3.1 years, 74% non-Hispanic white, 79% heterosexual and cisgender, and 48% in a committed relationship. Compared with those without FSA (N = 164), participants who completed an FSA (N = 96) reported greater attainment of developmental milestones (OR 2.20, 95%CI: 1.10-3.85, p = .027), greater desire for reproductive information (OR 1.86, 95%CI: 1.2-2.77, p = .001), greater knowledge regarding fertility-related procedures (OR 4.12, 95%CI: 2.36-7.57, p < .001) and fertility preservation (OR 1.76, 95%CI: 1.31-2.44, p < .001), having made an informed decision to pursue FSA (OR 1.82, 95%CI: 1.30-2.59, p = .001), clinical encounter with pediatric reproductive subspecialist (OR 3.37, 95%CI: 1.1-10.9, p = .032), and less knowledge regarding family building options (OR 0.47, 95%CI 0.27-0.79, p = .006). Diagnosis, infertility risk, and hormonal evaluation were not associated with FSA completion. Conclusions: Among emerging adult survivors, psychosocial factors associated with FSA completion include developmental milestones and knowledge of reproductive health. Clinical encounters with pediatric reproductive subspecialists may provide an opportunity for survivors to learn about and receive referrals to a fertility clinic. Psychoeducation is warranted to support survivors’ pursuit of FSA. Integration and consideration of survivor development and knowledge in these clinical encounters should potentiate optimal uptake of FSA.
Effect of low-dose tamoxifen on IGF-I/IGFBP-3 and estradiol/SHBG ratio and their prognostic/predictive effect in DCIS/LCIS/ADH.
Authors: De Censi Andrea , Johansson Harriet , Puntoni Matteo , Macis Debora , Guerrieri-Gonzaga Aliana , Aristarco Valentina , Briata Irene Maria , Oliva Martino , Boni Luca , Lazzeroni Matteo , Serrano Davide , Giordano Livia , Digennaro Maria , Cortesi Laura , Millo Francesco , Cagossi Katia , Aprile Giuseppe , Falcini Fabio , Gallerani Elisa , Bonanni Bernardo
Published: June 2024

10510

Background: Babytam (BT), 5 mg/day for 3 years (y) is a popular choice for preventive therapy after breast DCIS/LCIS/ADH given its 10-y efficacy to prevent recurrence without adverse events (1). Here we investigated the effect of BT on serum biomarkers and their role as prognostic and predictive factors. Methods: In a phase-III trial of BT or placebo (P), 406 out of 500 women consented to blood sampling at baseline, 1 and 3 y. Serum estradiol (E2), SHBG, IGF-I, IGFBP-3 and their molar ratios were measured by CLIA. Biomarker changes were estimated with mixed-effects models for repeated measures and Incidence Rate Ratios (IRR) of the primary endpoint (invasive breast cancer or DCIS) were calculated after 5 and 10 y of follow-up with Poisson regression. Subgroup analyses were performed by interaction test. Results: There were no differences in event rates between women with blood samples and those w/out. Compared with P at 1 y, IGF-I/IGFBP-3 decreased by 0.039 (95%CI, 0.027-0.052), relative difference (rd), 22% (15-29) (p<0.001), whereas E2/SHBG increased by 2.967 (1.767-4.166), rd, 79% (47-111) in pre- and decreased by 0.121 (-1.117-0.874), rd, -9% (-84-66), in postmenopausal women on BT (p-interaction=0.001). The mean annual rate of events (x1000 PY) after 5 and 10 y follow-up according to baseline level of IGF-I/IGFBP-3 (all women) and E2/SHBG (postmenopausal). Conclusions: BT significantly lowers IGF-I/IGFBP-3 ratio, increases E2/SHBG in premenopause to a lesser extent than 20 mg/d and is effective in most subgroups regardless of baseline biomarker levels. While lower baseline IGF-I/IGFBP-3 levels were predictive of BT efficacy at 5 and 10 y, higher levels at 10 y were associated with a lower benefit of BT. E2/SHBG had a tendency to be prognostic and predictive of BT efficacy at 5 y, but softened down at 10 y. These biomarkers may help differentiate which women benefit most from BT. The role of IGF-I change as surrogate biomarker of BT effect requires further studies. 1. Lazzeroni et al: JCO 41:3116, 2023. Clinical trial information: NCT01357772 . [Table: see text]
Population attributable fraction of reproductive factors in triple negative breast cancer by race.
Authors: Jaber Chehayeb Rachel , Odzer Nicole , Albany Roberta A , Phipps Amanda I. , Meisner Allison , Pusztai Lajos
Published: June 2024

