Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice

Hepatocellular carcinoma (HCC) is associated with inflammation, and roughly 30 % of the global population shows serological evidence of current or past infection with hepatitis B or hepatitis C virus. Resident...

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Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague–Dawley rats

Abstract

Purpose

Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.

Methods

Male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon.

Results

All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury.

Conclusions

Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.

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Irinotecan- and 5-fluorouracil-induced intestinal mucositis: insights into pathogenesis and therapeutic perspectives

Abstract

Purpose

Intestinal mucositis and diarrhea are common manifestations of anticancer regimens that include irinotecan, 5-fluorouracil (5-FU), and other cytotoxic drugs. These side effects negatively impact therapeutic outcomes and delay subsequent cycles of chemotherapy, resulting in dose reductions and treatment discontinuation. Here, we aimed to review the experimental evidence regarding possible new targets for the management of irinotecan- and 5-FU-related intestinal mucositis.

Methods

A literature search was performed using the PubMed and MEDLINE databases. No publication time limit was set for article inclusion.

Results

Here, we found that clinical management of intestinal mucositis and diarrhea is somewhat ineffective at reducing symptoms, possibly due to a lack of specific targets for modulation. We observed that IL-1β contributes to the apoptosis of enterocytes in mucositis induced by 5-FU. However, 5-FU-related mucositis is far less thoroughly investigated with regard to specific molecular targets when compared to irinotecan-related disease. Several studies have proposed that a correlation exists between the intestinal microbiota, the enterohepatic recirculation of active metabolites of irinotecan, and the establishment of mucositis. However, as reviewed here, this association seems to be controversial. In addition, the pathogenesis of irinotecan-induced mucositis appears to be orchestrated by interleukin-1/Toll-like receptor family members, leading to epithelial cell apoptosis.

Conclusions

IL-1β, IL-18, and IL-33 and the receptors IL-1R, IL-18R, ST2, and TLR-2 are potential therapeutic targets that can be modulated to minimize anticancer agent-associated toxicity, optimize cancer treatment dosing, and improve clinical outcomes. In this context, the pathogenesis of mucositis caused by other anticancer agents should be further investigated.

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Intestinal permeability to iohexol as an in vivo marker of chemotherapy-induced gastrointestinal toxicity in Sprague–Dawley rats

Abstract

Purpose

Gastrointestinal toxicity is the most common adverse effect of chemotherapy. Chemotherapeutic drugs damage the intestinal mucosa and increase intestinal permeability. Intestinal permeability is one of the key markers of gastrointestinal function and measuring intestinal permeability could serve as a useful tool for assessing the severity of chemotherapy-induced gastrointestinal toxicity.

Methods

Male Sprague–Dawley rats were injected intraperitoneally either with 5-fluorouracil (150 mg/kg), oxaliplatin (15 mg/kg) or irinotecan (200 mg/kg). Clinical signs of gastrointestinal toxicity were assessed daily by weighing the animals and by checking for diarrhea. After 48 h, intestinal permeability to iohexol was measured in vivo by giving the animals 1 ml of 647 mg/ml iohexol solution by oral gavage and collecting all the excreted urine for 24 h. All of the animals were euthanized 72 h after drug administration and tissue samples were harvested from the jejunum and colon.

Results

All chemotherapeutics caused significant body weight loss and diarrhea. Intestinal permeability to iohexol was also increased in all treatment groups and histological analysis revealed significant intestinal damage in both jejunum and colon. Iohexol permeability correlated with the severity of clinical signs of gastrointestinal toxicity and with acute colonic injury.

Conclusions

Chemotherapeutic drugs, such as 5-fluorouracil, oxaliplatin, and irinotecan, increase intestinal permeability to iohexol. Measuring intestinal permeability to iohexol could provide a simple marker for assessing chemotherapy-induced gastrointestinal toxicity.

