Risk Of Toxicity Research Articles

Routine, prospective DPYD genotyping guided dose-individualisation for patients receiving fluoropyrimidines: Implementation, prevalence and patient safety outcomes from a multi-institutional clinical trial.

12121 Background: Prospective data regarding the prevalence of DPYD variant alleles and the impact of genotype guided dosing on safety and efficacy of fluoropyrimidines (FP) remains limited. We assessed the feasibility and safety impact of routine, prospective, DPYD genotype guided FP dosing. Methods: Adult patients (>18 years), commencing FP for the first time were enrolled. Sanger PCR sequencing was designed to target DPYD variants NM_000110.4:c.1905+1G>A (DPYD*2A), NM_000110.4:c.1679T>G (DPYD*13), NM_000110.4:c.1236G>A and NM_000110.4:c.2846A>T. Dose reductions were implemented as per current international pharmacogenomic guidelines. Gr3/4 toxicity, dose reductions/delays and hospital admissions were reviewed for the first 60 days after commencement. For comparison purposes, a retrospective review of patients receiving FP without testing in a prior year was completed. Results: Between July 2021 – May 2023, 334 patients were enrolled for testing. 95% ECOG 0-1. 57% curative treatment intent. Mean time from phlebotomy to result 6.9 days (range 2-15). Clinician/patient acceptance was high (>95% of eligible patients starting FP were enrolled). 20 (6.0%) variant DPYD allele carriers were detected. 11 heterozygous for c.1236G>A, 5 heterozygous for C.1905+1G>A, 3 heterozygous for c.2846A>T and 1 homozygous for c.1236G>A. 295 of patients tested proceeded to receive FP. 62% received Infusional-FP, 38% Capecitabine. 39 patients commenced treatment prior to DPYD result being available (treating clinician decision). Dose modification recommendations were followed in all but two patients. 24% experienced FP related Grade 3/4 toxicity within 60 days. (23% DPYD wild type, 37% DPYD variant) versus 35% in the retrospective cohort. 16% had FP related dose delays (16% DPYD wild type, 12% DPYD variant) versus 25% retrospective cohort. 14% had FP related dose reductions (13% DPYD wild type, 25% DPYD variant) versus 12% retrospective cohort. 13% had FP related hospital admissions (13% DPYD wild type, 19% DPYD variant) versus 17% retrospective cohort. 1 death in the DPYD wild type cohort was deemed potentially related to FP. Conclusions: Prospective DPYD genotype guided dosing was feasible in clinical practice, with prevalence of variant alleles comparable to published literature. There was a modest reduction in risk of FP related severe toxicity, dose delays, and hospital admissions with DPYD guided dosing compared to a historical, untested cohort. Clinical trial information: ACTRN12621001117808.

The influence of sarcopenia and myosteatosis on severe laboratory toxicity and overall mortality in older adults with cancer receiving chemotherapy.

12131 Background: Older adults with cancer often present with suboptimal muscle quantity and quality prior to treatment due to disease-related catabolic effects combined with the aging process. Muscle catabolism is further exacerbated by cancer treatments leading to worse metabolic health, patient quality of life, and clinical outcomes. Our objective was to examine the impact of sarcopenia and myosteatosis on severe laboratory toxicity and overall mortality in older adults with cancer receiving chemotherapy. Methods: This was a retrospective cohort study of older adults who had undergone chemotherapy at the Princess Margaret Cancer Centre, Toronto, Canada from June 2015 to June 2022. A computed tomography scan after diagnosis but prior to treatment was used to assess skeletal muscle index (SMI) and skeletal muscle density (SMD) for each participant. Sarcopenia was defined as the presence of low muscle strength (grip strength <35.5kg for males and <20kg for females), low SMI, and low physical performance (walking speed <0.8m/s or a total Short Physical Performance Battery score of ≤8) prior to chemotherapy initiation. Myosteatosis was assessed through SMD in Hounsfield Units using previously published cut-offs. Severe laboratory toxicity was defined as occurrence of a grade ≥3 adverse event per the Common Terminology Criteria for Adverse Events (version 4.0). Severe laboratory toxicity and overall mortality were assessed from treatment initiation until treatment termination or loss to follow up. Multivariable logistic regression was used to determine the role of sarcopenia and myosteatosis in predicting occurrence of severe laboratory toxicity. Multivariable Cox regression was used to assess the risk of overall mortality. Results: A total of 115 older adults (mean age: 77.1 y) were included, of whom 63.5% had metastatic disease. Sarcopenia was identified in 27% of the cohort, whereas 80% had myosteatosis. A total of 132 severe laboratory toxicities occurred during the study period in 41 participants (35.7%). Sarcopenia was a significant predictor of severe laboratory toxicity (adjusted odds ratio (aOR)=3.19, 95%CI= 1.19 to 8.52, p= 0.012) after adjusting for sex, body mass index, and hemoglobin. Myosteatosis was significantly associated with overall mortality (adjusted hazard ratio (aHR)= 2.51, 95%CI= 1.12-5.61, p=0.025) after adjusting for albumin, alkaline phosphatase, and treatment intent. Conclusions: Sarcopenia may be used to inform the risk of severe laboratory toxicity in older adults prior to chemotherapy. Pre-treatment myosteatosis defined by low SMD predicts overall mortality in the same cohort. Optimization of skeletal muscle health through targeted exercise and nutritional interventions may improve patient quality of life and clinical outcomes in older adults with cancer receiving chemotherapy.