10522

Background: Age-adjusted incidence rates of triple negative breast cancer (TNBC) are higher in African American (AA) women than in non-Hispanic White (White) women. The disproportionate incidence of TNBC in AA women partially drives the 40% higher mortality rate from breast cancer in AA women compared to White women. Several studies have identified lack of breastfeeding and younger age at first birth as risk factors for TNBC. There are large differences in breastfeeding uptake and duration in the US: only 44% of AA women breastfeed for 6 months or longer, compared to 60% of White women. To quantify the contribution of differences in breastfeeding patterns and younger age at first birth to disparities in incidence of TNBC, we calculate the population-attributable fraction (PAF), which is the proportion of the incidence of a disease that may be attributable to a particular exposure. Methods: A systematic review was performed to identify relevant case-control studies. Pooled odds ratios (ORs) for breastfeeding for < 6 months and age at first birth < 25 years were calculated from data extracted from studies using a common effect model. PAF was calculated using the Levin formula. Risk factor population prevalences were extracted from national surveys. Pooled ORs were used as estimates of relative risk (RR). A combined PAF was calculated using the polychoric correlation coefficient between breastfeeding duration and age at first birth to account for contributions of multiple risk factors. Results: Using race specific ORs, the PAF of breastfeeding for < 6 months was 12% (95% confidence interval (CI) 5-20%) among White women and 15% (95% CI 3-26%) among AA women. The PAF of having a child before age 25 was not significantly different from zero for White women (2% (CI -6-11%)) but was significantly different from zero for AA women (21% (CI 5-25%)). The combined PAF was 27% for AA women and 17% for all women in the US. Extrapolating to the US population, we estimated that 4,850 annual cases of TNBC (2,421 among White women and 1,533 among AA women) could be attributed to breastfeeding for < 6 months and age at first birth < 25 years. Conclusions: Given the protective role of breastfeeding against TNBC, policy changes aimed at supporting breastfeeding, addressing structural barriers, and promoting a culture shift could reduce racial disparities in TNBC incidence in the US. [Table: see text]
Improving a polygenic risk score (PRS) for breast cancer (BC) risk assessment in diverse ancestries.
Authors: Simmons Timothy , Hughes Elisha , Pruss Dmitry , Kucera Matthew , Roa Benjamin , Judkins Thaddeus , Younus Adib , Cummings Shelly Ann , Jammulapati Srikanth , Timms Kirsten , Kurian Allison W. , Pederson Holly Jane , Whitworth Pat W. , Wagner Susanne , Muzzey Dale , Lanchbury Jerry S. , Gutin Alexander
Published: June 2024

