Development Of Gastrointestinal Toxicity Research Articles

Safety of Carbon-ion Radiotherapy for Prostate Cancer After Rectal Cancer Surgery.

The safety of carbon-ion radiotherapy (CIRT) for patients with prostate cancer after rectal cancer surgery remains unknown. This is a retrospective analysis of the safety of CIRT in patients with prostate cancer after rectal cancer surgery. The subjects were 13 consecutive patients with prostate cancer who underwent CIRT after rectal cancer surgery at the Kanagawa Cancer Center from December 2015 to April 2022. A total dose of 51.6 Gy (relative biological effectiveness) was administered in 12 fractions over 3 weeks. The criteria stated in the Common Terminology Criteria for Adverse Events, version 5.0, were used to assess toxicity. Fisher's exact test was performed to assess the associations between patient clinical factors and rectal toxicity. The median patient age was 71 years (range=66-83 years). The median observation period was 27.4 months (range=10.6-82.4 months). The median duration from rectal surgery to CIRT was 6.9 years (1.0-16.8 years). Five (38.5%) and six (46.2%) patients had a planning target volume (PTV)-adjacent rectal anastomosis and diabetes mellitus, respectively, and two (15.4%) patients had both. Grades 1 and 2 late gastrointestinal toxicities were observed in one case each. Development of gastrointestinal toxicity was significantly associated with both a PTV adjacent rectal anastomosis and diabetes mellitus (p=0.013). Late gastrointestinal toxicity was tolerable in patients with prostate cancer treated with CIRT after rectal cancer surgery. Patients with both a PTV adjacent rectal anastomosis and diabetes mellitus were more likely to experience late gastrointestinal toxicity.

Toll-like receptor/interleukin-1 domain innate immune signalling pathway genetic variants are candidate predictors for severe gastrointestinal toxicity risk following 5-fluorouracil-based chemotherapy

Severe gastrointestinal (GI) toxicity is a common adverse effect following 5-fluorouracil (5-FU)-based chemotherapy treatment. The presence of severe GI toxicity leads to treatment revisions, sub-optimal therapy outcomes, and decreases to patients' quality of life. There are no adequate predictors for 5-FU-induced severe GI toxicity risk. The Toll-like receptor/interleukin-1 (TIR) domain innate immune signalling pathway is known to be a mediating pathway in the development of GI toxicity. Hence, genetic variability in this signalling pathway may alter the pathophysiology of GI toxicity and, therefore, be predictive of risk. However, little research has investigated the effects of TIR domain innate immune signalling pathway single nucleotide polymorphism (SNPs) on the risk and development of severe GI toxicity. This critical review surveyed the literature and reported on the in vitro, ex vivo and in vivo effects, as well as the genetic association, of selected TIR domain innate immune signalling pathway SNPs on disease susceptibility and gene functioning. Of the TIR domain innate immune signalling pathway SNPs reviewed, evidence suggests interleukin-1 beta (IL1B) and tumour necrosis factor alpha (TNF) SNPs have the greatest potential as predictors for severe GI toxicity risk. These results warrant further research into the effect of IL1B and TNF SNPs on the risk and development of severe GI toxicity. SNPs of the TIR domain innate immune signalling pathway have profound effects on disease susceptibility and gene functioning, making them candidate predictors for severe GI toxicity risk. The identification of a predictor for 5-FU-induced severe GI toxicity will allow the personalization of supportive care measures.

The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapy-induced gastrointestinal toxicity.

Chemotherapy-induced gastrointestinal toxicity (CIGT) occurs in up to 80% of all patients undergoing cancer treatment, and leads to symptoms such as diarrhoea, abdominal bleeding and pain. There is currently limited understanding of how to predict an individual patient's risk of CIGT. It is believed the gut microbiome and its interactions with the host's innate immune system plays a key role in the development of this toxicity and potentially other toxicities, however comprehensive bioinformatics modelling has not been rigorously performed. The innate immune system is strongly influenced by the microbial environment and vice-versa. Ways this may occur include the immune system controlling composition and compartmentalisation of the microbiome, the microbiome affecting development of antigen-presenting cells, and finally, the NLRP6 inflammasome orchestrating the colonic host-microbiome interface. This evidence calls into question the role of pre-treatment risk factors in the development of gastrointestinal toxicity after chemotherapy. This review aims to examine evidence of a bidirectional interaction between the gut microbiome and innate immunity, and how these interactions occur in CIGT. In the future, knowledge of these interactions may lead to improved personalised cancer medicine, predictive risk stratification methods and the development of targeted interventions to reduce, or even prevent, CIGT severity.

Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators

Damage to the mucous membrane is a serious issue associated with chemotherapy. Gastrointestinal (GI) toxicity is complex and multistep process and unregulated production of reactive oxygen species (ROS) and inflammatory mediators play vital role in the development of GI toxicity. In the present study we have investigated the attenuating potential of vitamin C (vit. C) on 5 fluorouracil (5-FU) induced GI toxicity by targeting oxidative stress and inflammatory markers in Sprague Dawley (SD) rats. Rats were gavaged with vit. C (500mg/kgb.wt.) or vehicle daily (day 1–10) and were given intraperitoneal injection of 5-FU (150mg/kgb.wt.) or saline (control) on day 8 to induce mucositis. We found that vit. C supplementation attenuated 5-FU induced lipid peroxidation, myeloperoxidase (MPO) activity, activation of NF-kB and expression of COX-2. Histological observations further supported the protective potential of vit. C against 5-FU induced intestinal anomalies such as neutrophil infiltration, loss of cellular integrity, villus and crypt deformities. Thus the biochemical, molecular and histological findings of the present study demonstrate that oxidative stress and inflammation play vital role in 5-FU induced GI toxicity and the inhibitory potential of vit. C is may be due to the modulation of oxidative stress, activation of redox sensitive transcription factor and also its downstream target molecules.

Association of a XRCC3 polymorphism and rectum mean dose with the risk of acute radio-induced gastrointestinal toxicity in prostate cancer patients

Background and purposeWe have performed a case–control study among prostate cancer patients treated with three-dimensional conformational radiotherapy (3D-CRT) in order to investigate the association between single nucleotide polymorphisms (SNPs), treatment and patient features with gastrointestinal and genitourinary acute toxicity. Material and methodsA total of 698 patients were screened for 14 SNPs located in the ATM, ERCC2, LIG4, MLH1 and XRCC3 genes. Gastrointestinal and genitourinary toxicities were recorded prospectively using the Common Terminology Criteria for Adverse Events v3.0. ResultsThe XRCC3 SNP rs1799794 (G/G OR=5.65; 95% CI: 1.95–16.38; G/A OR=2.75; 95% CI: 1.25–6.05; uncorrected p-value=2.8×10−03; corrected p-value=0.03; FDR q-value=0.06) as well as the mean dose received by the rectum (OR=1.06; 95% CI: 1.02–1.1; uncorrected p-value=2.49×10−03; corrected p-value=0.03; FDR q-value=0.06) were significantly associated with gastrointestinal toxicity after correction for multiple testing. Those patients who undergone previous prostatectomy were less prone to develop genitourinary toxicity (OR=0.38; 95% CI: 0.18–0.71; uncorrected p-value=4.95×10−03; corrected p-value=0.03; FDR q-value=0.08). Our study excludes the possibility of a >2-fold risk increase in genitourinary acute toxicity being due to rs1801516 ATM SNP, the rs1805386 and rs1805388 LIG4 markers, as well as all the SNPs evaluated in the ERCC2, MLH1 and XRCC3 genes. ConclusionsThe XRCC3 rs1799794 SNP and the mean dose received by the rectum are associated with the development of gastrointestinal toxicity after 3D-CRT.

The role of NOTCH1 signaling in T-ALL

The identification of activating mutations in NOTCH1 in over 50% of T-cell acute lymphoblastic leukemias (T-ALL) has generated major interest in the elucidation of the mechanisms of transformation downstream of oncogenic NOTCH and in the targeting of the NOTCH signaling pathway in this disease. Small molecule gamma-secretase inhibitors (GSIs) block NOTCH1 signaling in T-ALL lymphoblasts, yet the clinical development of GSIs has been held back by the development of gastrointestinal toxicity and their weak antileukemic effects against human T-ALL. However, new therapeutic strategies aiming to optimize the use of anti-NOTCH1 therapies for T-ALL, including combination therapies with molecularly targeted drugs and glucocorticoids, have started to emerge as a result of improved understanding of the molecular mechanisms that mediate the effects of GSIs in leukemic cells and the intestinal epithelium. This review focuses on the molecular basis of NOTCH1-induced transformation, the mechanisms of action of oncogenic NOTCH1 and clinical significance of NOTCH1 mutations in T-ALL.

The effect of 5-fluorouracil on small bowel mucosa.

AbstractPre‐ and post‐therapy small bowel biopsies were obtained in 19 of 20 patients who received 5‐fluorouracil for treatment of their malignant disease. Three parameters were evaluated: clinical response to therapy, which occurred in five cases (26%); development of gastrointestinal toxicity, which occurred in 13 (68%); and histopathologic change of small bowel mucosa, which was noted in 13 (68%). There was no correlation between clinical response to therapy and the development of toxicity, nor was there any between toxicity and histopathologic change in small bowel mucosa. Definite histopathologic change in each of the patients who responded to therapy was the only consistent relationship noted, although the appearance of such changes did not necessarily indicate that tumor response could be expected.