Risk Of Toxicity Research Articles

MB2033, an anti-PD-L1 × IL-2 variant fusion protein, demonstrates robust anti-tumor efficacy with minimal peripheral toxicity

Interleukin-2 (IL-2), a cytokine with pleiotropic immune effects, was the first approved cancer immunotherapy agent. However, IL-2 is associated with systemic toxicity due to binding with its ligand IL-2Rα, such as vascular leakage syndrome, limiting its clinical applications. Despite efforts to extend the half-life of IL-2 and abolish IL-2Rα interactions, the risk of toxicity remains unresolved. In this study, we developed the bispecific fusion protein MB2033, comprising a novel IL-2 variant (IL-2v) connected to anti-programmed death ligand 1 (PD-L1) via a silenced Fc domain. The IL-2v of MB2033 exhibits attenuated affinity for IL-2Rβγ without binding to IL-2Rα. The binding affinity of MB2033 for PD-L1 is greater than that for IL-2Rβγ, indicating its preferential targeting of PD-L1+ tumor cells to induce tumor-specific immune activation. Accordingly, MB2033 exhibited significantly reduced regulatory T cell activation, while inducing comparable CD8+ T cell activation to recombinant human IL-2 (rhIL-2). MB2033 induced lower immune cell expansion and reduced cytokine levels compared with rhIL-2 in human peripheral blood mononuclear cells, indicating a decreased risk of peripheral toxicity. MB2033 exhibited superior anti-tumor efficacy, including tumor growth inhibition and complete responses, compared with avelumab monotherapy in an MC38 syngeneic mouse model. In normal mice, MB2033 was safer than non-α IL-2v and tolerable up to 30 mg/kg. These preclinical results provide evidence of the dual advantages of MB2033 with an enhanced safety and potent clinical efficacy for cancer treatment.

Incidence of post-dural lumbar puncture headache (PDLPH) in comparison between emergency and elective lower segment cesarean section (LSCS) with 26G Quincke-Babcock cutting-beveled spinal needle.

C-section is usually performed under spinal anesthesia also known as a subarachnoid block (SAB) over general anesthesia. Because of the lesser amount of dose used, there is a lower risk of local anesthetic toxicity and minimal transfer of drugs to the fetus. Obstetric patients have a higher risk of having post-dural puncture headache (PDPH). PDPH occurs due to leakage of the cerebrospinal fluid (CSF) through the hole created by a spinal needle. There are many elements affecting the frequency of PDPH, these elements can also consist of age, female sex, needle size, and types, pregnancy, preceding records of PDPH, median-paramedian distinction in approach, a puncture level. PDPH is commonly in the form of a frontal, occipital, or retro-orbital headache that starts in 12-72 h after the dural puncture and will increase when standing and decrease when lying down or resting. We aimed to learn about headache frequency between elective and emergency lower segment cesarean section using 26-G Quincke spinal needle in full-term pregnant patients. To study the incidence of PDPH using the 26G Quincke spinal needle. To analyze the causal factors/determinants such as adequate preloading of fluids, size of spinal needle, number of pricks, and technique of lumbar puncture effects on the incidence of PDPH. This study is a prospective questionnaire-based comparative observational study using the convenience sampling method. The patients were interviewed with a structured questionnaire at the Symbiosis University Hospital and Research Centre, Lavale, Pune. The patients observed for the study were between 20 and 40 of age group, posted for emergency or elective lower segment cesarean section, with body mass index (BMI) less than 14.5 to 24.9 and with ASA I and II grades. Patients with any comorbidities, recurrent headaches, obesity, and spine deformity were excluded. According to the review of the literature and with the help of a formula, the sample size was calculated as 20; 10 patients for elective LSCS, and 10 patients for emergency LSCS. Out of 20 patients, 10 patients were posted for elective LSCS, and the rest 10 patients were for emergency LSCS under spinal anesthesia. The incidence of PDPH was found only in 2 out of 10 emergency LSCS patients, and no patients from elective LSCS cases showed up with the incidence of PDPH.

A scoping review of the toxicity and health impact of IQOS.

This work aims to summarize the current evidence on the toxicity and health impact of IQOS, taking into consideration the data source. On 1 June 2022, we searched PubMed, Web of Science, and Scopus databases using the terms: 'heated tobacco product', 'heat-not-burn', 'IQOS', and 'tobacco heating system'. The search was time-restricted to update a previous search conducted on 8 November 2021, on IQOS data from 2010-2021. The data source [independent, Philip Morris International (PMI), or other manufacturers] was retrieved from relevant sections of each publication. Publications were categorized into two general categories: 1) Toxicity assessments included in vitro, in vivo, and systems toxicology studies; and 2) The impact on human health included clinical studies assessing biomarkers of exposure and biomarkers of health effects. Generally, independent studies used classical in vitro and in vivo approaches, but PMI studies combined these with modeling of gene expression (i.e. systems toxicology). Toxicity assessment and health impact studies covered pulmonary, cardiovascular, and other systemic toxicity. PMI studies overall showed reduced toxicity and health risks of IQOS compared to cigarettes, but independent data did not always conform with this conclusion. This review highlights some discrepancies in IQOS risk assessment regarding methods, depth, and breadth of data collection, as well as conclusions based on the data source.

