Treatment-related Risk Factors Research Articles

The CROWN study: Cardiac outcomes with near-complete estrogen deprivation.

TPS12146 Background: Treatment for premenopausal women with high/intermediate risk hormone receptor (HR)-positive breast cancer (BC) includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near-complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV morbidity. Given the overall CV injury associated with BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study uses sophisticated imaging assessments of cardiac dysfunction and biomarker and demographic correlates to understand the evolution of CV injury with the goal of developing tools to assess and mitigate CV risk. Methods: This is an NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Duke University, Wake Forest University and Virginia Commonwealth University) that includes premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-2. HR-positive BC patients are receiving an AI and OFS. Women with HR-negative BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table). These assessments include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. Correlation of CMR imaging with CCTA detail of coronary plaque changes is planned. The relevance of pre-existing risk factors on study outcomes, including an emphasis on race and dynamic change in modifiable and treatment related risk factors will also be assessed. We plan to enroll 90 women,65 in the NCED group and 25 in the HR-negative group, allowing for a 10% drop out rate. The first primary statistical analyses will include testing hypotheses between group (NCED vs HR-negative) and within group (longitudinal changes within the NCED group). Secondary analyses involve developing predictive equations to determine if patient demographics, clinical parameters and serum biomarkers are associated with CV changes over time. We have currently enrolled 34 women (31 NCED and 3 HR-negative). 2 out of 3 patients entering the 2nd year of the study have returned for their year 1 imaging. Retention will be a key component of this study as analysis of the primary and secondary endpoints are dependent on completion of imaging. Clinical trial information: NCT05309655 . [Table: see text]

Circulating Levels of Soluble α-Klotho and FGF23 in Childhood Cancer Survivors: Lack of Association with Nephro- and Cardiotoxicity-A Preliminary Study.

Background/Objectives: The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. Methods: This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. Results: The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, p < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m2. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. Conclusions: In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation.

Abstract PO3-19-04: The CROWN STUDY: A multicenter prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor

Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. The CROWN study (CaRdiac Outcomes With Near complete estrogen deprivation) will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. A total of 17 patients are enrolled as of 07/2023. NCT05309655 Study Procedures XX- XX Citation Format: Susan Dent, Emily Douglas, Sarah Hatcher, Katherine Ansley, Carolyn Park, Nathaniel O'Connell, Mary Hackney, Ralph D'Agostino, Rani Bansal, Renee Avecilla, Monica Brown, Kacey Clayton-Stiglbauer, Igor Klem, Jennifer Jordan, Alexandra Thomas. The CROWN STUDY: A multicenter prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor [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 PO3-19-04.

Aseptic Diaphyseal Pseudarthrosis of the Forearm Initially Treated with Target Plate: Risk Factors and Management

Aseptic diaphyseal pseudarthrosis of the forearm is a major complication. There are patient-related and treatment-related risk factors. The aim of our work is to evaluate the functional and radiological results of aseptic diaphyseal pseudarthrosis of the forearm initially treated with a screw plate. A series of 12 patients were collected in the Orthopedic and Traumatological Surgery Department A of IBN TOFAIL Hospital, retrospectively over a 5-year period. The most frequent site of these pseudarthroses was the ulna (5 cases), followed by both bones (4 cases) and finally the radius (3 cases). 50% of pseudarthroses were atrophic (12 cases). The use of a screw-plate stabilization technique combined with bone grafting and osteo-muscular decortication yielded satisfactory results in terms of bone consolidation and clinical outcome. Smoking is a major risk factor. Solid restraint is necessary to immobilize the fracture site and protect it from forces detrimental to consolidation. De-periostealization and muscular deinsertion are iatrogenic factors that favour the occurrence of pseudarthrosis. Solid DCP plate osteosynthesis combined with autograft after decortication of the fracture site is an important therapeutic weapon with good results.

