Citations

Abstract Adolescent and young adults (AYAs) (15-39 years) have a heightened risk of developing a second primary malignancy due to extended periods of survivorship, higher incidence of germline cancer predisposing variants, and increased susceptibility to treatment-induced malignancies. Research on survivors of specific AYA cancer types, including breast cancer (BC) survivors, is limited. Among BC survivors, while much survivorship research focuses on risk of locoregional recurrence or contralateral BC, little is known about overall risk, and risk factors, of developing second non-breast primaries. This prospective cohort study examined women diagnosed with BC from 2006-2016 at age ≤40 years enrolled in the Young Women’s BC Study (YWS) (N=1297). Women were excluded from the analytic cohort if initially diagnosed with Stage IV breast cancer (N=64). To enable investigation of how BC treatments may impact second primary risk, women were also excluded if they reported another cancer before primary BC diagnosis (N=3). Patient characteristics, treatment information, and clinical events were collected via serial surveys. Tumor characteristics and detailed treatment data were obtained from medical record review. Five- and 10-year risk of second non-breast primary was estimated via the cumulative incidence function after applying the Fine-Gray competing risks model with time starting at primary BC diagnosis. Death, metastasis, or diagnosis with a second primary BC were considered as competing events. Univariate and multivariate Fine-Gray sub-distribution models were used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CI) for second non-breast primary cancer risk. Risk factors considered included age, race, body mass index, smoking, alcohol use, income, family history of cancer, germline pathogenic variant (PV) carrier status, tumor stage, grade, and ER status, primary surgery type, and receipt of radiation, chemotherapy, or endocrine therapy (yes/no). Multivariate models tested individual associations with additional adjustment for radiation therapy and PV carrier status, as both are consistently associated with second primary in the literature. Over a median follow-up of 10.1 years (inter-quartile range (IQR) =7.9-12.1 y), 47 patients (4%) developed a second non-breast primary cancer. Median age at second non-breast primary was 43 years (IQR=39-46), and median time between primary BC and second non-breast primary was 7.3 years (IQR=4.1-9.3). Second primary types included melanoma (n=10), thyroid (n=10), ovarian (n=4), sarcoma (n=4), uterine (n=3), rectal (n=3), bladder (n=2), cervical (n=2), head and neck (n=2), lung (n=2), lymphoma (n=2), pancreatic (n=2), and kidney (n=1). During the study, 22 patients (2%) developed a second primary BC, 167 (19%) developed metastasis, and 15 (1%) died from causes other than BC. Among the patients who developed a second primary BC, two later developed another non-breast cancer (ovarian and brain cancer). When incorporating competing risks, five and 10-year cumulative incidence of second non-breast primary was 1.4% and 3.2%, respectively. No patient or treatment factors were statistically significantly associated with second non-breast primary in univariate or multivariate models, including radiation and PV carrier status. In this population of young BC survivors, 10-year cumulative incidence of second non-breast primary cancer was 3.2%, with the most common second cancers being melanoma and thyroid cancer. Incidence rates of all second primary cancer types in this cohort were higher than population-based incidence rates for healthy women under 50 years of age, highlighting the importance of long-term surveillance for other cancer events in this young population. While risk of second non-breast primary was not associated with primary BC treatment in this study, cases were limited, and the follow-up interval was relatively short. Citation Format: Bessie Zhang, Kristen Brantley, Shoshana Rosenberg, Gregory Kirkner, Laura Collins, Kathryn Ruddy, Rulla Tamimi, Lidia Schapira, Virginia Borges, Ellen Warner, Steven Come, Eric Winer, Ann Partridge. Second primary non-breast cancers in young breast cancer survivors [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 PO3-11-10.