10533

Background: Accurate BC risk assessment is essential to identify women for whom screening and preventive interventions may be lifesaving. Incorporation of PRS into clinical models can improve risk prediction, but most PRS have shown suboptimal performance among non-Europeans. We previously described a multiple-ancestry PRS (MA-149) based on 56 ancestry-informative and 93 BC-associated single-nucleotide polymorphisms (SNPs). MA-149 achieved accuracy for diverse populations by characterizing genetic ancestry at each SNP in terms of fractions attributable to reference ancestries (African, East Asian, European) and applying ancestry-specific risks and frequencies. MA-149 significantly outperformed the Tyrer-Cuzick (TC) model, and integration of MA-149 with TC improved predictive accuracy by roughly two-fold over TC alone. Here, we aimed to improve MA-149 by expanding the set of BC SNPs and refining ancestry-specific risks. Methods: We developed a novel stepwise regression methodology accounting for linkage disequilibrium to select an optimal set of BC SNPs. Women referred for hereditary cancer testing and negative for pathogenic variants in BC genes were divided into consecutive cohorts to (1) refine ancestry-specific SNP risks ( N=58,191 Black/African; N=27,160 East Asian), (2) develop the PRS ( N=184,322), and (3) conduct independent validation ( N=146,110). Predictive accuracy and calibration of the new PRS were evaluated in the full cohort and subpopulations of different ancestries. Odds ratios (OR) from multivariable regression are reported per standard deviation. Results: A set of 385 SNPs (56 ancestry, 329 BC) was selected for the new PRS (MA-385). MA-385 improved upon clinical factors and outperformed MA-149 within each ancestry (Table). Among non-Europeans, MA-385 was a better BC risk predictor (OR=1.47, 95% CI: 1.42-1.52) than MA-149 (OR=1.40, 95% CI: 1.35-1.45). The strongest associations were observed in Ashkenazi Jewish and Hispanic women (Table). MA-385 identified more women at >2-fold increased risk than MA-149 (6.5 % vs 2%). Goodness-of-fit tests showed that MA-385 was well-calibrated while a 385-SNP PRS with European weights was miscalibrated for non-Europeans. Conclusions: MA-385 was well-calibrated, improved upon clinical factors, and outperformed existing PRS in all tested ancestries. Incorporation of MA-385 into risk assessment could improve the early detection and prevention of BC. [Table: see text]
Utility of colposcopy for the screening and management of cervical cancer in Africa: A cross-sectional analysis of providers’ training and practices.
Authors: Fokom Domgue Joel , Dille Issimouha , Gnangnon Freddy Houéhanou Rodrigue , Kapambwe Sharon , Bouchard Céline , Mbatani Nomonde , Gauroy Elodie , Ambounda Ledaga Nathalie , Yu Robert K , Sidibe Fatoumata Matokoma , Kamgno Joseph , Tebeu Pierre-Marie , Halle-Ekane Gregory , Diomande Mohenou Isidore , Dangou Jean-Marie , Lecuru Fabrice , Adewole Isaac Folorunso , Plante Marie-Elaine , Basu Partha , Shete Sanjay
Published: June 2024

10555

Background: Cervical cancer is a public health issue in Africa with devastating socioeconomic consequences due to the lack of organized screening programs. The success of screening programs depends on the appropriate investigation and management of women who test positive for screening. Colposcopic assessment following positive screening results is a critical issue in Africa. This study aimed to assess the utilization of colposcopy by providers in the region. Methods: A cross-sectional study was conducted in 2021-2022 among healthcare providers involved in cervical cancer prevention activities in Africa. They were invited to report prior colposcopy training, whether they performed colposcopy and the indications of colposcopy in their practice. Results: Of the 130 providers from 23 African countries who responded to the survey (mean age [SD]: 39.0 years [9.4]), half were female (65 [50.0%]), and 90.7% were working in urban areas. Overall, only 12.6% of respondents indicated having received prior training on colposcopy, and 11.7% reported that they were performing colposcopy in their current practice. Among the providers who reported performing colposcopy in their practice, colposcopy was indicated for routine visual screening in 21.2% of clinicians, to visualize the transformation zone in 15.2% of respondents, to assess vascularization of cervical mucosa in 33.3% of respondents, and to determine treatment modality in 12.1% of respondents. Conclusions: Providers’ training and utilization of colposcopy for cervical cancer screening remain suboptimal in Africa. To address this situation in the region, further training is needed to improve providers' knowledge and engagement. With the development of lower-cost and portable colposcopes, efforts to equip cervical cancer prevention programs and facilities with colposcopy should be enhanced to ensure that women can be screened and managed appropriately.
Patterns of cancer screening practice and mutational status of cancer-predisposing genes among individuals at high risk for cancer.
Authors: Freeman Jincong Q. , Manirakiza Achille Van Christ , Zhao Fangyuan , Keel Emma , Drogan Christine , Bradley Robin , Huo Dezheng , Olopade Olufunmilayo I.
Published: June 2024

