VueBox® for quantitative analysis of contrast-enhanced ultrasound in liver tumors

Dynamic contrast-enhanced ultrasound (DCE-US) enables quantification of tumor perfusion. VueBox is a platform independent external software using DICOM cine loops which objectively provides various DCE-US parameters of tumor vascularity. This review summaries its use for diagnosis and treatment monitoring of liver tumors. The existing literature provides evidence on the successful application of Vuebox based DCE-US for characterization and differential diagnosis of focal liver lesions, as well as on its use for monitoring of local ablative therapies and of modern systemic treatment in oncology.

Lack of benefit of temozolomide for MGMT methylated patients with high vascular glioblastoma: a confirmatory study

In this study we evaluated the benefit on survival of the combination of MGMT methylation and moderate vascularity in glioblastoma using a retrospective dataset of 123 patients from a multicenter cohort. MRI processing and calculation of relative cerebral blood volume (rCBV), used to define moderate- and high-vascular groups, were performed with the automatic ONCOhabitats method. We assessed the previously proposed rCBV threshold (10.7) and the new calculated ones (9.1 and 9.8) to analyze the association with survival for different populations according to vascularity and MGMT methylation status. We found that patients included at the moderate-vascular group had longer survival when MGMT is methylated (significant median survival difference of 174 days, p = 0.0129*). However, we did not find significant differences depending on the MGMT methylation status for the high-vascular group (p = 0.9119). In addition, we investigated the combined correlation of MGMT methylation status and rCBV with the prognostic effect of the number of temozolomide cycles, and only significant results were found for the moderate-vascular group. In conclusion, there is a lack of benefit of temozolomide for MGMT methylated patients with high vascular glioblastomas. Preliminary results suggest that patients with moderate vascularity and methylated MGMT would benefit more from prolonged adjuvant chemotherapy.Simple SummaryDespite the complete treatment with surgery, chemotherapy and radiotherapy, patients with glioblastoma have a devasting prognosis. Although the role of extending temozolomide treatment has been explored, the results are inconclusive. Recent evidence suggested that tumor vascularity may be a modulating factor in combination with MGMT methylation on the effect of temozolomide-based therapies, opening new possibilities for personalized treatments. Before proposing a prospective interventional clinical study, it is necessary to confirm the beneficial effect of the combined effect of MGMT methylation and moderate tumor vascularity. As well as the lack of benefit of temozolomide in patients with a highly vascular tumor.

Imaging of Noncalcified Ductal Carcinoma In Situ

Ductal carcinoma in situ (DCIS) is a commonly encountered malignancy, accounting for approximately 20% of new breast cancer diagnoses in the United States. DCIS is characterized by a proliferation of tumor cells within the terminal duct lobular unit with preservation of the basement membrane. Typically nonpalpable and asymptomatic, DCIS is most often detected as calcifications on screening mammography. However, DCIS may also be noncalcified. When compared to calcified DCIS, noncalcified DCIS is more likely to be symptomatic, with patients most often presenting with nipple discharge or a palpable mass. Diagnosing noncalcified DCIS is challenging since it may be occult or subtle on mammography, and ultrasound findings can be nonspecific and may be interpreted as benign fibrocystic changes. In cases with a calcified component of DCIS, the extent of DCIS may be underestimated by mammography because not all involved areas may calcify. Breast magnetic resonance imaging (MRI), although less readily available than mammography and ultrasound, is advantageous in detecting noncalcified DCIS, especially high grade DCIS, which may not develop microcalcifications. MRI relies on abnormal contrast uptake due to tumor vascularity and changes in vessel density and permeability. This pictoral review presents the spectrum of imaging findings of noncalcified DCIS to assist radiologists in accurately detecting and describing its key imaging findings. Utilizing different modalities, we review the differential diagnoses for noncalcified DCIS, show illustrative cases of noncalcified DCIS, and discuss the importance of this entity.

