Treatment Toxicity Research Articles

Assessment of nutritional status in elderly patients with gastroesophageal cancer: A post hoc analysis.

389 Background: Elderly patients with gastroesophageal cancer (GEC) frequently suffer from malnutrition due to tumor location and treatment-related toxicity. Malnutrition is associated with increased morbidity and mortality in this population. This study investigates the relationship between body mass index (BMI), Mini Nutritional Assessment (MNA) scores, unintentional weight loss (UWL), and chemotherapy toxicity while identifying key factors influencing nutritional status. Methods: This post hoc analysis utilized data from a prospective, multicenter study of patients aged 65 and older with all stages of GEC undergoing chemotherapy. Nutritional assessments were conducted using validated tools, focusing on BMI, MNA, and UWL over three months post enrollment. We defined malnourished patients as those with abnormal BMI (<18.5 or >30), low MNA (0-11), and significant UWL (≥10%). We analyzed associations between nutritional status and geriatric assessment comorbidities, depression score, functional status, cognition, hospitalization, treatment toxicity, and social support using Fisher’s exact tests. Results: Eighty-two patients were enrolled, with a median age of 73 years (range 65-91 years). The cohort was predominantly male (74%) and primarily presented with stage III-IV disease (82%), most receiving first-line therapy (79%). Primary sites included gastric (32%), esophageal (43%), and gastroesophageal junction (26%). Notably, 34% of patients had abnormal BMI, with 2 patients classified as underweight (BMI <18.5) and 19 as obese (BMI >30). Approximately 69% reported UWL, of 10% or greater. MNA scores indicated malnutrition in about 66% of patients (severe (0-7): 15 patients; moderate (8-11): 37 patients), while 31% scored within the normal range (12-14).Hospital admissions were significantly higher in patients with low MNA (33% vs. 3%; p=0.002) and UWL (29% vs. 8%; p=0.047). No significant correlations were observed between nutritional status and treatment type, treatment toxicity, or other geriatric assessment variables, including functional status and social support. Conclusions: MNA and UWL are effective indicators of nutritional status in elderly GEC patients, while BMI is not a reliable measure. Malnutrition significantly correlates with increased hospital admissions, highlighting the need for reliable tools to measure malnutrition to implement necessary interventions. Further research is required to explore the broader implications of malnutrition on treatment outcomes and quality of life in this vulnerable population.

Management of Low-Grade Gliomas.

The term "low-grade glioma" historically refers to adult diffuse gliomas that exhibit a less aggressive course than the more common high-grade gliomas. In the current molecular era, "low-grade" refers to World Health Organization central nervous system grade 2 gliomas almost always with an isocitrate dehydrogenase (IDH) mutation (astrocytomas and oligodendrogliomas). The term "lower-grade gliomas" has emerged encompassing grades 2 and 3 IDH-mutant astrocytomas and oligodendrogliomas, to acknowledge that histological grade is not as important a prognostic factor as molecular features, and distinguishing them from grade 4 glioblastomas, which lack an IDH mutation. These grades 2 and 3 IDH-mutant tumors are characterized by indolent growth but are ultimately incurable in most cases, presenting significant management challenges. Physicians must carefully weigh all available evidence to balance improvements in survival from new treatments against treatment toxicities. This review summarizes the evidence guiding the treatment of these patients.

The prognostic significance of sarcopenia in patients treated with definitive radiotherapy: A systematic review.

Sarcopenia describes the degenerative loss of muscle mass and strength, and is emerging as a pan-cancer prognostic biomarker. It is linked with increased treatment toxicity, decreased survival and significant healthcare financial burden. Systematic analyses of sarcopenia studies have focused on outcomes in patients treated surgically or with systemic therapies. There are few publications concerning patients treated with radiotherapy. This manuscript presents a pan-cancer systematic review of the association between sarcopenia and survival outcomes in patients treated with definitive (chemo-)radiotherapy. A literature search was performed, with 26 studies identified, including a total of 5,784 patients. The prognostic significance of sarcopenia was mixed. This may reflect lack of consensus in methods used to measure skeletal muscle mass and define sarcopenia. Many papers analyse small samples and present sarcopenia cutoffs optimised on the local population, which may not generalise to external populations. Recent advances in artificial intelligence allow for automatic measurement of body composition by segmenting the muscle compartment on routinely collected imaging. This provides opportunity for standardisation of measurement methods and definitions across populations. Adopting sarcopenia diagnosis into clinical workflows could reduce futile treatments and associated financial burden, by reducing treatment toxicities, and improving treatment completion, patient survival, and quality-of-life after cancer.

