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Gastrointestinal (GI) toxicosis is a common side effect of cytotoxic chemotherapy treatment in humans and dogs. Measurement of cytokeratin 18 (CK18), an intracellular structural protein released during epithelial apoptosis, and Alpha1‐Antitrypsin (A1AT) in faeces provides a mechanism for evaluating damage to the intestinal mucosa secondary to cytotoxic chemotherapy. Our goal was to evaluate the clinical utility of plasma CK18 and faecal A1‐AT levels as non‐invasive biomarkers of cytotoxic chemotherapy induced GI toxicity. We conducted a prospective cohort study in dogs (N = 10) with osteosarcoma undergoing amputation followed by carboplatin chemotherapy. We hypothesized that plasma CK18 and faecal A1‐AT levels would increase following carboplatin administration due to drug‐induced GI epithelial damage/apoptosis, and that plasma CK18 and faecal A1‐AT levels would correlate with severity of GI toxicity. Mean baseline plasma CK18 concentration was variable amongst patients; however, CK18 concentration prior to carboplatin chemotherapy treatment was not significantly different from CK18 levels after treatment. There was significant intra and inter‐patient variability in mean faecal A1‐AT levels at baseline. Mean A1‐AT concentration did not change significantly from day 0 to day 21. Gastrointestinal toxicity was minimal; therefore, we were unable to determine the association of plasma CK18 and faecal A1‐AT concentrations with development of GI toxicosis. In this study population, plasma CK18 and faecal A1‐AT concentration were not clinically useful biomarkers for the detection of GI toxicosis secondary to carboplatin administration. Further prospective evaluation of CK18 and A1‐AT as biomarkers of drug‐induced GI toxicity is warranted in a larger cohort of dogs receiving cytotoxic chemotherapy. AVMA clinical trial registration number: AAHSD004827. Gastrointestinal (GI) toxicosis is a common side effect of cytotoxic chemotherapy treatment in humans and dogs. This study investigated the clinical utility of plasma cytokeratin 18 and fecal alpha‐1 antitrypsin as non‐invasive biomarkers of GI epithelial cell damage. In this study population, plasma CK18 and fecal A1‐AT concentration were not clinically useful biomarkers for the detection of GI toxicosis secondary to carboplatin administration.

Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models.We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immunedeficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan’s effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

The intestinal microbiome encodes vast metabolic potential, and multidisciplinary approaches are enabling a mechanistic understanding of how bacterial enzymes impact the metabolism of diverse pharmaceutical compounds, including chemotherapeutics. Microbiota alter the activity of many drugs and chemotherapeutics via direct and indirect mechanisms; some of these alterations result in changes to the drug’s bioactivity and bioavailability, causing toxic gastrointestinal side effects. Gastrointestinal toxicity is one of the leading complications of systemic chemotherapy, with symptoms including nausea, vomiting, diarrhea, and constipation. Patients undergo dose reductions or drug holidays to manage these adverse events, which can significantly harm prognosis, and can result in mortality. Selective and precise targeting of the gut microbiota may alleviate these toxicities. Understanding the composition and function of the microbiota may serve as a biomarker for prognosis, and predict treatment efficacy and potential adverse effects, thereby facilitating personalized medicine strategies for cancer patients.

Cancer is the second leading cause of death worldwide. Around half of all cancer patients undergo some type of radiation therapy throughout the course of their treatment. Photon radiation remains (RT) the most widely utilized modality of radiotherapy despite recent advancements in proton radiation therapy (PBT). PBT makes use of the particle’s biological property known as the Bragg peak to better spare healthy tissue from radiation damage, with data to support that this treatment modality is less toxic than photon RT. Hence, proton radiation dosimetry looks better compared to photon dosimetry; however, due to proton-specific uncertainties, unexpected acute, subacute, and long-term toxicities can be encountered. Reported neurotoxicity resulting from proton radiation treatments include radiation necrosis, moyamoya syndrome, neurosensory toxicities, brain edema, neuromuscular toxicities, and neurocognitive toxicities. Pulmonary toxicities include pneumonitis and fibrosis, pleural effusions, and bronchial toxicities. Pericarditis, pericardial effusions, and atrial fibrillations are among the cardiac toxicities related to proton therapy. Gastrointestinal and hematological toxicities are also found in the literature. Genitourinary toxicities include urinary and reproductive-related toxicities. Osteological, oral, endocrine, and skin toxicities have also been reported. The side effects will be comparable to the ones following photon RT, nonetheless at an expected lower incidence. The toxicities collected mainly from case reports and clinical trials are described based on the organs affected and functions altered.