Optical Coherence Tomography Angiography Microvascular Variations in Pre- and Posttreatment of Retinoblastoma Tumors

<b><i>Introduction:</i></b> The purpose of this study is to describe variations in microvasculature before and after treatment of treatment-naive lesions and during consolidation therapy of retinoblastoma lesions using an investigational portable optical coherence tomography angiography (OCTA) system. <b><i>Methods:</i></b> This study is a single-center, prospective, observational case series. Recruited subjects were either undergoing surveillance for retinoblastoma or had newly detected retinoblastoma. Nine tumors from 7 eyes in 6 patients were included. During exams under anesthesia, the tumors were imaged with an investigational portable OCTA system. OCTA images were analyzed to assess vascular changes before and after treatment. <b><i>Results:</i></b> In all 6 presented cases, OCTA imaging revealed distinctive vascular patterns, such as dilated feeder arteries and draining veins, disorganized and complex branching patterns, irregular vessel calibers, and dilation and tortuosity of vessels. After treatment, OCTA imaging revealed decreased intrinsic tumor vascularity and reduced dilation of draining and feeder vessels. Tumor relapse demonstrated prominent vascularity (<i>n</i> = 1) that resolved on repeat OCTA after transpupillary thermotherapy treatment. Type 2 (<i>n</i> = 1), 3 (<i>n</i> = 6), and 4 (<i>n</i> = 1) tumor regression patterns were seen in our patients after treatment, and OCTA findings were consistent with a previously published report. Interestingly, in one of the presented cases, OCTA demonstrated clear feeder, draining, and intrinsic tumor vessels that were not as evident on fluorescein angiography. <b><i>Conclusions:</i></b> OCTA may offer a noninvasive and sensitive technique to evaluate the vasculature of both the tumor and the surrounding retina in retinoblastoma. With additional research and development into its use in patients with retinoblastoma, OCTA may one day be useful in assessing treatment response and residual tumor activity.

Near infrared photoimmunotherapy of cancer; possible clinical applications

Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer treatment that uses an antibody-photo-absorber conjugate (APC) composed of a targeting monoclonal antibody conjugated with a photoactivatable phthalocyanine-derivative dye, IRDye700DX (IR700). APCs injected into the body can bind to cancer cells where they are activated by local exposure to NIR light typically delivered by a NIR laser. NIR light alters the APC chemical conformation inducing damage to cancer cell membranes, resulting in necrotic cell death within minutes of light exposure. NIR-PIT selectivity kills cancer cells by immunogenic cell death (ICD) with minimal damage to adjacent normal cells thus, leading to rapid recovery by the patient. Moreover, since NIR-PIT induces ICD only on cancer cells, NIR-PIT initiates and activates antitumor host immunity that could be further enhanced when combined with immune checkpoint inhibition. NIR-PIT induces dramatic changes in the tumor vascularity causing the super-enhanced permeability and retention (SUPR) effect that dramatically enhances nanodrug delivery to the tumor bed. Currently, a worldwide Phase 3 study of NIR-PIT for recurrent or inoperable head and neck cancer patients is underway. In September 2020, the first APC and accompanying laser system were conditionally approved for clinical use in Japan. In this review, we introduce NIR-PIT and the SUPR effect and summarize possible applications of NIR-PIT in a variety of cancers.

A dose-escalating toxicology study of the candidate biologic ELP-VEGF

Vascular Endothelial Growth Factor (VEGF), a key mediator of angiogenesis and vascular repair, is reduced in chronic ischemic renal diseases, leading to microvascular rarefaction and deterioration of renal function. We developed a chimeric fusion of human VEGF-A121 with the carrier protein Elastin-like Polypeptide (ELP-VEGF) to induce therapeutic angiogenesis via targeted renal VEGF therapy. We previously showed that ELP-VEGF improves renal vascular density, renal fibrosis, and renal function in swine models of chronic renal diseases. However, VEGF is a potent cytokine that induces angiogenesis and increases vascular permeability, which could cause undesired off-target effects or be deleterious in a patient with a solid tumor. Therefore, the current study aims to define the toxicological profile of ELP-VEGF and assess its risk for exacerbating tumor progression and vascularity using rodent models. A dose escalating toxicology assessment of ELP-VEGF was performed by administering a bolus intravenous injection at doses ranging from 0.1 to 200 mg/kg in Sprague Dawley (SD) rats. Blood pressure, body weight, and glomerular filtration rate (GFR) were quantified longitudinally, and terminal blood sampling and renal vascular density measurements were made 14 days after treatment. Additionally, the effects of a single administration of ELP-VEGF (0.1–10 mg/kg) on tumor growth rate, mass, and vascular density were examined in a mouse model of breast cancer. At doses up to 200 mg/kg, ELP-VEGF had no effect on body weight, caused no changes in plasma or urinary markers of renal injury, and did not induce renal fibrosis or other histopathological findings in SD rats. At the highest doses (100–200 mg/kg), ELP-VEGF caused an acute, transient hypotension (30 min), increased GFR, and reduced renal microvascular density 14 days after injection. In a mouse tumor model, ELP-VEGF did not affect tumor growth rate or tumor mass, but analysis of tumor vascular density by micro-computed tomography (μCT) revealed significant, dose dependent increases in tumor vascularity after ELP-VEGF administration. ELP-VEGF did not induce toxicity in the therapeutic dosing range, and doses one hundred times higher than the expected maximum therapeutic dose were needed to observe any adverse signs in rats. In breast tumor—bearing mice, ELP-VEGF therapy induced a dose-dependent increase in tumor vascularity, demanding caution for potential use in a patient suffering from kidney disease but with known or suspected malignancy.

