Probability Of Toxicity Research Articles

Ecotoxicological risk of antibiotics and their mixtures to aquatic biota with the DGT technique in sediments

Antibiotics are emerging contaminants and widely used in human healthcare, livestock, and aquaculture. The toxicity posed by antibiotics and their mixtures in sediments depends on their bioavailability. Now, the bioavailability of organic materials can be determined accurately by the diffusive gradients in thin films (DGT) technique. This technique was used for the first time ever in this study to evaluate in detail the integral toxicity of antibiotics in sediments to aquatic biota. Zhelin Bay was selected as a case study, because it is the largest mariculture area in eastern Guangdong, South China. Two antibiotics, chlortetracycline (CTC) (A) and sulfachlorpyridazine (SCP), were detected at average concentrations of 2.83 and 1.14 ng/ml, respectively. The other fifteen antibiotics were undetectable. The single risk assessment based on the risk quotient (RQ) of CTC and SCP shows that a relatively low risk has occurred. After this careful assessment of probabilistic ecotoxicological risks, the combined toxicity of antibiotic mixtures (CTC and SCP) clearly indicates that the toxicity probability of surface sediments to aquatic organisms was relatively low (0.23%).

Abstract CT151: A phase II study of optimized individualized adaptive radiation therapy for hepatocellular carcinoma

Abstract Introduction: Stereotactic body radiation therapy (SBRT) for the treatment of hepatocellular carcinoma (HCC) remains a challenge due to high rates of toxicity in patients with impaired liver function or tumors not amenable to thermal ablation. We performed a single-arm prospective phase II clinical trial utilizing a novel treatment paradigm optimizing the utility of SBRT based on the individual patient’s probability for tumor control traded off against the risk of liver injury. We hypothesized that maximizing the utility of treatment would decrease toxicity while achieving the same tumor control rate as standard therapy. Methods: Patients with Child-Pugh (CP) A to B7 disease with tumors >3.5 cm, or CP ≥ B8 with any size tumor were prospectively enrolled on an IRB approved clinical trial to undergo SBRT with baseline dose optimization and mid-treatment response adaptation. Optimization and adaptation were based on the expected utility of treatment, calculated as a weighted average of the probability of 4 combinations of toxicity and efficacy outcomes. These calculations were based on the individual patient’s baseline indocyanine green retention at 15 minutes or albumin-bilirubin score (ALBI), CP score, intended dose and fractionation, and mean liver dose with the goal of maximizing the difference between the probability of local control compared to the probability of treatment-related toxicity. Primary endpoints were rate of liver decompensation as measured by ≥2 point change in CP score within 6 months, and lesion-specific local control. Overlap weighting was used to compare patients treated on protocol with patients receiving conventional SBRT at another high-volume cancer center. Results: 56 patients with 80 tumors met inclusion criteria and had a median follow-up of 11.2 months. 44 tumors with a median size of 3.8 cm were treated in CP-A to B7 patients, while 36 tumors with a median size of 2.1 cm were treated in CP ≥ B8 patients. Optimization resulted modification of initial dose for 38% of patients. Sixty-eight percent of patients underwent mid-treatment adaptation with either omission or dose reduction of the final two treatments based on change in expected utility. The 1 year freedom from local progression was 94%. A total of 21% of patients experienced a ≥ 2 point change in CP score within 6 months. Overlap weighted analysis revealed similar local control (HR 0.69, 95% CI [0.25-1.91], p = 0.48), and overall survival (HR 1.45, 95% CI [0.69-3.0], p = 0.33), with decreased toxicity (OR 0.26, 95% CI [0.07 - 0.99], p = 0.048) compared to conventional SBRT. Conclusion: SBRT for HCC patients with large tumors or poor liver function can be optimized via an individualized, utility-based treatment paradigm which may decrease treatment-related toxicity while maintaining tumor control. Citation Format: Daniel J. Herr, Chang Wang, Mishal Mendiratta-Lala, Martha Matuszak, Charles S. Mayo, Yue Cao, Neehar Parikh, Randy Ten Hanken, Dawn Owen, Teodor Stanescu, Michael Yan, Laura A. Dawson, Matthew Schipper, Theodore S. Lawrence, Kyle C. Cuneo. A phase II study of optimized individualized adaptive radiation therapy for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT151.

Abstract CT133: Trial in progress: a multicenter phase 1/1b dose escalation study of WTX-124 as a monotherapy and in combination with pembrolizumab in patients with selected advanced or metastatic solid tumors

