Excessive Toxicity Research Articles

Durvalumab impacts progression-free survival while high-dose radiation >66 Gy improves local control without excess toxicity in unresectable NSCLC stage III: Real-world data from the Austrian radio-oncological lung cancer study association registry (ALLSTAR)

BackgroundChemo-radioimmunotherapy with total radiation doses of 60–66 Gy in 2 Gy fractions is the standard of care for non-small cell lung cancer (NSCLC) UICC stage III. The Austrian radio-oncological lung cancer study association registry (ALLSTAR) is a prospective multicentre registry intended to document clinical practice at the beginning of the Durvalumab era. Patients and methodsPatients were eligible if they had pathologically verified unresectable NSCLC stage III with a curative treatment option. Chemo-radiation combined with immunotherapy was performed according to local treatment practices. The endpoints were local control (LC), progression-free survival (PFS) and toxicity. ResultsBetween 2020/03 and 2023/04, 12/14 (86 %) Austrian radiation-oncology centres recruited 188 patients (median 17, range: 1–89). PD-L1 testing was performed in 173/188 (93 %) patients. The median interval between the end of chemoradiotherapy and start of Durvalumab was 14 days (range: 1–65). About 40 % (75/188) of the patients received a total radiation dose of > 66 Gy (range: 67.1–100), which improved 2-year LC (86 % versus 60 %, HR = 0.41; 95 %-CI: 0.17–0.98; log-rank p-value < 0.05). Median PFS for patients with Durvalumab was 25.8 months (95 %-CI: 21.9-not reached) compared to 15.7 months (95 %-CI: 13.2–27.8) for those without (HR = 1.88; 95 %-CI: 1.16–3.05; log-rank p-value < 0.01). The rates of esophageal and pulmonary toxicities were 34.6 % and 23.9 %, respectively, including one case of grade 4 pneumonitis. In the subcohort of 75 patients who received > 66 Gy, 19 (25 %) cases of pulmonary toxicity grades 1–3 were observed. ConclusionWhile Durvalumab impacts PFS, LC can be improved by total radiation doses > 66 Gy without excess toxicity.

A phase IV study to evaluate the safety of fruquintinib in Chinese patients in real-world clinical practice.

Fruquintinib is approved in China for patients with metastatic colorectal cancer (CRC) who progressed after 2 lines of chemotherapy. This postmarketing study was conducted to evaluate the safety of fruquintinib in the Chinese population, including previously treated patients with advanced CRC and other solid tumors. Patients in the first cycle of fruquintinib or expected to start fruquintinib within a week were enrolled. Fruquintinib was administrated according to the label or per physicians' discretion. Patient characteristics and safety information were collected at baseline, 1 month, and 6 months after consent (or 30 days after the last dose). Overall, 3005 patients enrolled between April 24, 2019 and September 27, 2022. All enrolled patients received at least one dose of fruquintinib. Most patients had metastases at baseline. The median age was 60 years. More than half (64.0%) of the patients started fruquintinib at 5 mg, and the median treatment exposure was 2.7 months. Nearly one-third (32.5%) of patients with CRC received fruquintinib with concomitant antineoplastic agents. Treatment-emergent adverse events (TEAEs) leading to dose modification were reported in 626 (20.8%) patients, and 469 (15.6%) patients experienced TEAEs leading to treatment discontinuation. The most common grade ≥ 3 TEAEs were hypertension (6.6%), palmar-plantar erythrodysesthesia syndrome (2.2%), and platelet count decreased (1.0%). Combination therapy did not lead to excessive toxicities. The safety profile of fruquintinib in the real world was generally consistent with that in clinical studies, and the incidence of TEAEs was numerically lower than known VEGF/VEGFR inhibitor-related AEs. Fruquintinib exhibited manageable safety and tolerability in Chinese patients in the real-world setting.

Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and “KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240mg daily (mg/d). Thus, the current 80mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40mg/d is non-inferior to 80mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70years, using a regression discontinuity design. Osimertinib is administered at 40mg/d for body weight ≤50kg, and 80mg/d for body weight >50kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

Abstract 3211: Development of first in class zip code drug conjugate in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PC) is the fourth most common cancer-related cause of death in Western countries. It is projected that PC will become the second most prevalent cause of cancer-related mortality by the year 2030. Although chemotherapy may offer certain advantages to those who have been diagnosed with pancreatic cancer, its effectiveness is notably constrained by the emergence of chemoresistance and excessive toxicity. In recent studies, it has been established that circulating tumor DNA (ctDNA) serves as a mechanism for cell-specific genetic transfer. We discovered that transposon sequences (known as Zip Codes, ZC) were responsible for ctDNA cell targeting. Therefore, we investigated the possibility of hijacking these ZC to deliver drugs specifically. We began by determining whether PDCA ZC synthesized chemically could target PDCA cells selectively. To achieve this, ZC sequences were labeled with CY5 for high-throughput microscopy. Results show that numerous PDCA-ZC were specific and efficient at targeting PC cell lines while sparing other cancer cell lines. The AluSc8 (PCZC) sequence was chosen for further investigation. The specificity of PCZC for targeting cells was validated using pancreatic islet cells. Based on these findings, we developed a technique for conjugating PCZC with SN38 via a CL2A linker. The results indicated that PCZC-SN38 was a very effective agent at killing PC cells (IC50: 1 μg), but not other cancer cell lines. The therapeutic efficacy of PCZC-N38 was evaluated in vivo using PDX (patient-derived xenografts, Garcia et al Plos One 2013). Maximum tolerated dose testing (MTD) (dosing from 1 to 21 mg of PCZC-SN38/Kg) failed to reach an MTD. Subsequently, we evaluated the efficacy signal of PCZC-SN38 by administering PCZC-SN38 to animals three times per week for three weeks at concentrations of 3 and 30 mg/kg of DNA (equivalent to 0.05 and 0.5 SN38 mg/kg). We used animals treated with vehicle, PCZC alone, and irinotecan (either once per week (50 mg/kg) or three times per week (0.5 mg/Kg) as a comparison. PCZC-SN38 decreased tumor growth by 41% and 70%, respectively, when compared to the vehicle or PCZC alone. The observed efficacy did not result in a change in body weight. In contrast, every animal administered irinotecan at a dosage of 50 mg/kg died within a week. On the contrary, animals that were given irinotecan at a dosage of 0.5 mg/kg demonstrated a growth inhibition of 60% and exhibited remarkable tolerability. Currently, research is being undertaken to determine the therapeutic efficacy of PCZC-SN38 at higher doses. The results outlined in this study illustrate the preliminary application of PC targeted drug delivery using a PC zip code drug conjugate. The results of our study demonstrate an innovative methodology for targeting PC cells specifically with therapeutic cargo material and supports further preclinical development of PCZC-SN38 for PC. Citation Format: Munnever Cinar, Purnachandra Ganji, Andrey Pisarev, Lourdes Martinez-Medina, Dhana S. Bandi, Pavan K. Puvvula, Steven Chang, Daniel Maneval, Bassel El-Rayes, Leon Bernal-Mizrachi. Development of first in class zip code drug conjugate in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3211.

Abstract 5820: An antibody drug conjugate platform based on novel camptothecin payloads with branch hydrophilic linkers and site-specific conjugation

