Differentiation of Malignant Salivary Gland Tumors from Pleomorphic Adenomas and Warthin’s Tumors: Combined Diagnostic Value of Tumor Blood Flow and Apparent Diffusion Coefficient by Histogram Analysis

We aimed to evaluate the usefulness of tumor blood flow (TBF) obtained by pseudocontinuous arterial spin labeling (pCASL) and apparent diffusion coefficient (ADC) for differentiating salivary gland malignant tumors (MTs) from pleomorphic adenomas (PAs) and Warthin’s tumors (WTs). We used pCASL imaging and ADC map to evaluate 65 patients, including 16 with MT, 30 with PA, and 19 with WT. We evaluated all tumors by histogram analyses and compared various characteristics by one-way analysis of variance followed by Tukey post-hoc tests. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analysis. There were significant differences in the mean, 50th, 75th, and 90th percentiles of TBF among the tumor types, in the mean TBFs (ml/100g/min) between MTs (57.47 ± 35.14) and PAs (29.88 ± 22.53, p = 0.039) and between MTs and WTs (119.31 ± 50.11, p < 0.001), as well as in the mean ADCs (×10− 3 mm2/sec) between MTs (1.08 ± 0.28) and PAs (1.60 ± 0.34, p < 0.001), but not in the mean ADCs between MTs and WTs (0.87 ± 0.23, p = 0.117). In the ROC curve analysis, the highest areas under the curves (AUCs) were achieved by the 10th and 25th percentiles of ADC (AUC = 0.885) for differentiating MTs from PAs and the 50th percentile of TBF (AUC = 0.855) for differentiating MTs from WTs. The AUCs of TBF, ADC, and combination of TBF and ADC were 0.850, 0.885, and 0.950 for MT and PA differentiation and 0.855, 0.814, and 0.905 for MT and WT differentiation, respectively. The combination of TBF and ADC evaluated by histogram analysis helped differentiate salivary gland MTs from PAs and WTs.

Hydralazine augmented ultrasound hyperthermia for the treatment of hepatocellular carcinoma

This study investigates the use of hydralazine to enhance ultrasound hyperthermia for the treatment of hepatocellular carcinoma (HCC) by minimizing flow-mediated heat loss from the tumor. Murine HCC tumors were treated with a continuous mode ultrasound with or without an intravenous administration of hydralazine (5 mg/kg). Tumor blood flow and blood vessels were evaluated by contrast-enhanced ultrasound (CEUS) imaging and histology, respectively. Hydralazine markedly enhanced ultrasound hyperthermia through the disruption of tumor blood flow in HCC. Ultrasound treatment with hydralazine significantly reduced peak enhancement (PE), perfusion index (PI), and area under the curve (AUC) of the CEUS time-intensity curves by 91.9 ± 0.9%, 95.7 ± 0.7%, and 96.6 ± 0.5%, compared to 71.4 ± 1.9%, 84.7 ± 1.1%, and 85.6 ± 0.7% respectively without hydralazine. Tumor temperature measurements showed that the cumulative thermal dose delivered by ultrasound treatment with hydralazine (170.8 ± 11.8 min) was significantly higher than that without hydralazine (137.7 ± 10.7 min). Histological assessment of the ultrasound-treated tumors showed that hydralazine injection formed larger hemorrhagic pools and increased tumor vessel dilation consistent with CEUS observations illustrating the augmentation of hyperthermic effects by hydralazine. In conclusion, we demonstrated that ultrasound hyperthermia can be enhanced significantly by hydralazine in murine HCC tumors by modulating tumor blood flow. Future studies demonstrating the safety of the combined use of ultrasound and hydralazine would enable the clinical translation of the proposed technique.