Abstract Background: High-dose recombinant human IL-2 (HD IL-2) is an FDA-approved therapy that produces durable complete remissions in a subset of patients with advanced or metastatic cutaneous melanoma and renal cell carcinoma. However, the clinical benefit of HD IL-2 is counterbalanced by life-threatening toxicities such as capillary leak syndrome. WTX-124 is an engineered cytokine prodrug composed of a wild-type IL-2 fused via proprietary cleavable linkers to an inactivation domain and to a half-life extension domain. In the circulation and in normal tissues, WTX-124 is designed to remain inactive and not bind to high- (αβγ) and intermediate-affinity (βγ) IL-2 receptors. In contrast, proteolytic activation of WTX-124 in the tumor microenvironment (TME) is expected to liberate the IL-2 cytokine to stimulate antitumor immune responses. Preclinical data show that WTX-124 is activated by a range of dissociated human tumors in vitro but not by normal human cells or by patient serum. Moreover, WTX-124 demonstrates potent antitumor activity in multiple murine syngeneic tumor models with substantial expansion and activation of tumor-infiltrating lymphocytes. In the MC38 model, WTX-124 has a large therapeutic window of >19-fold compared to ~3-fold for recombinant human IL-2. Methods: This first-in-human, open-label phase 1/1b trial is investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity of WTX-124 administered as a monotherapy or in combination with the anti-PD-1 antibody pembrolizumab to patients with advanced or metastatic solid tumors (NCT05479812). All patients must have ≥ 1 measurable lesion per RECIST 1.1 and a tumor type for which immune checkpoint inhibitor (ICI) therapy is indicated. Dose escalation uses a modified toxicity probability interval-2 study design with WTX-124 administered intravenously (IV) every two weeks in 28-day cycles. If the safety of WTX-124 as a monotherapy is established in the first three cohorts, the study will then initiate dose escalation of WTX-124 in combination with pembrolizumab 400mg IV every six weeks. Dose expansion is anticipated to include four arms that will enroll patients with either advanced or metastatic cutaneous melanoma or renal cell carcinoma to receive WTX-124 monotherapy or combination therapy (N=20 patients per arm). Patients with melanoma assigned to the WTX-124/pembrolizumab combination arm may be naïve to all prior systemic therapy for advanced disease, but all other patients in expansion must have previously received a standard of care ICI regimen. Pre- and on-treatment tumor biopsies, archival tumor tissue, and blood samples will be used to investigate multiple exploratory biomarkers. As of January 12, 2023, WTX-124 monotherapy dose escalation is proceeding. Citation Format: Ildefonso Ismael Rodriguez-Rivera, Justin C. Moser, Mateusz Opyrchal, Brendan Curti, Mehmet A. Bilen, Saero Park, Marissa Bruno, Paul Windt, Kulandayan K. Subramanian, Sameer S. Chopra, Randi Isaacs. Trial in progress: a multicenter phase 1/1b dose escalation study of WTX-124 as a monotherapy and in combination with pembrolizumab in patients with selected advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT133.

Abstract CT119: A first-in-human phase 1 study of LOXO-435, a potent, highly isoform-selective FGFR3 inhibitor in advanced solid tumors with FGFR3 alterations (trial in progress)

Abstract Background: Alterations in the fibroblast growth factor receptor 3 (FGFR3) have been identified as oncogenic drivers in several solid tumor malignancies, including urothelial carcinoma (UC). Available pan-FGFR inhibitors target all 4 isoforms of FGFR (FGFR1 - 4) and consequently their efficacy can be limited by off-target toxicity (i.e. inhibition of other non-altered FGFR isoforms) including gastrointestinal, oral mucositis, and cutaneous/nail disorders, as well as FGFR1-mediated hyperphosphatemia. Moreover, clinical studies of pan-FGFR inhibitors have reported the development of drug resistance through acquired gatekeeper mutations (e.g. V555M and V565F) at the time of disease progression. LOXO-435 is a potent, highly isoform-selective FGFR3 inhibitor that is designed to preserve activity in the setting of gatekeeper resistance mutations. Preclinically, LOXO-435 has demonstrated potent in vitro and in vivo activity as a selective inhibitor of both wild-type and oncogenically activated FGFR3, including FGFR3 fusions, point mutations, and acquired gatekeeper resistance mutations without evidence of FGFR1-mediated hyperphosphatemia. Methods: LOXO-FG3-22001 is a multicenter, open-label, first-in-human phase 1a/b study of LOXO-435 in patients (pts) with FGFR3-altered advanced solid tumors, including metastatic UC (mUC) (NCT05614739). Eligible pts (≥ 18 years) must have an advanced or metastatic solid tumor with an FGFR3 alteration detected in tumor or ctDNA, ECOG PS of 0-1, and have received all standard therapy or have no known available options to provide benefit. The study will be conducted in 2 phases: phase 1a dose escalation and phase 1b dose expansion. Dose escalation (cohort A) will begin as a single-patient accelerated design, allowing intra-patient dose escalation, followed by the modified toxicity probability interval-2 method. Additional pts will be allowed to backfill to previously cleared dose levels that demonstrate therapeutically relevant exposures or direct evidence of clinical activity. Dose escalation will assess safety, PK/PD, and antitumor activity of LOXO-435 as monotherapy to determine the recommended phase 2 dose (RP2D). Dose expansion will include 4 cohorts of pts with prespecified activating FGFR3 alterations. Cohort B will enroll pts with mUC and include 2 cohorts to evaluate LOXO-435 as monotherapy (B1, B2) and 1 cohort to evaluate LOXO-435 in combination with pembrolizumab (B3). Cohort C will enroll pts with non-UC advanced solid tumors and will evaluate LOXO-435 as monotherapy (C1). Pts in cohort B1 must have progressed on or were intolerant to a prior FGFR inhibitor, and pts in cohorts B2, B3, and C1 must be FGFR inhibitor treatment naive. Dose expansion will evaluate the safety, PK/PD, and antitumor activity (per RECIST v1.1) of LOXO-435 at the RP2D. Citation Format: Gopa Iyer, Arlene Siefker-Radtke, Matthew Milowsky, Neal Shore, Xin Gao, Melissa A. Reimers, Noah Hahn, Rasha Cosman, Nobuaki Matsubara, Andrea Necchi, Debbie Robbrecht, Armelle Vinceneux, Enrique Grande, Jae-Lyun Lee, Tian Zhang, Tormod Guren, Ulrich M. Lauer, Michal Sarfaty, Bernhard Eigl, Syed Hussain, Xiang Zhao, Arjun V. Balar, Kaitlyn Francese, Ryan Widau, Benjamin Garmezy. A first-in-human phase 1 study of LOXO-435, a potent, highly isoform-selective FGFR3 inhibitor in advanced solid tumors with FGFR3 alterations (trial in progress) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT119.