Examining the risk of immune checkpoint inhibitor-related toxicity among patients with melanoma and their history of cannabis use.

e21539 Background: With cannabis use rising due to better availability for recreational and medicinal uses, there is a need for studies examining cannabinoids interactions. Immune Checkpoint Inhibitors have been increasing in popularity among metastatic cancer patients like those with melanoma. The biological impact of cannabis is mediated in part by the CB1 and CB2 receptors present in the endocannabinoid system that is present in the immune system. ICI therapy also targets the immune system through manipulating PD-1/PD-L1 receptors to induce cancer cell death. Therefore, concurrent cannabis use with ICI therapy could have potentiating effects on toxicities and negatively impact efficacy. There is limited information in the literature examining this and therefore the goal was to examine the impact of ICI toxicity risk among melanoma patients on any form of ICI therapy. Methods: A retrospective cohort study was conducted using TriNetX, a multicenter database comprised of ~100 million patients across 84 healthcare organizations. Adults ( > 17 years) from 2012-2023 were identified based on ICI-therapy initiation within 1 month of malignant melanoma diagnosis. Patients were then stratified by history of those with and without cannabis use disorder. ICI toxicity categories were determined a priori and included cardiac, nephrological, gastrointestinal, endocrine, respiratory, ocular, hematological, hepatological, musculoskeletal, and neurological toxicities. 1:1 propensity score matching was conducted to control for comorbidities and demographics. Adjusted hazard ratios (aHR) with 95% CI were calculated at 1-year follow-up after therapy initiation for ICI toxicities between the cohorts. aHR was estimated using the Cox proportional hazard model. Results: A total 14589 melanoma patients who underwent ICI therapy were identified where 2.3% had history of cannabis use. Matching revealed two balanced cohorts of 344 patients. Melanoma patients with a history of cannabis use did not have any significant differences with controls for cardiotoxicity (aHR[95%CI] = 0.94[0.54,1.6]), Nephrotoxicity (0.86[0.51,1.5]), GI toxicity (1.44[0.95,2.2]), endocrine toxicity (1.2[0.82,1.8]), respiratory toxicity (0.93[0.55,1.6]), ocular toxicity (0.63[0.25,1.6]), hematologic toxicity (1.04[0.7,1.6]), neurotoxicity (1.04[0.6,1.7]), liver toxicity (1.41[0.78,2.5]), or musculoskeletal toxicity (1.53[0.62,3.8]). Conclusions: With cannabis use rising due in part to recreational use and in part to medical marijuana, the implications of use must be a topic of research. Cannabis use among melanoma patients did not provide any significant differences in risk of developing ICI-therapy-related toxicities. Additional studies are needed to validate this finding.

Experimental study on coagulation and adsorption treatment of wastewater in combustion cavity for underground coal gasification

Underground Coal Gasification (UCG) is a promising mineral resource development technology that can transform in-situ coal into combustible gas by controlling combustion. However, wastewater generated during the UCG process can lead to environmental pollution in adjacent areas through diffusion or infiltration. In order to seek an efficient and inexpensive in-situ treatment method for underground gasification combustion zone wastewater, UCG model experiments were conducted to obtain wastewater, and the treatment effects of chemical coagulation and physical adsorption methods were compared in this work. The COD concentration in wastewater from underground combustion zone ranges between 555 ∼ 703 mg/L, with a pH value between 8.26 ∼ 8.85. The organic pollutants mainly come from the dissolution of high carbon components, mainly aromatic compounds in tar, which leads to high toxicity and pollution risk of wastewater. For chemical coagulation method, the removal effect of organic pollutants in combustion zone wastewater by ferric sulfate is better than that of aluminum sulfate due to excellent hydrolysis reaction of Fe3+. The corresponding COD removal rate and COD removal cost are 24.34 % and 0.176 ¥/g, respectively. For physical adsorption method, due to the large total pore volume and wide specific surface area of organic bentonite, it can effectively remove COD content. The COD removal rate and COD removal cost, and COD adsorption capacity are 60.23 %, 0.213 ¥/g, and 89.75 mg/g, respectively. Comprehensive comparison shows that physical adsorption is more suitable for in-situ treatment of combustion zone wastewater.

