In vivo Monitoring of Oxygen Levels in Human Brain Tumor Between Fractionated Radiotherapy Using Oxygen-enhanced MR Imaging

2020 ◽  
Vol 16 (4) ◽  
pp. 427-432
Author(s):  
Junchao Qian ◽  
Xiang Yu ◽  
Bingbing Li ◽  
Zhenle Fei ◽  
Xiang Huang ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Tumor Cells ◽  
Normal Tissue ◽  
Oxygen Level ◽  
Tissue Oxygen ◽  
Human Brain Tumor ◽  
Fractionated Radiotherapy ◽  
Oxygen Levels ◽  
Oxygen Breathing

Background:: It was known that the response of tumor cells to radiation is closely related to tissue oxygen level and fractionated radiotherapy allows reoxygenation of hypoxic tumor cells. Non-invasive mapping of tissue oxygen level may hold great importance in clinic. Objective: The aim of this study is to evaluate the role of oxygen-enhanced MR imaging in the detection of tissue oxygen levels between fractionated radiotherapy. Methods: A cohort of 10 patients with brain metastasis was recruited. Quantitative oxygen enhanced MR imaging was performed prior to, 30 minutes and 22 hours after first fractionated radiotherapy. Results: The ΔR1 (the difference of longitudinal relaxivity between 100% oxygen breathing and air breathing) increased in the ipsilateral tumor site and normal tissue by 242% and 152%, respectively, 30 minutes after first fractionated radiation compared to pre-radiation levels. Significant recovery of ΔR1 in the contralateral normal tissue (p < 0.05) was observed 22 hours compared to 30 minutes after radiation levels. Conclusion: R1-based oxygen-enhanced MR imaging may provide a sensitive endogenous marker for oxygen changes in the brain tissue between fractionated radiotherapy.

scholarly journals Optimization of Dose Fractionation for Radiotherapy of a Solid Tumor with Account of Oxygen Effect and Proliferative Heterogeneity

Mathematics ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 1204
Author(s):  
Maxim Kuznetsov ◽  
Andrey Kolobov
Keyword(s):  
Tumor Cells ◽  
Solid Tumor ◽  
Tissue Damage ◽  
Normal Tissue ◽  
Dose Fractionation ◽  
Oxygen Effect ◽  
Model Parameters ◽  
Time And Space ◽  
Fractionated Radiotherapy ◽  
Normal Tissue Damage

A spatially-distributed continuous mathematical model of solid tumor growth and treatment by fractionated radiotherapy is presented. The model explicitly accounts for three time and space-dependent factors that influence the efficiency of radiotherapy fractionation schemes—tumor cell repopulation, reoxygenation and redistribution of proliferative states. A special algorithm is developed, aimed at finding the fractionation schemes that provide increased tumor cure probability under the constraints of maximum normal tissue damage and maximum fractional dose. The optimization procedure is performed for varied radiosensitivity of tumor cells under the values of model parameters, corresponding to different degrees of tumor malignancy. The resulting optimized schemes consist of two stages. The first stages are aimed to increase the radiosensitivity of the tumor cells, remaining after their end, sparing the caused normal tissue damage. This allows to increase the doses during the second stages and thus take advantage of the obtained increased radiosensitivity. Such method leads to significant expansions in the curative ranges of the values of tumor radiosensitivity parameters. Overall, the results of this study represent the theoretical proof of concept that non-uniform radiotherapy fractionation schemes may be considerably more effective that uniform ones, due to the time and space-dependent effects.

Effect of acute hypoxia on microcirculatory and tissue oxygen levels in rat cremaster muscle

2005 ◽  
Vol 98 (4) ◽  
pp. 1177-1184 ◽  
Author(s):  
Paul C. Johnson ◽  
Kim Vandegriff ◽  
Amy G. Tsai ◽  
Marcos Intaglietta
Keyword(s):  
Acute Hypoxia ◽  
Hypoxic Exposure ◽  
Cremaster Muscle ◽  
Tissue Oxygen ◽  
Oxygen Levels ◽  
Oxygen Fraction ◽  
Arterial Blood ◽  
S Period ◽  
Inspired Oxygen