10557

Background: Research on cancer screening practice and prevention strategies among individuals at high risk for cancer is limited. We explored the patterns of screening practice of seven cancer types in high-risk patients (pts) at a single institution. Methods: Between June-September 2023, we conducted a follow-up survey on pts enrolled in the University of Chicago Cancer Prone Study, a longitudinal cohort of high-risk families initiated in 1992. We assessed breast, cervical, colorectal, prostate (PSA), ovarian, skin (full-body skin exam [FBSE]), and lung cancer screening by mutational status. Results: Of 912 respondents, 80.4% were female. 81.6% were White, followed by 10.6% Black, 4.0% other/multi-racial, and 3.8% Hispanic. Overall, 35.2% reported having cancer-predisposing gene mutations. Mutation carriers were younger than those non-carriers (54.8 [SD 13.7] vs 60.3 [SD 12.8] years). After adjusting for age, carriers were more likely than non-carriers to have had breast MRI ( p<.001), colorectal cancer screening ( p=.039), ovarian cancer screening ( p=.043), and an FBSE ( p=.007) (Table). No statistically significant differences in mammogram (OR=1.50, 95% CI=0.55-2.30; p=.13), cervical cancer (OR=0.92, 95% CI=0.54-1.59; p=.77), PSA (OR=0.70, 95% CI: 0.26-1.88; p=.48), or lung cancer (OR=1.18, 95% CI=0.72-1.92; p=.51) screening between carriers and non-carriers. By race/ethnicity, cervical cancer screening (Hispanic 92%, White 90.6%, other/multiracial 80.7% and Black 76%; p=.002) and colorectal cancer screening (White 83.3%, other/multiracial 71.8%, Black 71.4% and Hispanic 66.6%; p=.004) differed significantly. Conclusions: In this diverse cohort of individuals at high risk for cancer, findings highlight an increased awareness and uptake of cancer screening, though varying by race/ethnicity. Cancer risk assessment clinics can be great avenues to provide comprehensive cancer screening and prevention strategies while addressing racial/ethnic screening disparities. [Table: see text]
Germline variation and risk of immune-related adverse events (irAEs): A real-world BioVU study.
Authors: Balko Justin M. , Yao Lydia , Zhang Siwei , Fahey Catherine , Haugh Alexandra , Davis Andrea , Mukherjee Eric , Hammer Christian , Phillips Elizabeth J , Bejan Cosmin A , Xu Yaomin , Johnson Douglas Buckner
Published: June 2024

10582

Background: IrAEs are prevalent in patients treated with immune checkpoint inhibitors (ICI) and mimic classical autoimmune diseases. IrAE risk prediction could improve clinical decision making and patient safety for ICI-treated patients. Classical autoimmune diseases show strong associations with germline polymorphisms and with Human Leukocyte Antigen (HLA) variants, though it is unclear if these same genetic risk factors predispose to irAEs. To identify both tolerant and irAE patients, we mined Vanderbilt University Medical Center (VUMC) BioVU, a biorepository of >300K DNA samples linked to de-identified medical records and evaluated genome-wide and imputed HLA class I and II associations with irAE risk. Methods: We identified 1,472 ICI-treated BioVU subjects: 428 with ≥ 1 irAE, and 1044 with no irAEs ≤ 6 months from last ICI treatment. Genotyping was performed by Illumina MEGAEX array. Records were screened for use of irAE therapies ( e.g. systemic corticosteroids, infliximab, levothyroxine) after ICI treatment, with chart adjudication. Association tests were performed using Firth’s logistic regression adjusting for age, sex, ICI regimen, and 3 principal components to assess 1) HLA Class I and II alleles; 2) HLA evolutionary divergence; and 3) GWAS to evaluate total irAEs, organ-specific irAEs, or other specific irAEs (sample size permitting). Endocrine irAEs were excluded to be presented in a separate focused study. Results: In GWAS analyses, 53 SNPs and 23 SNPs were identified significantly (nominal p ≤ 5e-8) associated with GI and neuro-toxicity, respectively. We did not identify any significant HLA class I or II associations with irAE or organ-grouped irAEs, including most evolutionary divergence association tests. We noted marginal association (FDR=0.12, OR=6.85) of rheumatic irAEs with HLA-DRB1*10:01, an HLA class II allele with RA-specific epitope motif. Patients experiencing lung irAEs were more likely to have a high HLA class I and II evolutionary divergence sum (p = 0.013 and p=0.046, respectively). Assessment of associations with specific irAEs, validation of known associations with irAEs or autoimmune disorders, including polygenic risk scores, are underway. Conclusions: We had several SNP-irAE associations, though appropriate classification schemas to maximize power and detect genetic variation remain challenging. We will soon expand with 1,800 additional ICI-treated patients (n=~3,300 in toto), creating a robust resource for irAE genetic associations. [Table: see text]
Risk of secondary leukemias in patients with germline PALB2 pathogenic variants after chemotherapy exposure.
Authors: Ellaithy Hatem , Bear Lauren , Steinberg Kathleen , Micalizzi Douglas Scott , Brunner Andrew Mark , Saini Arushi
Published: June 2024

