Tumor Oxygenation Research Articles

Hypoxia Imaging As a Guide for Hypoxia-Modulated and Hypoxia-Activated Therapy.

Significance: Oxygen imaging techniques, which can probe the spatiotemporal heterogeneity of tumor oxygenation, could be of significant clinical utility in radiation treatment planning and in evaluating the effectiveness of hypoxia-activated prodrugs. To fulfill these goals, oxygen imaging techniques should be noninvasive, quantitative, and capable of serial imaging, as well as having sufficient temporal resolution to detect the dynamics of tumor oxygenation to distinguish regions of chronic and acute hypoxia. Recent Advances: No current technique meets all these requirements, although all have strengths in certain areas. The current status of positron emission tomography (PET)-based hypoxia imaging, oxygen-enhanced magnetic resonance imaging (MRI), 19F MRI, and electron paramagnetic resonance (EPR) oximetry are reviewed along with their strengths and weaknesses for planning hypoxia-guided, intensity-modulated radiation therapy and detecting treatment response for hypoxia-targeted prodrugs. Critical Issues: Spatial and temporal resolution emerges as a major concern for these areas along with specificity and quantitative response. Although multiple oxygen imaging techniques have reached the investigative stage, clinical trials to test the therapeutic effectiveness of hypoxia imaging have been limited. Future Directions: Imaging elements of the redox environment besides oxygen by EPR and hyperpolarized MRI may have a significant impact on our understanding of the basic biology of the reactive oxygen species response and may extend treatment possibilities.

The antitumor mechanisms of aerobic exercise: A review of recent preclinical studies.

Aerobic exercise is an important non‐pharmacological means of antitumor intervention, but related mechanisms are poorly understood. In this review, previous studies are summarized from the aspects of tumor oxygenation, autophagy versus apoptosis, and organismal immunity. Current findings on the antitumor effects of aerobic exercise involve AMPK signaling, PI3K/Akt signaling, Th1/Th2 cytokine balance related to immunity, PD‐1/PD‐L1 immunosuppressive signaling, and related cytokine pathways. Several directions for further research are proposed, including whether newly discovered subgroups of cytokines influence the effects of aerobic exercise on tumors, tailoring corresponding exercise prescriptions based on the bidirectional effects of certain cytokines at different stages, identifying the potential effects of exercise time and intensity, and elucidating details of the unclear mechanisms. Through the discussion of the existing data, we hope to provide new ideas for the future research of exercise therapy.

Early Detection of Response to Radiotherapy Treatment with 11C-Acetate PET Imaging

11C-Acetate radiotracer with Positron Emission Tomography (PET) imaging is currently used in cardiovascular imaging for perfusion and oxygen consumption measurement. It is also used, among other diseases, for prostate cancer as this radiotracer does not accumulate in the bladder. The present study reports the assessment of the radiotherapy treatment by measuring the tumor perfusion and oxygenation before and at mid-treatment by imaging with dynamic 11C-Acetate in patients with head and neck cancer. A pre-treatment dynamic 11C-Acetate and a clinical static 18F-FDG PET were conducted before initiation of the treatment, and the second 11C-Acetate dynamic scan was performed after four weeks of radiotherapy (i.e., after a dose of 35 Gy for a total of 70 Gy). The two-tissue compartment model was applied to 11C-Acetate images to extract the perfusion and oxygen consumption. The results showed a reduction in tumor volume by more than 50% compared to the initial volume in patient-1. Besides, patient-2 has displayed a more reduced tumor volume after 4 weeks of treatment. The 11C-Acetate rate constant k2 representing oxygen consumption increased after radiotherapy dose in both patients. This increase of k2 could reflect the reoxygenation process inside the tumor, and it can reflect the early treatment response. In conclusion, 11C-Acetate could predict the early changes in the tumor perfusion and the oxidative metabolism to optimally adjust the treatment.