Repeated exposure to brief periods of hypoxia leads to pathophysiological changes in experimental animals similar to those seen in sleep apnea. To determine the effects of such exposure on oxygen levels in vivo, we used an optical method to measure Po2 in microcirculatory vessels and tissue of the rat cremaster muscle during a 1-min step reduction of inspired oxygen fraction from 0.21 to 0.07. Under control conditions, Po2 was 98.1 ± 1.9 Torr in arterial blood, 52.2 ± 2.8 Torr in 29.0 ± 2.7-μm arterioles, 26.8 ± 1.7 Torr in the tissue interstitium near venous capillaries, and 35.1 ± 2.6 Torr in 29.7 ± 1.9-μm venules. The initial fall in Po2 during hypoxia was significantly greater in arterial blood, being 93% complete in the first 10 s, whereas it was 68% complete in arterioles, 47% at the tissue sites, and 38% in venules. In the 10- to 30-s period, the fall in normalized tissue and venular Po2 was significantly greater than in arterial Po2. At the end of hypoxic exposure, Po2 at all measurement sites had fallen very nearly in proportion to that in the inspired gas, but tissue oxygen levels did not reach critical Po2. Significant differences in oxyhemoglobin desaturation rate were also observed between arterial and microcirculatory vessels during hypoxia. In conclusion, the fall in microcirculatory and tissue oxygen levels in resting skeletal muscle is significantly slower than in arterial blood during a step reduction to an inspired oxygen fraction of 0.07, and tissue Po2 does not reach anaerobic levels.

scholarly journals In vivo oxygen measurement in cerebrospinal fluid of pigs to determine physiologic and pathophysiologic oxygen values during CNS infections

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Nicole de Buhr ◽  
Alexander Martens ◽  
Marita Meurer ◽  
Marta C. Bonilla ◽  
Franz Söbbeler ◽  
...  
Keyword(s):  
Partial Pressure ◽  
Ph Value ◽  
Cell Number ◽  
Bacterial Number ◽  
Oxygen Level ◽  
Partial Pressure Of Oxygen ◽  
Oxygen Levels ◽  
In Vivo Measurement ◽  
Cns Infections

AbstractDuring infection and inflammation, a reduced oxygen level clearly affects cellular functions. Oxygen levels during CNS infections are unknown. Here we established and evaluated an in vivo measurement system to characterize the oxygen level in parallel with bacterial numbers (CFU/mL), the cell number and pH level inside the CSF of healthy compared to Streptococcus suis-infected pigs. The animals were anesthetized over a seven-hour period with isoflurane in air/oxygen at physiologic arterial partial pressure of oxygen. Oxygen levels in CSF of anesthetized pigs were compared to euthanized pigs. The detected partial pressure of oxygen in the CSF remained constant in a range of 47–63 mmHg, independent of the infection status (bacterial or cell number). In contrast, the pH value showed a slight drop during infection, which correlated with cell and bacterial number in CSF. We present physiologic oxygen and pH values in CSF during the onset of bacterial meningitis.

scholarly journals Tissue Oxygen Saturation Mapping with Magnetic Resonance Imaging

2014 ◽  
Vol 34 (9) ◽  
pp. 1550-1557 ◽  
Author(s):  
Thomas Christen ◽  
Pierre Bouzat ◽  
Nicolas Pannetier ◽  
Nicolas Coquery ◽  
Anaïck Moisan ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Oxygen Saturation ◽  
Tissue Oxygen Saturation ◽  
Blood Oxygen ◽  
Oxygen Level ◽  
Resonance Imaging ◽  
Tissue Oxygen ◽  
Invasive Approach

A quantitative estimate of cerebral blood oxygen saturation is of critical importance in the investigation of cerebrovascular disease. While positron emission tomography can map in vivo the oxygen level in blood, it has limited availability and requires ionizing radiation. Magnetic resonance imaging (MRI) offers an alternative through the blood oxygen level-dependent contrast. Here, we describe an in vivo and non-invasive approach to map brain tissue oxygen saturation ( StO2) with high spatial resolution. StO2 obtained with MRI correlated well with results from blood gas analyses for various oxygen and hematocrit challenges. In a stroke model, the hypoxic areas delineated in vivo by MRI spatially matched those observed ex vivo by pimonidazole staining. In a model of diffuse traumatic brain injury, MRI was able to detect even a reduction in StO2 that was too small to be detected by histology. In a F98 glioma model, MRI was able to map oxygenation heterogeneity. Thus, the MRI technique may improve our understanding of the pathophysiology of several brain diseases involving impaired oxygenation.

