Major Toxicity Research Articles

Dynamic Prediction of Toxicities in Head and Neck Cancer Radiotherapy by 3D Convolutional Neural Network Using Daily Cone-Beam CTs

Radiotherapy (RT) is essential in head and neck cancer (HNC) treatments, but often causes significant toxicity. Different machine learning models have shown promise in predicting RT-induced toxicity, but none have yet integrated the fluctuating anatomical changes. By integrating daily cone-beam CTs (CBCT) allowing sequential anatomical views, our aim is to build a dynamic predictive model for three major HNC RT toxicities: reactive feeding tube placement, hospitalization and radionecrosis (RN). 292 HNC cases treated with curative RT between 2017 and 2019 at our institution were retrospectively analyzed for clinical and radiological data. VoxelMorph, a deep deformable registration model, integrated the daily anatomical deformations between each CBCT and the planning CT, then converted them to Jacobian determinant matrix (Jf). Resnet, a convolutional neural network with multiple layers was trained using a 5-fold cross validation to integrate both radiological and clinical data. Each toxicity was classified as a binary decision using the cross-entropy loss to account for a class imbalance. Its predictive performance was compared to the baseline model using only clinical data. The cohort included 78% men and 22% women, with a median age of 63 years (range 35-84). Primary cancer sites were 46% oropharynx, 19% larynx, 14% oral cavity, 7.5% nasopharynx, 5% hypopharynx, 4% unknown primary and 5% others; and stage ranged between Tx-4b N0 and 3b M0 (AJCC 8th Ed). Induction chemotherapy, concurrent chemotherapy, and adjuvant RT was used in 9%, 57% and 20% of patients, respectively. The incidence of feeding tube, hospitalization and RN was 19.9%, 7.2%, and 3.8%, respectively. Integrating Jf from the 10th RT CBCT showed better accuracy for each toxicity prediction: feeding tube (69.1% > 57.2%), hospitalization (75.3% > 63.1%) and RN (85.8% > 75.7%). Integrating both the raw CBCT and Jf improved hospitalization prediction (79.0% > 73.6%). Substituting Jf for the raw CBCT improved the prediction for RN (79.7% > 74.7%) and hospitalization (73.6% > 64.4%). For feeding tube, predictive performance of the Jf model trained against deformations showed a positive correlation between its performance and the RT received (r2 > 0.9) with increasing RT fractions, with a maximum accuracy of 83.1% at the 25th fraction. No such correlation was found for RN or hospitalization prediction. To our knowledge, this is the first study showing promising results to predict HNC RT toxicities using daily per-treatment CBCT. Next steps involve integrating both the radiomic and the dosimetric inputs to build a more powerful model. This could expand to predict therapeutic outcomes and, ultimately, could guide decisions in individualized RT.

Recent advances in therapies for primary myelofibrosis.

Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) form the classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) that are driven by a constitutive activation of JAK2 signaling. PMF as well as secondary MF (post-ET and post-PV MF) are the most aggressive MPNs. Presently, there is no curative treatment, except allogenic hematopoietic stem cell transplantation. JAK inhibitors, essentially ruxolitinib, are the therapy of reference for intermediate and high-risk MF. However, presently the current JAK inhibitors behave mainly as anti-inflammatory drugs, improving general symptoms and spleen size without major impact on disease progression. A better understanding of the genetics of MF, the biology of its leukemic stem cells (LSCs), the mechanisms of fibrosis and of cytopenia and the role of inflammatory cytokines has led to new approaches with the development of numerous therapeutic agents that target epigenetic regulation, telomerase, apoptosis, cell cycle, cytokines and signaling. Furthermore, the use of a new less toxic form of interferon-α has been revived, as it is presently one of the only molecules that targets the mutated clone. These new approaches have different aims: (a) to provide alternative therapy to JAK inhibition; (b) to correct cytopenia; and (c) to inhibit fibrosis development. However, the main important goal is to find new disease modifier treatments, which will profoundly modify the progression of the disease without major toxicity. Presently the most promising approaches consist of the inhibition of telomerase and the combination of JAK2 inhibitors (ruxolitinib) with either a BCL2/BCL-xL or BET inhibitor. Yet, the most straightforward future approaches can be considered to be the development of and/or selective inhibition of JAK2V617F and the targeting MPL and calreticulin mutants by immunotherapy. It can be expected that the therapy of MF will be significantly improved in the coming years.