Surufatinib combined with TAS-102 as a late-line therapy in patients with metastatic pancreatic cancer (mPDAC): Updated results of a single-arm, phase II trial.

739 Background: Patients (pts) with mPDAC recurrent after FOLFIRINOX and AG chemotherapies have few treatment options. Previous reports of NCT05481463 showed promising clinical benefits of surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) plus TAS-102 (combination of trifluridine and tipiracil hydrochloride) in recurrent mPDAC pts. Here, we report the updated results. Methods: This is a single-arm, phase II trial (NCT05481463). Eligible pts with histologically confirmed mPDAC, who had progressed after ≥ 2 lines of previous therapies were treated with surufatinib (250mg, qd, po, q4w) and TAS-102 (35 mg/m 2 , bid, po, days 1–5 and 8–12, q4w). The primary endpoint was progression-free survival (PFS). Key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: Up to Sep 18, 2024, 20 pts were enrolled (median age 58 years, male 70.0%, TNM stage IV 100.0%, ECOG PS 1 100.0%, liver metastasis 50.0%, peritoneum metastasis 50.0%). Median baseline CA19-9 level of the 20 pts was 996.7u/ml, with a range from 2u/ml to 16612u/ml. 40.0% of pts had received 3L prior therapies before enrollment and 70.0% with primary site on pancreatic body and tail. All pts had received at least one post-baseline tumor assessment (evaluable), among which ORR was 15.0% (3 PRs), DCR was 30.0% (3 PRs, 3SDs). 35.0% pts had stable or shrinking tumors. Median PFS was 2.35m (95% CI 1.91-3.94). Median OS was 6.44m (95% CI 3.81-NR). In subgroup analysis, significantly longer PFS&OS were observed in pts without liver metastasis (mPFS: 3.42m vs 2.01m, p=0.049; mOS: 9.92m vs 3.70m, p=0.026), or with ≤ 2 metastatic organs (mPFS: 3.94m vs 1.91m, p=0.005; mOS: 10.09m vs 3.81m, p=0.003). Additionally, OS was significantly prolonged in pts with baseline CA19-9 level ≤ 996.7u/ml, in contrast with those with baseline CA19-9 level more than 996.7u/ml (9.92m vs 3.70m, p=0.008). All pts experienced treatment emergent adverse events (TEAEs). Most common (≥ 10%) TEAEs (any grade) were anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%). Grade ≥ 3 TEAEs included neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%). Conclusions: Surufatinib plus TAS-102 showed encouraging survival benefits and promising anti-tumor activity with acceptable toxicity in the late-line treatment of refractory mPDAC, especially in patients without liver metastasis, with ≤ 2 metastatic organs, or with baseline CA19-9 level ≤ 996.7u/ml. The results warrant further investigations in a large cohort. Clinical trial information: NCT05481463 .

Surufatinib combined with locoregional therapies and immune checkpoint inhibitor (ICI) for treating unresectable or metastatic intrahepatic cholangiocarcinoma.

593 Background: Advanced metastatic ICC, characterized by poor survival and limited therapeutic options, may benefit from the combined use of surufatinib—a selective tyrosine kinase inhibitor targeting VEGFR 1, 2, and 3, FGFR1, and CSF-1R—and ICIs, alongside locoregional treatments like TACE, DEB-TACE, and HAIC. Methods: Eligible pts who were 18 -75 years old with histologically confirmed unresectable or metastatic intrahepatic cholangiocarcinoma were enrolled. Pts received surufatinib (250mg, orally daily), ICI, and locoregional therapies until surgery, disease progression, death, intolerable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), conversion to surgical resection rate and safety. Results: By July 31, 2024, 20 pts were enrolled and 10 pts were evaluated. Median age was 56.4 years (range: 36-69), with a majority being male (70%). 9 pts were pathologically confirmed as adenocarcinoma, 1patient was small bile tract type. Treatment included DEB-TACE (20%), TACE (30%), and HAIC (50%). 50% (5/10) pts achieved partial response (PR), 20% (2/10) pts accepted conversion surgery, 30% (3/10) pts achieved stable disease (SD), and the confirmed ORR was 50%, DCR was 80%. The median PFS (95%Cl: 6.9-NA months) had not yet matured, with no significant differences in survival benefits based on age or gender, though TACE showed potential benefits. The most common AEs of all grades were nausea (30%), dizziness (30%), and headache (10%), No grade ≥ 3 TEAEs or new safety signals occurred. Conclusions: Surufatinib plus immune checkpoint inhibitor, along with locoregional therapies showed preliminary anti-tumor activity and manageable toxicity for the 1L treatment of ICC, providing an additional treatment option for pts with ICC. Clinical trial information: NCT05236699 .