Abstract CT031: A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors

Abstract Background: BGB-3245 is a RAF dimer inhibitor with preclinical activity in MAPK-altered tumor models harboring BRAF V600 mutations, atypical BRAF mutations/fusions, and RAS mutations. This study is investigating the safety, pharmacokinetics, and preliminary antitumor activity of BGB-3245 in patients (pts) with advanced or refractory MAPK-altered solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG 0-1 and had solid tumors harboring MAPK pathway alterations. Dose-escalation and cohort-size decisions were made using the Modified Toxicity Probability Interval Design. The starting dose was 5 mg QD. Treatment emergent adverse events (TEAEs) were graded per NCI CTCAE v5.0. Tumor responses were assessed by investigators using RECIST v1.1. Results: As of 1 Sep 2022, 42 pts were treated across 6 cohorts (5-60 mg QD). The median age was 60 yrs; pts had received a median of 3 prior lines of treatment. All pts had TEAEs; 79% had treatment-related (TR) AEs. The most common TRAEs (≥ 10%) were rash acneiform (33%), rash maculopapular (24%), fever (17%), ALT elevations and nausea (both 12%). Gr ≥3 TRAEs were reported in 29% of pts, events in ≥ 2 pts included decreased platelet count and rash maculopapular (3 each), ALT and AST elevations, and fever (2 each). Dose reductions occurred in 5 pts: rhabdomyolysis (1), LVEF decreased (1), hand-foot syndrome (1), rash maculopapular (1), and liver function abnormalities (1). Dose interruptions due to AEs occurred in 60% of pts. Dose discontinuations occurred in 79% of pts, 57% due to disease progression or death, 21% due to AE. Dose limiting toxicities were observed at 10 mg, 40 mg, and 60 mg. 40 mg QD was determined as the MTD. PK results showed generally dose-proportional increases in exposure. Tmax was at ~2 h; BGB-3245 had a long terminal half-life and 7.4-fold average accumulation in exposure at steady-state. 79% of pts were efficacy evaluable. The disease control rate was 48% with 1 CR, 5 cPR, 2 uPR and 8 SD≥24 wks. Objective responders included BRAF V600E melanoma pts post-BRAF/MEK and checkpoint inhibitors (2; 1 CR, 1 cPR), 1 NRAS G12S melanoma and 1 NRAS Q61K melanoma (post checkpoint inhibitors), 1 BRAF V600E LGSOC (progressed on BRAF inhibitor), 1 BRAF V600E cholangiocarcinoma (progressed on BRAF/MEK inhibitors), 1 BRAF K601E/PIK3CA endometrial cancer, and 1 KRAS G12D appendiceal cancer. Preliminary analysis of circulating tumor DNA showed correspondence to clinical response. Conclusions: BGB-3245 has a manageable safety profile and a generally dose-proportional PK. Antitumor activity was observed in pts with no approved targeted therapy options. The safety and early efficacy profile of BGB-3245 supports further investigation in selected MAPK-altered tumors. Citation Format: Alison M. Schram, Vivek Subbiah, Ryan Sullivan, Rasha Cosman, Jia Liu, Eric I. Sbar, Thuy Hoang, Jiarong Chen, Mark Johnson, Vincent Amoruccio, Todd Shearer, Adeela Kamal, Jocelyn Lewis, Wenlin Shao, Badreddin Edris, Lusong Luo, Jayesh Desai. A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT031.

Abstract CT120: The randomized phase 1/2 LITESPARK-024 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma (RCC)

Abstract Background: First-line treatment with immunotherapy alone or in combination with antiangiogenic agents is a standard of care for advanced RCC. Many patients (pts) develop resistance to first-line treatment and effective second-line and beyond options are needed. The von Hippel-Lindau (VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α), a key oncogenic driver in RCC. The first-in-class HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in previously treated pts with advanced RCC. The cyclin-dependent kinase (CDK) pathway has also been implicated in RCC and is associated with poor clinical outcomes. In RCC cell lines, the CDK 4/6 inhibitor palbociclib inhibited cell growth. The addition of CDK 4/6 inhibition had synergistic antiproliferative effects with HIF-2α inhibition in HIF-2α-dependent VHL -/- RCC cell lines. Palbociclib could therefore potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: The two-part, open-label, multicenter, phase 1/2 randomized LITESPARK-024 study (NCT05468697) is intended to establish the recommended phase 2 dose (RP2D) of belzutifan + palbociclib in combination with a modified toxicity probability interval design (Part 1), followed by a direct comparison of belzutifan monotherapy to the combination with respect to safety and efficacy in pts with advanced RCC (Part 2). Pts with histologically confirmed unresectable stage IV RCC with a clear cell component, whose disease progressed on or after having received at least 2 systemic treatments (both an anti-PD-1/PD-L1 monoclonal antibody and a VEGF receptor-targeted tyrosine kinase inhibitor, in sequence or in combination), have measurable disease per RECIST v1.1 by blinded independent central review, and have KPS score of ≥70% will be enrolled. Up to 30 pts will be enrolled into 3 dose groups in Part 1 and will receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are CBR, DOR, PFS, OS, and safety and tolerability. This abstract was accepted and previously presented at the 2023 ASCO Genitourinary Cancers Symposium. All rights reserved. Citation Format: David F. McDermott, Avivit Peer, Neeraj Agarwal, Michael B. Atkins, Jerry Cornell, Rodolfo F. Perini, Kenneth F. Grossmann, Howard Gurney. The randomized phase 1/2 LITESPARK-024 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma (RCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT120.