Predicted Mechanism of Action of Venom Toxins On Testicular Toxicity: An In-Silico Approach

Snake envenomation is considered as a neglected disease from world health organization. Recent survey states Indiahas the highest rate of around 1.2 million deaths. As a pathophysiological effect, snake bite is contributing for major toxicity onhuman organ systems. As a secondary outcome of snake bite, testicular toxicity on the later stages of envenomation gaining moreinterest in recent years. But till date none of the studies have explored the field with the major toxins of the viper venom. Basedon the review, our aim of the study was to predict the possible mechanism of action of the viper toxins against testicular toxicity.Hence to achieve the aim of the study, the objectives framed to perform the in-silico docking of major viper venom toxins namelyVRV-PL-V and VRV-PL-VIIIa against human testicular tight junction and extra cellular matrix proteins. Docking results of our datademonstrated the prominent interaction of VRV-Pl-VIIIa with claudin, occludin, TGF-β and Tubulin α/β with the strong hydrogenbonds where as VRV-PL-V exhibited very poor hydrophobic interactions. VRV-PL-V structure was available and hence thestructure was predicted and its stability was confirmed before docking. Occludin, TGF-β and Tubulin-α proteins shared multiplehydrogen bonds with the toxin VRV-PL-VIIIa whereas claudin and Tubulin-α had numerous hydrophobic interactions with theVRV-PL-VIIIa toxin. On discussion, our docking studies state the impressive binding intensity of VRV-PL-VIIIa over VRV-PL-Vwhere it showed binding ability only with Tubulin α and β that too with weak interactions. In conclusion, our overall studies justifythe previous reports of VRV-PL-VIIIa on testicular toxicity.

Effects of point and nonpoint source pollution on urban rivers: From the perspective of pollutant composition and toxicity

Wastewater discharge is considered to be one of the anthropogenic factors affecting the water quality of urban rivers. The source and composition of wastewater are complex and diverse, and it is difficult to evaluate its effect on water quality and ecological health of receiving waters. Environmental DNA method can determine all species living in waters by examining DNA sequences, reflecting the impact of water quality changes on aquatic systems. In this study, water samples from two urban rivers were collected in dry and wet seasons, and the composition of pollutants was investigated by nontarget screening. Based on the pollutant composition, compound toxicity prediction and concentration addition model were used to predict the toxicity changes of pollutants in the urban rivers. More than 1500 suspect organic pollutants were nontarget screened, and silafluofen was found to be a major toxicity contributor. Environmental DNA analysis was combined with water quality measure and pollutant toxicity prediction to reveal the effects of pollutants from different sources on aquatic ecosystems. Fish diversity was negatively correlated with the mixed toxicity of organic pollutants, suggesting potential ecological risk in these two urban rivers. Our study developed a water quality assessment method based on pollutant composition and toxicity, and the potential risk of nonpoint source pollutants on aquatic ecosystems should not be neglected.

A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01.

This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.

Design, construction and validation of a simple, low-cost phi meter

The best correlation between the yields of the major toxicants in fire smoke and the fire condition is obtained by expressing the ventilation in terms of the equivalence ratio, phi. Phi meters allow this fuel-air equivalence ratio to be determined during a large-scale fire test. The original design used a platinum catalyst, a large furnace, and required pure oxygen. This work aimed to make a simple, low-cost device which could monitor the equivalence ratio during a large-scale fire test. The current design produces the same quality of measurement with a much smaller footprint and throughput. Benefits include enhanced portability, reduction in sample gas cleaning and drying requirements and lower cost. The work showed that normal furnace components (alumina and silica) provide suitably catalytic surfaces at 900 °C eliminating the requirement for platinum catalysts and the use of pure oxygen. The ISO/TS 19700 steady state tube furnace (SSTF) was used to validate the phi meter measurements as it can both pre-set and independently quantify the equivalence ratio during a test. Long sample collection times were overcome with a larger sampling pump and effluent being split between the phi meter furnace and the exhaust. It is hoped that this simpler, optimized apparatus will encourage more widespread use and lead to better prediction of smoke toxicity.