Ritonavir enhances the efficacy of amprenavir: A promising combination therapy by targeting Leishmania DNA topoisomerase I for treatment of visceral leishmaniasis.

Visceral leishmaniasis (VL) is an opportunistic infection in HIV patients with higher relapse and mortality rate. The number of HIV-VL patients is comparatively higher in areas where both infections are endemic. However, the conventional chemotherapeutic agents have limited success due to drug toxicity, efficacy variance and overall cost of treatment. Therefore, it is crucial to discover and develop newer potent antileishmanial agents for successful eradication of the disease. Our previous report, for the first time showed the leishminicidal effect of amprenavir (APV) mediated by inhibition of L.donovani Topoisomerase I (LdTopILS). So, we intended to demonstrate the effect of APV in combination with ritonavir (RTV). The present study revealed that the complete catalytic inhibition of LdTopILS by APV (10μM) in combination with RTV (5μM), compare to APV (20μM) as previously reported (Roy et al., 2021). Moreover, APV (5μM) in combination with RTV (4μM) exhibited promastigote inhibition with IC50 values of 2.4±0.6μMat 12h and 1.6±0.7μMat 24h, respectively. The study was extended in animal model where the in vivo antileishmanial efficacy of APV-RTV in BALB/c mice demonstrated that treatment of APV in combination with RTV led to significant splenic and hepatic protection as compared to single dose of APV. Moreover, the antileishmanial activity of APV in combination with RTV was exerted via inhibition of LdTopILS at much lower concentration of APV and this inhibition of the enzyme induced programmed cell death in Leishmania parasites by generating oxidative stress within the cells. From the in vitro, ex vivo and in vivo studies, it was indicated that lower dose of APV in combination with RTV elevated the effective killing of the parasites as compared to the single higher dose of APV. Thus, the current study highlights repurposing of available protease inhibitors in combination, which might be exploited further for the therapeutic development against VL as well as HIV-VL co-infection.

Nimotuzumab combined with chemotherapy plus immunotherapy as first-line treatment for advanced esophageal squamous cell carcinoma.

344 Background: Esophageal squamous cell carcinoma (ESCC) is the primary type of esophageal cancer with poor prognosis in China. Chemotherapy plus immunotherapy as first-line standard treatment has limited benefit in advanced ESCC patients. Nimotuzumab, a humanized anti-EGFR antibody, exhibited favorable efficacy in advanced ESCC with good safety profile. We explored the efficacy and safety of nimotuzumab as first-line therapy for patients with advanced ESCC. Methods: In this retrospective study, patients were aged ≥ 18 years with histologically diagnosed advanced ESCC, ECOG of 0-3, given nimotuzumab (400 mg, Q3W) combined with chemotherapy (paclitaxel: 300-400mg and platinum: 400-500mg or tegafur: 60mg/bid, Q3W) plus immunotherapy (PD-(L)1: 200-240 mg, Q3W). They assigned into two groups: metastasis group and locally advanced group. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), objective response rate (ORR) and safety. Results: As of July 2024, 58 patients were enrolled (metastasis group: n=20, locally advanced group: n=38). The median age was 59.5 years (range: 44-80). The median follow-up was 32.59 months (95% CI: 23.0, 36.7). The ORR was 74.1% (95% CI: 0.6, 0.8). Survival analysis showed that the 1-year OS was 79.16% (95% CI: 64.5, 88.3) and 2-year OS was 57.38% (95% CI: 41.3, 70.5), 1-year PFS and 2-year PFS was 64.41% (95% CI: 49.4, 76.0) and 32.80% (95% CI: 19.7, 46.5), respectively. The median OS (mOS) was 31.01months, the median PFS (mPFS) was 17.84 months. Nimotuzumab plus chemotherapy and immunotherapy displayed a favorable survival outcomes both in metastasis group and locally advanced group with OS (1-year OS: 77.76% and 80.37%; 2-year OS: 62.21% and 55.91%) and PFS (1-year PFS: 53.46% and 69.99%; 2-year PFS: 25.06% and 36.66%), the mOS was not reached and 31.01 months, mPFS was 18.27 months and 16.69 months, respectively. There were 74.1% patients occurred grade 1-2 adverse events (AEs), and 13.8% occurred grade 3-5 AEs. The most common AEs included nausea (60.3%), myelosuppression (51.7%), leukopenia (41.4%), thrombocytopenia (29.3%), and neutropenia (24.1%). No serious treatment-related AEs or death recorded. Conclusions: This study demonstrated a favorable survival profile and acceptable toxicity in first-line treatment of advanced ESCC patients with nimotuzumab regimen. Further prospective study needed to certify in order to benefit more patients.