Gene therapy as a treatment of oral cancer: An insight.

Oral cancer or oral squamous cell carcinoma comprises more than three-fourth of all the malignant neoplasms of the oral cavity. Worldwide, it is the 18th most common malignancy. The patients suffering from cancer usually remains immune to the standard therapies such as surgical resection of tumours, radiotherapy and chemotherapy; however, there can be probabilities of chronic and acute toxicities and secondary malignancies as well. Recently, gene therapy has been introduced in the arena of biomedicine to improve the treatment modality for oral malignant and potentially malignant disorders. It replaces the defective gene followed by repairing by a therapeutic gene. Gene therapy can attack cancerous cells without causing harmful effect to the normal tissue. It is useful to cope with the relapse of diseases and as a synergetic treatment. The present article reviewed the types of gene therapy, modes of delivery of the therapeutic genes and different techniques used along with pros and cons of gene therapy.

MP33-03 COMPARATIVE COST-EFFECTIVENESS OF TREATMENT STRATEGIES FOR STAGE IIA SEMINOMA: INSIGHTS FROM THE SEMS TRIAL

You have accessJournal of UrologyCME1 Apr 2023MP33-03 COMPARATIVE COST-EFFECTIVENESS OF TREATMENT STRATEGIES FOR STAGE IIA SEMINOMA: INSIGHTS FROM THE SEMS TRIAL Daniel D. Joyce, Kevin M. Wymer, Vidit Sharma, James P. Moriarty, Bijan J. Borah, Arman Walia, Brian A. Costello, Lance C. Pagliaro, Siamak Daneshmand, Bradley C. Leibovich, and Stephen A. Boorjian Daniel D. JoyceDaniel D. Joyce More articles by this author , Kevin M. WymerKevin M. Wymer More articles by this author , Vidit SharmaVidit Sharma More articles by this author , James P. MoriartyJames P. Moriarty More articles by this author , Bijan J. BorahBijan J. Borah More articles by this author , Arman WaliaArman Walia More articles by this author , Brian A. CostelloBrian A. Costello More articles by this author , Lance C. PagliaroLance C. Pagliaro More articles by this author , Siamak DaneshmandSiamak Daneshmand More articles by this author , Bradley C. LeibovichBradley C. Leibovich More articles by this author , and Stephen A. BoorjianStephen A. Boorjian More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003266.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The recent Surgery in Early Metastatic Seminoma (SEMS) trial examined retroperitoneal lymph node dissection (RPLND) as a first-line treatment for patients with isolated 1-3cm retroperitoneal lymphadenopathy. To date, the standard of care for these patients has been either chemotherapy or radiation (XRT). Herein, we evaluated the relative cost-effectiveness of these management strategies. METHODS: A decision-analytic Markov model was used to assess cost-effectiveness of RPLND, chemotherapy (3 cycles of cisplatin, etoposide, bleomycin), and XRT for management of stage IIA seminoma. Probabilities of progression for RPLND were obtained from SEMS trial presented abstract data. All other probability and utility values were obtained from published literature. Analyses were performed with a 3-month cycle for a lifetime horizon. Primary outcomes included costs from a commercial insurer’s perspective, effectiveness (quality adjusted life years, QALY), and incremental cost-effectiveness ratios (ICER). A willingness to pay threshold of $100,000/QALY was used. Sensitivity analyses were performed to evaluate model robustness. RESULTS: At a lifetime horizon, the mean costs per patient for RPLND, XRT, and chemotherapy were $41,291, $75,650, and $85,380, respectively. The mean QALYs per person were 41.65, 41.62, and 39.60 for RPLND, XRT, and chemotherapy, respectively. RPLND was found to be the most cost-effective approach due to high costs and the accrued disutility of chronic toxicities associated with both XRT (ICER: -$107,296/QALY) and chemotherapy (ICER: -$26,941/QALY). On one-way sensitivity analyses (Figure), RPLND was no longer cost-effective if the probabilities of infertility and cardiovascular toxicity after XRT were less than 4% and 1%, respectively. CONCLUSIONS: RPLND was the least costly and most effective treatment strategy for stage IIA seminoma. In particular, long-term toxicity costs and disutilities associated with chemotherapy and XRT resulted in lower cost-effectiveness for these two approaches. These findings support clinical guideline consideration of including RPLND as a treatment option for well selected patients with stage IIA seminoma . Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e450 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel D. Joyce More articles by this author Kevin M. Wymer More articles by this author Vidit Sharma More articles by this author James P. Moriarty More articles by this author Bijan J. Borah More articles by this author Arman Walia More articles by this author Brian A. Costello More articles by this author Lance C. Pagliaro More articles by this author Siamak Daneshmand More articles by this author Bradley C. Leibovich More articles by this author Stephen A. Boorjian More articles by this author Expand All Advertisement PDF downloadLoading ...