Effect of Pesticides on Human Health and Biodiversity: A Comprehensive Insight

Pesticides, whether naturally occurring or chemically synthesized, serve to combat various pests across sectors such as food production, forestry, agriculture, and aquaculture, but they also pose risks of toxicity to ecosystems. The World Health Organization classifies pesticides based on their harmful effects, underscoring the importance of public health considerations. By employing them judiciously and understanding their categorization, their usage can be minimized for the benefit of both human health and the environment. This review examines global perspectives on pesticides, including their distribution and environmental impacts, while literature highlights their potential uses, classification and adverse effects on natural systems, water, plants, human health and food preservation. Additionally, eco-friendly management strategies, like bacterial degradation, myco-remediation, phytoremediation, and microalgae-based bioremediation, are discussed as green solutions to mitigate pesticide pollution. The identification of potent microbes, novel genes and biotechnological applications for pesticide waste management is crucial for fostering a sustainable environment.

Real-world clinical outcomes and prognostic factors of olaparib maintenance in Korean patients with primary or recurrent high-grade ovarian cancer with exploratory analysis of location of BRCA1 and BRCA2 mutations.

e17561 Background: Olaparib is approved for first-line (1L) and second or subsequent-line (2L+) maintenance therapy in BRCA-mutated ovarian cancer (OC). However, the correlation between location of BRCA mutation and benefit of olaparib maintenance therapy has not been thoroughly investigated. We aimed to analyze real-world clinical outcomes and identify prognostic factors for olaparib maintenance therapy in Korean patients with BRCA-mutated OC, focusing on BRCA mutation sites. Methods: This retrospective cohort study included Korean patients with BRCA-mutated OC who received olaparib as 1L or 2L+ at the single center between January 2015 and April 2023. Survival outcomes and toxicity were correlated with BRCA mutation location summaries and patient characteristics by maintenance therapy line. Results: For the 1L group (n = 70), 2-year PFS and 3-year OS were 75.5% (95% CI, 56.4–87.1) and 98.5% (95% CI, 90.0–99.8). For the 2L+ group (n = 83), 2-year PFS and 3-year OS were 54.8% (95% CI, 56.4–87.1) and 87.3% (95% CI, 76.7–93.3). Primary stage (IV vs. ≤ III) was a prognostic factor for PFS in the 1L group (adjusted hazard ratio [aHR], 5.74; 95% CI, 1.23–26.73; P = 0.026). Notably, Korean-specific pathogenic variant p.Leu1780Pro BRCA1 mutation carriers (n= 8) showed significantly worse PFS than non-carriers (n = 32) in the 1L group (Log-rank P = 0.014). For the 2L+ group, platinum-free interval ≥ 12 months was a good prognostic factor for both PFS (aHR, 0.42; 95% CI, 0.23–0.75) and OS (aHR, 0.31; 95% CI, 0.11–0.91). Additionally, somatic BRCA1 mutation was a poor prognostic factor for PFS in the 2L+ group (hazard ratio [HR], 3.39; 95% CI, 1.22–9.38; P = 0.029). In the 1L group, the longer interval between the last chemotherapy and maintenance therapy was associated with the lower risk of hematologic toxicity induced by olaparib (odd ratio [OR], 0.75; 95% CI 0.57–0.99; P = 0.04). In addition, age ≥ 65 years (OR, 3.33; 95% CI, 1.05–10.63; P = 0.04) and the dose reduction of the last chemotherapy (OR, 3.80; 95% CI, 1.02–14.18; P = 0.047) were associated with a higher risk of hematologic toxicity in the 1L group. In the 2L+ group, germline BRCA1 (OR, 0.36; 95% CI, 0.14–0.92; P = 0.03) and BRCA2 (OR, 7.47; 95% CI, 1.96–28.39; P = 0.003) mutations showed contrariwise risks for hematologic toxicity. Drug discontinuation due to toxicity was 1.4% and 6.0% in the 1L and the 2L+ groups and no acute myeloid leukemia/myelodysplastic syndrome cases were observed. Conclusions: Olaparib maintenance therapy was effective and tolerable in Korean patients with BRCA-mutated OC. Prognostic factors for survival outcomes and risk factors of hematologic toxicity in olaparib maintenance therapy were different between 1L and 2L+. The prognostic significance of Korean-specific p.Leu1780Pro BRCA1 mutation on olaparib should be further researched.

Conditional Risk and Predictive Factors Associated With Late Toxicity in Patients With Prostate Cancer Treated With External Beam Radiation Therapy Alone in the Randomized Trial RTOG 0126

The objective of this study was to characterize the conditional risk of developing grade 2+ urinary or gastrointestinal (GI) toxicity for patients treated with external beam radiation therapy in Radiation Therapy Oncology Group 0126. A secondary objective was to analyze baseline patient and treatment characteristics and determine their relevance in predicting toxicity both at the time of trial enrollment and at later points of follow-up. One thousand five hundred thirty-two patients with localized prostate cancer were enrolled between March 2002 and August 2008, of whom 1499 were eligible and included in data analysis with a median follow-up of 8.4 years (range, 0.02-13 years). Patients were treated with either 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy according to institutional practice without the addition of androgen deprivation and randomized to receive either standard-dose radiation therapy of 70.2 Gy or dose-escalated radiation therapy of 79.2 Gy of radiation therapy to the prostate only with standard fractionation. Univariate and multivariate analyses were performed to determine whether initial factors were predictive of late toxicity at the time of treatment and at later time points. As patients proceed further from completion of radiation therapy without the development of toxicity, the subsequent risk of both grade 2+ genitourinary (GU) and GI toxicity decreases with time. At the time of enrollment, the risk of developing grade 2+ toxicity over the next 5 years was 9.57% and 17.89%, respectively. After 5 years of toxicity-free survival, the risk of developing grade 2+ GU or GI toxicity in the subsequent 5 years was 3.02% and 1.54%, respectively. Baseline treatment and patient-related factors predicted late toxicity both at trial enrollment and after 2 years of toxicity-free survivorship. Baseline urinary dysfunction and dose-escalated radiation therapy were associated with increased late GU toxicity. Acute GI toxicity and dose-escalated radiation therapy were associated with increased risk of late GI toxicity. Treatment with intensity-modulated radiation therapy was associated with reduced risk of either toxicity. The conditional risk of grade 2+ toxicities decreases as patients proceed further from treatment, with most toxicities occurring in the first few years after treatment completion. Baseline patient and treatment characteristics remain relevant at both enrollment and later time points.