Disparities in prophylactic tetracycline use among patients with metastatic colorectal cancer undergoing treatment with EGFR inhibitors.

109 Background: Epidermal growth factor receptor (EGFR) inhibitors have been shown to improve survival in metastatic colorectal cancer and are considered a standard of care option for patients with RAS/RAF wild-type disease. However, anti-EGFR agents are associated with an acneiform rash that can lead to decreased quality of life and early discontinuation of treatment. Prophylactic doxycycline has been shown in a randomized clinical trial to decrease any skin toxicity ≥ grade 2 by 50%. In this study we sought to determine the rate of prophylactic tetracycline use in metastatic colorectal cancer patients receiving anti-EGFR therapy in the United States. Methods: The Flatiron Health Electronic Health Record-derived, de-identified database was used to analyze the records of patients who were at least 18 years old, diagnosed with metastatic colorectal cancer, and received treatment with an anti-EGFR agent (cetuximab or panitumumab). Patients were stratified by receipt of prophylactic tetracycline versus not. This was defined by an order for a tetracycline 28 days before to 1 day after initiation of an anti-EGFR agent. Demographic and clinical characteristics were compared via multivariable logistic regression. The change in percentage of patients who received a prophylactic tetracycline over time was assessed and was compared to the rate of anti-emetic prescription which served as a control to ensure drug administration data was accurately captured. Results: The records of 6,713 patients who met inclusion criteria and received an anti-EGFR agent between 2013 and 2023 were included in our analysis. A logistic regression model assessing the association between patient characteristics and the receipt of a prophylactic tetracycline suggested that older age, race (black/African American or Other), presence of RAS mutation, and higher line of therapy were all significantly associated with not receiving prophylactic tetracyclines. Other patient characteristics including gender, ECOG status, mismatch repair status, and RAF mutation status did not appear to impact the likelihood of receiving a prophylactic tetracycline. The rate of prophylactic tetracycline use increased from 10.9% in 2013 to 22.3% in 2023 while the rate of prophylactic anti-emetic remained stable at around 82%. Conclusions: This real-world analysis suggests the use of preemptive treatment for skin toxicity in patients with metastatic colorectal cancer who are treated with an anti-EGFR in US is suboptimal. Disparities in cancer care are also evidenced by lower use of tetracyclines in elderly and African Americans. Randomized controlled trials support the use of prophylactic tetracycline in these patients; thus, further research into the reason for this practice gap is necessary. Educational efforts should be undertaken to improve tetracycline prescribing rates in this population.

Investigation of Cannabidiol's Protective Effects on Cadmium-Induced Toxicity in Mice.

Current chelation treatments used for cadmium poisoning may cause some serious side effects. Thus, safer novel treatments could be promising for clinical use. This study evaluated the effects of cannabidiol on Cd toxicity. Four groups of 10 mice were formed: Groups I and III were cadmium-free, while groups II and IV received 50 mg/L cadmium in drinking water. Groups III and IV received daily cannabidiol (25 mg/kg) via intragastric gavage. After 30 days, the animals were killed, and blood and tissue samples were collected. Oxidative stress and inflammation markers, including glutathione, catalase, myeloperoxidase, TNF-α, IL-1β and IL-6, were analysed using ELISA. Additionally, histological evaluations of the liver, kidney and testis were performed. Cadmium exposure reduced glutathione and catalase levels in the blood, liver, kidney and testis, while increasing myeloperoxidase. Cannabidiol mitigated these effects on oxidative stress markers. Cannabidiol also reduced the increase in proinflammatory cytokines. Histopathological analysis revealed reduced liver and kidney damage in cannabidiol-treated groups compared to cadmium-only groups. In addition, histopathological evaluation showed CBD had no protective effect on the testicular tissue against Cd toxicity. Our results indicate that cannabidiol protects against some toxic effects of cadmium. If confirmed by future studies, cannabidiol may be proposed as a novel treatment for cadmium toxicity.