Implementing financial toxicity and health-related social risks screening and referral.

11006 Background: Financial toxicity (FT), or cancer-related economic hardship, is associated with delayed/skipped care, reduced quality of life, and worse mortality. Screening for FT and health-related social risks (HRSR) as part of assessment for social determinates of health is currently being integrated into clinical care, but there is limited research on outcomes after patients screen positive for FT or HRSR. Methods: We conducted FT and HRSR screening for patients receiving treatment for breast, gynecologic, gastrointestinal, or thoracic cancer at an urban comprehensive cancer center. Screening included the 11-item Comprehensive Score for Financial Toxicity (COST) tool (scored 0-44, lower scores = worse FT) and a HRSR checklist to identify food, housing, medicine, and transportation insecurity. A COST score ≤20 or any endorsed HRSR was considered a positive screen, and financial/assistance counseling referral was offered. Multivariable logistic regression assessed associations of accepting referral, after controlling for demographic and clinical characteristics. Data were collected 09/2022-08/2023. Results: 28,606 patients completed screening, of which 32% (n = 9106) screened positive. Median COST was 16.0. Identified HRSR were: 23% food, 25% housing, 21% medicine, and 24% transportation insecurity. Of positive screens, 51% (n = 4683) requested some form of financial counseling. Associations with accepted referral include: higher FT (β = 1.15, 95% CI: 1.13, 1.16), younger age (β = 1.01, 95% CI: 1.008, 1.02), more essential needs (β = 1.19, 95% CI: 1.13, 1.25), non-White race/ethnicity (β = 1.70, 95% CI: 1.49, 1.93), and stage 3 (β = 1.29, 95% CI: 1.08, 1.53) or stage 4 (β = 1.26, 95% CI: 1.07, 1.49) diagnoses (vs. stage 0/1). Needs of patients who requested counseling included concerns relating to out-of-pocket expenses (68%), non-medical expenses (39%), health insurance coverage (23%), and paying for prescription medication (18%; not mutually exclusive). Of financial counseling sessions with available dispositions (n = 2336/4683, 50%), outcomes (not mutually exclusive) included general counseling (29%), referral to specific assistance programs (e.g., copay assistance, reduced cost care program; 15%), and insurance navigation (15%). One-third of patients requesting counseling did not respond to contact attempts; 21% reported no longer being interested in counseling upon contact. Conclusions: Screening for FT and HRSR was feasible, and one-third of patients were identified as at risk for FT or having an unmet essential need. Patients known to have worse FT outcomes (those with later-stage disease, younger age, higher FT, minoritized groups) were more likely to accept financial counseling; however, only one-half of those at risk accepted help. Future work will focus on improving workflows to ensure assistance meets patient needs, including addressing patient stigma around requesting help.

Toxic Metal Soil Speciation, Corn Accumulation and Health Risk Assessment in Acidic red soil Farmland in Mineral Industry Area

Toxic Metal Soil Speciation, Corn Accumulation and Health Risk Assessment in Acidic red soil Farmland in Mineral Industry Area

Association of neighborhood-level superfund sites with atmospheric toxic exposures and increasing cancer risk in the United States: A proof-of-concept geospatial study.