10598

Background: Pathogenic variants in germline cancer-predisposing genes (e.g. BRCA1/2, PALB2) confer an increased risk for solid tumors but not de novomyeloid malignancies. Many of these genes are related to DNA repair pathways. It is not known whether exposure to genotoxic therapy increases the risk of secondary hematologic malignancies. Here, we report the incidence of hematologic malignancy after a solid tumor diagnosis among patients with a germline PALB2 pathogenic variant. Methods: Patients were identified at the Massachusetts General Hospital Center for Cancer Risk Assessment among individuals seeking counseling and/or testing for hereditary cancer risk genes. Analyses were conducted using R version 4.2.2 “tidyverse” and “gtsummary” packages. Results: Of the 176 charts reviewed, 102 (57%) had a history of malignancy, of which 68 (66%) received genotoxic chemotherapy. The median follow-up after chemotherapy was 59mo (IQR =17,109). The most common malignancy and chemotherapy were breast cancer (n=76, 75%) and doxorubicin, cyclophosphamide, and paclitaxel (n = 21, 31%). We compared patient outcomes by receipt of chemotherapy or not. There was no difference in race, age at cancer diagnosis, surgery rate, treatment with hormone therapy, or secondary malignancy between the two groups (p > 0.05). There was higher incidence of radiation treatment in those receiving genotoxic therapy compared to those who did not (65% vs 41%, p = 0.024), but no difference Gray or in follow up after radiation. Mortality in the genotoxic therapy group was 15% (n=10) vs. 9% (n=2) in the no genotoxic therapy group (p =0.33). Two subjects developed a hematologic malignancy (one case each of CLL and CML); both had prior chemotherapy and radiation exposure (Table). Conclusions: Cancer survivors with a germline PALB2 pathogenic variant and subsequent exposure to genotoxic therapy appear to have low risk of secondary hematologic malignancy. Although two subjects in the chemotherapy group developed leukemias, given the cases seen it is unlikely that these relate to the treatment exposure. Given the small sample size and retrospective nature of this study, more investigation is necessary to fully quantify the risk of therapy-related myeloid neoplasm in patients with germline PALB2 pathogenic variants. [Table: see text]
Pathogenic germline variant discovery in plasma cell disorders: Insights from genetic counseling referrals and testing.
Authors: Bodnar Saoirse , Brander Tehilla , Balwani Manisha M , Jagannath Sundar , Parekh Samir , Thibaud Santiago
Published: June 2024