Risk factors for short-term all-cause mortality in patients with end stage renal disease: a scoping review

ObjectivesThere is a lack of prognostic information to guide the prediction of short-term all-cause mortality in patients with end-stage renal disease (ESRD). The aim was to review the risk factors that influenced the risk of short-term all-cause mortality in patients with ESRD.MethodsMEDLINE, Embase, PubMed, CINAHL, the Cochrane Library and Web of Science databases were searched for articles published between 2000 and 2020. Articles describing risk factors predicting short-term mortality (≤ 3 years) in patients with ESRD were included. Four reviewers independently performed title, abstract, full text screening and data extraction. Assessment of risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool checklist.Results20,840 articles were identified and 113 papers were included for this review. Of the 113 papers, 6.2% included only peritoneal dialysis (PD) patients, 67.3% included only hemodialysis (HD) patients, 20.4% included both PD and HD patients, with the remaining papers featuring patients on conservative management or awaiting renal transplant. Risk factors were categorised into 13 domains: 1)demographics/ lifestyle, 2) comorbidities 3)intradialytic blood pressure, 4)biomarkers, 5)cardiovascular measurements, 6)frailty status, 7)medications, 8)treatment related indicators, 9)renal related parameters, 10)health status, 11)cause of ESRD, 12)access to healthcare care/ information and, 13)proxy measures for poor health. C-reactive protein(CRP), age, and functional status were observed to have higher percentage of instances of being significantly associated with all-cause mortality.ConclusionCommonly examined risk factors observed from this review may be used to build a general prognostic model for patients with ESRD, with specific treatment related risk factors added on to enhance the accuracy of the models.

Treatment-Related Risk Factors for Adverse Outcomes of COVID-19 in Patients Treated for Lymphoid Malignancies in the Pre-Omicron Era-A Study of KroHem, the Croatian Group for Hematologic Diseases.

Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients (p = 0.0078) and those treated with purine analogues (p = 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p = 0.012), especially obinutuzumab, and purine analogues (p = 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies.

Longitudinal Patient Analysis Suggests a Positive Correlation of IL-10/IL-6 and FVIII Inhibitor Amount

Hemophilia A (HA) is the most common X-linked bleeding disorder caused by a deficiency in coagulation factor VIII (FVIII). Inhibitor development in up to 30% of HA patients is the most challenging complication in HA treatment and has been associated with several patient-related risk factors such as gene mutation and residual plasma factor VIII concentrations. Treatment related risk factors are under debate. However, HCV infections were recently shown to correlate with low level inhibitor abundance, potentially as a result of chemokine and cytokine regulation. Therefore, the aim of this study was to evaluate a potential connection between proinflammatory cytokine levels and FVIII-specific B cell responses in HA patients without infections, but with other comorbidities that might modulate cytokine levels. Thus, several clinical parameters and concentrations of plasmatic proinflammatory cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF, IFNa, IFNg, TNFa, MCP-,1 IL-17A, IL-18, IL-23 and IL-33) were quantified from different patient samples. At first, the influence of proinflammatory cytokines on inhibitor development was assessed in a HA patient, who had an intron 22 inversion and was also diagnosed with type 1 diabetes. Prophylactic treatment began at the age of 9 months with 30IU/kg Octanate, and after four days of exposure, the formation of inhibitors was initially detected. Longitudinal cytokine analysis in plasma samples of that patient revealed differential regulation patterns of cytokines. IL-1b, IFNg, TNFa, IL-6, IL-10 and IL-12p70 tended to increase upon inhibitor occurrence, whereas other cytokines remained unchanged (MCP-1, IL-8, IL-17A, IL-18 and IL-23) or decreased (IFNa2 and IL-33). Next, a correlation analysis was performed, assuming that proinflammatory cytokines might stimulate B cells to produce antibodies. This analysis involved all cytokines that were found to be elevated upon inhibitor formation. The comparison of clinical and laboratory data from that patient revealed a strong association of inhibitor levels and IL-10 expression (Pearson r = 0,9391; R squared = 0,8818) as well as with IL-6 (Pearson r = 0,9290; R squared = 0,8630). Furthermore, a modest correlation was observed for IL-1b (Pearson r = 0,5277; R squared = 0,2785), IFNg (Pearson r = 0,3413; R squared = 0,1165), IL-12p70 (Pearson r = 0,3547; R squared = 0,1258), and TNFa (Pearson r = 0,3070; R squared = 0,09422). Other proinflammatory cytokines with a rather stable profile upon inhibitor initiation like MCP-1 (Pearson r = -0,06810; R squared = 0,004638) and IL-18 (Pearson r = 0,2245; R squared = 0,05042) seemed not to be directly correlated with inhibitor occurrence. Finally, we aim to investigate the potential impact of IL-10 and IL-6 on inhibitor production and/or FVIII immune tolerization across various patient groups and conditions. Therefore, we will compare patients with detectable inhibitor titers, those who have successfully eradicated inhibitors, and individuals without inhibitor titers (with normal recovery). Preliminary data suggest a positive correlation between both cytokines and active inhibitor presence. However, to reach a definitive conclusion, the sample size will be/should be increased.