10577 Background: Decades of underinvestment have disproportionately exposed several neighborhoods in the US to hazardous conditions. Superfund is the name given to the environmental program established by the US Congress in 1980, to address abandoned hazardous waste sites. The extent to which Superfund sites have contributed to differences in cancer risk remains unknown. We investigated atmospheric toxic exposures increasing cancer risk by proximity to Superfund sites at the neighborhood level. Methods: In this cross-sectional study of US neighborhoods, census-tract level air toxic cancer risk data from the Environmental Protection Agency for 2019 were linked with census-tract level geolocation data of ~1300 Superfund sites from the Superfund Enterprise Management System database. Linear regression models were utilized to explore association between cancer risk and proximity to Superfunds. Geographically Weighted Regression models explored spatial non-stationarity by modeling spatial relationships that vary across the study area. Bivariate Local Indicators of Spatial Association (LISA) cluster maps were created for superfund site proximity and cancer risk (high-high, low-low, low-high, high-low). Kruskal-Wallis testing compared the distributions of different variables across the four LISA cluster types. Results: Study explored 82,770 census tracts nationwide. For every 10 percentile increase in Superfund proximity, there was an increase of 4% in cancer risk (p < 0.001). This association was strongest in the Intermountain West, South-Southeast, and Northeast regions. High-high clusters (high proximity to Superfund, high cancer risk) had higher percentage of non-White, low-income, unemployed and lower education attainment populations compared to low-low clusters (all p < 0.001). Within high-high clusters, non-White population had the strongest correlation with proximity to Superfunds. Cancer risk was much higher for the top 10% than the bottom 10% of proximity to Superfunds (Table). Conclusions: Our study highlights higher clustering of cancer risk around neighborhoods with existing Superfund sites. Further, we demonstrate the closer a neighborhood is to a Superfund site, the greater the cancer risk is with associated sociodemographic changes. Using a novel approach to geospatial analytics, the results demonstrate the first clear evidence of a dangerous association between Superfunds and healthcare, and encourage the urgent prioritization of Congressional policies that optimize investment in Superfund site clean up for public health. [Table: see text]

Social determinants of health and treatment outcomes among a retrospective cohort of patients receiving immunotherapy for cancer.

e13744 Background: Disparities due to socioeconomic status persist in the treatment of cancer. Newer therapies, such as immune checkpoint inhibitors (ICIs), offer easier administration, lower risk of toxicity, and may improve accessibility compared to cytotoxic chemotherapy. Prior studies on ICI outcomes have shown mixed results at the county level, and there is a need to investigate social determinants of health at a more granular level. Our study aims to compare long-term ICI outcomes between socioeconomic groups at the census tract level among patients with cancer. Methods: The investigators compiled data from 2/1/2011 to 4/7/2022 on patients who received at least one dose of an ICI at a comprehensive cancer center and its outreach clinics to create a retrospective patient registry. Investigators used a secure, cloud-based REDCap registry, validated it with data quality rules, and resolved discrepancies. Clinical research specialists at Vasta Global captured most of the data. Investigators correlated patients’ ZIP codes with 2010 US Department of Agriculture Rural-Urban Commuting Area (RUCA) classifications and census tracts with 2020 Center for Disease Control Social Vulnerability Index (SVI) data. The univariate analyses used the ANOVA or Kruskal-Wallis tests, chi-square tests, and Kaplan-Meier methods. The multivariate analyses used Cox and logistic regressions, adjusting for age, race, ethnicity, type of cancer, smoking status, age-adjusted Charlson Comorbidity Index, and other comorbidities. Results: Our cohort consisted of 1,807 patients who were an average of 66 years old, predominantly male (60.8%), white (84%), non-Hispanic (98%), and had lung cancer (45.1%) as the most common tumor type. Univariate analyses found no associations between either RUCA or SVI and overall survival (OS), progression-free survival (PFS), immune-related adverse events (irAE), or time to irAE. For RUCA, multivariate analysis found that rural location of residence was associated with shorter PFS (all covariates, p 0.0386). For SVI, multivariate analysis showed no significant association with OS, PFS, number of irAEs, or time until irAE (including high-grade irAEs). Conclusions: Rural residence by ZIP code was associated with shorter PFS, indicating that there may be decreased access to ICI for these patients. However, the overall findings suggest similar ICI treatment outcomes across patients with widely variable social determinants of health by census tract. Further research is needed to understand how newer therapies can be best positioned to overcome disparities in cancer care.

The Prevalence of Pretransplant Frailty and Mental Distress in Hematopoietic Cell Transplantation and Association with Clinical Outcomes