Real-World Impact of an In-House Dihydropyrimidine Dehydrogenase (DPYD) Genotype Test on Fluoropyrimidine Dosing, Toxicities, and Hospitalizations at a Multisite Cancer Center.

Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively (P = .085); 64%, 25%, and 13% were hospitalized (P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients (P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups (P < .001), with reactive carriers having the earliest onset and highest incidence. DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

Tumor Control Probability and Time-Dose-Response Modeling for Stereotactic Radiosurgery of Uveal Melanoma

IntroductionUveal melanoma (UM), while a rare malignancy, stands as the most prevalent intraocular malignancy in adults. Controversies persist regarding the dose dependency of local control (LC) through radiotherapy. This study seeks to elucidate the significance of the prescription dose by employing time-dose response models for UM patients receiving photon-based stereotactic radiosurgery (SRS). Materials and MethodsInclusion criteria comprised UM patients treated between 2005 and 2019. All patients underwent single-fraction SRS. Datapoints were separated into three dose groups, with Kaplan-Meier analysis performed on each group, from which time-dose response models for LC were created at 2, 4, and 7 years using maximum-likelihood fitted logistic models. ResultsOutcomes from 594 patients with 594 UM were used to create time-dose response models. The prescribed doses and the number of patients were as follows: 17-19 Gy (24 patients), 20 Gy (122 patients), 21 Gy (442 patients), and 22 Gy (6 patients). Averaged over all patients and doses, LC rates at 2, 4, and 7 years were 94.4%, 88.2%, and 69.0%, respectively. Time-dose response models for LC demonstrated a dose-dependent effect, showing 2-year LC rates of more than 90% with 20 Gy and 95% with 22 Gy. For four years and a LC of 90%, a dose of approximately 21 Gy was required. After seven years, the 21 Gy prescription dose is predicted to maintain a LC above 70%, sharply declining to less than 60% LC with 19 Gy and less than 40% with 18 Gy. ConclusionIn contrast to prior findings, the time-dose response models for UM undergoing photon-based SRS emphasize the critical role of the prescription dose in achieving lasting LC. The dose selection must be carefully balanced against toxicity risks, considering tumor geometry and individual patient characteristics to tailor treatments accordingly.

Soil pollution and elemental sources along Barapukuria coal mine, Bangladesh: Implications for eco-environmental and health risk assessment

For the first time, different pollution indices and a receptor model have been used to quantify eco-environmental and health risk assessments as well as identify the sources of potentially toxic elements in soil along the Barapukuria Coal Mine (BCM). Individual indices include enrichment and contamination factors showing the soil samples are moderately to highly contaminated by arsenic, cobalt, chromium, copper, lead, and zinc and heavily contaminated by sulfur. According to the geo-accumulation index, there is significant pollution with arsenic (1.24 ± 0.38), lead (1.49 ± 0.58), cobalt (1.49 ± 0.58), and sulfur (1.63 ± 0.38). Modified hazard quotient and ecological risk factor values also suggest low to moderate environmental risk hazards from the same elements. The nemerow pollution index, pollution load index, nemerow risk index, ecological risk index, and toxic risk index of soil range from 1.65 to 3.03, 0.82–1.23, 11–26, 77–165, and 6.82–11.76 suggest low toxic risk and moderate pollution, among other synergistic indices. Health risk assessment indicates that iron poses lower cancer risk for children than adults, while both face unacceptable cancer risks from inhaling chromium, cobalt, or arsenic. Principal component and phylogenetic cluster analysis extracted by the multiple linear regression with the absolute principal component score (APCS-MLR) model refer to the fact that manganese, iron, titanium, and nickel have originated from geogenic sources, while coal mine effluents enrich elements like arsenic, chromium, zinc, lead, uranium, sulfur, thorium, and zinc and phosphorous sourced from agriculture. In addition, geogenic and anthropogenic sources, including mine and agriculture activities, could potentially pollute the soil and ecosystem. The findings are crucial for regional and national planners in devising strategies to mitigate potentially toxic element pollution in soil along coal mine areas.

A randomised phase 2 study of liposomal irinotecan in combination with 5-fluorouracil/leucovorin and oxalipalatin versus nab-paclitaxel plus gemcitabine in unresectable locally advanced or metastatic pancreatic cancer.