Leveraging Metabolomics and Ionomics to Illuminate Aluminum-Induced Toxicity in Mouse Organs

Aluminum, a widely prevalent environmental pollutant, has been established to exert toxic effects on multiple organs in the human body. To gain a comprehensive understanding of these toxic effects and the mechanisms involved, this study aimed to assess potential correlations between metabolites and ion data through metabolomic and ionomic analyses. We sought to explore the intricate impact of aluminum on various organs in mice. Gas chromatography-mass spectrometry (GC-MS) and inductively coupled plasma-mass spectrometry (ICP-MS) were employed to conduct metabolomic and ionomic analyses on the hippocampus, cortex, heart, liver, spleen, lung, kidney, bone, intestine, stomach, and serum of both control and aluminum-exposed mice. Besides, histological examinations and behavioral experiments were conducted. Multivariate analysis revealed 91 differential metabolites across various organs, primarily encompassing amino acids, fatty acids, and carbohydrates. The implicated abnormal metabolic pathways included amino acid metabolism, arachidonic acid metabolism, and glutathione metabolism. Additionally, alterations in the homeostasis of ions such as manganese, zinc, selenium, iron, copper, phosphorus, magnesium, and calcium were observed in various organs, potentially influencing the activity of critical enzymes. The changes in these potential biomarkers and ions suggest toxic mechanisms of aluminum exposure involving oxidative stress, inflammatory responses, cellular signal dysregulation, disruption of key enzyme activities, and impaired energy metabolism. This study provides a novel perspective on understanding the toxic mechanisms of aluminum exposure, potentially contributing to the prevention and treatment of aluminum toxicity.

A comparative study of dosage strategies in HIPEC: BSA-based vs fixed dose methods.

832 Background: Peritoneal metastases commonly occur in ovarian, gastric, and colorectal cancers, significantly contributing to patient morbidity and mortality. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is a promising approach for managing peritoneal surface cancers. This procedure involves cytoreductive surgery to remove visible tumors, followed by the perfusion of heated chemotherapy (41-42°C) directly into the peritoneal cavity. HIPEC addresses the limitation of systemic chemotherapy, which often fails to penetrate the peritoneal cavity effectively. HIPEC dosing may either be a flat-fixed dose or be calculated based on Body Surface Area (BSA). BSA can be determined using three methods: actual BSA (based on weight and height), ideal BSA (based on sex and height), and adjusted BSA (considering lean and fat mass). Methods: A retrospective chart review was conducted on 151 metastatic cancer patients at UVMMC. Patient BMI, weight, and height at diagnosis were collected to calculate BSA values (actual, adjusted, and ideal) for estimating a hypothetical chemotherapy dosage. Statistical analysis using SPSS involved linear mixed models and paired t-tests to compare Mitomycin-C dosages between a fixed dose (40 mg) and a BSA-derived dose (30 mg/m²). Results: The average dosage of Mitomycin-C differed significantly depending on whether the dose was calculated using actual, adjusted, or ideal BSA. The largest discrepancy in dosage was observed between the actual BSA method and the flat-fixed dose, with an average difference of 16 mg. The smallest difference in dose was between the adjusted and ideal BSA methods. When stratifying by BMI, the greatest variation in Mitomycin-C dosage was found among overweight and obese patients (BMI ≥ 25). For these patients, the average dosage difference between the flat fixed dose and the actual BSA dose was 20 mg. In comparison, in patients with a BMI under 18.5 (underweight) the actual BSA dose was comparable to the fixed dose. Conclusions: Different institutions utilize a variety of dosing strategies for the HIPEC procedure. Differences in BSA calculation methods and perfusate volumes (literature values of 2, 3 and 4 L is most common) contribute to the complexity of establishing standardized dosing. The significant dosing variations observed, especially in overweight and obese patients, are of concern, as 70% of the U.S. population has a BMI ≥ 25. Our study demonstrates significant variability in HIPEC chemotherapy dosing, especially among patients with higher BMI. The discrepancy between BSA-based methods and flat-fixed doses may impact treatment efficacy and toxicity. Standardizing dosing approaches is important to ensure consistent therapeutic outcomes and patient safety.