Frailty is a phenotype of decreased physiologic reserve associated with increased risk of toxicities and nonrelapse mortality (NRM) in hematopoietic cell transplant (HCT) recipients. The incidence, predictors, and adverse effects of pre-HCT frailty are not well known. We evaluated the association of pre-HCT frailty, defined using Fried's criteria, with age and baseline characteristics in patients ≥18 years undergoing autologous (auto) or allogeneic (allo) HCT for hematological malignancies. Assessments were performed as part of routine pre-HCT evaluations and then retrospectively analyzed. We additionally investigated the association of mental health distress indicators with frailty and the association between frailty and transplant outcomes including NRM and overall survival (OS) plus healthcare utilization. Patients undergoing HCT for hematological malignancies were analyzed (total n = 300; 162 auto, 138 allo). The overall prevalence of frailty was 18%, 21.7% among alloHCT, and 14.8% among autoHCT recipients, with similar distributions of frailty domains. Logistic regression analysis of the overall cohort revealed that older age was associated with an increased risk of frailty (odds ratio [OR] 1.37, 95% confidence interval [CI] [1.02-1.82]; P = 0.04). AlloHCT (OR 2.03, CI [1.07-3.84]; P = .03), and patient health questionnaire-9 (PHQ-9) (health depression) score ≥10 (OR 6.28, CI 1.93-20.43; P < .01) were each independently associated with pre-HCT frailty. In alloHCT patients, older age (OR 1.44, CI [1.00-2.06]; P = .05) was the only significant risk factor for pre-HCT frailty, while for autoHCT patients, only a higher PHQ-9 score was associated with frailty (OR 6.43, CI [1.34-30.82]; P = .02). For the whole cohort OS at 1 year was lower in frail recipients at 83% (95% CI, 70-91%) versus 92% (95% CI, 88-95%) in nonfrail (P = .04); with multivariate analysis showing higher risk of death in the frail group (hazard ratio [HR] 2.31, CI 0.97-5.46; P = .06). In the alloHCT cohort, multivariate analysis showed greater 1-year mortality in frail recipients (HR 2.55, CI [0.99-6.56]; P = .053). In the alloHCT recipients, we observed a 1-year NRM of 20% in frail patients versus 9% in nonfrail, and multivariate analysis showed a marginally higher risk of NRM in the frail group (HR 2.70, CI 0.90-8.10; P = .08). Frailty was not associated with higher risk of relapse in alloHCT or autoHCT recipients. Frail alloHCT patients experienced a longer initial hospital stay following HCT compared to nonfrail recipients (P < .01). We observed a high prevalence of pre-HCT frailty across all age groups, and identify older age is a risk factor for frailty, particularly in alloHCT recipients. Frailty is associated with a greater risk of NRM and lower survival which needs investigation in a larger cohort. Frailty associates with greater HCT complexity suggesting a need for early assessments and targeted interventions for this vulnerable population. Our findings suggest the utility of frailty and mental distress screening along with multidisciplinary interventions in pre-HCT to limit the morbidity of HCT.

The anti-infective effect of β-glucans in children.

Background: β-glucans are bioactive β-D-glucose polysaccharides of natural origin, presenting antimicrobial and immunomodulation properties, with a low risk of toxicity. Objectives: This scoping review aims to present the current knowledge on the anti-infective properties of β-glucans in the pediatric population. Methods: We used the PRISMA Extension for Scoping Reviews Checklist to prepare this review. Studies were identified by electronic searches of Pubmed, Embase, and Cochrane databases up to May 2021. Results: The primary search allowed us to find 6232 studies, twelve of which were finally included in the analysis. Eight studies were designed as randomized, placebo-controlled trials, while in four studies the intervention outcome was compared with the pre-intervention period in the same group. The type of preparation and doses varied between studies: in five trials pleuran was administered (in dose 10 mg/5 kg of body weight/day), and in one study baker's yeast β-glucan was used (in two doses: 35mg/day and 75 mg/day). In six other studies, the analyzed preparation comprised β-glucan and other substances. The shortest study lasted seven days, while the most prolonged intervention lasted six months, followed by six months of follow-up. Ten out of twelve trials demonstrated the effectiveness of β-glucans in reducing respiratory tract infection incidence or alleviation of upper respiratory tract infection symptoms. Ten out of twelve studies have reported a good tolerance and safety profile. Conclusions: Good tolerance of β-glucans shows a favorable benefit-risk ratio of this type of intervention. Nevertheless, further monitoring of their efficacy and safety in high-quality research is necessary.

Accuracy of a mobile sensor-based system for the detection of chemotherapy toxicity in older adults with cancer.