Accounting for fractionation and heterogeneous dose distributions in the modelling of osteoradionecrosis in oropharyngeal carcinoma treatment

Background and purposeOsteoradionecrosis (ORN) of the mandible is a severe complication following radiotherapy (RT). With a renewed interest in hypofractionation for head and neck radiotherapy, more information concerning ORN development after high fraction doses is important. The aim of this explorative study was to develop a model for ORN risk prediction applicable across different fractionation schemes using Equivalent Uniform Doses (EUD). Material and methodsWe performed a retrospective cohort study in 334 oropharyngeal squamous cell carcinoma (OPSCC) patients treated with either a hypofractionated Stereotactic Body Radiation Therapy (HF-SBRT) boost or conventional Intensity Modulated Radiation Therapy (IMRT). ORN was scored with the CTCAE v5.0. HF-SBRT and IMRT dose distributions were converted into equivalent dose in 2 Gy fractions (α/β = 0.85 Gy) and analyzed using EUD. The parameter a that led to an EUD that best discriminated patients with and without grade ≥ 2 ORN was selected. Patient and treatment-related risk factors of ORN were analyzed with uni- and multivariable regression analysis. ResultsA total of 32 patients (9.6%) developed ORN grade ≥ 2. An EUD(a = 8) best discriminated between ORN and non-ORN (AUC = 0.71). In multivariable regression, pre-RT extractions (SHR = 2.34; p = 0.012), mandibular volume (SHR = 1.04; p = 0.003), and the EUD(a = 8) (SHR = 1.14; p < 0.001) were significantly associated with ORN. ConclusionRisk models for ORN based on conventional DVH parameters cannot be directly applied to HF-SBRT fractionation schemes and dose distributions. However, after correcting for fractionation and non-uniform dose distributions using EUD, a single model can distinguish between ORN and non-ORN after conventionally fractionated radiotherapy and hypofractionated boost treatments.

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study.

Childhood cancer survivors (CCS) are at risk for cardiotoxicity. We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors. This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397≥5-year CCS and 277 siblings. Of CCS, n=1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n=143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression. CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as<52% in men,<54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunctiongrade ≥II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors. Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among long-termCCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained riskof cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATERstudy; NTR7481).

Onconephrology: Acute kidney injury in cancer patients

Acute kidney injury (AKI) is a common complication of cancer, occurring in up to 50% of neoplastic patients during the natural course of their disease. Furthermore, it has a significant impact on key outcomes, such as overall prognosis, length of hospitalization, and costs. AKI in cancer patients has various causes, including patient-related, tumor-related, or treatment-related factors.&#x0D; Patient-related risk factors for AKI are similar to those in the general population. Tumor-related risk factors can involve compression, obstruction, direct kidney infiltration by the tumor, as well as precipitation, aggregation, crystallization, or misfolding of paraproteins in conditions like multiple myeloma. Treatment-related risk factors are the most commonly observed in clinical practice and can present as features of tumor lysis syndrome or, for example, immune checkpoint inhibitor-related AKI.&#x0D; In the absence of validated biomarkers for AKI, a multidisciplinary clinical approach involving oncologists, intensivists, nephrologists, or onconephrologists is essential. This approach incorporates thorough assessment, the use of appropriate preventive measures, and early intervention to reduce the incidence of AKI in cancer patients. Understanding the essence of preventive measures, timely initiation of treatment, and knowing when to terminate treatment will reduce the frequency of this life-threatening condition and improve the effectiveness of cancer treatment and the quality of life and life expectancy of cancer patients.&#x0D; This work aims to improve physicians' awareness of the latest data on the prevention, diagnosis, and treatment of AKI specifically related to oncopathology, tumor lysis syndrome, and acute kidney injury induced by cancer immunotherapy drugs.

