Browsing by Subject "Tumor Burden"

Now showing 1 - 9 of 9
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    A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer.
    (2011) Curtis, Valerie Forbes
    In many cancer types, infiltration of bone marrow-derived myeloid cells in the tumor microenvironment is often associated with enhanced angiogenesis and tumor progression, resulting in poor prognosis. The polypeptide chemokine PK2 (Bv8) regulates myeloid cell mobilization from the bone marrow, leading to activation of angiogenesis as well as accumulation of macrophages and neutrophils in the tumor site. Neutralizing antibodies against PK2 display potent anti-tumor efficacy, illustrating the potential of PK2-antagonists as therapeutic agents for the treatment of cancer. However, antibody-based therapies can be too large to treat certain diseases and too expensive to manufacture while small molecule therapeutics are not prohibitive in these ways. In this study, we demonstrate the anti-tumor activity of a small molecule PK2 antagonist, PKRA7, in the contexts of glioblastoma and pancreatic cancer xenograft tumor models. In the highly vascularized glioblastoma, PKRA7 decreased blood vessel density while increasing necrotic areas in the tumor mass. Consistent with the anti-angiogenic activity of PKRA7 in vivo, this compound effectively reduced PK2-induced microvascular endothelial cell branching in vitro. For the poorly vascularized pancreatic cancer, the primary anti-tumor effect of PKRA7 is mediated by the blockage of myeloid cell migration and infiltration. At the molecular level, PKRA7 inhibits PK2-induced expression of several pro-migratory chemokines and chemokine receptors in macrophages. Combining PKRA7 treatment with standard chemotherapeutic agents resulted in enhanced effects in xenograft models for both glioblastoma and pancreatic tumors. Taken together, our results indicate that the anti-tumor activity of PKRA7 can be mediated by distinct mechanisms that are relevant to the pathological features of the specific type of cancer. This small molecule PK2 antagonist holds the promise to be further developed as an effective agent for combinational cancer therapy.
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    Adaptive stereotactic body radiation therapy planning for lung cancer.
    (Int J Radiat Oncol Biol Phys, 2013-09-01) Qin, Y; Zhang, F; Yoo, DS; Kelsey, CR; Yin, FF; Cai, J
    PURPOSE: To investigate the dosimetric effects of adaptive planning on lung stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Forty of 66 consecutive lung SBRT patients were selected for a retrospective adaptive planning study. CBCT images acquired at each fraction were used for treatment planning. Adaptive plans were created using the same planning parameters as the original CT-based plan, with the goal to achieve comparable comformality index (CI). For each patient, 2 cumulative plans, nonadaptive plan (PNON) and adaptive plan (PADP), were generated and compared for the following organs-at-risks (OARs): cord, esophagus, chest wall, and the lungs. Dosimetric comparison was performed between PNON and PADP for all 40 patients. Correlations were evaluated between changes in dosimetric metrics induced by adaptive planning and potential impacting factors, including tumor-to-OAR distances (dT-OAR), initial internal target volume (ITV1), ITV change (ΔITV), and effective ITV diameter change (ΔdITV). RESULTS: 34 (85%) patients showed ITV decrease and 6 (15%) patients showed ITV increase throughout the course of lung SBRT. Percentage ITV change ranged from -59.6% to 13.0%, with a mean (±SD) of -21.0% (±21.4%). On average of all patients, PADP resulted in significantly (P=0 to .045) lower values for all dosimetric metrics. ΔdITV/dT-OAR was found to correlate with changes in dose to 5 cc (ΔD5cc) of esophagus (r=0.61) and dose to 30 cc (ΔD30cc) of chest wall (r=0.81). Stronger correlations between ΔdITV/dT-OAR and ΔD30cc of chest wall were discovered for peripheral (r=0.81) and central (r=0.84) tumors, respectively. CONCLUSIONS: Dosimetric effects of adaptive lung SBRT planning depend upon target volume changes and tumor-to-OAR distances. Adaptive lung SBRT can potentially reduce dose to adjacent OARs if patients present large tumor volume shrinkage during the treatment.
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    Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
    (Nature cell biology, 2022-02) Huang, De; Wang, Yan; Thompson, J Will; Yin, Tao; Alexander, Peter B; Qin, Diyuan; Mudgal, Poorva; Wu, Haiyang; Liang, Yaosi; Tan, Lianmei; Pan, Christopher; Yuan, Lifeng; Wan, Ying; Li, Qi-Jing; Wang, Xiao-Fan
    Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.
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    Computed tomography imaging of primary lung cancer in mice using a liposomal-iodinated contrast agent.