1515 Background: Older adults receiving chemotherapy (CT) are at a high risk of toxicity (Tox) and of functional decline. Promptly acting upon CT Tox in older adults is difficult, particularly in developing countries where triage systems and personnel are limited. We previously showed that monitoring older patients using an accelerometer-equipped smartphone is feasible, and that a decline in the number of steps/day may represent a marker of Tox. We aimed to evaluate the diagnostic accuracy of an objective patient-centered measure of physical function (steps/day) for the remote detection of Tox in older adults receiving CT. Methods: We included consecutive patients aged ≥65 years starting first line CT for solid tumors at a single center in Mexico City. Patients underwent a geriatric assessment and were provided with an accelerometer-equipped smartphone. Daily steps were recorded for ≥7 days pre-CT initiation, and median number of pre-CT steps/day was calculated. Patients with ≤600 median pre-CT steps/day, and those using walking aids, were excluded (16% of recruited patients). Steps were monitored daily, compared with median pre-CT steps/day, and % decline was calculated. Patients were called daily, and Tox was assessed using PRO-CTCAE questionnaires. The % decline in steps/day from pre-CT was considered as the index test for Tox, while patient report was considered the reference standard. The association between % step decline and moderate/severe Tox was examined using generalized linear-mixed models. AUC was calculated and Youden’s index used to choose cutoff points for Tox detection. Results: 116 patients were included (96 development cohort, 20 validation cohort). Median age was 73y (range 65-91), 55% were female, and 65% had ≤high school education. The most common tumors were colon (21.5%), pancreas (17.5%), and gastric (12%). 28% of participants had never used a smartphone. The median number of pre-CT steps/day was 2979. Patients were followed for 6764 days, with Tox detected on 64.4% of days. Moderate/severe self-reported toxicity was detected on 1245 days (22.1%), while mild/no toxicity was detected on 4378 days (77.9%). AUC analysis for the development cohort demonstrated that a 32% decrease in steps/day from pre-CT median showed a sensitivity of 77.6% and a specificity of 67.3% for detecting moderate/severe Tox. Sensitivity and specificity of the cutoff in the validation cohort were 75.8% and 69.6%, respectively. Tox associated with a decline in steps/day included fatigue, pain, and nausea. Conclusions: A decline in the number of steps/day measured using an accelerometer-equipped smartphone was useful for the remote detection of moderate/severe Tox in older adults with cancer receiving CT, with a high sensitivity and specificity. This patient-centric measure could be used in clinical practice and research to detect and act promptly on Tox and, potentially, improve outcomes.

Tailoring Therapy in Older Adults With Hematologic Malignancies.

Hematologic malignancies most often present in the sixth or seventh decade of life. Even so, many older adults may be unable to tolerate standard chemotherapy or require supplementary care or dose adjustments to do so. Both in community and academic centers, geriatric assessment (GA) can be used to improve the care of older adults with blood cancers. For example, hematologic oncologists can use GA to guide treatment selection, adjusting for patient frailty and goals, as well as prompt initiation of enhanced supportive care. After initial therapy, GA can improve the identification of older adults with aggressive myeloid malignancies who would benefit from hematopoietic cell transplantation (HCT), inform shared decision making, as well as allow transplanters to tailor conditioning regimen, donor selection, graft-versus-host disease prophylaxis, and pre- and post-HCT treatments. As in HCT, GA can improve the care of older patients with relapsed lymphoma or multiple myeloma eligible for chimeric antigen receptor-T therapy, identifying patients at higher risk for toxicity and providing a baseline for subsequent neurocognitive testing. Here, we review the data supporting GA for the care of older adults with blood cancers, from the community to the academic center. In addition, we explore future directions to optimize outcomes for older adults with hematologic malignancies.

Patient-reported fatigue and risk of treatment-related adverse events (AEs) in patients receiving systemic therapy in cancer clinical trials.

11015 Background: Fatigue in patients with cancer is common and negatively impacts quality of life. Patient-reported outcomes (PROs) assess a patient’s direct report of their symptoms and well-being; research has highlighted their potential to predict cancer outcomes. We examined whether fatigue prior to treatment was associated with AEs. Methods: We analyzed 18 phase II and III cancer treatment clinical trials with baseline fatigue data conducted by SWOG between 1988-2018. The Common Terminology Criteria for Adverse Events was used. Symptomatic AEs were defined as those aligned with the NCI’s PRO-CTCAE; laboratory-based or measurable AEs were designated as objective (hematologic v nonhematologic). Thirteen symptomatic and 14 objective AE categories were examined. Fatigue was derived from multiple scales (e.g., FACT, EORTC QLQ-C30 and PROMIS-Fatigue 7a). Each measure was mapped to a 5-point Likert scale. Binary categories were compared (e.g., &lt; some vs. &gt; = some fatigue). Generalized estimating equations were used with a binomial distribution and logit link, adjusting for age, sex, race, and BMI, with clustering by study. Results: We examined N = 8,040 patients receiving systemic therapy. Among 18 trials (prostate, 5; lung, 3; colorectal, 2; lymphoma, 2; breast, 2; bladder, 1; melanoma, 1; ovarian, 1, pancreas, 1), n = 108,059 AEs were examined. Patient fatigue was present at levels of “a little” or greater in 75.8%, “some” or greater in 42.8%, and “quite a lot” or “very much” in 17.7%. Patients with some or greater fatigue were nearly twice as likely to have severe or worse toxicity (OR = 1.92, 95% CI, 1.53-2.40, p &lt; .001) or life-threatening toxicity (OR = 1.93, 95% CI, 1.44-2.59, p &lt; .001) and nearly threefold more likely to have fatal toxicity (OR = 2.76, 95% CI, 1.37-5.53, p = .004). Similar patterns were seen at a threshold of “quite a lot”. A dose response pattern was evident; patients reporting quite a lot/very much compared to no fatigue were &gt; 5 times more likely to experience fatal toxicity (OR = 5.63, p = .002). These patterns were consistent in symptomatic, objective hematologic, and objective non-hematologic AEs. Conclusions: Baseline fatigue was highly predictive of subsequent risk of AEs. These findings suggest that in an era of precision medicine, patient-reported fatigue may be an important component of determining toxicity risk and could aid in treatment decision making.[Table: see text]