Prediction of Intraoperative Fluorescence of Brain Gliomas: Correlation between Tumor Blood Flow and the Fluorescence

Introduction: The prediction of the fluorescent effect of 5-aminolevulinic acid (5-ALA) in patients with diffuse gliomas can improve the selection of patients. The degree of enhancement of gliomas has been reported to predict 5-ALA fluorescence, while, at the same time, rarer cases of fluorescence have been described in non-enhancing gliomas. Perfusion studies, in particular arterial spin labeling perfusion, have demonstrated high efficiency in determining the degree of malignancy of brain gliomas and may be better for predicting fluorescence than contrast enhancement. The aim of the study was to investigate the relationship between tumor blood flow, measured by ASL, and intraoperative fluorescent glow of gliomas of different grades. Materials and methods: Tumoral blood flow was assessed in 75 patients by pCASL (pseudo-continuous arterial spin labeling) within 1 week prior to surgery. In all cases of tumor removal, 5-ALA had been administered preoperatively. Maximum values of tumoral blood flow (TBF max) were measured, and normalized tumor blood flow (nTBF) was calculated. Results: A total of 76% of patients had significant contrast enhancement, while 24% were non-enhancing. The histopathology revealed 17 WHO grade II gliomas, 12 WHO grade III gliomas and 46 glioblastomas. Overall, there was a relationship between the degree of intraoperative tumor fluorescence and ASL-TBF (Rs = 0.28, p = 0.02 or the TBF; Rs = 0.34, p = 0.003 for nTBF). Non-enhancing gliomas were fluorescent in 9/18 patients, with nTBF in fluorescent gliomas being 54.58 ± 32.34 mL/100 mg/s and in non-fluorescent gliomas being 52.99 ± 53.61 mL/100 g/s (p > 0.05). Enhancing gliomas were fluorescent in 53/57 patients, with nTBF being 170.17 ± 107.65 mL/100 g/s in fluorescent and 165.52 ± 141.71 in non-fluorescent gliomas (p > 0.05). Conclusion: Tumoral blood flow levels measured by non-contrast ASL perfusion method predict the fluorescence by 5-ALA; however, the additional value beyond contrast enhancement is not clear. ASL is, however, useful in cases with contraindication to contrast.

ASL-Perfusion for Intrinsic Brain Tumor Diagnosis. Analysis of 253 Patients.

Purpose The aim of the study was to evaluate the role of pseudo-continuous ASL-perfusion (pCASL-perfusion) in preoperative assessing of cerebral glioma grades. Methods The study group consisted of 253 patients aged 7 to 78 years with supratentorial gliomas (65 had low-grade gliomas (LGG), 188 – high-grade gliomas (HGG)). Maximal tumor blood flow (maxTBF) in small ROIs (20 mm2 ± 10 mm2) were evaluated by subsequently normalized tumor blood flow (nTBF) calculation which was compared with normal appearing white matter of center semiovale of the contralateral hemisphere. Results TBF and nTBF values were significantly differed in HGG and LGG groups, as well as grade II and grade III gliomas; grade III and grade IV gliomas (p < 0.001). ASL-perfusion has demonstrated both high sensitivity and specificity in differentiating LGG and HGG, grade II and grade III gliomas, but low sensitivity and specificity in distinguishing grade III and grade IV gliomas. We did not observe a significant difference in TBF in astrocytomas and oligodendrogliomas. Conclusion Current results demonstrate that 3D pCASL-perfusion is an effective diagnostic tool for preoperative differentiation of low and high grade gliomas.

Greater reductions in blood flow after anti-angiogenic treatment in non-small cell lung cancer patients are associated with shorter progression-free survival

To evaluate tumor blood flow using 15O-water positron emission tomography (PET) in patients with non-small cell lung cancer (NSCLC) before and after chemotherapy with bevacizumab, and to investigate the effects of bevacizumab on tumor blood flow changes and progression-free survival (PFS). Twelve patients with NSCLC were enrolled. Six patients underwent chemotherapy with bevacizumab and the other six without bevacizumab. 15O-water dynamic PET scans were performed within 1 week before the start of chemotherapy and within 1 week after the first day of chemotherapy. Tumor blood flow was analyzed quantitatively using a single one-tissue compartment model with the correction of pulmonary circulation blood volume and arterial blood volume via an image-derived input function. In the bevacizumab group, mean tumor blood flow was statistically significantly reduced post-chemotherapy (pre-chemotherapy 0.27 ± 0.14 mL/cm3/min, post-chemotherapy 0.18 ± 0.12 mL/cm3/min). In the no bevacizumab group, there was no significant difference between mean tumor perfusion pre-chemotherapy (0.42 ± 0.42 mL/cm3/min) and post-chemotherapy (0.40 ± 0.27 mL/cm3/min). In the bevacizumab group, there was a positive correlation between the blood flow ratio (tumor blood flow post-chemotherapy/tumor blood flow pre-chemotherapy) and PFS (correlation coefficient 0.94). Mean tumor blood flow decreases after bevacizumab administration and was positively correlated with longer PFS.