PO-1805 In silico tumour modelling accounting for tumour oxygenation and its dynamics

PO-1805 In silico tumour modelling accounting for tumour oxygenation and its dynamics

Highly Stable Silica-Coated Bismuth Nanoparticles Deliver Tumor Microenvironment-Responsive Prodrugs to Enhance Tumor-Specific Photoradiotherapy.

Radiosensitizers are agents capable of amplifying injury to tumor tissues by enhancing DNA damage and fortifying production of radical oxygen species (ROS). The use of such radiosensitizers in the clinic, however, remains limited by an insufficient ability to differentiate between cancer and normal cells and by the presence of a reversible glutathione system that can diminish the amount of ROS generated. Here, to address these limitations, we design an H2O2-responsive prodrug which can be premixed with lauric acid (melting point ∼43 °C) and loaded around the surface of silica-coated bismuth nanoparticles (BSNPs) for cancer-specific photoradiotherapy. Particularly, silica coating confers BSNPs with improved chemical stability against both near-infrared light and X-rays. Upon photothermal heating, lauric acid is melted to trigger prodrug release, followed by its transformation into p-quinone methide via H2O2 stimulation to irreversibly alkylate glutathione. Concurrently, this heat boosts tumor oxygenation and helps relieve the hypoxic microenvironment. Following sequential irradiation by X-rays, BSNPs generate plentiful ROS, which act in combination with these events to synergistically induce cell death via DNA breakage and mitochondria-mediated apoptosis pathways, ultimately enabling effective inhibition of tumor growth in vivo with high tumor specificity and reduced side effects. Collectively, this work presents a promising approach for the improvement of other ROS-responsive proalkylating agents, while simultaneously highlighting a robust nanosystem for combining these prodrugs with photoradiosensitizers to realize precision photoradiotherapy.

A Robust Oxygen-Carrying Hemoglobin-Based Natural Sonosensitizer for Sonodynamic Cancer Therapy.

The development of novel sonosensitizers with outstanding reactive oxygen (ROS) generation capacity and great biocompatibility poses a significant challenge for the clinical practice of sonodynamic therapy (SDT). In this work, hemoglobin (Hb) with natural metalloporphyrin was first shown to possess great potential as a sonosensitizer. Compared with traditional organic sonosensitizers, Hb had satisfactory sono-sensitizing efficiency because four the porphyrin molecules were separated by four polypeptide chains. This effectively avoided the problem of low ROS quantum yield caused by the stacking of hydrophobic porphyrins. Meanwhile, Hb is an efficient and safe oxygen carrier that may release O2 at hypoxic tumors site, which improved tumor oxygenation and subsequently enhanced SDT efficacy. Therefore, Hb was integrated with zeolitic imidazolate framework 8 (ZIF-8) to form a nanoplatform that demonstrated a potent suppression effect on deep-seated tumors under ultrasound irradiation.

Tumor Modeling and Microwave Heating for Increasing Oxygen in Tumors during Photodynamic Therapy

Tumor destruction due to Photodynamic Therapy (PDT) is mainly governed by the amount of molecular oxygen present in the tumor. Oxygen is one of the rate-limiting factors in PDT. This rate-limiting factor always makes PDT a lengthy process, as it necessitates interruption in treatment in order to restore the depleted oxygen levels to normal range. In this paper, a microwave (MW) heating technique is proposed as a mechanism to elevate the local tissue temperature for oxygen enhancement.