SB221: A proof-of-concept study to assess the combination of SON-1010 (IL12-FHAB) and atezolizumab in patients with platinum-resistant ovarian cancer.

TPS5629 Background: Recombinant interleukins (rIL) have had limited clinical success due to inefficient tumor targeting and short PK, requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 potently activates T and NK cells to produce IFNγ and kill tumor cells, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. We developed a novel platform that delivers immunomodulator(s) linked to a fully-human albumin binding (FHAB) domain (Cini, Front Immunol 2023). Single-chain native IL-12 genetically linked to the FHAB provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC in the tumor microenvironment (TME), with an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Tumor growth inhibition in an immunologically ‘cold’ B16-F10 mouse melanoma model showed the efficacy of IL12-FHAB compared with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. SON-1010 is being studied clinically as monotherapy (study SB101) in advanced solid tumors and in healthy volunteers (study SB102) (Chawla, AACR 2023). Atezolizumab (Tecentriq), an anti-PD-L1 immune checkpoint inhibitor (ICI), has shown preliminary clinical activity in Phase 1 studies of patients with platinum-resistant ovarian cancer (PROC) (Liu, Gyn Onc 2019; Moroney, Clin Canc Res 2020). SON-1010 may ‘warm up’ the TME to improve ICI effectiveness in these immunologically-active tumors that have high levels of SPARC. Methods: Study SB221 is a Phase 1b/2a multicenter, dose-escalation and proof-of-concept study to assess the safety, tolerability, PK, PD, and efficacy of SON-1010 administered SC, either alone or in combination with a fixed dose of atezolizumab given IV (NCT05756907). The study is designed in Part 1 to rapidly establish the maximum tolerated dose (MTD) of the combination in patients with advanced solid tumors with up to 5 dose-escalation groups and to expand the dataset using patients with PROC to establish the Recommended Phase 2 Dose (RP2D). Once the likelihood of efficacy is shown in a Simon 2-stage design, this will be followed in Part 2 by an assessment of the potential for improved efficacy of the combination in patients with PROC over SON-1010 alone or the standard of care (SOC). The first dose-escalation cohorts have been enrolled and additional sites are being added to help with recruitment of patients with PROC. Combination of SON-1010 with an ICI offers a unique opportunity to use this extended PK version of IL-12 to augment the potential for tumor control in PROC, which represents a significant unmet medical need. Clinical trial information: NCT05756907 .

Multi-Elemental Characterization of Soils in the Vicinity of Siderurgical Industry: Levels, Depth Migration and Toxic Risk

Multi-Elemental Characterization of Soils in the Vicinity of Siderurgical Industry: Levels, Depth Migration and Toxic Risk

The estimation and translation uncertainties in applying NOAEL to clinical dose escalation.

The systemic exposure at the no-observed-adverse-effect-level (NOAEL) estimated from animals is an important criterion commonly applied to guard the safety of participants in clinical trials of investigational drugs. However, the discrepancy in toxicity profile between species is widely recognized. The objective of the work reported here was to assess, via simulation, the level of uncertainty in the NOAEL estimated from an animal species and the effectiveness of applying its associated exposure value to minimizing the toxicity risk to human. Simulations were conducted for dose escalation of an investigational new chemical entity with hypothetical exposure-response models for the dose-limiting toxicity under a variety of conditions, in terms of between-species relative sensitivity to the toxicity and the between-subject variability in the key parameters determining the sensitivity and pharmacokinetics. Results show a high uncertainty in the NOAEL estimation. Notably, even when the animal species and humans are assumed to have the same sensitivity, which may not be realistic, limiting clinical dose to the exposure at the NOAEL that has been identified in the animals carries a high risk of either causing toxicity or under-dosing, hence undermining the therapeutic potential of the drug candidate. These findings highlight the importance of understanding the mechanism of the toxicity profile and its cross-species translatability, as well as the importance of understanding the dose requirement for achieving adequate pharmacology.