Abstract Antibody-drug conjugates (ADCs) have recently gained momentum as a therapeutic modality for the cell-specific delivery of small molecules beyond their originally-intended purpose of treating cancer. However, the selection of combinations of an optimum target, antibody, payload, linker as well conjugation, to achieve maximal therapeutic efficacy without excessive toxicity, still presents a significant challenge. Topoisomerase I (Topo I) inhibitors such as camptothecin (CPT) analogs represent the much success in ADC payload applications as two CPT analog-ADCs, trastuzumab deruxtecan (DS-8201a—Enhertu®) with Dxd payload and sacituzumab govitecan (TrodelvyTM) with SN38 payload have been approved and over 20 CPT analog-ADCs are in the clinical trials now. Topo I inhibitors trigger cell apoptosis through their specific binding at the DNA-topoisomerase interface, leading to the inhibition of DNA supercoiling and entanglement, resulting in DNA damage and cell death. This class of payloads in ADCs has demonstrated more wider therapeutic windows in clinical trials than regular antitubulin payloads, such as maytansine and MMAE, based ADCs. Here, we detail the discovery of CPT analogs, as payloads with a branch hydrophilic linker and site-specific conjugation for ADCs designed to have a widened therapeutic window compared with Dxd-GGFG linked ADCs. The CPT analogs based on the core structure of SN-38, wherein the hydrogen of C-11 was replaced with fluorine, and the hydroxyl group of C-10 was optionally replaced with an amino or a ether group. Many of the novel CPT analogs were at single to tens of pM of IC50 potency in vitro against several tested tumor cell lines, and some were more potent than Exatecan in the comparison tests. The ADCs constructed with branch hydrophilic linkers and the CrossConjuTM technology of chemically site-specific conjugation at Fab region of an antibody through C-10 position of the CPT payloads either with amide bond, either bond or carbamide bonds, or through C-20 position of the CPT payloads with carbamide or carbonate bonds, exhibited much better antitumor efficacy in vivo CDX tumor models, while having higher or similar MTDs in mice toxicity study in comparison with the ADC constructed with GGFG-Dxd, demonstrated wider therapeutic widows than that conjugated with GGFG-Dxd. Moreover, some of the constructed ADCs can overcomes in vitro- and in vivo-acquired resistance of commercial therapeutic drugs. Herein, we showcase our platform approach in CPT-ADC designs and constructions and can be thereby broadly applicable to construction of various CPT-ADCs for targeted treatment of cancers. Citation Format: Yuanyuan Huang, Hangbo Ye, Qingliang Yang, Lingli Zhang, Huihui Guo, Xiaolei Liu, Wenjun Li, Lu Bai, Junxiang Jia, Juan Wang, Xiangfei Kong, Jun Zheng, Yifang Xu, Gengxiang Zhao, Linyao Zhao, Xiang Cai, Ziyu Zhao, Hui Xia, Xia Zhou, You Zhou, Robert Y. Zhao. An antibody drug conjugate platform based on novel camptothecin payloads with branch hydrophilic linkers and site-specific conjugation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5820.

Abstract 4689: 4HF CancerDataMiner platform accelerates target discovery and evaluation

Abstract For the management of metastasized cancer, tumor-targeted chemotherapies with improved therapeutic index are urgently needed. Over the last 25 years, antibody drug conjugates (ADCs) targeting cancer-associated proteins have emerged as a promising new treatment modality. While the first ADCs were registered for the treatment of acute leukemias and lymphomas, more recently at least six ADCs were approved by the FDA for solid tumors. Despite these successes, clinical development of ADCs remains a risky exercise as evident from the failure of more than 20 pivotal clinical phase III trials. A narrow therapeutic index due to excessive toxicity of potent payloads, little therapeutic activity, and difficulties in chemistry, manufacturing, and controls were among the limiting factors. Meanwhile, ADC technology and production have advanced substantially. More than 100 ADCs are currently in clinical development in approximately 600 clinical trials, with some of the investigated ADCs being close to approval. While issues related to ADC linkers and payloads have been extensively investigated and many problems have been solved, the choice of molecular targets for ADCs remains challenging. This is, in part, due to a lack of information about candidate targets: while knowledge about generally accepted cancer targets such as ERBB2 is abundant, data about many novel targets is still scarce. In particular, reliable information about expression in normal tissues, subcellular localization and protein function is often missing. 4HF Biotec has established the CancerDataMiner, an in-silico platform dedicated to cancer data mining by integrating large OMICS datasets that are connected and aligned. It allows molecular analyses of all human genes in &amp;gt;12,000 tumor samples and &amp;gt;14,000 normal tissues, using proprietary tools and widgets for visualization and statistics. Target evaluations are performed at the DNA, RNA and protein levels and employ complementary tools such as pathway analysis and literature search to obtain a comprehensive picture of candidate targets. Using this approach, we recently reviewed the molecular targets of all ADCs that either have already received approval or are in clinical development. As proof-of-concept for the CancerDataMiner, here we analyze targets of ADCs and compare our findings with the clinical data obtained for those ADCs. The profiles of selected ADC targets will be discussed, among them CD79B and CD33 for hematologic malignancies and FOLR1 and Claudin 18.2 for solid cancers. We will demonstrate that proteins with very diverse profiles can make good ADC targets. In conclusion, the 4HF CancerDataMiner is a platform which has proven its value for the identification and characterization of cancer-associated targets for ADC development for all tumor types. Citation Format: Heinz-Herbert Fiebig, Anne-Lise Peille, Mirko Schmitz, Vincent Vuaroqueaux, Thomas Metz. 4HF CancerDataMiner platform accelerates target discovery and evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4689.