OUTC-04. SUBSEQUENT CNS MALIGNANCY AMONG SURVIVORS OF CHILDHOOD CANCER: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY (CCSS)

Abstract Subsequent malignant neoplasms (SMNs) of the central nervous system (CNS) following childhood cancer are a frequently fatal late effect of cancer therapy. We used the CCSS (5-year childhood cancer survivors, diagnosed 1970-1999) to assess whether temporal changes in therapy have reduced CNS SMN risk. Twenty-year cumulative incidence rates (95% confidence interval) were estimated, and standardized incidence ratios (SIR, 95% CI) were calculated comparing observed to expected rates from SEER. Multivariable models assessed demographic and treatment-related risk factors for CNS SMN. Among survivors diagnosed between 1970-1979 (N=6223), 1980-1989 (N=9680), and 1990–1999 (N=8999) with median follow-up of 40.5, 32.2, and 22.6 years, respectively, 157 CNS SMNs (1970s, 52; 1980s, 63; 1990s, 42) were identified, excluding meningiomas. Malignant gliomas (N=131) were the most common SMNs. Cranial radiotherapy (CRT) exposure decreased by treatment decade, with the proportion of survivors receiving no CRT increasing from 23.0% (1970s), to 45.7% (1980s), and 66% (1990s). Decreases in &amp;gt;0–10Gy exposure (39.0% to 14.1%) and 20.1–30Gy (19.2% to 2.4%) were observed while those receiving &amp;gt;30Gy CRT has not substantially changed (12%, 11.1%, and 8.8%, respectively). Twenty-year cumulative incidence and SIR for development of SMN were 0.32% (0.18-0.46%) and 6.6 (5.0–8.7); 0.55% (0.41-0.70%) and 8.3 (6.6-10.4); and 0.43% (0.31-0.55%) and 9.2 (7.0–12.0), respectively, with no statistically significant differences between treatment eras, including when stratified by attained age. Multivariate analysis showed increased risk for all CRT dose levels &amp;gt;10Gy and for primary diagnoses of medulloblastoma/PNET (HR 3.6, 2.0-6.6) and astrocytoma (HR 2.4, 1.4-3.9). Three-year cumulative incidences of death after SMN, by treatment decade, were 70%, 73%, and 69%, respectively. In conclusion, CNS SMN incidence has not decreased despite fewer survivors being treated with CRT, and CNS SMNs remain a significant source of mortality for affected patients.

The CROWN study (CaRdiac outcomes with near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor.

TPS12142 Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. Taken together with the CV morbidity associated with other aspects of BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. Present accrual is 4. Clinical trial information: NCT05309655 . [Table: see text]

Subsequent meningiomas in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).