Evaluation of Mitochondrial Dysfunction and Idebenone Responsiveness in Fibroblasts from Leber's Hereditary Optic Neuropathy (LHON) Subjects.

Leber's hereditary optic neuropathy (LHON) is a disease that affects the optical nerve, causing visual loss. The diagnosis of LHON is mostly defined by the identification of three pathogenic variants in the mitochondrial DNA. Idebenone is widely used to treat LHON patients, but only some of them are responders to treatment. In our study, we assessed the maximal respiration rate (MRR) and other respiratory parameters in eight fibroblast lines from subjects carrying LHON pathogenic variants. We measured also the effects of idebenone treatment on cell growth and mtDNA amounts. Results showed that LHON fibroblasts had significantly reduced respiratory parameters in untreated conditions, but no significant gain in MRR after idebenone supplementation. No major toxicity toward mitochondrial function and no relevant compensatory effect in terms of mtDNA quantity were found for the treatment at the tested conditions. Our findings confirmed that fibroblasts from subjects harboring LHON pathogenic variants displayed impaired respiration, regardless of the disease penetrance and severity. Testing responsiveness to idebenone treatment in cultured cells did not fully recapitulate in vivo data. The in-depth evaluation of cellular respiration in fibroblasts is a good approach to evaluating novel mtDNA variants associated with LHON but needs further evaluation as a potential biomarker for disease prognosis and treatment responsiveness.

Evidences for the augmented Cd(II) biosorption by Cd(II) resistant strain Candida tropicalis XTA1874 from contaminated aqueous medium

Cadmium is one of the most dreadful heavy metals and is becoming a major toxicant in ground water with increasing concentration above the WHO Guidelines in drinking water (0.003 mg/L). The potential sources of cadmium include sewage sludge, phosphate fertilizers and ingredients like Ni–Cd batteries, pigments, plating and plastics. Cadmium levels are increased in water owing to the use and disposal of cadmium containing ingredients. Water draining from a landfill may contain higher cadmium levels. The authors have tried to evaluate the optimized nutritional conditions for the optimal growth and Cd(II) remediation capacity for a developed Cd(II) resistant yeast strain named Candida tropicalis XTA 1874 isolated from contaminated water-body in West Bengal. By analyzing the optimization conditions, a synthetic medium was developed and the composition has been given in the main text. The strain showed much better Cd(II) adsorption capacity under the optimized nutritional conditions (Mean removal = 88.077 ± 0.097%).

Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia.

Relapsed T-acute lymphoblastic leukemia (T-ALL) has limited treatment options. We investigated mechanisms of resistance to BH3 mimetics in T-ALL to develop rational combination strategies. We also looked at the preclinical efficacy of NWP-0476, a novel BCL-2/BCL-xL inhibitor, as single agent and combination therapy in T-ALL. We used BH3 profiling as a predictive tool for BH3 mimetic response in T-ALL. Using isogenic control, venetoclax-resistant (ven-R) and NWP-0476-resistant (NWP-R) cells, phosphokinase array was performed to identify differentially regulated signaling pathways. Typical T-ALL cells had increased dependence on BCL-xL, whereas early T-precursor (ETP)-ALL cells had higher BCL-2 dependence for survival. BCL-2/BCL-xL dual inhibitors were effective against both subtypes of T-lineage ALL. A 71-protein human phosphokinase array showed increased LCK activity in ven-R cells, and increased ACK1 activity in ven-R and NWP-R cells. We hypothesized that pre-TCR and ACK1 signaling pathways are drivers of resistance to BCL-2 and BCL-xL inhibition, respectively. First, we silenced LCK gene in T-ALL cell lines, which resulted in increased sensitivity to BCL-2 inhibition. Mechanistically, LCK activated NF-κB pathway and the expression of BCL-xL. Silencing ACK1 gene resulted in increased sensitivity to both BCL-2 and BCL-xL inhibitors. ACK1 signaling upregulated AKT pathway, which inhibited the pro-apoptotic function of BAD. In a T-ALL patient-derived xenograft model, combination of NWP-0476 and dasatinib demonstrated synergy without major organ toxicity. LCK and ACK1 signaling pathways are critical regulators of BH3 mimetic resistance in T-ALL. Combination of BH3 mimetics with tyrosine kinase inhibitors might be effective against relapsed T-ALL.