STUDY OF CHANGES IN TUMOR BLOOD FLOW FOR THE ASSESSMENT OF EARLY RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN BREAST CANCER PATIENTS

Background. Over the past 20 years, there has been a change in approaches to the treatment of breast cancer, in particular, a significant increase in the role of drug therapy. Breast cancer response to neoadjuvant chemotherapy is currently considered as a surrogate biomarker, which allows evaluation of the clinical course and prognosis of the disease. To solve this problem, it is necessary to assess the functional and metabolic changes in tumor tissue during treatment. Doppler ultrasound is a non-invasive, affordable, and low-cost imaging technique that can be safely used for repeated measurements.The purpose of the study was to study vascular changes in the tumor by power Doppler ultrasound for the evaluation of the early breast cancer response to neoadjuvant chemotherapy.Material and Methods. From May 2017 to August 2019, 63 patients with breast cancer received neoadjuvant chemotherapy. Changes in the tumor blood flow were assessed before starting the treatment and prior to the second course of neoadjuvant chemotherapy using Doppler scanning. Changes in tumor blood floor after chemotherapy were compared with the pathological tumor response after surgical treatment.Results. In the vast majority of cases (78 %), there was a decrease in the number of tumor vessels after the first cycle of neoadjuvant chemotherapy independent of the grade of pathological response. In 8 cases with increased vascularization after the first cycle of neoadjuvant chemotherapy, histological examination of the removed tumor showed no response / weak response to treatment in the absence of peritumoral inflammation. In 5 cases, a sharp increase in the number of vessels around large areas of intranodular necrosis and peritumoral inflammation was observed. In general, a comparison of changes in tumor vascularization and pathological response revealed a weak, although statistically significant, negative correlation between changes in the tumor blood flow after neoadjuvant chemotherapy and pathological response.Conclusion. It was not possible to establish an unambiguous relationship between the reaction of the vascular bed and the tumor response to the cytostatic effect. An increase in the number of tumor vessels in the absence of peritumoral inflammation was the only situation when changes in tumor blood flow during chemotherapy can be unambiguously interpreted as a predictive criterion for the absence / weak response of the tumor to treatment.

MODERN CONCEPTS ON THE ROLE OF HYPOXIA IN THE DEVELOPMENT OF TUMOR RADIORESISTANCE

The purpose of the study was to systematize and summarize modern ideas about the role of hypoxia in the development of tumor radioresistance.Material and Methods. PubMed, eLibrary and Springer databases were used to identify reviews published from 1953 to 2020, of which 57 were selected to write our review.Results. Radiation therapy is one of the most important components in cancer treatment. The major drawback of radiation therapy is the development radiation resistance in cancerous cells and secondary malignancies. The mechanisms of cancer radioresistance are very complicated and affected by many factors, of which hypoxia is the most important. Hypoxia is able to activate the mechanisms of angiogenesis, epithelial-mesenchymal transformation and contribute to the formation of the pool of cancer stem cell, which are characterized by chemo- and radioresistance. In turn, the severity of hypoxia largely dependent on tumor blood flow. Moreover, not only the quantitative but also the qualitative characteristics of blood vessels can affect the development of tissue hypoxia in the tumor.Conclusion. A comprehensive assessment of the severity of hypoxia, as well as characteristics of angiogenesis and EMT can contribute to a better understanding of the mechanisms of development of cancer radioresistance.