Multi-responsive nanotheranostics with enhanced tumor penetration and oxygen self-producing capacities for multimodal synergistic cancer therapy

Incorporation of multiple functions into one nanoplatform can improve cancer diagnostic efficacy and enhance anti-cancer outcomes. Here, we constructed doxorubicin (DOX)-loaded silk fibroin-based nanoparticles (NPs) with surface functionalization by photosensitizer (N770). The obtained nanotheranostics (N770-DOX@NPs) had desirable particle size (157 nm) and negative surface charge (−25 mV). These NPs presented excellent oxygen-generating capacity and responded to a quadruple of stimuli (acidic solution, reactive oxygen species, glutathione, and hyperthermia). Surface functionalization of DOX@NPs with N770 could endow them with active internalization by cancerous cell lines, but not by normal cells. Furthermore, the intracellular NPs were found to be preferentially retained in mitochondria, which were also efficient for near-infrared (NIR) fluorescence imaging, photothermal imaging, and photoacoustic imaging. Meanwhile, DOX could spontaneously accumulate in the nucleus. Importantly, a mouse test group treated with N770-DOX@NPs plus NIR irradiation achieved the best tumor retardation effect among all treatment groups based on tumor-bearing mouse models and a patient-derived xenograft model, demonstrating the unprecedented therapeutic effects of trimodal imaging-guided mitochondrial phototherapy (photothermal therapy and photodynamic therapy) and chemotherapy. Therefore, the present study brings new insight into the exploitation of an easy-to-use, versatile, and robust nanoplatform for programmable targeting, imaging, and applying synergistic therapy to tumors.

Abstract 3058: Molecular imaging of hypoxia to evaluate synergy between HER2 targeted therapy and fractionated radiation in murine models of HER2+ breast cancer

Abstract Introduction: Tumor hypoxia contributes to intra-tumoral heterogeneity and decreases efficacy of cytotoxic therapy. Fractionated radiation is a component of standard-of-care therapy for patients with unresectable human epidermal growth factor receptor 2 (HER2+) breast cancer. This study investigates if [18F]-fluoromisonidazole (FMISO)-PET imaging can quantify anti-HER2 therapy-induced changes in tumor oxygenation and utilize imaging metrics to monitor the synergy of combination targeted and fractionated radiation. Improving treatment synergy in HER2+ breast cancer has potential to increase therapeutic efficacy without increasing cytotoxic therapy. Methods: For in vivo studies, HER2+ cell line (BT474 and MDA-MB-361) and HER2+ patient derived xenograft (BCM 3472) tumor models were engrafted in mice and treated with single agent or combination trastuzumab (4 mg/kg) and fractionated radiation (6/3 Gy). Mice were imaged with FMISO-PET imaging on days 0, 3, and 7 to monitor changes in tumor hypoxia. Hypoxic fraction within the tumor was quantified by a voxel-wise basis with a hypoxic threshold of mean standardized uptake value (SUV) of the muscle + 1 STD. Tumors were either extracted for biological validation of imaging or continued to measure tumor size changes for longitudinal assessment of response. Immunohistochemical analysis included staining for pimonidazole (hypoxia), CD-31 (microvessel), cleaved caspase-3 (apoptosis) and Ki-67 (proliferation). Bliss test of independence and a non-parametric T-test was used to assess for treatment synergy and significance, respectively. Results: In vivo, MDA-MB-361 tumors treated with trastuzumab and fractionated radiation revealed a SUVmean of 0.20 ± 0.09 on day 7, while tumors treated with fractionated radiation had a FMISO SUVmean of 0.31 ± 0.06 (p=0.05). MDA-MB-361 tumors treated with a control or fractionated radiation were 93.7% and 87.7% hypoxic, respectively; whereas, tumors treated with trastuzumab + fractionated radiation were significantly decreased (76.3% hypoxic, p=0.05 and p=0.26, respectively). 30 days after start of therapy, BCM3472 tumors treated with single agent fractionated radiation had a tumor volume of 285.3 ± 59 mm3, whereas tumors treated with trastuzumab and fractionated radiation had a tumor volume of 104 ± 24 mm3 (p<0.05). Treatment synergy started 14 days after start of therapy. Conclusion: HER2+ breast cancer treated with trastuzumab prior to fractionated radiation decreases hypoxia and synergistically increases efficacy of radiotherapy. FMISO-PET imaging has potential to identify in vivo response to combination therapies and better understand changes in the tumor microenvironment to guide combination therapy. Citation Format: Patrick Song, Yun Lu, Sharon Samuel, Katherine Heinzman, Suzanne Lapi, Anna Sorace. Molecular imaging of hypoxia to evaluate synergy between HER2 targeted therapy and fractionated radiation in murine models of HER2+ breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3058.