Bioactive compounds profile of extracts from Pereskia aculeata Miller leaves prepared with different solvents by ultrasound-assisted extraction

The ultrasound-assisted extraction (UAE) technique is an emerging method of recovering bioactive molecules, which has the advantages of low cost and good yield, in addition to meeting the requirements of green chemistry. The present work aimed to optimize the UAE in obtaining bioactive compounds from ora-pro-nobis leaves using seven different solvents in the extraction process. The analysis of the crude extracts by chromatographic methods (GC-MS and LC-MS/MS) revealed a nonpolar hydrocarbon mixture rich in triacontan, steroids, flavonoids and diterpene, among which we highlight the acids (malic, ferulic, palmitic, linoleic, gluconic), as well as phytol, campesterol, γ-sitosterol and silicic acid. The exploratory multivariate statistical analysis performed through principal component analysis (major chemical compounds, chemical class and solvent toxicity) allowed the election of ethanol as the best solvent for the recovery of interest compounds via UAE. Taken together, the results indicate that P. acuelata has a large number of bioactive compounds in its cellular structure, and that UAE is an efficient technique for the recovery of such molecules.

Preclinical Evaluation of a 64Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma.

Although the concept of theranostics is neither new nor exclusive to nuclear medicine, it is a particularly promising approach for the future of nuclear oncology. This approach is based on the use of molecules targeting specific biomarkers in the tumour or its microenvironment, associated with optimal radionuclides which, depending on their emission properties, allow the combination of diagnosis by molecular imaging and targeted radionuclide therapy (TRT). Copper-64 has suitable decay properties (both β+ and β- decays) for PET imaging and potentially for TRT, making it both an imaging and therapy agent. We developed and evaluated a theranostic approach using a copper-64 radiolabelled anti-CD138 antibody, [64Cu]Cu-TE1PA-9E7.4 in a MOPC315.BM mouse model of multiple myeloma. PET imaging using [64Cu]Cu-TE1PA-9E7.4 allows for high-resolution PET images. Dosimetric estimation from ex vivo biodistribution data revealed acceptable delivered doses to healthy organs and tissues, and a very encouraging tumour absorbed dose for TRT applications. Therapeutic efficacy resulting in delayed tumour growth and increased survival without inducing major or irreversible toxicity has been observed with 2 doses of 35 MBq administered at a 2-week interval. Repeated injections of [64Cu]Cu-TE1PA-9E7.4 are safe and can be effective for TRT application in this syngeneic preclinical model of MM.

Graphite Furnace Atomic Absorption Spectrometry for Biomonitoring of Blood Lead Level in Quality Control Blood Materials

Background & Objective: Lead (Pb) is a major toxicant that has threatened human health for years. There is no safe level of exposure and deposition of a small amount of Pb in the human body has a negative impact on an individual's health. Despite recent reductions in its use, it has caused extensive environmental contamination as well. In the present study,the intralaboratory quality control assessment is reported as an initial step in lead determination by Graphite furnace atomic absorption spectrometry (GFAAS).
 Materials & Methods: Varian SpectrAA-220 with partition tube and deuterium background correction was used for the analysis. The evaluation quality control blood material was Seronorm trace elements whole blood (levels I &II).
 Results: The lowest method limit of detection was 0.74 μg/dL, and based on the regression analysis, the lowest quantification concentration was 3.00 μg/dL (CV = 4.6 %). In addition, obtained %CV for Seronorm (I) & Seronorm (II) was 7.3% & 5.4% respectively.
 Conclusion: In recent years, several diverse technological advancements in blood lead level determination have occurred. At the same time, demands for blood lead (BPb) level determination by GFAAS has been increased by public health in order to identify children exposed to lead in the environment, and by occupational health to reduce excessive exposure in the lead industries. The obtained results indicated that for BPb analysis, the method described by GFAAS is still a reference routine analytical technique that requires less time and no matrix matched standard curve, allowing blood samples to be run against aqueous calibration standards which eliminates the need for standard additions.