Association between skeletal muscle morphometrics and overall survival among older adults with gastrointestinal cancers.

808 Background: Older adults with gastrointestinal (GI) cancers face a higher risk of treatment toxicities and adverse survival outcomes. However, the variability in these outcomes remains poorly understood. Age-related changes, including the progressive loss of skeletal muscle and gain in adipose tissue, contribute to this heterogeneity. Recent studies highlight an association between skeletal muscle gauge (SMG) and overall survival (OS) in older cancer patients, but its relevance among those with GI cancers is unclear. Methods: We included adults aged ≥ 60 years with newly diagnosed GI cancers, enrolled in the University of Alabama at Birmingham (UAB) Cancer and Aging Resilience Evaluation (CARE) registry between October 2017 and April 2024. Skeletal muscle index (SMI; skeletal muscle area in m²/height in cm) and skeletal muscle radiodensity (SMD; Hounsfield units) were derived from single-slice computed tomography (CT) staging scans at the third lumbar vertebra (L3) using validated methods. SMG was calculated as the product of SMI and SMD, reported in arbitrary units (AU). Participants were followed until death or the study cutoff date of July 10, 2024. Kaplan-Meier survival analysis was used to estimate OS by SMG status (low: < median; high: ≥ median). Cox proportional hazards models were employed to assess the relationship between SMG and OS, adjusting for age, sex, race/ethnicity, and cancer stage. Results: A total of 568 patients were included in the study, with a median age at diagnosis of 68 years (interquartile range, IQR: 64-74), 55% male, 73% non-Hispanic White, and 43% were diagnosed with Stage IV disease. Colorectal (33%) and pancreatic (27%) cancers were the most common diagnoses. The median SMG was 1,529 AU (IQR: 1,151–1,967). Over a median follow-up of 60 months, 367 patients (64%) died. Median OS was 19 months for those with low SMG and 26 months for those with high SMG (log-rank test, p < .05). After adjustment for confounders, SMG remained independently associated with OS (adjusted Hazard Ratio: 0.678 per IQR increase; 95% CI: 0.57– 0.807; p < .001), indicating that each IQR increase in SMG is associated with a decrease in all-cause mortality risk by 32.2%. Conclusions: Skeletal muscle gauge, an integrated measure of SMI and SMD, is significantly associated with improved survival among older adults with GI cancers. Further research is needed to determine whether SMG has a causal impact on survival in this population.

Cyclophosphamide is not associated with clinically relevant late pulmonary dysfunction in Dutch survivors of childhood cancer - The DCCSS-LATER 2 PULM sub-study.

Treatment for childhood cancer may increase the risk of long-term pulmonary complications and dysfunction. Pulmonary surveillance is recommended after established pulmonary toxic exposures, including bleomycin, busulfan, carmustine (BCNU), lomustine (CCNU), radiotherapy to a field exposing the lungs, and pulmonary surgery. However, the role of cyclophosphamide as a pulmonary toxic agent is debated. To establish whether cyclophosphamide is associated with late pulmonary dysfunction among survivors of childhood cancer. In this multicenter Dutch Childhood Cancer Survivor Study (DCCSS)-LATER 2 PULM sub-study, we included 828 survivors with a median follow-up of 26.6 years, treated with cyclophosphamide and/or established pulmonary toxic treatment, or neither. Pulmonary function tests were used to measure the primary outcomes of diffusion impairment (diffusing capacity for carbon monoxide (DLCO) z-score), restriction (total lung capacity (TLC) z-score), and obstruction (forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) z-score). Secondary outcomes comprised chronic cough, recurrent respiratory tract infections, shortness of breath, and supplemental oxygen need. Diffusion and restrictive abnormalities were highly prevalent among those treated with established pulmonary toxic treatment, with cyclophosphamide (41.0% and 50.4%, respectively) and without (34.3% and 41.9%, respectively), and occurred less frequently in survivors treated with cyclophosphamide only (12.9% and 7.3%, respectively) or in survivor controls (9.9% and 12.4%, respectively). In multivariable analyses, cyclophosphamide did not have a clinically relevant effect on the primary or secondary outcomes. This study suggests that cyclophosphamide is not associated with clinically relevant pulmonary dysfunction in long-term childhood cancer survivors.