4141 Background: FOLFIRINOX remained as first-line standard of care. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery. Liposomal irinotecan (HE072) is a liposomal formulation that encapsulates irinotecan in a lipid bilayer vesicle, as a generic drug, had been approved for marketing in China on September 15, 2022, and was used in combination with 5-fluorouracil (5-FU) and leucovorin for patients with metastatic pancreatic cancer who progressed after receiving gemcitabine treatment. This study aims to compare with nab-paclitaxel+gemcitabine (AG), which is another first-line stand of care, through substitute HE072 for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective delivery. Methods: HE072-CSP-004 was a randomised, open-label, multi-center, phase 2 study. Patients with unresectable locally advanced or metastatic pancreatic cancer were randomly assigned (2:1) to receive NALIRIFOX (HE072 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m², administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or AG (nab-paclitaxel 125 mg/m² and gemcitabine 1000 mg/m²), administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Other key eligibility criteria include ECOG performance status of 0 to 1, untreated with systematic anti-tumor regimens; Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and duration of response (DOR). Results: As of Dec 12, 2023, 117 patients were randomly assigned (NALIRIFOX, 78; AG, 39). The two groups were comparable on baseline characteristics. The median PFS differences was statistically significant as 7.6 months (95%CI 5.49-9.17) with NALIRIFOX versus 3.7 months (95%CI 3.15-5.06) with AG (hazard ratio 0.55; 95% CI 0.34-0.87; p=0.0104). Median OS was 13.4 months (95%CI 9.89-NE) with NALIRIFOX versus 8.8 months (95%CI 6.87-12.16) with AG (hazard ratio 0.66; 95% CI 0.39-1.11; p=0.1125). Grade 3 or higher treatment-emergent adverse events (TRAE) occurred in 52 (66.7%) of 78 patients receiving NALIRIFOX and 30 (76.9%) of 39 patients receiving AG. No new safety signal was observed. Conclusions: The study met the primary endpoint of PFS demonstrating statistically significant and clinically meaningful improvements in PFS and with a trend of OS benefit for NALIRIFOX over AG. The safety profile was consistent with the known risks of the individual toxicity. This study is consistent with the existing NAPOLI 3 study. Clinical trial information: NCT05047991 .

BY101921: Restoring interferon signaling and anti-tumor immunity through PARP7 inhibition.

3123 Background: PARP7( TIPARP), a member of monoPARP family, catalyzes ADP-ribose transfer to specific amino acids within itself and other substrate proteins, utilizing nicotinamide adenine dinucleotide (NAD+) as substrate. It plays a vital role in various biological processes such as gene expression, protein degradation, and cellular stress response. PARP7 amplification has been observed in various cancers, including squamous cell carcinoma, ovarian cancer, breast cancer, and pancreatic ductal adenocarcinoma. Over expression of PARP7 correlates with reduced survival in squamous cell carcinoma. PARP7's MARylation of α-tubulin induces microtubule instability, promoting proliferation and migration of ovarian cancer cells. As a negative regulator of tumor cell nucleic acid sensing, PARP7 inhibits TBK1 through. This, in turn, hampers the cGAS-STING signal pathway and downregulates the type Ⅰ interferon expression. BY101921, developed by Chengdu Baiyu Pharmaceutical, is a highly selective PARP7 inhibitor demonstrating significant anti-tumor effect in vitro and in vivo, both alone and in combination with anti-PD-1. Methods: Enzymatic evaluation was conducted on BY101921 to assess its selectivity among major PARP family members. PK studies were investigated in both mouse and dog species. The anti-tumor activity of BY101921, both as a monotherapy and in combo with anti-PD-1, was investigated in NCI-H1373 and CT26 tumor-bearing mice, respectively. In terms of anti-tumor mechanism, pSTAT1, IFN-β and CXCL10 levels were analyzed in RAW264.7 cells and CT26 tumor-bearing tissues. In addition, the effect of BY101921 on the type Ⅰ interferon signaling pathway was systematically evaluated. Results: BY101921 demonstrated outstanding selectivity as a PARP7 inhibitor, displaying limited off-target effects on PARP1/2, reducing the risk of systemic toxicity, especially hematologic effects. In mice and dogs, BY101921 revealed favorable PK characteristics following oral administration. In vivo, BY101921 exhibited potent inhibition of tumor growth as a monotherapy, and its combination with anti-PD-1 further enhanced its anti-tumor efficacy, with excellent tolerability in animals. Mechanism of action studies showed that BY101921 generated an anti-tumor immune response by upregulating pSTAT1 levels and promoting the secretion of IFN-β and CXCL10, thereby restoring the type Ⅰ interferon signaling pathway. Conclusions: BY101921, a potent and selective PARP7 inhibitor, demonstrates significant anti-tumor efficacy both as a monotherapy and in combo with anti-PD-1, while maintaining excellent tolerability in animal models. With favorable drug-like properties and a promising safety profile, BY101921 holds potential as an enhanced therapeutic option for cancer patients. At present, clinical studies investigating BY101921 as a single agent and in combo with anti-PD-1 are in the recruitment phase.