Severe radiation exposure may cause acute radiation syndrome, a possibly fatal condition requiring effective therapy. Gut microbiota can be manipulated to fight against many diseases. We explored whether intestinal microbe transplantation could alleviate radiation‐induced toxicity. High‐throughput sequencing showed that gastrointestinal bacterial community composition differed between male and female mice and was associated with susceptibility to radiation toxicity. Faecal microbiota transplantation (FMT) increased the survival rate of irradiated animals, elevated peripheral white blood cell counts and improved gastrointestinal tract function and intestinal epithelial integrity in irradiated male and female mice. FMT preserved the intestinal bacterial composition and retained mRNA and long non‐coding RNA expression profiles of host small intestines in a sex‐specific fashion. Despite promoting angiogenesis, sex‐matched FMT did not accelerate the proliferation of cancer cells in vivo . FMT might serve as a therapeutic to mitigate radiation‐induced toxicity and improve the prognosis of tumour patients after radiotherapy. Synopsis Faecal microbiota transplantation ameliorates radiation‐induced toxicity in irradiated mice by improving gastrointestinal tract function and epithelial integrity, preserving gut bacterial composition and maintaining the small intestine transcriptome. Gut microbiota determines the radiosensitivity of hosts. Faecal microbiota transplantation (FMT) fights against radiation‐induced gastrointestinal toxicity. FMT preserves enteric bacterial composition and retains the RNA expression profile of irradiated hosts. FMT might emerge as a therapeutic schedule in tumour radiotherapy to improve prognosis. Graphical Abstract Faecal microbiota transplantation ameliorates radiation‐induced toxicity in irradiated mice by improving gastrointestinal tract function and epithelial integrity, preserving gut bacterial composition and maintaining the small intestine transcriptome.

FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used.

Background Colorectal cancer (CRC) is the second leading cause of cancer-related mortality globally. While chemotherapy remains a cornerstone of CRC treatment, gastrointestinal (GI) toxicity—manifesting as abdominal pain, diarrhea, constipation, and reflux—affects 40%–100% of patients, severely impairing quality of life. Despite the prevalence of these symptoms, there is a lack of effective non-pharmacological interventions. This study aims to evaluate the efficacy of electroacupuncture (EA) in alleviating chemotherapy-induced GI dysfunction in CRC patients. Methods In this multicenter, three-arm, randomized controlled trial (RCT), 231 CRC patients with post-chemotherapy GI symptoms will be centrally randomized to EA plus standard care, sham acupuncture (SA) plus standard care, or standard care alone. The EA and SA groups will receive three 30-min sessions over consecutive days, delivered by certified acupuncturists (EA: LI11, PC6, ST36 and ST37 with electrical stimulation; SA: non-acupoints with blunt-tip needles without stimulation). The primary outcome is the change in Gastrointestinal Symptom Rating Scale (GSRS) total scores from baseline to post-treatment (day 3). Secondary outcomes include GSRS subscale scores, Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scores, and Self-Rating Anxiety Scale/Self-Rating Depression Scale (SAS/SDS) scores. All outcomes will be assessed at baseline (T0), post-intervention (T1: day 3), and follow-up (T2: day 10). Statistical analysis will employ intention-to-treat linear mixed-effects models. Conclusion This multicenter RCT is designed to generate high-quality evidence on the comprehensive efficacy of EA in addressing chemotherapy-induced GI toxicity in CRC patients. If proven effective, EA could provide a safe, non-pharmacological adjunct to standard care, helping to reduce symptom burden and improve patient adherence to chemotherapy. Trial registration  ChiCTR2200062317. Registered on 1 August 2022.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely but produce gastrointestinal (GI) toxicities in both short- and long-term users. Previous studies have shown that the intestinal microbiota play an important role in gut damage and that gut microbial β-glucuronidase (GUS) inhibitors can alleviate NSAID-induced injury in male mice by blocking the GI reactivation of NSAID-glucuronides. Here, in both male and female C57BL/6 mice, we examine the effects of indomethacin alone and with the GUS inhibitor UNC10201652. Oral delivery of 5 mg/kg body weight indomethacin over 5 days decreased body weight, induced colonic and hepatic inflammatory cytokine gene expression, and enlarged the spleens of both male and female mice. However, sex-specific inflammatory responses to indomethacin were observed, with males demonstrating more colonic injury while females presented greater splenic and hepatic toxic responses. Females also showed a unique indomethacin-induced bloom of fecal Verrucomicrobia as measured by 16S rRNA metagenomic sequencing. UNC10201652 alleviated aspects of these indomethacin-induced toxicities, including features of the male-specific colonic damage and the female-specific compositional changes and spleen and liver toxicities. Thus, GI and non-GI tissues in male and female mice respond distinctly to indomethacin-induced damage. These findings advance our understanding of how sex impacts systemic responses to xenobiotic exposure and may lead to improved therapeutic outcomes with these widely used drugs.