Unlocking PARP inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform inhibitor efficacy for HRD-negative cancers using the alphalex tumor targeting platform.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14664-e14664
Author(s):  
Ranjit Bindra ◽  
Ranjini K Sundaram ◽  
Robert J Aiello ◽  
Dan Marshall ◽  
Patricia Bourassa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tumor Cells ◽  
Normal Tissue ◽  
Tumor Targeting ◽  
Dependent Manner ◽  
Diverse Range ◽  
Major Barrier ◽  
Anti Cancer

e14664 Background: Poly(ADP-ribose)polymerase inhibitors (PARPi’s) are a promising new class of anti-cancer agents, but their clinical application has largely been limited to tumors with homologous recombination deficiency (HRD), such as those with BRCA1/2 mutations. One strategy to target HRD-negative tumors with PARPi’s is to combine them with chemotherapy, although clinical trials indicate that dose-limiting toxicities are a major barrier to achieving synergistic efficacy with these combinations. Methods: We sought to test the hypothesis that HRD-negative cancers can be effectively treated with tumor-targeted PARPi’s in combination with chemotherapy, using our recently developed alphalex platform. This platform allows small molecule anti-cancer agents to penetrate cell membranes only at the low pH associated with the tumor microenvironment and tumor cells, directly delivering drugs to tumors while sparing normal tissue. We tested whether alphalex PARPi-conjugates in combination with chemotherapy could selectively kill cancers independent of HRD status, using a range of in vitro and in vivo tumor models. Results: We conjugated a diverse range of structurally unique PARPi’s using the alphalex platform, and demonstrated that these molecules are delivered directly into tumor cells in a pH-dependent manner. We observed significant reductions in PARylation activity and exquisite synergy with DNA damaging agents in vitro. We then demonstrated that alphalex-PARPi conjugates in combination with both temozolomide (TMZ) and irinotecan induce significant tumor cell killing in HRD-negative tumors in vivo. Importantly, we found that our tumor-targeting approach significantly reduced normal tissue toxicity, with almost complete sparing of the bone marrow relative to TMZ alone. Conclusions: The alphalex platform enables PARPi combinations with clinically relevant chemotherapies, as a means to target HRD-negative cancers without significant bone marrow toxicity. Based on these successful proof-of-concept data, we are now performing IND-enabling studies for an alphalex PARPi conjugate (CBX-11), and we anticipate initiating a Phase I clinical trial in January 2020 in solid tumors independent of HRD status.

Exogenous stress proteins enhance the immunogenicity of apoptotic tumor cells and stimulate antitumor immunity

Blood ◽  
2003 ◽  
Vol 101 (1) ◽  
pp. 245-252 ◽  
Author(s):  
Hanping Feng ◽  
Yi Zeng ◽  
Michael W. Graner ◽  
Anna Likhacheva ◽  
Emmanuel Katsanis
Keyword(s):  
Heat Shock ◽  
Tumor Cells ◽  
Normal Tissue ◽  
Antitumor Immunity ◽  
Plasma Membranes ◽  
Stress Proteins ◽  
Severe Combined Immunodeficiency ◽  
Apoptotic Cells ◽  
Antitumor Effects

Abstract We have previously reported that apoptotic tumor cells can be either immunogenic or nonimmunogenic in vivo, depending on whether or not these cells are heat stressed before induction of apoptosis. Stressed apoptotic cells express heat shock proteins on their plasma membranes and dendritic cells are capable of distinguishing them from nonstressed apoptotic cells. Here we provide evidence that when purified heat shock protein 70 or chaperone-rich cell lysate (CRCL) from syngeneic normal tissue is used as an adjuvant with nonimmunogenic apoptotic tumor cells in vaccination, potent antitumor immunity can be generated. This antitumor immunity is mediated by T cells because antitumor effects are not observed in either severe combined immunodeficiency or T cell–depleted mice. We further demonstrate that vaccination of mice with apoptotic tumor cells mixed with liver-derived CRCL as adjuvant were capable of enhancing the production of TH1 cytokines, inducing specific cytotoxic T lymphocytes and eliciting long-lasting antitumor immunity. Stress proteins from autologous normal tissue components therefore can serve as danger signals to enhance the immunogenicity of apoptotic tumor cells and stimulate tumor-specific immunity

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