Radiotherapy(R) Integration(I) Strategy for Small(S)-Cell Lung Cancer in Extensive(E) Stage (RISE) with up to 10 metastases- a study protocol of a randomized phase II trial

Background The current standard of care (SoC) for patients with extensive-disease small-cell lung cancer (ED-SCLC) is chemo-immunotherapy. The efficacy of radiotherapy (RT) for chest consolidation has been established for patients with ED-SCLC who have responded to chemotherapy. There is a lack of data on incorporating RT as chest consolidation and metastasis-directed therapy for ED-SCLC. The RISE (Radiotherapy for Extensive-Stage Small-Cell Lung Cancer) study aims to evaluate the effectiveness of different RT strategies for residual lesions for patients with ED-SCLC who receive chemo-immunotherapy.MethodsA total of 165 patients with ED-SCLC will be recruited, with 55 patients assigned to each of the three study arms. Patients with stabilization or partial regression, according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, during chemo-immunotherapy will be included.• Arm I will serve as the control group, comprising patients who continue SoC of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) immunotherapy (durvalumab or atezolizumab) following platinum-based chemo-immunotherapy.• Arm II will receive the SoC with consolidative RT to the chest area and potentially, according to palliative indications to metastatic lesions, delivered in 30 Gy in 3-Gy fractions.• Arm III will receive SoC with RT of 45 Gy in 3-Gy fractions to the chest area and stereotactic body radiotherapy (SBRT) with 24 Gy in 8-Gy fractions to the metastatic lesions.Blood samples for circulating tumor DNA (ctDNA) will be collected before RT, during each week of treatment, and at the time of disease progression.The primary endpoint is progression-free survival (PFS) based on RECIST 1.1 or patient death. 1. Secondary endpoints are OS, treatment toxicity (frequency of G3 toxicity according to CTCAE v.5.0), area of progression (primary tumor localization/new lesions), Overall response rate (ORR), and the response rate in non-irradiated lesions.DiscussionThe study population of patients with ED-SCLC has a poor prognosis. Dose-escalated chest RT and SBRT (for up to 10 metastases) administered with modern techniques offer the possibility to improve OS and PFS.Trial registrationClinicaltrials.gov NCT06529081 (Registered 26th Jul 2024).

Selenomethionine Attenuates Aflatoxin B1-induced Liver Injury by Modulating the Gut Microbiota and Metabolites in Rabbits.

Dietary contamination with aflatoxin B1 (AFB1), which can lead to severe liver damage, poses a great threat to livestock and poultry breeding and has detrimental impacts on food safety. Selenomethionine (SeMet), with anti-inflammatory, antioxidative, and detoxifying effects, is regarded as a beneficial food additive. However, whether SeMet can reduce AFB1-induced liver injury and intestinal microbial disorders in rabbits remains to be revealed. Forty 35-day-old rabbits were randomly divided into a control group, an AFB1 group, and 0.2 mg/kg Se and 0.4 mg/kg Se groups. The SeMet treatment group was fed different doses of the SeMet diet every day for 21 days. On Days 17-21, the AFB1 group, 0.2 mg/kg Se, and 0.4 mg/kg Se groups were intragastrically administered 0.3 mg AFB1/kg b.w. Results showed that SeMet restored alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, alleviating AFB1-induced liver function damage. This was linked to changes in intestinal metabolites and activation of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway. In this study, the relationships between intestinal microorganisms and their metabolites and AFB1-induced liver injury are investigated, and the potential protective role of SeMet against liver damage induced by AFB1 offers novel insights into strategies for the prevention and treatment of AFB1-related toxicity.

Radioprotective effects of coenzyme Q10 on X-ray radiation-induced intestinal damage via oxidative stress and apoptosis.