Implantable cardioverter-defibrillator (ICD) therapy in children and congenital heart disease (CHD) patients is hampered by poor long-term lead survival. Lead extraction is technically difficult and carries substantial morbidity. Manufacturers developed distinct strategies for this issue: thinner lead bodies or a Gore ePTFE coil coating. Both design changes were thought to improve ease of lead removal, but have not been directly compared in children or adults. The purpose of this study was to assess thin and ePTFE-coated ICD lead survival in pediatric and CHD pts. Methods: The Pediatric Lead Extractability and Survival Evaluation (PLEASE) Study began as a Phase IV multicenter open-label prospective study [ NCT00335036 ], facilitated by the Pediatric & Congenital EP Society. Initially designed as a randomized study, it changed to a parallel assignment registry when 1 lead had an advisory due to high incidence of failure, prompting concern about continued clinical equipoise. Pediatric and CHD pts who underwent ICD lead implant from 2005-2010 were eligible. The end date was NCDR ICD Registry v2.0 release (includes pediatric & lead data). 23 centers participated; each site obtained IRB approval. De-identified data was sent to the PI center for verification and statistical analyses. Results: A total of 982 ICD pts (357 VVI, 558 DDD, 67 CRT-D) entered the PLEASE study, incl. 423 pts (43%) with CHD. Mean age at implant = 18.3 ± 9.9 yrs. Thin (< 7Fr) ICD leads accounted for 51%, 23% were ePTFE-coated, 26% neither thin nor coated. There were 113 ICD lead failures (11.5%) at a mean lead-age of 2.2 ± 1.7 yrs, causing shocks in 55 pts. Failure occurred in 21% of thin leads vs 3.5% of ePTFE leads (p<0.01). Extraction was performed on 142 (14.5%) leads overall; 21% of thin leads (incl. extraction of 29 functioning leads due to recall) vs. 4.4% of ePTFE leads (p<0.01). There were 7 major extraction complications (4.9%), but no procedural mortality. Among thin leads, 90/270 (33.3%) of recalled leads failed vs 15/229 (6.6%) non-recalled thin leads. Conclusions: This Phase IV study demonstrates that ICD leads in children and CHD pts have suboptimal performance overall. Thinner leads were much more likely to fail and/or be extracted compared with ePTFE leads, chiefly driven by one lead type.

Importance Among women diagnosed with primary breast cancer (BC) at or younger than age 40 years, prior data suggest that their risk of a second primary BC (SPBC) is higher than that of women who are older when they develop a first primary BC. Objective To estimate cumulative incidence and characterize risk factors of SPBC among young patients with BC. Design, Setting, and Participants Participants were enrolled in the Young Women’s Breast Cancer Study, a prospective study of 1297 women aged 40 years or younger who were diagnosed with stage 0 to III BC from August 2006 to June 2015. Demographic, genetic testing, treatment, and outcome data were collected by patient surveys and medical record review. A time-to-event analysis was used to account for competing risks when determining cumulative incidence of SPBC, and Fine-Gray subdistribution hazard models were used to evaluate associations between clinical factors and SPBC risk. Data were analyzed from January to May 2023. Main Outcomes and Measures The 5- and 10- year cumulative incidence of SPBC. Results In all, 685 women with stage 0 to III BC (mean [SD] age at primary BC diagnosis, 36 [4] years) who underwent unilateral mastectomy or lumpectomy as the primary surgery for BC were included in the analysis. Over a median (IQR) follow-up of 10.0 (7.4-12.1) years, 17 patients (2.5%) developed an SPBC; 2 of these patients had cancer in the ipsilateral breast after lumpectomy. The median (IQR) time from primary BC diagnosis to SPBC was 4.2 (3.3-5.6) years. Among 577 women who underwent genetic testing, the 10-year risk of SPBC was 2.2% for women who did not carry a pathogenic variant (12 of 544) and 8.9% for carriers of a pathogenic variant (3 of 33). In multivariate analyses, the risk of SPBC was higher among PV carriers vs noncarriers (subdistribution hazard ratio [sHR], 5.27; 95% CI, 1.43-19.43) and women with primary in situ BC vs invasive BC (sHR, 5.61; 95% CI, 1.52-20.70). Conclusions Findings of this cohort study suggest that young BC survivors without a germline pathogenic variant have a low risk of developing a SPBC in the first 10 years after diagnosis. Findings from germline genetic testing may inform treatment decision-making and follow-up care considerations in this population.