Phase II Study of Myeloablative 7-8/8-Matched Allotransplantation with Post-Transplantation Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil

Graft-versus-host disease (GVHD) is the major toxicity of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that a GVHD prophylaxis regimen of post-transplantation cyclophosphamide (PTCy), tacrolimus (Tac), and mycophenolate mofetil (MMF) would be associated with incidences of acute and chronic GVHD in patients receiving a matched or single antigen mismatched HCT. This Phase II study was conducted at the University of Minnesota using a myeloablative regimen of either total body irradiation (TBI) at a total dose of 1320 cGy, administered in 165-cGy fractions, twice daily from day -4 to day -1, or busulfan (Bu) 3.2 mg/kg daily (cumulative area under the curve, 19,000 to 21,000 μmol/min/L) plus fludarabine (Flu) 40 mg/m2 once daily on days -5 to -2, followed by a GVHD prophylaxis regimen of PTCy 50 mg/kg on days +3 and +4, Tac, and MMF beginning on day +5. The primary endpoint was the cumulative incidence of chronic GVHD necessitating systemic immunosuppression (IST) at 1 year post-transplantation. Between March 2018 and May 2022, we enrolled 125 pediatric and adult patients, with a median follow-up of 813 days. The incidence of chronic GVHD necessitating systemic IST at 1 year was 5.5%. The rate of grade II-IV acute GVHD was 17.1%, and that of grade III-IV acute GVHD was 5.5%. Two-year overall survival was 73.7%, and 2-year graft-versus-host disease-free, relapse-free survival was 52.2%. The 2-year cumulative incidence of nonrelapse mortality was 10.2%, and the rate of relapse was 39.1%. There was no statistically significant difference in survival outcomes between recipients of matched donor transplants versus recipients of 7/8 matched donor transplants. Our data show that myeloablative HCT with PTCy/Tac/MMF results in an extremely low incidence of severe acute and chronic GVHD in well-matched allogeneic HCT.

Impact of acute kidney injury on overall survival in postoperative patients with head and neck cancer who received chemoradiotherapy with cisplatin: A supplementary analysis of a phase II/III trial of JCOG1008.

6079 Background: A randomized phase II/III trial of JCOG1008 demonstrated that chemoradiotherapy (CRT) with weekly cisplatin at 40 mg/m2 (Weekly arm) was noninferior to 3-weekly cisplatin at 100 mg/m2 (3-weekly arm) in terms of overall survival (OS) for postoperative high-risk head and neck cancer (hazard ratio [HR], 0.69 [99.1% CI, 0.37 to 1.27 < 1.32]; J Clin Oncol 2022; 40: 1980-90). Acute kidney injury (AKI) is a major dose-limiting toxicity of cisplatin. Here, we investigated the impact of AKI on OS in patients treated with CRT in JCOG1008. Methods: A total of 251 patients who were treated with CRT in JCOG1008 were analyzed. AKI was defined as an increase in serum creatinine of ≥0.3 mg/dL or a 1.5-fold or more increase from baseline (≥stage I) within 30 days after completion of CRT, based on the AKI Network classification/staging system. OS in the two arms was compared by the development of AKI using the log-rank test. Results: The total incidence of AKI in the weekly arm was lower than that in the 3-weekly arm (38 of 122 [31.1%] vs. 56 of 129 [43.4%]). The incidence of stage II/III AKI was also lower in the weekly arm (8 of 122 [6.6%] vs. 19 of 129 [14.7%]). Total cisplatin dose was similar in patients who did and did not develop AKI in the weekly arm, but was lower in patients who developed AKI in the 3-weekly arm (Table). Moreover, no difference in OS was observed between patients who did and did not develop AKI in the weekly arm (HR, 1.06 [95% CI, 0.53 to 2.10]), whereas patients who developed AKI in the 3-weekly arm had poorer OS than those who did not (HR, 1.83 [95% CI, 1.04 to 3.21]). Conclusions: In this supplementary analysis of JCOG1008, development of AKI impacted OS in the 3-weekly arm, but not in the weekly arm. Consistent exposure to cisplatin through weekly fractionated administration appears of greater clinical significance than cumulative dose, providing maintenance of treatment intensity and better kidney safety, and likely also improving outcomes. Clinical trial information: jRCTs031180135 . [Table: see text]

Pharmacodynamic Model-Based Safety Management of Eribulin-Induced Myelosuppression in Patients With Breast Cancer.