Orally administered oxygen nanobubbles enhance tumor response to sonodynamic therapy

AbstractSuspensions of oxygen‐filled bubbles are under active investigation as potential means of relieving tissue hypoxia. Intravenous administration of large quantities of bubbles is, however, undesirable. Previous work by the authors has demonstrated that tumor oxygen levels can be increased following oral administration of phospholipid stabilized oxygen nanobubbles. The aim of this study was to determine whether this would enhance the efficacy of sonodynamic therapy (SDT), which is known to be inhibited in hypoxic tissue. Experiments were conducted in a murine model of pancreatic cancer. Animals were treated with SDT (intratumoural injection of 1 mM Rose Bengal followed by exposure to 1 MHz ultrasound, 0.1 kHz pulse repetition frequency, 30% duty cycle, 3.5 W cm−2 for 3.5 minutes) either with or without a prior gavage of oxygen bubbles. A statistically significant reduction in the rate of tumor growth was observed in the groups receiving oxygen nanobubbles either 5 or 20 minutes before SDT. Separate measurements of tumor oxygen using a fiber optic probe and expression of hypoxia inducible factor (HIF)1α following tumor excision, confirmed the change in tumor oxygen levels. These findings offer a potentially promising new approach to relieving tissue hypoxia in order to facilitate cancer therapy.

Targeting tumor vascularization: promising strategies for vascular normalization.

Tumor recurrence after the clinical cure of tumor often results from the presence of an abnormal microenvironment, including an aberrant vasculature. The tumor microenvironment is rich in pro-angiogenic factors but lacks pro-maturation factors. Pro-angiogenic conditions in the tumor microenvironment, such as hypoxia, are double-edged swords, promoting both the repair of normal tissues and the development of an abnormal blood vessel network. The coexistence of perfusion and hypoxic zones and uneven blood vessel distribution in tumor tissues profoundly influence tumor deterioration, recurrence, and metastasis. Traditional anti-angiogenic therapies have shown limited efficacy, and promote drug resistance, and even metastasis. In contrast, vascular normalization therapy induces a more physiological-like state, leading to better outcomes and fewer side effects. Vascular normalization entails modifying the tumor vascular system to improve tumor oxygenation and substance transport, thereby contributing to improving the efficacy of radiotherapy, chemotherapy, and immunotherapy. This review mainly focuses on the process of tumor vascularization; potential therapeutic targets, including cells, metabolism, signaling pathways, and angiogenesis-related genes; and possible strategies to normalize blood vessels through regulating tumor vessel generation, the development of tumor vessels, and blood vessel fusion and pruning.

Compressed vessels bias red blood cell partitioning at bifurcations in a hematocrit-dependent manner: Implications in tumor blood flow

The tumor microenvironment is abnormal and associated with tumor tissue hypoxia, immunosuppression, and poor response to treatment. One important abnormality present in tumors is vessel compression. Vessel decompression has been shown to increase survival rates in animal models via enhanced and more homogeneous oxygenation. However, our knowledge of the biophysical mechanisms linking tumor decompression to improved tumor oxygenation is limited. In this study, we propose a computational model to investigate the impact of vessel compression on red blood cell (RBC) dynamics in tumor vascular networks. Our results demonstrate that vessel compression can alter RBC partitioning at bifurcations in a hematocrit-dependent and flow rate-independent manner. We identify RBC focusing due to cross-streamline migration as the mechanism responsible and characterize the spatiotemporal recovery dynamics controlling downstream partitioning. Based on this knowledge, we formulate a reduced-order model that will help future research to elucidate how these effects propagate at a whole vascular network level. These findings contribute to the mechanistic understanding of hemodilution in tumor vascular networks and oxygen homogenization following pharmacological solid tumor decompression.