10058 Background: Meningiomas are the most common subsequent central nervous system tumor among aging survivors of childhood cancer, yet incidence across the lifespan, occurrence of multiple meningiomas, and risk for mortality are not established. Methods: Meningiomas were identified by self-report and validated with pathology/medical records. Twenty-year cumulative incidence of meningioma (95% confidence interval) was estimated and multivariable models assessed demographic- and treatment-related meningioma risk factors. Results: Among 24,902 5-year survivors of childhood cancer diagnosed 1970-1999, we identified 472 survivors with 710 meningiomas, 145 (20.4%) of which were WHO grade 2/3. Among survivors with meningioma, 137 (28%) had ≥2 meningiomas, and 80 (16%) met criteria for meningiomatosis. The median latency from childhood cancer to first meningioma diagnosis was 26.2 years (range 5.6-48.2), and the median time from first to second meningioma (among those without meningiomatosis) was 1.4 years (range 0-30.2 years). The twenty-year cumulative incidence did not significantly decrease between survivors diagnosed in the 1970s (0.58, 95% CI 0.41-0.79) and the 1990s (0.42, 95% CI 0.32-0.55). In multivariable analysis, female sex (HR 1.52, 95% CI 1.21-1.91) and all cranial radiotherapy dose levels ( &gt; 0-30Gy, HR 57.0, 95% CI 7.93-419.60; 30.1-50 Gy, HR 228.90, 95% CI 30.89-1695.99; &gt; 50 Gy, HR 113.29, 95% CI 15.09-850.34) were associated with increased meningioma risk, while older age at diagnosis (10-14 years, HR 0.60, 95% CI 0.44-0.82; 15-20 years, HR 0.35, 95% CI 0.22-0.55) was associated with reduced meningioma risk. Among 71 deaths in survivors with meningioma, the most prevalent cause of death was meningioma (N = 25, 35.2%). The 5-year all-cause mortality from first meningioma diagnosis was 4.20% (95% CI: 2.44-5.96%). Conclusions: In conclusion, cranial radiation, younger diagnostic age and female sex were identified as independent meningioma risk factors in, to our knowledge, the largest study to date. The risk for meningioma-associated mortality argues for assertive meningioma surveillance and treatment in this population.

Dental caries and dental developmental defects as adverse effects of antineoplastic treatment in childhood cancer survivors.

To evaluate the prevalence of dental caries and dental developmental defects (DDD) in childhood cancer survivors (CCS) and identify disease and treatment-related risk factors. CCS aged up to 21years, diagnosed with a malignancy before the age of 10years and in remission for at least one year were included. Data were collected from patients' medical records and through a clinical examination where presence of dental caries and prevalence of DDD were recorded. Fisher's exact test was used to assess possible correlations and multivariate regression analysis to determine risk factors for defect development. Seventy CCS with a mean chronological age of 11.2years at the time of examination, mean age at cancer diagnosis of 4.17years, and a mean post-treatment follow-up time of 5.48years were included. Mean DMFT/dmft was 1.31, with 29% of survivors presenting with at least one carious lesion. Younger patients on the day of examination and patients treated with higher radiation dose, showed significantly higher prevalence of dental caries. The prevalence of DDD was 59%, with demarcated opacities being the defect most commonly observed (40%). Age at dental examination, diagnosis, age at diagnosis, and time that have elapsed since the end of treatment were the factors significantly affecting its prevalence. Regression analysis revealed that age at examination was the only factor significantly associated with the presence of coronal defects. A great number of CCS presented with at least one carious lesion or a DDD, with the prevalence being significantly associated with various disease-specific characteristics, but age at dental examination the only significant predictor.

Abstract OT2-01-05: The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor

Abstract Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) therapy to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in the non-cancer population is associated with CV disease, including atherosclerosis and coronary artery disease, which can be detected pre-clinically by myocardial perfusion imaging and coronary artery plaques. This, together with the CV morbidity associated with other aspects of BC treatment and future life-years of these women, warrants further investigation with the goal of identifying pre-clinical markers of myocardial compromise. We seek to do this with the following specific aims: 1. Characterize and quantify the extent of coronary microvascular injury and perfusion changes experienced during early NCED therapy. 2. Characterize and quantify the extent of structural and functional alterations to the aorta and left ventricle while on NCED therapy. 3. Identify potential biomarkers and additional risk factors for CV morbidity in patients receiving NCEDTrial Design: This is a federally funded (NHLBI) prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary outcome is myocardial perfusion reserve (MPR) as measured by CMR imaging stress studies. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors, including an emphasis on racial disparities, on study outcomes, and dynamic change in modifiable and treatment related risk factors. Statistical Methods: We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group) for Aims 1 and 2. Comparisons will be made using longitudinal mixed models to examine effects on outcomes measured. The second analyses, for Aim 3, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with MPR. The sample size allows 80% power to address specific aims for between and within group comparisons, including a between group difference of 2.8% in our primary outcome, MPR. Present Accrual: 0 Target Accrual: 90 Contact information: Emily Douglas, MD; edouglas@wakehealth.edu Table 1: Study Procedures Citation Format: Emily Douglas, Nathaniel O’Connell, Mary Hackney, Wendy Bottinor, John Grizzard, Igor Klem, Carolyn Park, Sujethra Vasu, Karl Richardson, Susan Dent, Ralph D’Agostino, Gregory Hundley, Jennifer Jordan, Alexandra Thomas. The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-05.