Neutropenia is a major dose-limiting toxicity of cancer chemotherapy. Semimechanistic mathematical models have been applied to describe the time course of neutrophil counts. The objectives of this study were to develop a mathematical model describing changes in neutrophil counts during eribulin treatment, to apply the empirical Bayes method to predict the probability of developing neutropenia ≥ grade 3 during eribulin treatment in each patient, and to propose the implementation of this mathematical tool in clinical practice for individual safety management. The present model analysis and subsequent external evaluation were performed using the data of 481 patients with breast cancer, previously obtained from a postmarketing surveillance (training set) and a phase 2 clinical study (validation set). The model we previously reported (Kawamura et al 2018) was modified to improve its predictive capability. The individual time course of neutrophil changes during the treatment period was predicted by the empirical Bayes method using the observed neutrophil counts at baseline and the first measurement after the first eribulin dose. To evaluate the predictability of this method, the predicted neutrophil counts were compared with those of the observed values. The developed model provided good individual predictions, as indicated by the goodness-of-fit plots between the predicted and observed neutrophil counts, especially for a lower neutrophil count range. Days required to reach the nadir after the dose were also well-predicted. The sensitivity, specificity, and accuracy of the prediction of neutropenia grade ≥3 were 76%, 53%, and 71%, respectively. We developed a mathematical method for predicting and managing the risk of neutropenia during eribulin treatment. This method is generally applicable to other cases of chemotherapy-induced neutropenia and can be a new practical tool for individual safety management.

Plinabulin to shorten neutropenia and improve quality of life peri-autologous hematopoietic cell transplant.

8023 Background: Plinabulin is a selective immunomodulating microtubule-binding agent, which prevents chemotherapy induced neutropenia (CIN) via a mechanism of action different from that of G-CSF analogues. It has been studied for CIN and anti-solid tumor activity in phase 3 trials. To decrease the period of myelosuppression and obligate neutropenia after high dose melphalan with autologous hematopoietic stem cell transplantation (AHCT) for patients with multiple myeloma, we studied the addition of plinabulin to standard growth factors. Methods: To achieve the primary objective of reducing the duration of absolute neutropenia post AHCT, 40mg of intravenous plinabulin was given 1-3 hours after stem cell infusion (Day 0) with pegfilgrastim on Day +1 in this pilot trial (NCT05130827). Secondary objectives include the safety, tolerability, and toxicity profile of plinabulin in combination with pegfilgrastim, neutrophil and platelet engraftment rate, disease response, progression free and overall survival, patient reported outcome (PRO) assessment of symptom burden, and plinabulin pharmacokinetic profiling. Exploratory objectives include transfusion requirements, phenotypic characterization of neutrophil population through day 30, and analysis of cytokine levels early post AHCT. Results: Between January 2022 and February 2023, 15 patients with median age of 64 (range 54-74) and 33% female received plinabulin after melphalan 140 (n = 4) or 200mg/m2 (n = 11). Median CD34+ cells/kg infused was 4.12 x 10^6 (range 2.18 – 7.85). Half of the patients had hypertension immediately after the plinabulin infusion, which is a known toxicity and resolved within a few hours. Median WBC on Day 0, 1, and 2 was 7.67(3.6 – 11.5), 5.2 (3.2 – 13.6), and 17.1 (5.1-59.1), respectively. Of the 14 patients who have engrafted to date, median time to ANC > 0.5 x 10^9 cell/L was 11 days (range 9-16) with median days from AHCT to ANC < 0.5 of 5 days (range 5-6). The median number of days of ANC < 0.1 and < 0.5 were 2 (range 1-5) and 5 days (range 4-9), respectively. For the 7 patients who had a fever, the median time to fever was 8 days from AHCT (range 8-12), and all except one were peri-engraftment. Median length of stay was 17 days (range 15-21). Median pRBC and platelet transfusions were 0 (range 0-3) and 3 (range 0-11), respectively. Conclusions: Plinabulin appears well tolerated without additional major toxicities post AHCT and provided a high WBC on Day +2 and decreased rate of neutropenic fever. Plinabulin PK, quality of life data, and PROs will be presented. Adjusting the schedule of plinabulin to later post AHCT pre engraftment may further shorten the duration of neutropenia using this novel mechanism of action. Clinical trial information: NCT05130827 .