Results of ponatinib as frontline therapy for chronic myeloid leukemia in chronic phase.

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n=34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.

Potentially Toxic Elements Risk Assessment and Source Identification of an At-Risk International Wetland in SW Iran

Potentially Toxic Elements Risk Assessment and Source Identification of an At-Risk International Wetland in SW Iran

Impact of Comorbidities and Drug Interactions in Patients With Metastatic Castration-Resistant Prostate Cancer Receiving Androgen Receptor Pathway Inhibitors.

Androgen receptor pathway inhibitors (ARPIs) are widely prescribed in metastatic castration-resistant prostate cancer (mCRPC). Real-world frequencies and potential impacts of comorbidities and concomitant medication (conmed) interactions with ARPIs are not well described. Patients receiving ARPIs for mCRPC were identified from the electronic Prostate Cancer Australian Database (ePAD). Demographics, clinicopathologic characteristics, and outcome data were extracted. Conmeds and comorbidities were collected from medical records. Potential interacting comorbidities were defined from trial and post-trial data. Clinically significant drug-drug interactions (DDIs) were identified using UpToDate Lexicomp and Stockley's databases. Patient characteristics, comorbidity interactions, DDIs, and outcomes were analyzed. Two hundred thirty-five patients received first- or second-line ARPIs for mCRPC from 2012 to 2021, with a median follow-up of 27 months. One hundred sixteen received abiraterone acetate (AAP) and 135 received enzalutamide (ENZ). The median age was 74 years, and the median number of conmeds was 4. Clinically significant DDIs occurred in 55 (47%) AAP patients and 90 (67%) ENZ patients. Only 5% of DDIs were predicted to affect ARPI pharmacokinetics (PK) or pharmacodynamics, whereas 95% were predicted to impact conmed PK or increase toxicity risk. In patients receiving ENZ, DDIs were associated with lower PSA50 (50% v 74%, P = .04) and poorer overall survival (28 v 45 months, P = .04), although statistical significance was not maintained on multivariate analysis. No significant survival differences were seen with DDIs in patients receiving AAP. Potential interactions between comorbidities and ARPI were present in 72% on AAP and 14% on ENZ with no significant associated survival differences. DDIs and drug-comorbidity interactions in real-world patients receiving ARPIs for mCRPC are common and may affect outcomes. Ongoing clinician education regarding DDIs is necessary to optimize patient outcomes.

Toxicity assessment of dioxins and their transformation by-products from inferred degradation pathways

Due to the significant POPs characteristics, dioxins caused concern in public health and environmental protection. Evaluating the toxicity risk of dioxin degradation pathways is critical. OCDD, 1,2,3,4,6,7,8-HpCDD, and 1,2,3,4,6,7,8-HpCDF, which are highly abundant in the environment and have strong biodegradation capabilities, were selected as precursor molecules in this study. Firstly, their transformation pathways were deduced during the metabolism of biometabolism, microbial aerobic, microbial anaerobic, and photodegradation pathways, and density function theory (DFT) was used to calculate the Gibbs free energy to infer the possibility of the occurrence of the transformation pathway. Secondly, the carcinogenic potential of the precursors and their degradation products was evaluated using the TOPKAT modeling method. With the help of the positive indicator (0–1) normalization method and heat map analysis, a significant increase in the toxic effect of some of the transformation products was found, and it was inferred that it was related to the structure of the transformation products. Meanwhile, the strength of the endocrine disrupting effect of dioxin transformation products was quantitatively assessed using molecular docking and subjective assignment methods, and it was found that dioxin transformation products with a higher content of chlorine atoms and molecules similar to those of thyroid hormones exhibited a higher risk of endocrine disruption. Finally, the environmental health risks caused by each degradation pathway were comprehensively assessed with the help of the negative indicator (1–2) standardization method, which provides a theoretical basis for avoiding the toxicity risks caused by dioxin degradation transformation. In addition, the 3D-QSAR model was used to verify the necessity and rationality of this study. This paper provides theoretical support and reference significance for the toxicity assessment of dioxin degradation by-products from inferred degradation pathways.