Decade of insights: Bleomycin-induced pneumonitis and use of G-CSF in chemotherapy-treated germ cell testicular tumors and Hodgkin lymphoma—Real-world outcomes from an academic cancer center.

e17013 Background: Bleomycin induced pulmonary toxicity (BIP) occurs in 4-10% of treated patients. Preclinical reports suggest G-CSF use may increase BIP risk, due to neutrophil migration to lung tissues. Limited real-world clinical data is available and G-CSF use may reduce risk of treatment related toxicity with curative bleomycin combination treatment. Methods: We conducted a retrospective study of patients with GCT (Germ cell tumor) and HL (Hodgkin’s lymphoma) receiving bleomycin containing chemotherapy and at-least on dose of G-CSF at The James Cancer Center from 2010-2022 using the institutional database. BIP was diagnosed mainly using clinical symptoms complemented by radiological evidence when possible. We reviewed 361 patients, 145 in GCT group and 216 in HL group and clinically relevant information was recorded.Descriptive statistics for the study variables were presented using frequencies and percentages overall. The bivariate associations between G-CSF use and clinical outcomes were assessed using chi-square tests or fisher’s exact tests for the overall sample, and by chemotherapy type. We used SPSS 26.0 for all the statistical analyses, and an alpha level of 0.05 (two-sided) was used for all the tests. Results: Data on 361 patients, including 145 GCT and 216 HL patients treated with at least one dose of bleomycin was available. The median age was 36.3 years in the GCT group and 44.2 years in the HL group.144 patients in the GCT and 50 patients in the HL group received at least 1 dose of G-CSF. BIP occurred in 4.8% in the GCT and 7.4% of patients in the HL group. Only 2 out of 16 patients developing BIP in the HL group received G-CSF. All patients with BIP developed symptomatic disease. On bivariate analysis, no association was noted between BIP and G-CSF in either group (p-value =1.00 in GCT and p-value = 0.32 in HL). Febrile neutropenia (FN) was reported in 4 patients in the GCT group and 29 in the HL group. In the HL subgroup, 28 (28/29) patients developing FN did not receive G-CSF (p-value=0.0008). All patients who developed FN required hospital admission. Conclusions: Use of G-CSF in patients receiving bleomycin was not associated with an increased incidence of BIP. Incidence of FN was higher in patients not receiving G-CSF leading to hospital admissions. [Table: see text]

Recommendations for the assessment of glomerular filtration rate in patients with cancer: A position statement and systematic review on behalf of the American Society of Onco-Nephrology (ASON).

e24143 Background: Accurate assessment of glomerular filtration rate (GFR) is crucial to guiding drug eligibility, dose-adjusting systemic therapy, and minimizing the risks of both undertreatment and toxicity in patients with cancer. To date, there has been a lack of guidance to standardize approaches to GFR estimation in the cancer population based on the available evidence. We aim to present data on the first systematic review (SR) of GFR estimating equations in patients with cancer. Methods: We conducted a SR on behalf of the American Society of Onco-Nephrology (ASON) on the accuracy of equations to estimate GFR in adult patients with cancer, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We required that studies use a reference methodology as comparator involving measured GFR via urinary or plasma clearance of an exogenous filtration marker or carboplatin. Two search strategies focusing on studies using serum creatinine (Cr) and cystatin C (Cys) were developed. Risk of bias and quality assessment was performed for all studies. Results: A total of 39 studies (21,949 patients in total, 19,025 with solid cancers) were included. Studies assessing populations in Europe were most frequent (50%), followed by Asia (27%) and the remaining from Australia/New Zealand and North and South America. Risk of bias and quality assessment allocated 15 studies (38%) as low or very low quality, and 24 (62%) as low-moderate or moderate quality. The most commonly assessed GFR estimating equations included Cockroft-Gault (32 studies), Modification of Diet Renal Disease (MDRD) (24 studies), Chronic Kidney Disese Epidemiology Collaboration Study (CKD-EPI)Cr (22 studies), Wright (13 studies), CKD-EPICys (8 studies), CKD-EPICr-Cys (8 studies), and Jeliffe (8 studies). Given the importance of accurate and timely eGFR assessment and the evidence supporting the performance (i.e., accuracy) of the CKD-EPI incorporating both Cr and Cys, we suggest the use of this equation in patients with cancer (grade 2C). Where Cys is unavailable, CKD-EPICr is the next preferred equation given the supporting data for its performance and widespread availability. Since included studies were moderate quality or lower, the ASON rated the certainty of evidence as low. Also, additional data on clinical outcomes related to the selection of eGFR equations is needed. We suggest measurement of GFR via an exogenous filtration marker in patients with cancer for whom eGFR results in borderline eligibility for therapies or clinical trials (ungraded). Conclusions: Based on the results of this SR, we suggest use of contemporary methods for estimation of GFR (CKD-EPICr-Cys and CKD-EPICr-Cr) and avoidance of older and less accurate formulae such as Cockcroft-Gault.

A United Kingdom prospective, multicentre, observational cohort study investigating tolerance of anti-cancer systemic therapy in the elderly: The TOASTIE study.