Eco-Toxicological Risk Assessment of Heavy Metals and Polycyclic Aromatic Hydrocarbons in Sediments of Tigris River, Iraq

The Tigris River is an important source for domestic, agricultural, industrial, fisheries, and ‎even recreational activities. Therefore, environmental assessment of river sediments is vital, as sediments can be considered ‎reservoirs of pollutants that are re-released into the water during floods or human activities. ‎This research aimed to assess Tigris river sediments‎ ‎ from Al ‎Qayyarah to Al Tarmiyah.‎ Nine samples of sediment were collected for analysing seven heavy metals and a metalloid (i.e. Cu, Cd, Cr, Pb, Zn, Ni, and As) and sixteen PAHs compounds. The concentrations of heavy metals Cd, Pb, As, Cr, and Ni in some locations have exceeded ‎their background concentrations in the earth's crust. For assessing the contamination of sediments by metals, three indices, viz, SPI, TRI, and MERMQ were used. According to the results of the three indices, Al ‎Qayyarah‎ and Baiji sites were more contaminated than other sites. This may be attributed to anthropogenic activities represented by the petroleum industry which enriches sediments with metals. Also, three indices for evaluating the environmental risk of PAHs, i.e., MERMQ, ‎SQGQ‎, and RQ, were used. Based on Mean ERM Quotient values, the toxicity probability of PAHs in sediments ranged from 49% at Al ‎Qayyarah and Baiji to 21% and 9% at other sites. The SQGS index values showed that Al ‎Qayyarah‎ and Baiji sites‎ were highly affected by PAHs contaminants.‎ ‎According to the Risk Quotient (RQ) values of the sum PAHs, the environmental risk of river sediments ranged from low to moderate.

A novel model of the continual reassessment method in Phase I trial

For the model-based designs, the continual reassessment method (CRM) is widely used to identify the maximum tolerated dose (MTD) in phase I clinical trials. To improve the performance of classic CRM models, we propose a new CRM and its dose-toxicity probability function based on the Cox model whatever the treatment response is immediately observed or delayed. In the process of dose-finding trial, we can use our model in situations when either the response is delayed or not and can derive the likelihood function and posterior mean toxicity probabilities to find the MTD. Simulation is carried out to evaluate the performance of the proposed model with the classic CRM models. We also evaluate the operating characteristics of the proposed model by the Efficiency, Accuracy, Reliability, and Safety (EARS) criteria.

Abstract OT3-08-01: A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress)

Abstract Background: Phosphoinositide 3-kinase alpha (PI3Kα) H1047R mutations are activating oncogenic events that occur in ~15% of breast cancers (BC). Available PI3Kα inhibitors target both wild-type (WT) and mutant PI3Kα and, as a result, their efficacy may be limited by on-target WT PI3Kα-mediated toxicities, including hyperglycemia, skin rash, and diarrhea. LOXO-783 is an oral, potent and highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor. Preclinically, LOXO-783 is highly selective for PI3Kα H1047R over WT PI3Kα and other PI3K isoforms and induces single-agent tumor regressions in ER+, HER2- PI3Kα H1047R-mutant BC models without causing hyperglycemia or increases in plasma insulin/C-peptide. LOXO-783 also demonstrates brain penetration in vivo with dose-dependent tumor growth inhibition in brain metastasis models. This trial investigates LOXO-783 alone and in combination with other anticancer therapies in patients with PIK3CA H1047R-mutant aBC and other solid tumors. Trial Design: This global, first-in-human phase 1a/b study of LOXO-783 includes dose escalation of LOXO-783 monotherapy followed by dose expansion of LOXO-783 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using a modified toxicity probability interval-2 (mTPI-2) design. In dose expansion (Parts A-E), each combination cohort will include a safety lead-in of 3-6 patients. Men and premenopausal women with ER+ aBC must receive concomitant treatment with a GnRH agonist. An optional pharmacodynamic (PD) biomarker sub-study will be conducted at select dose levels during dose escalation in patients with ER+, HER2- aBC with soft tissue disease amenable to safe repeat tumor biopsies. Eligibility criteria: Eligible patients must have PIK3CA H1047R-mutant aBC or other solid tumors with measurable disease or non-measurable bone-only disease (aBC patients only). In dose escalation, patients may have received up to 5 prior regimens. In dose expansion, prior therapy requirements are outlined in the Table below. Key exclusion criteria include prior inhibitor(s) of PI3K/AKT/mTOR (except in dose escalation or in select patients with prior intolerance of these inhibitors), colorectal cancer, endometrial cancer with concurrent PI3K/AKT/mTOR and/or RAS/RAF alterations and diabetes mellitus (DM) requiring medication (except in Part C). Study objectives: Recommended phase 2 dose (RP2D) determination; safety and tolerability assessment, PK and PD evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment is ongoing (PIKASSO-01, NCT05307705). Table. Dose Expansion (Phase 1b) Citation Format: Dejan Juric, Komal Jhaveri, Muralidhar Beeram, Erika Hamilton, Vincent Chau, Matthew P. Hanley, Shiyao Liu, Lillian M. Smyth, Funda Meric-Bernstam. A phase 1 trial of LOXO-783, a potent, highly mutant-selective, brain-penetrant allosteric PI3Kα H1047R inhibitor in PIK3CA H1047R-mutant advanced breast cancer (aBC) and other solid tumors (PIKASSO-01, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-08-01.

LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma.

TPS747 Background: The combination of immunotherapy with antiangiogenic agents is a well-established first-line treatment option for patients (pts) with advanced renal cell carcinoma (RCC), but many pts develop resistance, and effective second- or subsequent-line options are needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α) signaling. HIF-2α is involved in angiogenesis, tumor growth, proliferation, and metastasis, and is a key oncogenic driver in RCC. The HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in pts with heavily pretreated RCC. The cyclin-dependent kinase (CDK) pathway is altered in several cancer types, including RCC, and is associated with poor clinical outcomes. The CDK 4/6 inhibitor palbociclib inhibited cell growth in RCC cell lines, and the antiproliferative effects of CDK 4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL -/- clear cell RCC cell lines. We hypothesized palbociclib could potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 (NCT05468697) is an open-label, multicenter, phase 1/2 randomized study of belzutifan + palbociclib versus belzutifan monotherapy in pts with advanced RCC. Pts must have histologically confirmed unresectable stage IV RCC with a clear cell component, received at least 2 prior systemic regimens (both an anti–PD-1/PD-L1 monoclonal antibody and a VEGF receptor–targeted TKI, in sequence or in combination), have measurable disease per RECIST v1.1 by BICR, have KPS score of ≥70%, and have radiographic disease progression on or after the most recent regimen per investigator. Part 1 will evaluate the safety of belzutifan + palbociclib and determine the recommended phase 2 dose (RP2D) for the combination using a modified toxicity probability interval design. Part 2 will evaluate the safety and efficacy of belzutifan + palbociclib versus belzutifan alone. In part 1, ≤30 pts will be enrolled into 3 dose groups and receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, DOR, PFS, OS, and safety and tolerability. Clinical trial information: NCT05468697 .

Distribution, Multi-Index Assessment, and Sources of Heavy Metals in Surface Sediments of Zhelin Bay, a Typical Mariculture Area in Southern China

The occurrence, multi-index assessment, and sources of heavy metals in surface sediments of Zhelin Bay were investigated. Average heavy metal concentrations (mg/kg) were 81.89 (Cr), 770.76 (Mn), 16.81 (Co), 62.25 (Ni), 96.30 (Cu), 162.04 (Zn), and 73.40 (Pb), with the concentrations of studied seven heavy metals being significantly higher than their corresponding background values. Geo-accumulation index (Igeo) and pollution load index (PLI) were implemented to assess degree of heavy metal contamination. The Igeo and PLI indicated that Cr, Mn, Co, Zn, and Pb were slightly polluted, and Cu and Ni were moderately polluted in the region. Potential ecological risk index (RI) and mean possible effect level (PEL) quotient were conducted to assess ecological risk. The RI and mean PEL quotient demonstrated that surface sediments of Zhelin Bay were slight ecological risks and exhibited a 21% probability of toxicity. Principal component analysis (PCA) combined with the correlation analysis (CA) and hierarchical cluster analysis (HAC) revealed that the heavy metal contamination in Zhelin Bay might originate from three type sources.

Implementing Vancomycin Population Pharmacokinetic Models: An App for Individualized Antibiotic Therapy in Critically Ill Patients.

In individualized therapy, the Bayesian approach integrated with population pharmacokinetic models (PopPK) for predictions together with therapeutic drug monitoring (TDM) to maintain adequate objectives is useful to maximize the efficacy and minimize the probability of toxicity of vancomycin in critically ill patients. Although there are limitations to implementation, model-informed precision dosing (MIPD) is an approach to integrate these elements, which has the potential to optimize the TDM process and maximize the success of antibacterial therapy. The objective of this work was to present an app for individualized therapy and perform a validation of the implemented vancomycin PopPK models. A pragmatic approach was used for selecting the models of Llopis, Goti and Revilla for developing a Shiny app with R. Through ordinary differential equation (ODE)-based mixed effects models from the mlxR package, the app simulates the concentrations' behavior, estimates whether the model was simulated without variability and predicts whether the model was simulated with variability. Moreover, we evaluated the predictive performance with retrospective trough concentration data from patients admitted to the adult critical care unit. Although there were no significant differences in the performance of the estimates, the Llopis model showed better accuracy (mean 80.88%; SD 46.5%); however, it had greater bias (mean -34.47%, SD 63.38%) compared to the Revilla et al. (mean 10.61%, SD 66.37%) and Goti et al. (mean of 13.54%, SD 64.93%) models. With respect to the RMSE (root mean square error), the Llopis (mean of 10.69 mg/L, SD 12.23 mg/L) and Revilla models (mean of 10.65 mg/L, SD 12.81 mg/L) were comparable, and the lowest RMSE was found in the Goti model (mean 9.06 mg/L, SD 9 mg/L). Regarding the predictions, this behavior did not change, and the results varied relatively little. Although our results are satisfactory, the predictive performance in recent studies with vancomycin is heterogeneous, and although these three models have proven to be useful for clinical application, further research and adaptation of PopPK models is required, as well as implementation in the clinical practice of MIPD and TDM in real time.

Phase 1b study to assess the safety of neoadjuvant trifluridine/tipiracil with concurrent radiation in resectable stage II/III rectal cancer.