10619

Background: Our research has shown that 10% of multiple myeloma (MM) patients harbor pathogenic or likely-pathogenic germline variants (PGVs) in cancer predisposition genes, with a significant enrichment observed in BRCA1/2 genes. PGVs are notably more common in younger MM patients and those with a personal or familial cancer history. This study presents our experience in referring plasma cell disorder (PCD) patients at increased risk for carrying PGVs, due to either clinical history or suspicious tumor NGS findings, for genetic counseling and subsequent germline testing. Methods: This retrospective study reviewed patient records from our institution's PCD clinic, focusing on those referred for a genetic evaluation between 2020 and 2024 due to suspected cancer predisposition. We compiled demographic and clinical data for these patients, reasons for referral, and cancer history of patients and their families. The uptake of germline testing, identified mutations, and subsequent recommendations for advanced cancer surveillance and prevention, including cascade testing, were also analyzed. Germline testing utilized targeted hereditary cancer panels from five companies and was conducted on DNA samples extracted from peripheral blood, saliva/buccal swabs, or skin biopsies. Results: 52 PCD patients underwent a genetic evaluation and were included in this review, comprising 31 MM, 9 smoldering MM, and 12 MGUS cases. Median age at the time of referral was 63, and 54% of patients were female. Racial composition was 62% White, 15% Black/African-American, 12% Hispanic, 2% Asian, with 10% undisclosed. 8 patients were referred due to suspicious findings in tumor NGS, while the rest were referred due to clinical suspicion. A personal history of cancer was reported by 19 patients (37%), and 49 had a first- or second-degree relative with cancer (94%). 38 patients (73%) underwent germline testing, of which 15 (39%) harbored PGVs (11 had MM, 4 had smoldering MM). 8 PGV carriers had well-established founder variants. The remaining 7 had PGVs in genes including BRCA2 (n=3), PALB2 (n=1), BLM (n=1), SMAD4 (n=1) and NTHL1 (n=1). Of note, all 8 referred for suspicious findings in tumor NGS were confirmed to harbor PGVs. All PGV-positive patients were recommended for cascade testing and enhanced cancer screening. Conclusions: Our findings indicate a 39% PGV detection rate in PCD patients referred for genetic evaluation, underscoring the potential benefit of implementing screening guidelines in this population. PGV detection led to recommendations for intensified surveillance and cascade testing in all cases, impacting both patients and their families. The discovery of BRCA2PGVs in 20% (3/15) of cases reinforces its potential role as a predisposition gene in MM, corroborating our prior findings.
The science of getting published: Key factors influencing publication in pediatric oncology.
Authors: Hovsepyan Shushan , Bedirian Karen , Papyan Ruzanna , Hoveyan Julieta , Sargsyan Amalya , Baloyan Elen , Bardakhchyan Samvel , Tamamyan Gevorg
Published: June 2024

11024

Background: Childhood cancer is rare, with an annual global incidence of 400,000 cases. Research articles play a crucial role in disseminating significant advancements in this rare field; however, it often experiences delays. We investigated the key factors influencing the transition from abstracts presented at the American Society of Clinical Oncology (ASCO) Annual Meetings to publication of articles in the pediatric oncology field. Methods: We analyzed oral (OA), poster (PA), and publication-only abstracts (PO) presented during pediatric oncology sessions at ASCO Annual Meetings from 2017 to 2023. We cross-referenced abstract titles and authors with PubMed-indexed journals. Each predictor was assessed for its correlation with the publication status using the chi-square test. Additionally, logistic regression was performed to understand the influence of each predictor while controlling for other variables. Results: A total of 521 abstracts were identified. Among these, 93 were OA, 270 were PA, and 158 were PO. Of these, 67%, 60%, and 32% were eventually published, respectively. The mean time to publication was 21.3 months for OA, 17.15 months for PA, and 23.4 months for PO. Female authors comprised 56% of the first authors. Funding was provided for 96% of OA, 87.7% of PA, and 63% of PO. Only 7% of all abstracts were from low-middle-income countries (LMICs). A significant correlation was found between the likelihood of publication and the income level of the authors' country of affiliation (p<0.0001), the number of authors (p=0.001), presentation type (p<0.0001), availability of funding (p<0.0001), and the number of institutions involved (p=0.0001). The gender of the first author was not a significant predictor of publication (p=0.46). However, according to the logistic regression model, only the availability of funding and presentation type had a significant impact on the likelihood of publication (p<0.05), while the other variables were found to be insignificant. Conclusions: Our study underscores the critical role of funding as a driver in the publication process. Researchers from LMICs are less likely to publish, likely due to a lack of funding. Furthermore, we observed a delay in publication, with an average time exceeding a year and a half. These findings emphasize the importance of equitable funding access and enhanced publication processes to improve research dissemination.