Emerging Biomaterials-Based Strategies for Inhibiting Vasculature Function in Cancer Therapy.

The constant feeding of oxygen and nutrients through the blood vasculature has a vital role in maintaining tumor growth. Interestingly, recent endeavors have shown that nanotherapeutics with the strategy to block tumor blood vessels feeding nutrients and oxygen for starvation therapy can be helpful in cancer treatment. However, this field has not been detailed. Hence, this review will present an exhaustive summary of the existing biomaterial based strategies to disrupt tumor vascular function for effective cancer treatment, including hydrogel or nanogel-mediated local arterial embolism, thrombosis activator loaded nano-material-mediated vascular occlusion and anti-vascular drugs that block tumor vascular function, which may be beneficial to the design of anti-cancer nanomedicine by targeting the tumor vascular system.

Convection enhanced delivery of light responsive antigen capturing oxygen generators for chemo-phototherapy triggered adaptive immunity

In recent years, combination therapy has emerged as the cornerstone of clinical practice in treating glioblastoma multiforme. However, their ability to trigger and leverage the body's adaptive immunity has rarely been studied. Tumour heterogeneity, the presence of the blood-brain barrier, and an immunosuppressive tumor microenvironment play a crucial role in the 90% local tumor recurrence post-treatment. Herein, we report an improved combination therapy approach capable of stimulating an immune response that utilizes Light responsive antigen-capturing oxygen generators (LAGs). The engineered LAGs loaded with a non-genotoxic molecule, Nutlin-3a, and a photosensitizer, Protoporphyrin IX, can release the payload on-demand when exposed to light of a specific wavelength. The in-situ oxygen generation capability of LAGs enables tumor oxygenation enhancement, thereby alleviating the tumor hypoxia and enhancing the efficacy of chemo-photodynamic therapy. Furthermore, by modulating the surface properties of LAGs, we demonstrated that the tumor-derived protein antigens released can be captured and retained in-situ, which improves antigen uptake and presentation by the antigen-presenting cells. Dual drug-loaded LAGs (DD-LAGs) upregulated the expression of cell surface CD83 maturation and CD86 costimulatory markers on monocyte-derived-dendritic cells, suggesting intrinsic immune adjuvancy. In the presence of 3D printed hypoxic U87 spheroids (h-U87), DD-LAGs induced cancer cell death, upregulated IL-1β, and downregulated IL-10 resulting in CD3+, helper CD4+, and cytotoxic CD8+ proliferation. Finally, we have investigated convection-enhanced delivery as a potential route of administration for DD-LAGs. Our work presents a novel strategy to induce tumor cell death both during and post-treatment, thereby reducing the possibility of recurrence.

Longitudinal monitoring of tumor response to immune checkpoint inhibitors using noninvasive diffuse reflectance spectroscopy.

Immune checkpoint inhibitors have revolutionized cancer treatment. However, there are currently no methods for noninvasively and nondestructively evaluating tumor response to immune checkpoint inhibitors. We used diffuse reflectance spectroscopy to monitor in vivo tumor microenvironmental changes in response to immune checkpoint inhibitors in a CT26 murine colorectal cancer model. Mice growing CT26 tumor xenografts were treated with either anti-PD-L1, anti-CTLA-4, a combination of both inhibitors, or isotype control on 3 separate days. Monotherapy with either anti-PD-L1 or anti-CTLA-4 led to a large increase in tumor vascular oxygenation within the first 6 days. Reoxygenation in anti-CTLA-4-treated tumors was due to a combination of increased oxygenated hemoglobin and decreased deoxygenated hemoglobin, pointing to a possible change in tumor oxygen consumption following treatment. Within the anti-PD-L1-treated tumors, reoxygenation was primarily due to an increase in oxygenated hemoglobin with the minimal change in deoxygenated hemoglobin, indicative of a likely increase in tumor perfusion. The tumors in the combined treatment group did not show any significant changes in tumor oxygenation following therapy. These studies demonstrate the sensitivity of diffuse reflectance spectroscopy to tumor microenvironmental changes following immunotherapy and the potential of such non-invasive techniques to determine early tumor response to immune checkpoint inhibitors.