AbstractPersons with amyotrophic lateral sclerosis (PALS) are at risk of developing cognitive impairments and frontotemporal dementia (FTD). This study examined the relationship between performance of the ALS-Cognitive Behavioral Screen (ALS-CBS) and the demographic parameters of sex, education, time post–ALS diagnosis, and severity of symptoms. Data were collected retrospectively from 69 participants seen at the Mayo Clinic. Correlations were conducted on the ALS-CBS total scores and subsection scores and the above listed parameters; t-tests were conducted between participant subgroups. No statistically significant relationships or differences occurred between the ALS-CBS or its subsections and the variables measured with exception of age and the attention subsection. Older participants had lower ALS-CBS attention subsection scores. Based on the ALS-CBS scores, most participants had some degree of cognitive impairments: 43 had suspected cognitive impairment, 8 had suspected FTD; 18 fell within the normal range of cognitive function. Overall, the variables of sex, education, time post-diagnosis, and severity of symptoms do not appear to influence ALS-CBS scores. It is recommended cognitive screenings be completed for all PALS due to the high risk for developing cognitive impairments and FTD. Such knowledge can help clinicians develop assessment and treatment plans.

Proton radiography is a promising development in proton therapy, and researchers are currently exploring optimal detector materials to construct proton radiography detector arrays. High-density glass scintillators may improve integrating-mode proton radiography detectors by increasing spatial resolution and decreasing detector thickness. We evaluated several new scintillators, activated with europium or terbium, with proton response measurements and Monte Carlo simulations, characterizing relative luminosity, ionization quenching, and proton radiograph spatial resolution. We applied a correction based on Birks’s analytical model for ionization quenching. The data demonstrate increased relative luminosity with increased activation element concentration, and higher relative luminosity for samples activated with europium. An increased glass density enables more compact detector geometries and higher spatial resolution. These findings suggest that a tungsten and gadolinium oxide-based glass activated with 4% europium is an ideal scintillator for testing in a full-size proton radiography detector.

PURPOSE Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL. METHODS Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation. RESULTS We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41). CONCLUSION In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase–CML. The primary goal of TKI therapy in patients with chronic phase–CML is to prevent disease progression to accelerated phase–CML or blast phase–CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase–CML.

Background Acute ischemic stroke complicates 2% to 3% of transcatheter aortic valve replacements (TAVRs). This study aimed to identify the aortic anatomic correlates in patients after TAVR stroke. Methods and Results This is a single‐center, retrospective study of patients who underwent TAVR at the Mayo Clinic between 2012 and 2022. The aortic arch morphology was determined via a manual review of the pre‐TAVR computed tomography images. An “a priori” approach was used to select the covariates for the following: (1) the logistic regression model assessing the association between a bovine arch and periprocedural stroke (defined as stroke within 7 days after TAVR); and (2) the Cox proportional hazards regression model assessing the association between a bovine arch and long‐term stroke after TAVR. A total of 2775 patients were included (59.6% men; 97.8% White race; mean±SD age, 79.3±8.4 years), of whom 495 (17.8%) had a bovine arch morphology. Fifty‐seven patients (1.7%) experienced a periprocedural stroke. The incidence of acute stroke was significantly higher among patients with a bovine arch compared with those with a nonbovine arch (3.6% versus 1.7%; P =0.01). After adjustment, a bovine arch was independently associated with increased periprocedural strokes (adjusted odds ratio, 2.16 [95% CI, 1.22–3.83]). At a median follow‐up of 2.7 years, the overall incidence of post‐TAVR stroke was 6.0% and was significantly higher in patients with a bovine arch even after adjusting for potential confounders (10.5% versus 5.0%; adjusted hazard ratio, 2.11 [95% CI, 1.51–2.93]; P <0.001). Conclusions A bovine arch anatomy is associated with a significantly higher risk of periprocedural and long‐term stroke after TAVR.