COMBINED MODALITY ULTRA‐LOW‐DOSE ADAPTIVE RADIOTHERAPY AND RITUXIMAB AS TREATMENT STRATEGY FOR INDOLENT NON‐HODGKIN LYMPHOMAS: THE UT SOUTHWESTERN EXPERIENCE

Introduction: For indolent non-Hodgkin lymphomas (iNHL), ultra-low-dose radiation therapy (ULDRT) with 4 Gy (2 Gy × 2 or “boom-boom”) has demonstrated durable local control (70%), though distal relapses may occur. Concurrent systemic chemotherapy with RT extends PFS but is often avoided due to toxicity. We hypothesize that the combination of adaptive ULDRT and single-agent rituximab results in excellent local and systemic control with minimal toxicity. Methods: We conducted an IRB approved retrospective review of patients with iNHL who were treated with both ULDRT and rituximab (4 weekly doses of 375 mg/m2) as frontline therapy, either concurrently, or within a short interval (median 13 days), at our institution from 2017-2023. Treatment response and disease control (local and distant) were measured. Overall and progression-free survival (OS and PFS) were analyzed using the Kaplan-Meier method. Results: Baseline patient characteristics and treatment sites are shown in Table 1. The overall response rate at first follow up was 21/22 (95%), of which 17 sites (77%) achieved complete response (CR), 4 (18%) partial response (PR), and 1 (5%) stable disease (SD). Of those with PR, 1 had residual disease in-field, 1 out-of-field, and 2 both in- and out-of-field of RT. Repeat ULDRT was given to sites of PR with all achieving CR except for 1 patient with both in and out-of-field PR who declined salvage RT and was managed with active surveillance with SD on last follow up. Two patients experienced mild acute RT-related toxicities (diarrhea and dysgeusia), and 1 patient with Sjogren’s syndrome experienced long-term mild dry mouth. There were no major toxicities associated with rituximab. Of 14/22 initially symptomatic treatment sites, 12/14 (86%) noted resolution after treatment. In our cohort, the 2-year PFS and OS were 86% and 100%, respectively. The median time to relapse was 23 months. Of the patients who relapsed, 1 relapsed in-field, and 2 relapsed both in- and out-of-field of ULDRT. Two of these patients were retreated with ULDRT, while one is undergoing systemic treatment with bendamustine/rituximab. Conclusion: The combination of rituximab and ULDRT demonstrates sustained local and distant disease control with minimal side effects in iNHL. In situations where there is prohibitive toxicity risk for chemotherapy and/or higher radiation doses, this strategy presents a reasonable alternative. Further studies are needed to elucidate potential mechanisms of synergy and define the optimal use of this treatment paradigm. Keywords: combination therapies, indolent non-Hodgkin lymphoma, radiation therapy Conflicts of interests pertinent to the abstract G. Kaur Employment or leadership position: SANOFI, BMS, Janssen, Cellectar, Arcellx Consultant or advisory role Advisory

Correction: Bringolf et al. Major Ion Toxicity to Glochidia of Common and Imperiled Freshwater Mussel Species. Diversity 2022, 14, 95

Figures 5 and 6 (and their corresponding legends) were inadvertently omitted from the final publication of the original paper [...]