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Potential influence of being overweight on the development of hepatic dysfunction in Japanese patients with EGFR-mutated non-small cell lung cancer undergoing gefitinib monotherapy: the Okayama Lung Cancer Study Group experience

Abstract

Background

Being overweight has been reported to induce hepatic dysfunction during cytotoxic chemotherapy. Severe hepatic dysfunction can also be observed during gefitinib monotherapy, leading to interrupted or discontinued treatment. However, whether being overweight is a risk factor during gefitinib therapy is unknown.

Methods

We retrospectively reviewed 183 Japanese patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor-naïve non-small cell lung cancer (NSCLC) harboring EGFR mutations, who received gefitinib monotherapy between July 2007 and February 2014. We defined being overweight as having a body mass index (BMI) ≥ 25 kg/m² and assessed its potential relationship with ≥grade 2 hepatic dysfunction.

Results

The patient demographics were as follows: 114 women; median age 72 years (range 42–95 years); BMI ≥ 25 kg/m², n = 32; performance status 0–1, n = 136; stage IIIB/IV, n = 141; and major EGFR mutations, n = 171. Hepatic dysfunction ≥grade 2 during the gefitinib therapy was observed in 44 (24.0 %) patients, 22 (50.0 %) of whom interrupted or discontinued treatment. The median duration from gefitinib administration to the development of hepatic dysfunction was 56 days (range 6–1,352 days). Overweight patients were more likely to develop hepatic dysfunction ≥grade 2 compared to non-overweight patients according to a multivariate analysis adjusted for several confounding factors (hazard ratio 2.24; 95 % confidence interval 1.01–4.95; p = 0.046).

Conclusion

These results suggest that being overweight may induce hepatic dysfunction during gefitinib monotherapy in Japanese patients with EGFR-mutated NSCLC.

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Development of three-dimensional transperineal ultrasound for image-guided radiation therapy of the prostate: Early evaluations of feasibility and use for inter- and intrafractional prostate localization

Publication date: Available online 2 September 2016
Source:Practical Radiation Oncology
Author(s): Apoorva Trivedi, Takamura Ashikaga, Daphne Hard, Jessica Archambault, Martin Lachaine, David T. Cooper, Harold James Wallace
Transperineal ultrasound (TPUS) allows for continuous imaging of the prostate gland, but the accuracy of TPUS has not been rigorously studied. We determined the feasibility of prostate imaging with TPUS and subsequently compared prostate localization with TPUS and Computed Tomography (CT).Methods and MaterialsWe completed two sequential evaluations of TPUS. The feasibility study included 15 men with localized prostate cancer and tested if TPUS adequately imaged the prostate. Image qualities of the prostate and adjacent normal structures were measured. The subsequent study included 17 men who at the time of initial radiation treatment planning and in three subsequent sessions had CT and TPUS imaging performed and compared.ResultsFeasibility of TPUS was confirmed in the first trial. After expected hardware and software modifications were completed, TPUS provided near complete edge definition of the prostate in the final 5 patients in the feasibility trial. The second study allowed for the comparison of 30 image sets. The differences between TPUS and CT in each direction (mean+standard deviation) were found to be 0.06±2.86mm (A/P), 0.49±3.49mm (S/I), and 0.63±3.27mm (L/R), with no significant difference between the two modalities (all p's>0.32). The Euclidean distance variance using the two techniques was 5.25±1.79mm, which was significantly different.ConclusionsTPUS provides good imaging of the prostate gland. We noted excellent correlation in gland localization when TPUS is compared to CT when comparing routine three-dimensional positional data. Euclidean distance variation suggests the potential that summation of small errors may in fact lead to significant differences in actual gland positional certainty. The reported difference is within the range of standard planning target volume (PTV) expansion however requires additional evaluation.



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Regarding “The dosimetric impact of image guided radiation therapy by intratumoral fiducial markers” by Yu et al. (Vol 6, Issue 4, p276–283)

Publication date: Available online 2 September 2016
Source:Practical Radiation Oncology
Author(s): Jeffrey V. Siebers, J. James Gordon




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