MET alterations in advanced non-small cell lung cancer

Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.

Nano-enabled pesticides: a comprehensive toxicity assessment of tebuconazole nanoformulations with nematodes at single species and community level

There is an increasing imperative to explore safer alternatives for pesticides due to their indiscriminate use and consequential health impacts on the environment and humans. Nanoformulations of pesticides are being developed as potential alternatives due to their beneficial properties, including enhanced solubility, targeted delivery to the site of action, improved stability and efficacy and reduced non-target effects. Nevertheless, a comprehensive assessment is necessary for these emerging nanopesticides compared to existing formulations, aiming to ascertain whether their "nano" characteristics exacerbate toxicity for non-target organisms. This study investigated the toxicity of tebuconazole (TBZ) in different formulations, including nanoformulations (poly-ε-caprolactone [PCL] and nanostructured lipid carrier [NLC] loaded with TBZ), as well as a commercial formulation, on the reproduction of the nematode Caenorhabditis elegans in both aqueous and soil matrices. Additionally, the impact of the correspondent nanocarriers without TBZ on C. elegans was examined. In water, TBZ in the form of nano and commercial formulations exhibited higher toxicity on the nematodes' reproduction than the TBZ (a.s.) attributable to higher freely dissolved concentrations of TBZ, which resulted in a toxicity order, ranging from the most to the least toxic as follows: NLC-TBZ > PCL-TBZ > commercial formulation > TBZ (a.s.). For NLC-TBZ, the excess toxicity could be clearly explained by combined toxicity of TBZ (a.s.) and nanocarriers, with the effect addition of the separate single compounds matching the observed effects of the nanoformulation. For PCL-TBZ, effects were stronger than expected from the effect addition of TBZ (a.s.) and PCL nanocarriers, potentially due to enhanced bioavailability of encapsulated TBZ in the gut of the nematodes. In soil, NLC with and without loaded TBZ showed higher toxicity than other tested compounds, while PCL nanocarriers without TBZ did not exhibit negative effects on the reproduction of C. elegans. Microcosm experiment, where long-term effects on native soil nematode fauna were tested, confirmed that TBZ-nanoformulations act via combined toxic effects of TBZ and nanocarriers. These findings contribute valuable insights to understanding nanopesticides' ecotoxicity and underscore the need for harmonized regulatory assessments to evaluate these novel formulations adequately.

