Hypoxia exists to some degree in most solid tumors due to inadequate oxygen delivery of the abnormal vasculature which cannot meet the demands of the rapidly proliferating cancer cells. The levels of oxygenation within the same tumor are highly variable from one area to another and can change over time. Tumor hypoxia is an important impediment to effective cancer therapy. In radiotherapy, the primary mechanism is the creation of reactive oxygen species; hypoxic tumors are therefore radiation resistant. A number of chemotherapeutic drugs have been shown to be less effective when exposed to a hypoxic environment which can lead to further disease progression. Hypoxia is also a potent barrier to effective immunotherapy in cancer treatment. Because of the recognition of hypoxia as an important barrier to cancer treatment, a variety of approaches have been undertaken to overcome or reverse tumor hypoxia. Such approaches have included breathing hyperbaric oxygen, artificial hemoglobins, allosteric hemoglobin modifiers, hypoxia activated prodrugs and fluorocarbons (FCs). These approaches have largely failed due to limited efficacy and/or adverse side effects. Oxygen therapeutics, based on liquid FCs, can potentially increase the oxygen-carrying capacity of the blood to reverse tumor hypoxia. Currently, at least two drugs are in clinical trials to reverse tumor hypoxia; one of these is designed to improve permeability of oxygen into the tumor tissue and the other is based upon a low boiling point FC that transports higher amounts of oxygen per gram than previously tested FCs.
The hypothesis that infection with Schistosoma japonicum causes decreased nutritional status was studied in a randomized trial among 170 males and females, mean (SD) age 11.4 (3.5) years, residing in an endemic region of northeastern Leyte, Philippines. The S. japonicum-infected children were randomized to receive praziquantel or placebo and followed-up six months after randomization. Stature, weight, triceps, subscapular, and calf skinfold thicknesses and their sum, and hemoglobin level were measured at baseline and follow-up. Schistosoma japonicum eggs were detected in Kato-Katz stool smears and the intensity of infection was assessed by quantitative egg count. Intensities of hookworm, ascaris, and trichuris infections were also measured. The six-month levels of the anthropometric measures and hemoglobin were adjusted for age and their baseline levels and then compared between the praziquantel and placebo groups. Treatment interactions were also analyzed by sex. Baseline anthropometric and hemoglobin levels and parasite infection intensities were the same in the two groups. At six months, the praziquantel group had significantly higher hemoglobin levels (P < 0.001) and sum of skinfolds (P < 0.001) than the placebo group. Males had a significantly greater increase in hemoglobin levels with treatment than did females. The hemoglobin increase was not due to changes in hookworm intensity. The results show that schistosomiasis japonica caused decreased nutritional status in children and probably is partly responsible for the malnutrition and reduction in growth for age described in prior cross-sectional studies.
Dodecafluoropentane emulsion (DDFPe) is a novel nanotechnology for oxygen delivery with therapeutic potential for hemorrhagic shock and/or traumatic brain injury (TBI). DDFPe demonstrates efficacy at smaller doses than previously tested perfluorocarbon oxygen therapeutics. This smaller dose potentially eliminates toxicities exhibited by previous oxygen therapeutics, while anti-inflammatory properties of DDFPe may alleviate damage from ischemia reperfusion injury. This mini-review summarizes our progress in developing a battle-field ready product to prevent combat death due to hemorrhagic shock and/or TBI. Preclinical studies, for both indications, show promising effects of DDFPe as a resuscitation fluid. DDFPe may become a part of the toolkit for tactical healthcare professionals in battlefield and domestic emergency medicine.
The aim of this paper was to create an in vitro setup to quantify the oxygen offloading capabilities of dodecafluoropentane emulsion (DDFPe) in a hypoxic environment. Oxygen offloading from DDFPe was characterized under different gaseous environments and under pre-oxygenated conditions. Results of this study showed that (1) oxygen offloading is inversely related to the solubility of the selected sparging gas in saline and (2) both pre-oxygenated and simultaneously oxygenated DDFPe display similar magnitudes of oxygen transport. These results could be applicable to on-going and future studies involving a variety of hypoxic conditions where oxygen delivery might be therapeutically beneficial.
2561 Background: Tumor hypoxia limits the response of glioblastoma multiforme (GBM) to radiotherapy (RT) and chemotherapy (temozolomide[TMZ]). Additionally, patient biomarkers are strong predictors of responsiveness to TMZ. The purpose of this study is to evaluate the use of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM and stratify the results based on predicted TMZ response. Methods: 11 adult GBM patients have been enrolled. Patients were administered DDFPe via IV infusion (2% w/vol at doses of 0.05, 0.1 or 0.17 mL/kg) an hour prior to each 2 Gy fraction of RT (30 fractions over 6-weeks) with supplemental oxygen. Patients also received standard concurrent and adjuvant TMZ. To confirm tumor re-oxygenation, patients underwent TOLD MRI before and after DDFPe administration. Archived tumor specimens were studied with GliomaSTRAT assay for methylated genes predictive of response. Patients were also studied with serial MRI scans per standard of care and followed for survival. Results: There were minimal acute adverse events related to DDFPe administration. One patient at each of dose levels 0.1 and 0.17 mL/kg developed symptomatic radiation necrosis, which was judged to be related to DDFPe. Enrollment has continued at the 0.1 mL/kg dose without additional significant DDFPe-related toxicity. TOLD MRI showed significant decrease in T1of tumor tissue consistent with tumor re-oxygenation (p=0.015) with no significant change in oxygenation of normal brain tissue. Historically, the average overall survival for GBM patients, for both TMZ responders and non-responders, is about 14.6 months. The progress chart for patient overall survival is listed below, 4 patients have died. All other patients are alive. Conclusions: DDFPe is a promising oxygen therapeutic for reversing tumor hypoxia. A Phase II study is being planned to assess its effectiveness. Clinical trial information: NCT02189109. [Table: see text]
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