Prolactin-Raising and Prolactin-Sparing Antipsychotic Drugs and the Risk of Fracture and Fragility Fracture in Patients With Schizophrenia, Dementia, and Other Disorders

Patients who require antipsychotic drug treatment are at increased risk of fractures, including osteoporosis-related fragility fractures, for reasons related to demographics, illness-related factors, and treatment-related factors. As examples, patients with dementia may be vulnerable to falls due to cognitive and psychomotor impairment, patients with schizophrenia may be vulnerable to injury related to physical restlessness or physical aggression, and patients receiving antipsychotics may suffer falls related to sedation, psychomotor impairment, bradykinesia, or postural hypotension. Antipsychotics may also increase the risk of fracture through long-term hyperprolactinemia and resultant osteoporosis. A meta-analysis of 36 observational studies conducted in mostly elderly samples found that antipsychotic exposure was associated with an increased risk of hip fracture as well as increased risk of any fracture; the findings were consistent in almost all subgroup analyses. An observational study that controlled for confounding by indication and illness severity found that fragility fractures in patients with schizophrenia were associated with higher daily doses, higher cumulative doses, longer duration of treatment, and prolactin-raising rather than prolactin-sparing antipsychotics; in patients receiving prolactin-raising antipsychotics, the concurrent use of aripiprazole appeared protective. The absolute risks of fracture are unknown and could vary depending on patient age, patient sex, indication for antipsychotic use, nature of the antipsychotic (and associated risk of sedation, psychomotor impairment, bradykinesia, and postural hypotension), daily dose prescribed, duration of antipsychotic exposure, baseline risk of fracture, and other risk factors. Patients should therefore be individually evaluated for risk factors for falls and fractures related to sociodemographic, clinical, and treatment-related risk factors. Patients identified to be at risk should be advised about risk-mitigating strategies. If prolactin-raising antipsychotics are required in the long term, prolactin levels should be monitored and prolactin-lowering strategies should be considered. Osteoporosis should be investigated and managed, if identified, to prevent fragility fractures.

Gutted: constipation in children with chronic kidney disease and on dialysis

Functional constipation is a common problem in otherwise healthy children. Children with chronic kidney disease (CKD) and on dialysis have additional disease-related risk factors including the uremic milieu, fluid and dietary restrictions, and decreased physical activity, as well as treatment-related risk factors such as dialysis therapy and polypharmacy that contribute to and compound the problem. Constipation causes significant distress for children and their caregivers. In children on peritoneal dialysis, severe constipation can impede catheter function and ultrafiltration. Accumulating evidence points to a possible bidirectional relationship between constipation and CKD, potentially mediated by gut dysbiosis with consequent increased generation of gut-derived uremic toxins and disruption of intestinal epithelium integrity leading to translocation of noxious luminal contents into the circulation inducing systemic inflammation. Effective management of constipation is required but there is little published data on the safety and effectiveness of treatments in adults or children with CKD. In this review, we discuss the diagnosis and epidemiology of functional constipation, provide an overview of its pathophysiology, summarize the therapeutic management, and reflect on the challenges in children with CKD.

Germline Genetic and Treatment-Related Risk Factors for Diabetes Mellitus in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study and St Jude Lifetime Cohorts.