1521 Background: Older adults have a higher risk of developing chemotherapy (CTx) related toxicity. The Cancer Aging Research Group (CARG) score was developed and validated in the USA to predict risk of severe CTx induced toxicity in older adults; subsequent validation studies have had varying results. The TOASTIE study sought to evaluate the CARG score prospectively in a United Kingdom (UK) population. Methods: This multicentre, prospective, observational study recruited patients aged ≥65 years commencing first-line neo-adjuvant, adjuvant or palliative CTx for any solid organ malignancy. Those receiving non-CTx agents were excluded. Baseline demographics and established frailty measures were recorded, including Eastern Cooperative Oncology Group performance status (ECOG PS), Rockwood Clinical Frailty Scale (CFS), Geriatric-8 (G8) score and Charlson Co-morbidity Index (CCI). CARG score was calculated after initial Oncology consultation. Follow-up data including CTCAEv5 toxicity and hospital admissions were collected retrospectively. Results: 19 centres recruited 330 patients between Nov 2019 - Dec 2022. Median age was 73 years (range 65-92) and 51.9% were male. 54.9% had a primary tumour of gastrointestinal origin, 48.7% received CTx with palliative intent and 70.8% received doublet therapy. At baseline, 85% patients had an ECOG PS 0 or 1, with median CFS 3 (range 0-8), G8 score 12 (range 6-16) and CCI 6 (range 2-12). Follow-up data was available for 314 (92.6%) patients; the median CTx cycles received was 4 (range 1-16) with 124 (39%) patients dose reduced at cycle one. Treatment delays occurred in 83 (26.4%) patients and 123 (39.2%) stopped treatment early, with 60 (48.8%) cases due to treatment-related toxicity. 69(22.3%) patients experienced a CTCAE grade ≥3 toxicity and 84 (27%) requiring hospital admission. CARG score was available for 313 patients; 107 (34.2%) low risk, 167 (53.4%) medium risk and 39 (12.5%) high risk. Increasing CARG risk groups had increased toxicity rates (low 19.6%, medium 22.2%, high 28.2%) however this was non-significant with no evidence of robust predictive performance (Table). The performance of CFS and ECOG PS was superior to CARG. Conclusions: In this UK older patient population, baseline frailty was prevalent. CARG score was unable to robustly discriminate or predict risk of high-grade toxicity. ECOG showed superior, albeit limited, ability to predict and discriminate toxicity risk. This study highlights the need for development of further tools predictive of toxicity in this population. [Table: see text]

A phase 1/2 study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.

TPS4626 Background: High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with adjuvant intravesical Bacille Calmette-Guérin (BCG). However, approximately 50% of patients experience recurrence and/or progression after BCG treatment and are considered unresponsive. EG-70 (detalimogene voraplasmid) is an investigational drug product that was specifically engineered for intravesical administration to elicit local stimulation of anti-tumor immune responses in the bladder and drive durable efficacy in patients with BCG-unresponsive NMIBC, while mitigating the risk of systemic toxicities from immune stimulation. The phase 1 (dose-escalation) part of the first-in-human LEGEND (NCT04752722) phase 1/2, open-label, multicenter study of EG-70 in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) is complete: intravesical instillation of EG-70 was well tolerated with an overall complete response (CR) rate of 73%; and the recommended phase 2 dose (RP2D) was identified. Here we describe the ongoing phase 2 part of the study, which opened to enrollment in May 2023. Methods: Patient eligibility criteria: age ≥18 years; ECOG PS 0−2; BCG-unresponsive NMIBC with CIS, with or without resected coexisting papillary tumors, ineligible for, or have elected not to undergo, cystectomy; satisfactory bladder function with ability to retain study drug for ≥60 minutes. Prior checkpoint inhibitor treatment is allowed if completed within 30 days before study entry. Patients are treated with EG-70 at the RP2D (800 µg in 50 mL) by intravesical administration on weeks 1, 2, 5, and 6 of a 12-week cycle, for 4 cycles in one of two cohorts: BCG-unresponsive (Cohort 1); BCG-naïve or BCG-incompletely treated (Cohort 2). Patients in either cohort who exhibit stable disease (SD) or CR at week 12 will continue treatment until week 24; patients with progressive disease (PD) will discontinue treatment. Patients who experience or maintain CR at week 24 will receive additional cycles every 12 weeks until week 48; patients with SD or PD at week 24 will discontinue treatment. Patients with PD at any time after week 24 will discontinue treatment. Phase 2 primary objective: evaluate efficacy (CR rate at week 48) and safety of EG-70. Secondary objectives: evaluate progression-free survival, CR rate at 12, 24, 36 and 48 weeks, and duration of response. The study is being conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and with the principles of the Declaration of Helsinki. All patients provide written informed consent. The ongoing, registration-enabling phase 2 portion of the LEGEND study is anticipated to recruit approximately 100 patients from sites in North America, Europe, and the Asia-Pacific region. Clinical trial information: NCT04752722 .

Immunotherapy for local/regional control of locally advanced orbital and periocular squamous cell carcinoma.

e18034 Background: Periocular squamous cell carcinoma can be of eyelid skin, ocular surface (bulbar) or palpebral conjunctival, or of lacrimal sac/nasolacrimal duct mucosal origin, is relatively rare, and presents unique anatomic considerations due to proximity to the eye and inherent risk to ocular structures associated with high dose radiation therapy. We herein report on 17 patients with orbital or periocular SCC who were treated with immunotherapy (IO) to decrease surgical morbidity or to avoid high dose radiation therapy. Methods: Retrospective review of all previously unreported patients with orbital, conjunctival, or periocular SCC who were treated with IO either in the neoadjuvant setting prior to surgery or for treatment of periocular SCC with perineural spread into the orbit and skull base. Results: 17 patients, 12 men and 5 women (Age range: 44-92; median=70 years old) with orbital (n=6), conjunctival (n=5), or lacrimal sac/duct (n=2) squamous cell carcinoma (SCC), or periocular SCC with perineural spread into the orbit and skull base (n=4) who were treated with IO either as single drug (n= 11) or in combination with chemotherapy (n= 6 ). In all patients either cemiplimab or pembolizumab was used. In 13 patients IO was used in the neoadjuvant setting prior to planned surgery. In 4 patients with perineural spread as they had non surgically resectable disease, IO was used to avoid high dose radiation therapy with its inherent significant risk of ocular toxicity. Overall, 3 patients achieved complete response, 10 patients achieved partial response, and 4 patients had stable disease, using RECIST criteria. One of 5 patients with conjunctival SCC also had nodal metastasis at presentation and achieved a dramatic complete response of both the conjunctival tumor and the nodal metastasis and managed to avoid surgery altogether. This patient had a very high tumor mutation burden (TMB). One patient developed diabetic ketoacidosis as a side effect of IO; otherwise the adverse effects were low grade. Conclusions: IO either as single drug or in combination with chemotherapy has a fairly high response rate in patients with ocular adnexal, conjunctival or orbital SCC and in patients with periocular SCC with perineural spread in the orbit and skull base. Future prospective trails using IO for orbital and ocular adnexal SCC should be planned and should aim to correlate molecular data such as TMB with response.