    (PLoS One, 2012) Badea, CT; Athreya, KK; Espinosa, G; Clark, D; Ghafoori, AP; Li, Y; Kirsch, DG; Johnson, GA; Annapragada, A; Ghaghada, KB
    PURPOSE: To investigate the utility of a liposomal-iodinated nanoparticle contrast agent and computed tomography (CT) imaging for characterization of primary nodules in genetically engineered mouse models of non-small cell lung cancer. METHODS: Primary lung cancers with mutations in K-ras alone (Kras(LA1)) or in combination with p53 (LSL-Kras(G12D);p53(FL/FL)) were generated. A liposomal-iodine contrast agent containing 120 mg Iodine/mL was administered systemically at a dose of 16 µl/gm body weight. Longitudinal micro-CT imaging with cardio-respiratory gating was performed pre-contrast and at 0 hr, day 3, and day 7 post-contrast administration. CT-derived nodule sizes were used to assess tumor growth. Signal attenuation was measured in individual nodules to study dynamic enhancement of lung nodules. RESULTS: A good correlation was seen between volume and diameter-based assessment of nodules (R(2)>0.8) for both lung cancer models. The LSL-Kras(G12D);p53(FL/FL) model showed rapid growth as demonstrated by systemically higher volume changes compared to the lung nodules in Kras(LA1) mice (p<0.05). Early phase imaging using the nanoparticle contrast agent enabled visualization of nodule blood supply. Delayed-phase imaging demonstrated significant differential signal enhancement in the lung nodules of LSL-Kras(G12D);p53(FL/FL) mice compared to nodules in Kras(LA1) mice (p<0.05) indicating higher uptake and accumulation of the nanoparticle contrast agent in rapidly growing nodules. CONCLUSIONS: The nanoparticle iodinated contrast agent enabled visualization of blood supply to the nodules during the early-phase imaging. Delayed-phase imaging enabled characterization of slow growing and rapidly growing nodules based on signal enhancement. The use of this agent could facilitate early detection and diagnosis of pulmonary lesions as well as have implications on treatment response and monitoring.
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    Dual-energy micro-CT functional imaging of primary lung cancer in mice using gold and iodine nanoparticle contrast agents: a validation study.
    (PLoS One, 2014) Ashton, Jeffrey R; Clark, Darin P; Moding, Everett J; Ghaghada, Ketan; Kirsch, David G; West, Jennifer L; Badea, Cristian T
    PURPOSE: To provide additional functional information for tumor characterization, we investigated the use of dual-energy computed tomography for imaging murine lung tumors. Tumor blood volume and vascular permeability were quantified using gold and iodine nanoparticles. This approach was compared with a single contrast agent/single-energy CT method. Ex vivo validation studies were performed to demonstrate the accuracy of in vivo contrast agent quantification by CT. METHODS: Primary lung tumors were generated in LSL-Kras(G12D); p53(FL/FL) mice. Gold nanoparticles were injected, followed by iodine nanoparticles two days later. The gold accumulated in tumors, while the iodine provided intravascular contrast. Three dual-energy CT scans were performed-two for the single contrast agent method and one for the dual contrast agent method. Gold and iodine concentrations in each scan were calculated using a dual-energy decomposition. For each method, the tumor fractional blood volume was calculated based on iodine concentration, and tumor vascular permeability was estimated based on accumulated gold concentration. For validation, the CT-derived measurements were compared with histology and inductively-coupled plasma optical emission spectroscopy measurements of gold concentrations in tissues. RESULTS: Dual-energy CT enabled in vivo separation of gold and iodine contrast agents and showed uptake of gold nanoparticles in the spleen, liver, and tumors. The tumor fractional blood volume measurements determined from the two imaging methods were in agreement, and a high correlation (R(2) = 0.81) was found between measured fractional blood volume and histology-derived microvascular density. Vascular permeability measurements obtained from the two imaging methods agreed well with ex vivo measurements. CONCLUSIONS: Dual-energy CT using two types of nanoparticles is equivalent to the single nanoparticle method, but allows for measurement of fractional blood volume and permeability with a single scan. As confirmed by ex vivo methods, CT-derived nanoparticle concentrations are accurate. This method could play an important role in lung tumor characterization by CT.
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    Early 18F-FDG-PET Response During Radiation Therapy for HPV-Related Oropharyngeal Cancer May Predict Disease Recurrence.
    (International journal of radiation oncology, biology, physics, 2020-11) Mowery, Yvonne M; Vergalasova, Irina; Rushing, Christel N; Choudhury, Kingshuk Roy; Niedzwiecki, Donna; Wu, Qiuwen; Yoo, David S; Das, Shiva; Wong, Terence Z; Brizel, David M