The World Health Organization reported that cancer was the cause of death for 9.7 million people in 2022, and the numbers continue to rise every day. The present study examines the potential radioprotective effects of ubiquinone against x-ray radiation-induced intestinal damage and offers insight into new near-future methods for the treatment of radiation-induced tissue toxicity. Thirty-two male Sprague-Dawley rats were randomly divided into four groups. Group I (control) received no treatment during the experiment; Group II (IR [a single dose of 2 Gy pelvic/abdominal ionizing radiation]) received radiation only; Group III (a low dose of CoQ10 [30 mg/kg CoQ10 by oral gavage for 7 d] + IR) and Group IV (a high dose of CoQ10 [150 mg/kg CoQ10 by oral gavage for 7 d] + IR). The rats were sacrificed 24 h after x-ray radiation, and tissues were collected from the small intestine and subjected to histochemical analysis. Diffuse villous fusion, enterocyte loss, hemorrhagic areas, inflammation, and fibrosis were observed in the IR group, as well as an increase in apoptotic enterocytes. In contrast, a decrease was observed in the IR+LD-CoQ10 and IR+HD-CoQ10 groups, along with a decrease, especially in villous fusion and enterocyte loss, hemorrhagic areas, inflammation, and fibrosis. CoQ10 was found to reduce duodenal damage, oxidative stress, and apoptosis induced by x-ray radiation exposure and had a radioprotective effect.

The Role of the Microbiome in Cancer Therapies: Current Evidence and Future Directions.

The microbiome is essential for maintaining human health and is also a key factor in the development and progression of various diseases, including cancer. Growing evidence has highlighted the microbiome's significant impact on cancer development, progression, and treatment outcomes. As research continues to unfold, the microbiome and its modulation stand out as a promising frontier in cancer research and therapy. This review highlights current literature on the interplay between various cancer treatment modalities and human microbiotas, focusing on how the microbiome may affect treatment efficacy and toxicity and its potential as a therapeutic target to enhance future outcomes.

Management of inhalation injuries in emergency and critical care: immediate interventions and long-term outcomes

Inhalation injury is respiratory injury caused by inhalation of substances such as toxic gas, fire fumes and chemical products. It can lead to hypoxia, ventilation dysfunction, increased airway resistance, and massive pulmonary edema. Immediate intervention is crucial for inhalation injuries. Current management strategies include endotracheal intubation, tracheostomy, fluid resuscitation, mechanical ventilation, and treatment of systemic toxicity. Many factors can affect the outcomes of inhalation injury such as age, severity of inhalation injury, and total body surface area burned. The following databases were used in systematic research: Medline (PubMed), Web of Science, and Scopus till 22 December 2024. Inclusion criteria is any study that discusses management of inhalation injuries in emergency and critical care and their outcomes and published in peer-reviewed journals was included with the inclusion of full-text articles, abstracts, and case series with the related topics are included. All languages are included. Animal studies, case reports, letters and comments were excluded. Endotracheal intubation, mechanical ventilation, and tracheostomy are considered important interventions in the inhalation injury emergency setting. However, studies reported poor long-term outcomes of these interventions. The objective of this review is to discuss the different approaches of management of inhalation injuries in emergency department and the obtained outcomes.

Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST.

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

Musician's Experience After Breast Cancer Treatment: Defining Musical Toxicity and its Frequency.

Over 50% of households in the United States have at least one musician-many musicians are also breast cancer survivors. This group has not been well studied, and given the level of fine sensory-motor skill required for musicianship, we hypothesized that musicians experience unique manifestations of breast cancer treatment toxicities. A nine-item Musical Toxicity Questionnaire (MTQ) was distributed to patients who had consented to participate in the Mayo Clinic Breast Cancer Registry. The MTQ screened participants by asking if they played a musical instrument or sang in the last 10 years: questions populated for those who answered yes. Respondents were asked if they noticed difficulty with their musical endeavor during or after breast cancer treatment, defined as acute musical toxicity (AMT). The questionnaire asked which side effect and cancer-directed therapy most influenced musical ability, what musical attributes were affected, and the timeline of resolution. Multivariable and classification tree analyses assessed relationships between AMT and treatment characteristics. Of 1,871 survey respondents, 29% (535/1,871) self-identified as musicians. Over a quarter (27%, 144/535) reported AMT, and for 57% (82/144), AMT had not resolved at the time of survey. Of the treatments each participant received, chemotherapy was most often reported as most negatively impactful (63/89 who received chemotherapy, 71%). Decreased endurance was the most common musical difficulty (64% of those with AMT, 92/144), followed by decreased accuracy, trouble playing/singing quickly, and difficulty using proper technique. Multivariable and classification tree analyses revealed that receipt of chemotherapy was most strongly correlated with AMT. These results will help oncology care teams counsel musicians, answer questions about impacts on musicality, and provide a timeline for resolution of musical symptoms.