TPS274 Background: Treatment of locally advanced rectal cancer currently involves tri-modal therapy with pre-operative chemo-radiation (CRT), surgery, and combination chemotherapy. Total neoadjuvant therapy (TNT) is emerging as an important treatment pathway that can increase rates of complete response (CR) leading to better overall outcomes. Novel radio-sensitizing agents may improve rates of CR. Trifluridine/tipiracil (TFD/TPI) is a novel fluoropyrimidine that has demonstrated clinical efficacy in patients with treatment-refractory metastatic colorectal cancer. Importantly, TFD/TPI has superior radio-sensitization in vitro compared to 5-fluorouracil, and we hypothesize that this can improve the tumor response of patients. This phase 1 study assesses the safety and preliminary efficacy of using TFD/TPI for long-course CRT for rectal cancer followed by FOLFOX chemotherapy in the TNT setting. Methods: NCT04104139 is a prospective, dose-finding phase I study using Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) of TFD/TPI with concurrent standard dose/fractionation radiation for resectable rectal cancer. Adults with previously untreated rectal adenocarcinoma, with clinical stage II (T3-4aN0) and stage III (T1-4aN1+) by MRI and endoscopy are eligible. Patients must first receive CRT with standard radiation (45-50 Gy over 25-28 fractions) followed by up to 8 cycles of standard FOLFOX, or alternatively 5 cycles of CAPOX chemotherapy. During CRT, the first dose level of TFD/TPI is PO 25mg/m2 twice a day from Mon to Fri (5 weekdays) alternating on weeks 1, 3, and 5 concurrent with 5-6 weeks of radiation. The second dose level is 30mg/m2, and third dose level is 35mg/m2. The MTD of TFD/TPI in combination with radiation is the dose corresponding to a dose limiting toxicity (DLT) probability of 30% using the BOIN design with escalation/de-escalation of each dose level occurring in cohorts of 3 participants until a maximum total of 18 participants, sub-total of 12 patients within one dose level, or another stopping rule based on serious toxicities. The primary endpoint is proportion of DLTs for TFD/TPI at MTD. Secondary endpoints include overall tolerability profile, delayed toxicities during FOLFOX, rates of clinical CR, rates of pathologic CR, and correlative biomarkers. The study was activated December 2019 and has accrued 8 of intended 18 patients. Clinical trial information: NCT04104139 .

Casper: A phase I, open-label, dose finding study of calaspargase pegol-mnkl (cala) in combination with cobimetinib (cobi) in locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC).

TPS772 Background: Metabolic adaptation provides rapidly dividing cancer cells the flexibility to maintain homeostasis as nutrient supplies are continuously exhausted in the tumor microenvironment. Asparagine synthetase (ASNS) catalyzes ATP-dependent biosynthesis of the non-essential amino acid asparagine from aspartate and glutamine. Cells lacking ASNS, however, are auxotrophic for asparagine. Use of L-asparaginase (ASNase) to promote asparagine starvation in PDAC and other solid tumors with low ASNS levels is a rationale treatment strategy; however, aberrant RAS/MAPK signaling can circumvent effects of ASNase. Preclinical data shows that targeted inhibition of MAPK signaling along with ASNase is active against PDAC; however, this has not been tested in patients to date. Methods: CASPER is an open-label, phase IB, single-arm, dose-escalation study to evaluate the safety and tolerability of combining cala and cobi in patients with locally-advanced or metastatic PDAC. Participants receive cala and cobi at assigned dose level. The study uses a Bayesian Optimal Interval (BOIN) design to determine the maximum tolerated dose (MTD) for the combination of study agents. Up to 15 participants will be enrolled and treated, with a cohort of 3 participants assessed before a decision is made to escalate, de-escalate, or maintain the current dose level before initiating the next cohort. MTD is defined as the dose level where dose-limiting toxicity (DLT) probability is closest to the target toxicity rate of 30% after applying isotonic regression to the observed dose-level-specific DLT rate. Per BOIN, the dose level is escalated, maintained, or de-escalated based on comparisons of the observed DLT rate and pre-specified boundaries (0.236, 0.359). Starting in Cycle (C) 1, patients receive cobi (at assigned dose level) for Days (D) 1-14, and their assigned dose of cala on D1 of each 21-day cycle. If the combination of cala and cobi is tolerated and does not incur DLTs, participants will continue receiving their assigned dose of cala and cobi until evidence of disease progression, unacceptable toxicity, or study withdrawal. The DLT period starts on C1D1 and ends C2D21. Secondary endpoints include preliminary assessment of overall response rate (ORR), disease control rate (DCR), and mean levels of plasma ASNase. Paired tumor biopsies and serial blood will be used for exploratory objectives combining deep multi-omic analytics with clinical data. The trial is currently open with 1 patient enrolled at time of submission. Clinical trial information: NCT05034627 . [Table: see text]

Dose evaluations of organs at risk and predictions of gastrointestinal toxicity after re-irradiation with stereotactic body radiation therapy for pancreatic cancer by deformable image registration.