    Purpose

    Early indication of treatment outcome may guide therapeutic de-escalation strategies in patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC). This study investigated the relationships between tumor volume and 18F-fluorodeoxyglucose positron emission tomography (PET) parameters before and during definitive radiation therapy with treatment outcomes.

    Methods and materials

    Patients undergoing definitive (chemo)radiation for HPV-related/p16-positive OPC were prospectively enrolled on an institutional review board-approved study. 18F-fluorodeoxyglucose PET/computed tomography scans were performed at simulation and after 2 weeks at a dose of ∼20 Gy. Tumor volume and standardized uptake value (SUV) characteristics were measured. SUV was normalized to blood pool uptake. Tumor volume and PET parameters associated with recurrence were identified through recursive partitioning (RPART). Recurrence-free survival (RFS) and overall survival (OS) curves between RPART-identified cohorts were estimated using the Kaplan-Meier method, and Cox models were used to estimate the hazard ratios (HRs).

    Results

    From 2012 to 2016, 62 patients with HPV-related OPC were enrolled. Median follow-up was 4.4 years. RPART identified patients with intratreatment SUVmax (normalized to blood pool SUVmean) <6.7 or SUVmax (normalized to blood pool SUVmean) ≥6.7 with intratreatment SUV40% ≥2.75 as less likely to recur. For identified subgroups, results of Cox models showed unadjusted HRs for RFS and OS (more likely to recur vs less likely) of 7.33 (90% confidence interval [CI], 2.97-18.12) and 6.09 (90% CI, 2.22-16.71), respectively, and adjusted HRs of 6.57 (90% CI, 2.53-17.05) and 5.61 (90% CI, 1.90-16.54) for RFS and OS, respectively.