High-Performance Electrochemical Sensor Based on Layer-by-Layer Assembly of [CQDs-PAH] Thin Film for Lead Ions Detection

According to the extraordinarily excessive toxicity of lead ions (Pb2+) to humans even by tiny dose nowadays, the development of transportable and pocketed electrochemical sensor to detect tiny amount of Pb2+ ions with excessive sensitivity is in a pressing need. In this study, the carbon quantum dots (CQDs) synthesized from glutathione (GSH) were applied as the sensing materials for sensitive lead ions detection via square wave voltammetry (SWV) analysis, which can specific adsorb lead ions owing to the abundant functional group especially sulfhydryl. To enhance the performance of this sensing strategy, we constructed layer-by-layer [LBL] assembled [CQDs-PAH] thin films, the thin films performed a LBL three-dimensional network structure, which provided larger contact area for CQDs and Pb2+ ions, and also accelerated electron transfer of the active materials, thus improved the electrochemical sensing performance efficiently. The [CQDs-PAH] thin films would offer a new paradigm to design high-efficient electrochemical sensor for Pb2+ ions detection.

Treatment patterns and outcomes by age in metastatic urothelial carcinoma (mUC): A retrospective tertiary cancer center analysis.

582 Background: Older adults with locally advanced or mUC often do not receive optimal first-line (1L) therapy (Rx) and subsequent treatments (Lara et al. ASCO 2016). There are limited randomized data for age-appropriate Rx in older mUC adults. Through our real-world study, we describe the clinical characteristics, treatment patterns, and outcomes among pts with mUC, comparing older to younger adults receiving 1L systemic Rx. Methods: This retrospective IRB-approved study included pts receiving care between 2014 and 2023 at the University of Utah, Huntsman Cancer Institute, a tertiary care National Cancer Institute-Designated Comprehensive Cancer Center. Eligible pts had a confirmed diagnosis of mUC and received 1L chemotherapy or 1L immunotherapy-based regimens. Based on age at receipt of 1L Rx, pts aged 70 years or above were grouped in the ‘older’ group, while rest were included in the ‘younger’ cohort. Survival and Rx-related outcomes of those enrolled inwere excluded. Overall survival (OS) between the two groups was compared using Kaplan-Meier and Cox Regression analysis. All statistical analyses were implemented in R-Studio (v.4.2). Results: We identified 212 eligible mUC pts (103 older vs. 109 younger). Older pts received more immunotherapy-based Rx in the 1L (52.4% vs 35.7%, p=0.02), were more likely to be (73.6% vs. 45.4%, p&lt;0.001), less likely to receive subsequent lines of Rx (median; range: 0 (0-3) vs 1 (0-5), p=0.005) and had lower clinical trial participation (69.9% vs 81.6%, p=0.04)compared to younger pts. For survival outcomes and treatment-related analysis, 160 patients (72 older vs. 88 younger) undergoing approved standard of care were included. Among mUC treated with 1L chemotherapy (n=108), more pts required dose adjustments in older group (23/43 vs 15/65 younger). Older adults received less number of cycles of chemotherapy (median; range: 4 (0-6) vs 5 (1-12), p= 0.03). Older pts had OS comparable to younger pts (11.2 mos vs. 14 mos, p=0.06). Pts from both age groups had similar rates of Rx-related toxicity and healthcare visits, independent of the type of systemic Rx. Conclusions: Older pts with mUC tend to be cis-ineligible and have lower bone marrow reserve. Nevertheless, select pts can be treated with risk-adjusted regimens of chemotherapy and with immunotherapy with comparable outcomes to younger mUC pts in terms of toxicity and outcomes. Validated tools to predict vulnerabilities and excessive chemotherapy-related toxicity in older adults with mUC are available and may help mitigate toxicity by informing Rx adjustments.

Nelarabine-containing salvage therapy and conditioning regimen in transplants for pediatric T-cell acute lymphoblastic leukemia and lymphoma.