Background Colorectal cancer (CRC) is a prevalent malignant malignancy affecting the gastrointestinal tract that is usually treated clinically with chemotherapeutic agents, whereas chemotherapeutic agents can cause severe gastrointestinal toxicity, which brings great pain to patients. Therefore, finding effective adjuvant agents for chemotherapy is crucial. Methods In this study, a CRC mouse model was successfully constructed using AOM/DSS, and the treatment was carried out by probiotic Bifidobacterium longum SX-1326 ( B. longum SX-1326) in combination with irinotecan. Combining with various techniques of modern biomedical research, such as Hematoxylin and Eosin (H&E), Immunohistochemistry (IHC), Western blotting and 16S rDNA sequencing, we intend to elucidate the effect and mechanism of B. longum SX-1326 in improving the anticancer efficacy and reducing the side effects on the different levels of molecules, animals, and bacteria. Results Our results showed that B. longum SX-1326 enhanced the expression of Cleaved Caspase-3 (M vs. U =  p  < 0.01) and down-regulated the expression level of B-cell lymphoma-2 (Bcl-2) through up-regulation of the p53 signaling pathway in CRC mice, which resulted in an adjuvant effect on the treatment of CRC with irinotecan. Moreover, B. longum SX-1326 was also able to regulate the gut-brain-axis (GBA) by restoring damaged enterochromaffin cells, reducing the release of 5-hydroxytryptamine (5-HT) in brain tissue (I vs. U = 89.26 vs. 75.03, p  < 0.05), and further alleviating the adverse effects of nausea and vomiting. In addition, B. longum SX-1326 reversed dysbiosis in CRC model mice by increasing the levels of Dehalobacterium , Ruminnococcus , and Mucispirillum . And further alleviated colorectal inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway. Conclusions In conclusion, our work reveals that B. longum SX-1326 has a favorable effect in adjuvant irinotecan for CRC and amelioration of post-chemotherapy side effects, and also provides the theoretical basis and data for finding a safe and efficient chemotherapeutic adjuvant.

Objectives While moderately hypofractionated radiotherapy (HFRT) has been recommended as the standard regimen in localized prostate cancer (LPCa) based on non-inferiority trials compared to conventionally fractionated radiotherapy(CFRT), the conclusions on its efficacy and toxicity have not been consistent among all trials. This study aims to systematically compare the efficacy and safety of HFRT with CFRT for LPCa based on the present randomized controlled trials. The longest follow-up data from all the trials were adopted. Methods and materials This research followed the steps outlined in the PRISMA statement for meta-analyses and systematic reviews. This study presents a meta-analysis of phase III trials comparing CFRT with HFRT for LPCa. The included trials reported relapse-free survival over five years and the incidence of acute or at least 3 years of late gastrointestinal (GI) and genitourinary (GU) toxicity. Results We were able to include 18 papers in our final analysis. There was no statistically significant difference in relapse-free survival after five years of treatment between the HFRT and CFRT groups. In subgroup analyses, with an α/β of 1.5, a higher equivalent dose of HFRT compared to CFRT is associated with improved relapse-free survival over five years. Acute GI toxicity of Grade 2 or worse was more common in the HFRT group compared to the CFRT group ( p  < 0.00001). The incidence of acute GI toxicity of Grade 2 or worse rose by 8.78% when moderate HFRT was administered (95% CI = 4.69%-12.87%, p  < 0.0001). Subgroup analyses suggested that a single dose of 2.4–3.0 Gy in HFRT may not contribute to an increase in acute GI complications. Moreover, in other outcomes, including acute GI toxicity Grade 3 or worse, acute GU toxicity, and late GI/GU toxicity, no significant differences were observed between the CFRT and HFRT groups. Conclusion The clinical outcomes of HFRT and CFRT were comparable, with similar five-year relapse-free survival, and without different risks of acute or late, severe GI or GU toxicity. HFRT treatment may increase the risk of Grade 2 or worse acute GI toxicity. Thus, proper monitoring and management are required. Less than 3.0 Gy of a single dose or a lower α/β value may be worth considering in the HFRT scheme. Further comprehensive examination of the findings in subgroup analyses is required, such as appropriate dose ranges and management of acute toxicity.