Continuous glucose monitoring and rates of hyperglycemia during chemotherapy for early-stage breast cancer.

e24134 Background: Diabetes (DM) and hyperglycemia (HG) during chemotherapy increase the risk of treatment-related toxicities. The prevalence of HG and daily patterns of HG over the course of chemotherapy in patients with early-stage breast cancer (ESBC) are currently unknown. Methods: We conducted a prospective single-arm pilot study of continuous glucose monitoring in patients with ESBC receiving chemotherapy from 12/2020 – 2/2022. Eligibility criteria included: diagnosis of Stage I-III BC, age ≥18, and planned chemotherapy with concurrent corticosteroid supportive care use. Patients were excluded if they were receiving other systemic corticosteroids or insulin. Patients wore FreeStyle Libre Pro continuous glucose monitoring sensors from the time of chemotherapy initiation (± 7 days) through completion. The sensors detected interstitial glucose levels every 15 minutes and were reapplied by the study team every 2-3 weeks. Primary endpoints were: (1) prevalence of HG, defined as number of patients with ≥1 glucose reading ≥140 mg/dL and (2) among those who developed HG, the proportion of time spent hyperglycemic, defined as number of readings ≥140 mg/dL divided by total number of readings. Key secondary endpoints included prevalence of prediabetes (pre-DM) and diabetes (DM) at baseline and changes in A1c from baseline to weeks 12 and 24. The analysis was stratified by baseline A1c (euglycemia [A1c &lt; 5.7%], pre-DM [A1c 5.7%-6.4%], or DM [A1c ≥6.5% and clinical diagnosis of DM prior to study enrollment]). Results: Among 20 evaluable patients, the median age at baseline was 59 (range 34-78) and median body mass index (BMI) was 29.5 kg/m2 (range 19.5-41.6). The most common chemotherapy regimens included docetaxel/cyclophosphamide (25%), weekly paclitaxel ± trastuzumab (20%), paclitaxel followed by doxorubicin/cyclophosphamide (15%), docetaxel/carboplatin/trastuzumab/pertuzumab (15%), and cyclophosphamide/methotrexate/fluorouracil (15%). All 20 patients developed HG. Of 124,165 total readings, 17% were ≥140 mg/dL and mean glucose was 112.7 mg/dL. At baseline, n = 10 were euglycemic, n = 7 had pre-DM, and n = 3 had DM. By cohort, the proportion of time spent hyperglycemic was 3.9% (euglycemia group), 10% (pre-DM group), and 73.3% (DM group) (p &lt; .0001). Mean glucose values were 95.5 mg/dL (euglycemia group), 104.5 mg/dL (pre-DM group), and 183.0 mg/dL (DM group) (p &lt; .0001). Change in mean A1c from baseline to weeks 12 and 24 varied significantly across groups. Conclusions: Among patients receiving chemotherapy for ESBC, we found evidence of HG in all patients, and the proportion of time spent hyperglycemic during chemotherapy varied significantly by baseline A1c. Further interventions should evaluate the benefits of improved glucose control among patients with baseline A1c &gt; 5.7%. Clinical trial information: NCT04473378 .

The toxicity swimmer plot: A novel approach for evaluating patient-level toxicity following immune checkpoint inhibitor (ICI) therapy on the Checkmate 214 trial.

11014 Background: Treatment with ICIs creates the possibility of prolonged disease control or remission but also creates the possibility of prolonged toxicity even after treatment is discontinued. Treatment-free survival (TFS) with and without toxicity has previously been described as an integral piece of a partitioned survival analysis in advanced renal cell carcinoma (aRCC). Prior analyses have reported further partition of TFS as mean duration of TFS with and without treatment-related adverse events (TRAEs), but this metric fails to provide more granular information regarding individual patients experiencing toxicity during TFS. We present a novel extended swimmer plot that characterizes patient-level toxicity data within TFS using the example of the Checkmate 214 trial to complement analyses of the population average experience. Methods: Data were analyzed from the Checkmate 214 trial which randomized 1096 patients with aRCC to receive either first-line (1L) nivolumab plus ipilimumab (n = 550) or sunitinib (n = 546). The minimum follow-up from protocol therapy initiation was 42 months. Patients’ overall survival was partitioned into 3 survival states: time on 1L protocol therapy, TFS, and survival after subsequent therapy initiation. With a re-defined time origin relative to cessation of 1L protocol therapy, we generated swimmer plots highlighting the TFS period and documenting each patient’s experience with and without grade 2+ and grade 3+ TRAEs during TFS. The swimmer plot was sorted by duration of TFS and duration of TFS with grade 2+ TRAEs in order to illustrate patterns of individuals’ experiences. Results: The 42-month mean TFS was 7.8 months (with grade 2+ TRAEs: 3.2 months) for patients treated with nivolumab plus ipilimumab and 3.3 months (1.6 months) for patients treated with sunitinib. In the respective treatment groups, TFS with grade 2+ TRAEs was experienced by 32% and 25% of patients and comprised of 13% and 9% of patients for whom it was the entire TFS period. These percentages were consistent regardless of TFS duration. TFS with grade 3+ TRAEs was experienced by 15% and 3% of patients, respectively. For most patients having TFS with TRAEs, the TRAEs persisted from the protocol therapy period, but 7% and 1% of patients in the respective treatment groups had new-onset grade 3+ TRAE during TFS. A swimmer plot will be presented as a visual presentation of this study’s results. Conclusions: We describe a novel extension of swimmer plots for presenting patient-level information and illustrating patterns in toxicity duration relative to TFS by incorporating individual toxicity data into a swimmer plot of partitioned survival. This approach allows for a more comprehensive understanding of toxicity trends and risk of prolonged toxicity after treatment is discontinued.