Therapy for relapsed or refractory (r/r) T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) in children is challenging, and new treatment methods are needed. We retrospectively analyzed eight patients with r/r T-ALL (five patients) and T-LBL (three patients) who were treated with nelarabine (NEL) plus etoposide, cyclophosphamide, and intrathecal therapy, administered 3days apart. Five patients achieved a complete response, and the other three achieved a partial response (PR). All patients underwent hematopoietic stem cell transplantation (HSCT) after two cycles of treatment, except for one patient who received one cycle. Three patients who had previously received HSCT were treated with reduced-intensity conditioning regimens, including fludarabine, melphalan, and NEL; one survived for over 5years after the second HSCT. Grade 2 neuropathy occurred in one patient, but other severe toxicities commonly associated with NEL were not observed during NEL administration in combination with chemotherapy. The 2-year overall survival and event-free survival rates were 60.0% and 36.5%, respectively. The addition of NEL to reinduction chemotherapy was useful in achieving remission and did not lead to excessive toxicity. In addition, a conditioning regimen, including NEL, appeared to be effective in patients who had previously undergone HSCT.

Improving the Efficacy of Common Cancer Treatments via Targeted Therapeutics towards the Tumour and Its Microenvironment.

Cancer is defined as the uncontrolled proliferation of heterogeneous cell cultures in the body that develop abnormalities and mutations, leading to their resistance to many forms of treatment. Left untreated, these abnormal cell growths can lead to detrimental and even fatal complications for patients. Radiation therapy is involved in around 50% of cancer treatment workflows; however, it presents significant recurrence rates and normal tissue toxicity, given the inevitable deposition of the dose to the surrounding healthy tissue. Chemotherapy is another treatment modality with excessive normal tissue toxicity that significantly affects patients' quality of life. To improve the therapeutic efficacy of radiotherapy and chemotherapy, multiple conjunctive modalities have been proposed, which include the targeting of components of the tumour microenvironment inhibiting tumour spread and anti-therapeutic pathways, increasing the oxygen content within the tumour to revert the hypoxic nature of the malignancy, improving the local dose deposition with metal nanoparticles, and the restriction of the cell cycle within radiosensitive phases. The tumour microenvironment is largely responsible for inhibiting nanoparticle capture within the tumour itself and improving resistance to various forms of cancer therapy. In this review, we discuss the current literature surrounding the administration of molecular and nanoparticle therapeutics, their pharmacokinetics, and contrasting mechanisms of action. The review aims to demonstrate the advancements in the field of conjugated nanomaterials and radiotherapeutics targeting, inhibiting, or bypassing the tumour microenvironment to promote further research that can improve treatment outcomes and toxicity rates.

Cleistocalyx nervosum var. paniala berry extract and cyanidin-3-glucoside inhibit hepatotoxicity and apoptosis.

Excessive oxidative toxicity in liver cells is a significant risk factor that can cause cellular injury, leading to the development of chronic liver disease (CLD). Natural anthocyanins have been shown to prevent the harmful effects of oxidative toxicity in mammalian cells. Ripe Cleistocalyx nervosum var. paniala berry fruits are rich in anthocyanins, which have been reported to possess many health benefits. Therefore, this study examined the protective effect of ethanolic fruit extract of C. nervosum var. paniala (CNPE) against hydrogen peroxide (H2O2)-induced oxidative damage and cell death in human hepatoma HepG2 cells. Results showed that CNPE had strong antioxidant capabilities and high amounts of total phenolics and anthocyanins. HPLC analysis showed that CNPE consists of cyanidin-3-glucoside (C3G). Our investigations found that HepG2 cells pretreated with CNPE or anthocyanin C3G inhibited H2O2-induced cellular damage and apoptosis by increasing the viability of cells, the expression of antiapoptotic Bcl-2 protein, and the activities of cellular antioxidant enzymes, namely SOD, CAT, and GPx. Moreover, both CNPE and C3G significantly suppressed expression of apoptotic proteins (Bax and cytochrome c) and the activities of cleaved caspase-9 and caspase-3 caused by H2O2. Our results indicate that CNPE and C3G can suppress H2O2-induced hepatotoxicity and cell death through stimulation of endogenous antioxidant enzyme activities and inhibition of apoptosis pathway in HepG2 cells. These findings might support development of CNPE as an alternative natural product for preventing CLD.