An Albumin-Based Therapeutic Nanosystem for Photosensitizer/Protein Co-Delivery to Realize Synergistic Cancer Therapy.

Oxygen-dependent photodynamic therapy (PDT) is hindered by the limited availability of endogenous oxygen in solid tumors and low tumor accumulation of photosensitizers. Herein, we developed a biocompatible cancer-targeted therapeutic nanosystem based on cRGD conjugated bovine serum albumin (CBSA) co-loaded with a photosensitizer (chlorin e6, Ce6) and a therapeutic protein (cytochrome c, Cytc) for synergistic photodynamic and protein therapy. The nanosystem (Ce6/Cytc@CBSA) can target αVβ3 integrin overexpressed cancer cells to improve tumor accumulation due to incorporation of cRGD. In the intracellular environment, Ce6 is released to produce toxic singlet oxygen upon near-infrared irradiation. At the same time, the therapeutic protein, Cytc, can induce programmed cell death by activating the downstream caspase pathway. Most importantly, Cytc with the catalase-like activity accelerates O2 generation by decomposing excess H2O2 in cancer cells, thereby relieving the PDT-induced hypoxia to enhance therapeutic efficacy. Both in vitro and in vivo studies reveal the significantly improved antitumor effects of the combined photodynamic/protein therapy, indicating that Ce6/Cytc@CBSA shows great potential in synergetic cancer treatments.

Tumor hypoxia: The major culprit behind cisplatin resistance in cancer patients.

Cisplatin is the most commonly used first-line drug for cancer treatment. However, many patients develop resistance to cisplatin therapy which ultimately results in therapy failure and increased mortality. A growing body of evidence shows that the hypoxic microenvironment is the prime factor underlying tumor insensitivity to cisplatin treatment. Since tumors in the majority of cancer patients are under hypoxic stress (low oxygen supply), it becomes necessary to understand the pathobiology behind hypoxia-induced cisplatin resistance in cancer cells. Here, we discuss the molecular events that render hypoxic tumors insensitive to cisplatin therapy. Furthermore, various drugs and tumor oxygenation techniques have been developed to circumvent cisplatin resistance in hypoxic tumors. However, their pharmaceutical applications are limited due to failures in clinical investigations and a lack of preclinical studies in the hypoxic tumor microenvironment. This review addresses these challenges and provides new directions for the strategic deployment of cisplatin sensitizers in the hypoxic tumor microenvironment.

Phenotypic variation modulates the growth dynamics and response to radiotherapy of solid tumours under normoxia and hypoxia

In cancer, treatment failure and disease recurrence have been associated with small subpopulations of cancer cells with a stem-like phenotype. In this paper, we develop and investigate a phenotype-structured model of solid tumour growth in which cells are structured by a stemness level, which varies continuously between stem-like and terminally differentiated behaviours. Cell evolution is driven by proliferation and death, as well as advection and diffusion with respect to the stemness structure variable. Here, the magnitude and sign of the advective flux are allowed to vary with the oxygen level. We use the model to investigate how the environment, in particular oxygen levels, affects the tumour’s population dynamics and composition, and its response to radiotherapy. We use a combination of numerical and analytical techniques to quantify how under physiological oxygen levels the cells evolve to a differentiated phenotype and under low oxygen level (i.e., hypoxia) they de-differentiate. Under normoxia, the proportion of cancer stem cells is typically negligible and the tumour may ultimately become extinct whereas under hypoxia cancer stem cells comprise a dominant proportion of the tumour volume, enhancing radio-resistance and favouring the tumour’s long-term survival. We then investigate how such phenotypic heterogeneity impacts the tumour’s response to treatment with radiotherapy under normoxia and hypoxia. Of particular interest is establishing how the presence of radio-resistant cancer stem cells can facilitate a tumour’s regrowth following radiotherapy. We also use the model to show how radiation-induced changes in tumour oxygen levels can give rise to complex re-growth dynamics. For example, transient periods of hypoxia induced by damage to tumour blood vessels may rescue the cancer cell population from extinction and drive secondary regrowth.