    Conclusions

    PET parameters after 2 weeks of definitive radiation therapy for HPV-related OPC are associated with RFS and OS, thus potentially informing an adaptive treatment approach.
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    Effect of machine learning methods on predicting NSCLC overall survival time based on Radiomics analysis.
    (Radiation oncology (London, England), 2018-10-05) Sun, Wenzheng; Jiang, Mingyan; Dang, Jun; Chang, Panchun; Yin, Fang-Fang
    BACKGROUND:To investigate the effect of machine learning methods on predicting the Overall Survival (OS) for non-small cell lung cancer based on radiomics features analysis. METHODS:A total of 339 radiomic features were extracted from the segmented tumor volumes of pretreatment computed tomography (CT) images. These radiomic features quantify the tumor phenotypic characteristics on the medical images using tumor shape and size, the intensity statistics and the textures. The performance of 5 feature selection methods and 8 machine learning methods were investigated for OS prediction. The predicted performance was evaluated with concordance index between predicted and true OS for the non-small cell lung cancer patients. The survival curves were evaluated by the Kaplan-Meier algorithm and compared by the log-rank tests. RESULTS:The gradient boosting linear models based on Cox's partial likelihood method using the concordance index feature selection method obtained the best performance (Concordance Index: 0.68, 95% Confidence Interval: 0.62~ 0.74). CONCLUSIONS:The preliminary results demonstrated that certain machine learning and radiomics analysis method could predict OS of non-small cell lung cancer accuracy.
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    Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.
    (PLoS One, 2011) Philips, GM; Chan, IS; Swiderska, M; Schroder, VT; Guy, C; Karaca, GF; Moylan, C; Venkatraman, T; Feuerlein, S; Syn, WK; Jung, Y; Witek, RP; Choi, S; Michelotti, GA; Rangwala, F; Merkle, E; Lascola, C; Diehl, AM
    OBJECTIVE: Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC. METHODS: Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging. RESULTS: Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality. CONCLUSIONS: Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
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    Impact of collimator leaf width and treatment technique on stereotactic radiosurgery and radiotherapy plans for intra- and extracranial lesions.
    (Radiation oncology (London, England), 2009-01-21) Wu, Q Jackie; Wang, Zhiheng; Kirkpatrick, John P; Chang, Zheng; Meyer, Jeffrey J; Lu, Mei; Huntzinger, Calvin; Yin, Fang-Fang
    BACKGROUND: This study evaluated the dosimetric impact of various treatment techniques as well as collimator leaf width (2.5 vs 5 mm) for three groups of tumors -- spine tumors, brain tumors abutting the brainstem, and liver tumors. These lesions often present challenges in maximizing dose to target volumes without exceeding critical organ tolerance. Specifically, this study evaluated the dosimetric benefits of various techniques and collimator leaf sizes as a function of lesion size and shape. METHODS: Fifteen cases (5 for each site) were studied retrospectively. All lesions either abutted or were an integral part of critical structures (brainstem, liver or spinal cord). For brain and liver lesions, treatment plans using a 3D-conformal static technique (3D), dynamic conformal arcs (DARC) or intensity modulation (IMRT) were designed with a conventional linear accelerator with standard 5 mm leaf width multi-leaf collimator, and a linear accelerator dedicated for radiosurgery and hypofractionated therapy with a 2.5 mm leaf width collimator. For the concave spine lesions, intensity modulation was required to provide adequate conformality; hence, only IMRT plans were evaluated using either the standard or small leaf-width collimators.A total of 70 treatment plans were generated and each plan was individually optimized according to the technique employed. The Generalized Estimating Equation (GEE) was used to separate the impact of treatment technique from the MLC system on plan outcome, and t-tests were performed to evaluate statistical differences in target coverage and organ sparing between plans. RESULTS: The lesions ranged in size from 2.6 to 12.5 cc, 17.5 to 153 cc, and 20.9 to 87.7 cc for the brain, liver, and spine groups, respectively. As a group, brain lesions were smaller than spine and liver lesions. While brain and liver lesions were primarily ellipsoidal, spine lesions were more complex in shape, as they were all concave. Therefore, the brain and the liver groups were compared for volume effect, and the liver and spine groups were compared for shape. For the brain and liver groups, both the radiosurgery MLC and the IMRT technique contributed to the dose sparing of organs-at-risk(OARs), as dose in the high-dose regions of these OARs was reduced up to 15%, compared to the non-IMRT techniques employing a 5 mm leaf-width collimator. Also, the dose reduction contributed by the fine leaf-width MLC decreased, as dose savings at all levels diminished from 4 - 11% for the brain group to 1 - 5% for the liver group, as the target structures decreased in volume. The fine leaf-width collimator significantly improved spinal cord sparing, with dose reductions of 14 - 19% in high to middle dose regions, compared to the 5 mm leaf width collimator. CONCLUSION: The fine leaf-width MLC in combination with the IMRT technique can yield dosimetric benefits in radiosurgery and hypofractionated radiotherapy. Treatment of small lesions in cases involving complex target/OAR geometry will especially benefit from use of a fine leaf-width MLC and the use of IMRT.