Advanced Body Measurement Techniques Can Complement Current Methods of Cytotoxic Chemotherapy Dose Prescription

Within chemotherapy, estimates of a patient’s body surface area (BSA) are used to calculate drug dosages. However, the use of BSA for calculating chemotherapy dosage has been heavily criticised in previous literature, with potentially significant implications for the effectiveness and toxicity of treatment. BSA has been found to be a poor indicator of optimal drug exposure that does not account for the complex processes of cytotoxic drug distribution and elimination. In addition, differences in BSA estimates between existing formulae have been shown to be so large that they can affect patients’ mortality, particularly in patients with atypical body types. This uncertainty associated with BSA prediction may decrease the confidence of practitioners when determining chemotherapy dosages, particularly with regards to the risk of excess toxicity from over-dosing, or a reduced anti-cancer effect due to under-dosing. The use of national dose-banding in the UK may in some cases account for possible inaccuracies, but the threshold of variance in this case is small (+/−6%). Advanced body measurement techniques, utilising digital tools such as three-dimensional (3D) surface imaging, capture accurate external dimensions and detailed shape characteristics of the human body. Measures of body shape describe morphological variations that cannot be identified by traditional anthropometric techniques and improve the prediction of total body fat and distribution. It is our view that the use of advanced body measurement techniques can provide practitioners with tools for prescribing chemotherapy dosages that are valid for individuals, regardless of their body type.

Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.

Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear. MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-). Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP. We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.

Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. The Mitogen-Activated Protein kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. The sensor histidine kinase SlnASln1 is important for modulation of MpkA phosphorylation. Our work emphasizes the importance of MpkA and compartmentalization of cellular events for GT production and self-defense.

Alterations in Astrocyte Subpopulations in Glioma and Identification of Cuproptosis-Related Genes Using Single-Cell RNA Sequencing.

Mitochondrial metabolism is essential for energy production and the survival of brain cells, particularly in astrocytes. Cuproptosis is a newly identified form of programmed cell death that occurs due to the disruption of mitochondrial metabolism caused by excessive copper toxicity. However, the relationship between cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) and the prognosis of gliomas remains unclear. In this study, we utilized 32,293 cells obtained from three in-house single-cell RNA sequencing (scRNA-seq) datasets, along with 6,148 cells acquired from the Chinese Glioma Genome Atlas (CGGA) involving 14 glioma patients, to identify and validate the TME of gliomas. Based on an analysis of 32,293 single cells, we investigated intra-tumor heterogeneity, intercellular communication, and astrocyte differentiation trajectories in gliomas. Our findings revealed that the TGFβ signaling pathway exhibited a higher relative strength in astrocyte subpopulations. Additionally, we identified a novel three-gene signature (CDKN2A, SOX2, and MPC1) was identified for prognostic prediction. Furthermore, glioma patients with a high-risk score demonstrated poorer overall survival (OS) compared to those with a low-risk score in both training and testing datasets (P training set < 0.001; P test set = 0.037). Our study revealed the prognostic value of the CRGs in astrocytes exhibiting tumor immunosuppressive characteristics in glioma. We established a novel three-gene prognostic model that offers new insights into the prognosis and treatment strategies for gliomas.

You can't always get as much iron as you want: how rice plants deal with excess of an essential nutrient.

Iron (Fe) is an essential nutrient for almost all organisms. However, free Fe within cells can lead to damage to macromolecules and oxidative stress, making Fe concentrations tightly controlled. In plants, Fe deficiency is a common problem, especially in well-aerated, calcareous soils. Rice (Oryza sativa L.) is commonly cultivated in waterlogged soils, which are hypoxic and can cause Fe reduction from Fe3+ to Fe2+, especially in low pH acidic soils, leading to high Fe availability and accumulation. Therefore, Fe excess decreases rice growth and productivity. Despite the widespread occurrence of Fe excess toxicity, we still know little about the genetic basis of how rice plants respond to Fe overload and what genes are involved in variation when comparing genotypes with different tolerance levels. Here, we review the current knowledge about physiological and molecular data on Fe excess in rice, providing a comprehensive summary of the field.

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.