To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer. Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS. There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10-8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10-7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation. There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.

Body Composition and Immunonutritional Status Impact Survival Outcomes after CD19 CAR T-Cell Therapy

Introduction: While CD19 chimeric antigen receptor T-cell therapy (CD19.CART) has altered the treatment landscape for multiple relapsed/refractory (r/r) B-cell malignancies, over 50% of patients ultimately relapse. To elucidate relapse mechanisms, previous studies have predominantly focused on disease- and treatment-related risk factors, while few studies have looked at systemic, host-intrinsic features. In this context, we recently demonstrated that an increase of metabolically high-risk adipose tissue sites, particularly visceral fat, impacts cytokine release syndrome onset and severity via IL-6 (Dos Santos & Rejeski et al, Haematologica 2022). We therefore hypothesized that body composition and nutritional status may also affect post-CAR-T survival outcomes. Methods: In this single-center, retrospective observational analysis, we studied patients receiving CD19.CAR-T for r/r B-cell malignancies between 01/2019 and 03/2022 in a real-world setting. We comprehensively analyzed the impact of immunometabolic host features including body composition (BC) measurements on clinical outcomes. We extracted psoas and skeletal muscle indices (PMI/SMI) as well as subcutaneous, visceral and epicardial adipose tissue (SAT/VAT/EAT) distributions from pre-lymphodepletion CT images. We further assessed the laboratory-based immuno-nutritional scores Glasgow Prognostic Score (GPS), CRP/Albumin Ratio and the Prognostic Nutritional Index (PNI). Efficacy outcomes were assessed according to Lugano criteria for B-NHL (LBCL, MCL) and according to MRD status for BCP-ALL. Durable responders were defined as reaching at least a partial remission (PR) or better by day 90, while non-responders had stable disease (SD), progressive disease (PD), or died due to treatment-related causes. Results: 66 consecutively treated patients were included in this analysis (53 LBCL, 9 MCL, 4 BCP-ALL). The following CD19.CART products were applied: axi-cel in 22 patients, tisa-cel in 25 patients and brexu-cel in 9 patients. Patients received a median of four prior treatment lines, which included a stem cell transplantation in 24 patients. The best 90-day overall response rate was 51.5%, with a complete remission rate of 40.9%. At a median follow-up time of 19 months, median PFS was 3.2 months and median OS 14 months. Based on the BC analysis, we found that CAR-responders displayed increased visceral adipose tissue deposits compared to CAR-non-responders (VAT: 120 vs. 67 cm2, p=0.01). Furthermore, immuno-nutritional scores (GPS, CRP/Albumin-Ratio, PNI) were significantly altered in non-responding patients. Next, we defined cut-off values for further analyses based on receiver operating characteristics for adipose tissue parameters and immunonutritional scores, and on optimal log-rank test separation for sarcopenia parameters. On univariate cox regression analysis, patients with VAT > 61.8 cm² exhibited a significantly lower risk of poor OS (Hazard Ratio [HR] = 0.35, 95% CI 0.18-0.70). Concomitantly, median PFS (5.1 vs. 1.9 months, p=0.04) and median OS (not-reached vs. 2.9 months, Fig. 1A) were significantly extended in patients with excess visceral adipose tissue. On the other hand, a SMI < 34.5 cm²/m², an indicator for sarcopenia, was associated with inferior OS (median 2.4 vs. 16.8 months, Fig. 1B). In a multivariate analysis adjusting for baseline CRP, LDH and ECOG performance status, increased VAT > 61.8 cm² was associated with improved clinical outcomes (high VAT: adjusted HROS: 0.28, 95% CI 0.13-0.59, p=<0.001). Conversely, sarcopenia significantly increased the risk of poor survival (low SMI: aHROS: 3.63, 95% CI 1.47-8.99, p=0.005). Moreover, malnutrition, defined by a PNI < 39.7, was associated with worse PFS and OS (low PNI: aHROS: 3.27, 95% CI 1.38-7.77, p=0.007). Conclusions: These findings highlight that body composition and nutritional status play a role as host-intrinsic prognostic factors in the context of CD19.CART. The link between visceral adipose tissue and improved survival suggests that the obesity paradox may extend to patients receiving T-cell based immunotherapies. If validated in future prospective studies, data on body composition and nutritional status may complement existing risk-stratification tools for patients receiving CD19-CART, and may lead to exercise- and diet-based interventional strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Modifiable Risk Factors Are Associated with Reduced Bone Mineral Density and Fractures in a National Cohort of 2,003 Dutch Childhood Cancer Survivors