Phase 2 study of bizaxofusp, an IL-4R targeted toxin payload, in nonresectable recurrent GBM: Comparison of overall survival with contemporaneous eligibility-matched and propensity score balanced external control arm.

2079 Background: Bizaxofusp (MDNA55) is designed to selectively deliver a potent toxin payload to tumor cells by targeting the IL-4 receptor (IL-4R) overexpressed by GBM, but not normal brain. Localized delivery of bizaxofusp minimizes risk of off-target toxicities and systemic exposure while eliciting effective tumor cell killing. Bizaxofusp was evaluated using convection-enhanced delivery in MDNA55-05 (NCT02858895), a single-arm, open-label, multi-center Ph2 study in nonresectable recurrent GBM (rGBM). Methods: The study population comprised of de novo IDH wild-type GBM patients with 1st or 2nd relapse that were non-resectable. Forty-four patients were administered a single treatment of bizaxofusp (range: 18-240 μg). The primary endpoint was OS; secondary endpoints were safety and tumor response. IL-4R expression in tumor biopsies was determined using a validated assay. OS was compared to an eligibility matched external control arm (emECA) of 81 contemporaneous rGBM subjects receiving standard of care. The emECA was further refined by propensity-score balancing (pbECA) to the bizaxofusp arm based on known prognostic factors, resulting in a weighted sample size of 40.8. OS was defined as time from relapse (to unify index date in both arms) or treatment start (for analysis of tumor response) to death/censor. Tumor response was assessed following RANO and mRANO criteria. Results: Bizaxofusp showed an acceptable safety profile at doses up to 240 μg. TRAEs were primarily neurological or aggravation of pre-existing neurological deficits associated with GBM and were manageable with standard measures. Results showed that IL-4R expression did not impact mOS except in patients receiving low doses of bizaxofusp. The bizaxofusp arm had significantly longer median OS (mOS) than contemporaneous emECA (12.4 vs 7.7 months; HR: 0.64, 95% CI 0.46-0.93; p = 0.02). Survival benefit was also evident when compared to the pbECA: (12.4 vs 7.2 months; HR: 0.72, 95% CI 0.46-1.1; p = 0.27). Patients with tumor control (SD or PR/CR, n=21) had significantly longer mOS than patients with tumor progression (n=23) (16.7 vs 8.5 months; HR = 0.5, 95% CI 0.27-0.9; p = 0.01). Among patients with tumor control who had pseudoprogression (PsP) per mRANO, mOS (22.8 months) was significantly longer than patients with tumor progression (HR: 0.49, 95% CI 0.25-0.98; p = 0.049). Conclusions: Bizaxofusp achieved significant OS benefit in patients with nonresectable rGBM compared to contemporaneous emECA. Patients who experienced tumor control, including those with PsP, showed significantly longer survival than patients with tumor progression. Phase 3 ready registrational trial will comprise a high dose bizaxofusp arm and a hybrid control arm with 1/3 randomized subjects and 2/3 pmECA. Clinical trial information: NCT02858895 .

Statin use in total joint arthroplasty: a systematic review

Introduction: There has been increased interest in the use of Statins in total hip and knee arthroplasty (THA and TKA) patients to improve outcomes and reduce postoperative complications. This study was performed to systematically review the evidence on Statin use in total joint arthroplasty, specifically its benefits and complications. Methods: Adhering to the PRISMA guidelines, a systematic review of PubMed, Embase, Scopus, Web of Science, and the Cochrane database was performed to find studies reporting on the effects of Statin use on outcomes of THA and TKA. Two authors independently selected relevant papers to include. Results: A total of 18 papers were included in the final analysis. Most were retrospective studies, with heterogeneous patient selection and outcome measures. The evidence on the risks and benefits of Statin use on outcomes of total joint arthroplasty was very limited and heterogeneous. Studies were focusing on perioperative cardiac outcomes, clinical outcomes and complications, renal, pulmonary, and gastrointestinal outcomes. Due to the heterogeneity of reported data, a formal meta-analysis was not possible. Conclusions: There is some evidence in the literature suggesting that perioperative use of Statins, especially in Statin-naïve patients, may reduce cardiac (e.g. atrial fibrillation) and noncardiac (e.g. delirium) complications, while not increasing the risk of muscle or liver toxicity. The authors also found low levels of evidence that Statin use may reduce the long-term risk for revision surgery and osteolysis.