Advanced imaging to assess longitudinal vascular changes in brain metastases treated with checkpoint inhibition.

3059 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) in melanoma and lung cancer. Several studies demonstrate that 20-50% of BM patients respond to ICI. The reasons behind this wide variability in treatment response is not clear. Therefore, using physiologic imaging, we seek to identify the longitudinal biological changes exerted on BM as a result of ICI administration. Methods: Given the importance of aberrant tumor vasculature in cancer proliferation, we have focused on assessing changes in vascular physiology. We analyzed standard post-contrast and dynamic susceptibility contrast (DSC) MRI to identify characteristic vascular signatures as part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology. Tumor volume measurements were calculated by summating all enhancing voxels. As per modified RECIST and RANO criteria for immunotherapy, volumetric increase of > 40% was defined as progressive disease (PD), a decrease of > 60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 35 patients, out of the total cohort of 60, have undergone DSC-MRI analysis. Histologies include 15 with breast cancer, 6 with non-small cell lung cancer, 4 with melanoma, and 10 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 35 evaluable patients include 4 PR, 12 SD, and 19 PD. Thus far, we found that ICI-resistant BM had a 50% increase in cerebral blood flow (CBF), 105% increase in cerebral blood volume (CBV), a 15% increase in mean transit time (MTT), and an 80% increase in vessel caliber at 6 weeks post-treatment. On the other hand, ICI-responsive BM had no change in CBF, a 33% increase in CBV, a 10% decrease in MTT, and no change in vessel caliber. Ongoing analysis to uncover additional vascular changes (e.g. tumor oxygenation, vessel size index) within BM to ICI are pending. Conclusions: Our data provides evidence that effective ICI for BM is associated with unique intra-tumoral vascular physiology. With final analysis, we will uncover other facets of vascular physiology that correlate with ICI response, and may reveal mechanisms of response/resistance within tumors to ICI.

Assessment of Hypoxic Tissue Fraction and Prediction of Survival in Cervical Carcinoma by Dynamic Contrast-Enhanced MRI.

Tumor hypoxia is a major cause of treatment resistance and poor survival in locally-advanced cervical carcinoma (LACC). It has been suggested that K trans and v e maps derived by dynamic contrast-enhanced magnetic resonance imaging can provide information on the oxygen supply and oxygen consumption of tumors, but it is not clear whether and how these maps can be combined to identify tumor hypoxia. The aim of the current study was to find the optimal strategy for calculating hypoxic fraction and predicting survival from K trans and v e maps in cervical carcinoma. K trans and v e maps of 98 tumors of four patient-derived xenograft models of cervical carcinoma as well as 80 patients with LACC were investigated. Hypoxic fraction calculated by using K trans maps correlated strongly (P < 0.0001) to hypoxic fraction assessed with immunohistochemistry using pimonidazole as a hypoxia marker and was associated with disease-free and overall survival in LACC patients. Maps of v e did not provide information on hypoxic fraction and patient outcome, and combinations of K trans and v e were not superior to K trans alone for calculating hypoxic fraction. These observations imply that K trans maps reflect oxygen supply and may be used to identify hypoxia and predict outcome in cervical carcinoma, whereas v e is a poor parameter of oxygen consumption and does not provide information on tumor oxygenation status.