Introduction Childhood cancer survivors are at risk of developing skeletal late effects. However, evidence on risk factors for very low bone mineral density (BMD, Z-score ≤-2), as well as on risk and risk factors of (vertebral) fractures is limited. We investigated this in a national cohort of Dutch childhood cancer survivors treated from 1963-2002. Methods This cross-sectional study is part of the Dutch Childhood Cancer Survivor Study (DCCSS) LATER cohort. Individuals who survived at least five years after cancer diagnosis and aged 18-45 years at invitation were included. BMD was assessed by dual-energy X-ray absorptiometry (DXA, n=1,548). We defined low BMD as a Z-score ≤-1 and very low BMD as a Z-score ≤-2. Fractures that occurred >5 years after cancer diagnosis were assessed by medical history (n=1,892). Fracture incidence was compared with Swedish normative data by calculating a standardized incidence ratio (SIR). Vertebral fractures were evaluated by DXA-assisted vertebral fracture assessment using the Genant semiquantitative method (n=249). Associations between demographic, treatment-related, endocrine, as well as lifestyle-related factors and reduced BMD and (vertebral) fractures were evaluated using univariable or multivariable logistic regression models. Results A total of 2,003 childhood cancer survivors participated in this study (32.3% lymphoid leukemia, 5.1% myeloid and other leukemia, 18.6% lymphoma, 28.0% solid tumors, and 16.0% CNS and brain tumors) with a mean age of 33.1 (standard deviation ±7.2) years. Low BMD at any site occurred in 35.3% (95%CI=32.1-38.5%) of survivors with hematologic malignancies, and very low BMD in 9.6% (95%CI=7.7-11.2%). Additionally, 32.3% (95%CI=29.5-35.2%), 16.8% (95%CI=14.6-19.2%), and 13.3% (95%CI=11.3-15.5%) of survivors with hematologic malignancies had experienced any fracture, a long bone fracture, or a fragility fracture, respectively. The SIR of any first fracture that occurred at least 5 years after cancer diagnosis was 3.53 (95%CI=3.06-4.06) for male survivors and 5.35 (95%CI=4.46-6.52) for female survivors. Vertebral fractures were prevalent in 13.3% of evaluable survivors. In the models for low or very low BMD, male sex, underweight, shorter follow-up time (continuous), total body irradiation, cranial irradiation, carboplatin (≥2,000 mg/m2), alkylating agents (≥8,000 g/m2), hypogonadism, growth hormone deficiency (GHD), hyperthyroidism, low physical activity, severe vitamin D deficiency, vitamin B12 deficiency, and folic acid deficiency were statistically significant. Male sex, obesity, previous/current smoking, and very low lumbar spine BMD were significantly associated with reported clinical fractures. Older attained age, platinum compounds, GHD, and low physical activity were significantly associated with vertebral fractures. Conclusions: Childhood cancer survivors are at increased risk of any fracture. Reduced BMD at follow-up (especially very low lumbar spine BMD) was significantly associated with fractures, which underscores the importance of active BMD surveillance for high-risk survivors (i.e. those treated with cranial/craniospinal or total body irradiation). We identified high-dose carboplatin as a new treatment-related risk factor for low BMD, whereas corticosteroid (dose) was not significantly associated with reduced BMD or fractures. In addition, several modifiable risk factors for reduced BMD (i.e. hypogonadism, GHD, low physical activity, severe vitamin D deficiency, vitamin B12 deficiency, and folic acid deficiency) and vertebral fractures (i.e. GHD and low physical activity) were identified.