Vitamin D and calcium co-therapy mitigates pre-established cadmium nephropathy by regulating renal calcium homeostatic molecules and improving anti-oxidative and anti-inflammatory activities in rat

BackgroundCadmium (Cd) is a major environmental pollutant and chronic toxicity could induce nephropathy by increasing renal oxidative stress and inflammation. Although vitamin D (VD) and calcium (Ca) prophylactic treatments attenuated Cd-induced cell injury, none of the prior studies measure their renoprotective effects against pre-established Cd-nephropathy. AimsTo measure the alleviating effects of VD and/or Ca single and dual therapies against pre-established nephrotoxicity induced by chronic Cd toxicity prior to treatment initiation. MethodsForty male adult rats were allocated into: negative controls (NC), positive controls (PC), Ca, VD and VC groups. The study lasted for eight weeks and all animals, except the NC, received CdCl2 in drinking water (44 mg/L) throughout the study. Ca (100 mg/kg) and/or VD (350 IU/kg) were given (five times/week) during the last four weeks to the designated groups. Subsequently, the expression of transforming growth factor-β (TGF-β1), inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), VD synthesising (Cyp27b1) and catabolizing (Cyp24a1) enzymes with VD receptor (VDR) and binding protein (VDBP) was measured in renal tissues. Similarly, renal expression of Ca voltage-dependent channels (CaV1.1/CaV3.1), store-operated channels (RyR1/ITPR1), and binding proteins (CAM/CAMKIIA/S100A1/S100B) were measured. Serum markers of renal function alongside several markers of oxidative stress (MDA/H2O2/GSH/GPx/CAT) and inflammation (IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 were also measured. ResultsThe PC group exhibited hypovitaminosis D, hypocalcaemia, hypercalciuria, proteinuria, reduced creatinine clearance, and increased renal apoptosis/necrosis with higher caspase-3 expression. Markers of renal tissue damage (TGF-β1/iNOS/NGAL/KIM-1), oxidative stress (MDA/H2O2), and inflammation (TNF-α/IL-1β/IL-6) increased, whilst the antioxidants (GSH/GPx/CAT) and IL-10 decreased, in the PC group. The PC renal tissues also showed abnormal expression of Cyp27b1, Cyp24a1, VDR, and VDBP, alongside Ca-membranous (CaV1.1/CaV3.1) and store-operated channels (RyR1/ITPR1) and cytosolic Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B). Although VD was superior to Ca monotherapy, their combination revealed the best mitigation effects by attenuating serum and renal tissue Cd concentrations, inflammation and oxidative stress, alongside modulating the expression of VD/Ca-molecules. ConclusionsThis study is the first to show improved alleviations against Cd-nephropathy by co-supplementing VD and Ca, possibly by better regulation of Ca-dependent anti-oxidative and anti-inflammatory actions.

Caesalpinia bonducella mitigates oxidative damage by paracetamol intoxication in the kidney and intestine via modulating pro/anti-inflammatory and apoptotic signaling: an In vivo mechanistic insight.

Protracted use of paracetamol at therapeutic/toxic doses readily induces major organ toxicity and poor clinical efficacy. Caesalpinia bonducella seeds possess a diverse range of biological and therapeutic activities. Thus, our study aimed to scrutinize the toxic effects of paracetamol and the potential renal and intestinal protective effects of Caesalpinia bonducella seed extract (CBSE). To Wistar rats, CBSE was administered for 8days (300mg/kg, p.o.) with or without paracetamol (2000mg/kg, p.o.) on the 8th day. Pertinent toxicity assessments in the kidney and intestine were analyzed at the end of the study. The CBASE's phytochemical components were examined using gas chromatography-mass spectrometry (GC-MS). After the study period, study findings evidenced that paracetamol intoxication induced elevation of renal enzyme indicators, oxidative damage, imbalance with the pro/anti-inflammatory production and pro/anti-apoptotic mediators, and tissue injury; all repercussions were alleviated by pre-treatment with CBASE. CBASE considerably reduced (P < 0.05) paracetamol-induced kidney and intestine injury by limiting caspase-8/3 signaling and amplification of inflammation in renal and intestinal tissue by significantly reducing pro-inflammatory cytokine production. As per the GC-MS report, three main bioactive components-Piperine, Isocaryophyllene, and Tetradec-13-en-11-yn-1-ol were predominant and have protective activities. Our study ascertains that CBSE pre-treatment exerts potent renal and intestine protection against paracetamol intoxication. Thus, CBSE could be a prospective therapeutic candidate for protecting the kidney and intestine from the severity of paracetamol intoxication.