Re-irradiation of locally recurrent pancreatic cancer may be an optimal choice as a local ablative therapy. However, dose constraints of organs at risk (OARs) predictive of severe toxicity remain unknown. Therefore, we aim to calculate and identify accumulated dose distributions of OARs correlating with severe adverse effects and determine possible dose constraints regarding re-irradiation. Patients receiving two courses of stereotactic body radiation therapy (SBRT) for the same irradiated regions (the primary tumors) due to local recurrence were included. All doses of the first and second plans were recalculated to an equivalent dose of 2 Gy per fraction (EQD2). Deformable image registration with the workflow "Dose Accumulation-Deformable" of the MIM® System (version: 6.6.8) was performed for dose summations. Dose-volume parameters predictive of grade 2 or more toxicities were identified, and the receiver operating characteristic (ROC) curve was used to determine optimal thresholds of dose constraints. Forty patients were included in the analysis. Only the V 10 of the stomach [hazard ratio (HR): 1.02 (95% CI:1.00-1.04), P = 0.035] and D mean of the intestine [HR: 1.78 (95% CI: 1.00-3.18), P = 0.049] correlated with grade 2 or more gastrointestinal toxicity. Hence, the equation of probability of such toxicity was Additionally, the area under the ROC curve and threshold of dose constraints of V 10 of the stomach and D mean of the intestine were 0.779 and 77.575 cc, 0.769 and 4.22 Gy3 (α/β = 3), respectively. The area under the ROC curve of the equation was 0.821. The V 10 of the stomach and D mean of the intestine may be vital parameters to predict grade 2 or more gastrointestinal toxicity, of which the threshold of dose constraints may be beneficial for the practice of re-irradiation of locally relapsed pancreatic cancer.

Prediction of Occupational Fluorosis in Aluminum Production Workers in View of Comorbidities

Introduction: Modern research on occupational medicine has shown that general diseases contribute the most to health deterioration in workers of hazardous industries and significantly affect the timing of the onset of occupational diseases. Objective: To assess the impact of comorbid disorders on the probability of occupational fluoride toxicity in aluminum production workers. Materials and methods: The paper describes existing international scales used to assess comorbid disorders and emphasizes the relevance of publications on the comorbidity of workers of hazardous and harmful industries. The comorbidity index was calculated for each of 201 aluminum production workers. Comorbidity index calculations, health indicators, and parameters of working conditions were entered in the electronic database. The article presents a method for determining the probability of occupational disease development using a logistic regression. Results: A prognostic model was built using a logistic regression and comorbidity indices to determine the influence of human body systems on the probability of developing occupational fluoride poisoning (fluorosis). Conclusion: Using the logistic regression, we have determined combinations of comorbidity indices having a strongest effect on the probability of fluoride poisoning for prediction and implementation of appropriate preventive measures. To reduce the likelihood of occupational diseases, it is necessary to treat comorbid disorders in workers of harmful industries.

Critical Evaluation of Secondary Cancer Risk After Breast Radiation Therapy with Hybrid Radiotherapy Techniques.

As hybrid radiotherapy technique can effectively balance dose distribution between targets and organs, it is necessary to evaluate the late effects related to radiotherapy. The aim of the study was to calculate and provide individual estimates of the risks for hybrid radiotherapy techniques in breast cancer patients. Whole-breast irradiation was performed in 43 breast cancer patients by using 3D conformal, intensity-modulated and hybrid techniques. The excess absolute risk (EAR), lifetime attributable risk (LAR) and normal tissue complication probability (NTCP) were calculated to estimate risks in organs. The risk variability in contralateral breast was assessed by using the patient's anatomic parameters. Compared with IMRT and FinF, hybrid techniques achieved satisfactory dose distribution and comparable or lower estimated risks in organs. The LAR was estimated to be up to 0.549% for contralateral lung with advantages of tangential techniques over H-VMAT. For ipsilateral lung, the LAR was estimated to be up to 9.021%, but lower in H-VMAT and FinF without significant difference. The risk of thyroid was negligible in overall estimation. For contralateral breast, the LAR was estimated to be up to 0.865% with advantages of MH-IMRT and H-VMAT over TF-IMRT. The fraction of individual variability could be explained by using anatomic parameters of minimum breast distance (MBD) and minimum target concave angle (θMTCA). NTCP for all analyzed endpoints was significantly higher in TF-IMRT relative to FinF and hybrid techniques, while TH-IMRT and H-VMAT were presenting lower toxicity risk. However, MH-IMRT presented a higher probability of toxicity in lung. For most cases, H-VMAT demonstrated a benefit for contralateral breast, heart and lung sparing. The optimal treatment should be performed individually according to anatomic parameters and balances between EAR and NTCP. Individual assessment may assist in achieving optimal balances between targets and organs as well as supporting clinical decision-making processes.

SEMIPARAMETRIC DOSE FINDING METHODS FOR PARTIALLY ORDERED DRUG COMBINATIONS.

We investigate a statistical framework for Phase I clinical trials that test the safety of two or more agents in combination. For such studies, the traditional assumption of a simple monotonic relation between dose and the probability of an adverse event no longer holds. Nonetheless, the dose toxicity (adverse event) relationship will obey an assumption of partial ordering in that there will be pairs of combinations for which the ordering of the toxicity probabilities is known. Some authors have considered how to best estimate the maximum tolerated dose (a dose providing a rate of toxicity as close as possible to some target rate) in this setting. A related, and equally interesting, problem is to partition the 2-dimensional dose space into two sub-regions: doses with probabilities of toxicity lower and greater than the target. We carry out a detailed investigation of this problem. The theoretical framework for this is the recently presented semiparametric dose finding method. This results in a number of proposals one of which can be viewed as an extension of the Product of Independent beta Priors Escalation method (PIPE). We derive useful asymptotic properties which also apply to the PIPE method when seen as a special case of the more general method given here. Simulation studies provide added confidence concerning the good behaviour of the operating characteristics.