Transarterial Embolization of Acute Gastrointestinal Bleeding

Transarterial embolization (TAE) is a minimally invasive treatment method developed alternative to surgery for acute gastrointestinal bleeding (AGIB). The aim of this study was to evaluate the efficacy and outcome of TAE in AGIB patients. The data of 30 patients who underwent TAE with complaint of AGIB between January 2007- May 2020 was collected retrospectively. The etiology of hemorrhage, localization and type of lesion, embolizing agent used, and postprocedural complications were recorded. Lesions were classified as pseudoaneurysm (PA), extravasation, pathological tumor vascularity and vasospasm. A total of 22 patients, 5 females, were included in the study. The most common underlying cause was tumors (n=15, 50%). The most common lesion detected on angiograms was pathological tumor vascularity. Embolizing agents used were Nbutyl-2-cyanoacrylate in five patients, coils in three patients, polyvinyl alcohol particles in six patients and microsphere in seven patients. The technical success rate was 90.9%, and two patients developed rebleeding in the early postprocedural period. TAE is a safe, effective and minimally invasive method in emergency treatment of patients with AGIB.

Use of Contrast-Enhanced Ultrasound with Sonazoid for Evaluating the Radiotherapy Efficacy for Hepatocellular Carcinoma

Radiotherapy is one of the available curative therapies for hepatocellular carcinoma (HCC). We investigate the use of contrast-enhanced ultrasound using Sonazoid (SCEUS) in evaluating the efficacy of radiotherapy for HCC. We enrolled 59 patients with 59 HCCs in this retrospective study. Tumor size and tumor vascularity were evaluated using SCEUS before and 1, 3, 7, 10, and 13 months after radiotherapy. The median follow-up period was 44.5 months (range: 16–82 months). Of the HCCs, 95% (56/59) had no local recurrence, while 5% (3/59) did. At 13 months after radiotherapy, in cases with no local recurrence, SCEUS showed a reduction in tumor vascularity in all cases, while tumor size reduction (>30% reduction, compared with pre-radiotherapy) was observed in 82.1% (46/56). In all three cases of local recurrence, vascularity and tumor size reduction were not observed during the follow-up period and residual HCCs were demonstrated pathologically. Compared with cases with local recurrence, tumor size reduction and reduction in tumor vascularity (p < 0.001) were significantly greater in cases with no local recurrence at 13 months after radiotherapy. SCEUS may be useful in evaluating radiotherapy efficacy for HCC.

Photoacoustic monitoring of oxygenation changes induced by therapeutic ultrasound in murine hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly vascular solid tumor. We have previously shown that ultrasound (US) therapy significantly reduces tumor vascularity. This study monitors US-induced changes in tumor oxygenation on murine HCC by photoacoustic imaging (PAI). Oxygen saturation and total hemoglobin were assessed by PAI before and after US treatments performed at different intensities of continuous wave (CW) bursts and pulsed wave (PW) bursts US. PAI revealed significant reduction both in HCC oxygen saturation and in total hemoglobin, proportional to the US intensity. Both CW bursts US (1.6 W/cm2) and the PW bursts US (0.8 W/cm2) significantly reduced HCC oxygen saturation and total hemoglobin which continued to diminish with time following the US treatment. The effects of US therapy were confirmed by power Doppler and histological examination of the hemorrhage in tumors. By each measure, the changes observed in US-treated HCC were more prevalent than those in sham-treated tumors and were statistically significant. In conclusion, the results show that US is an effective vascular-targeting therapy for HCC. The changes in oxygenation induced by the US treatment can be noninvasively monitored longitudinally by PAI without the use of exogenous image-enhancing agents. The combined use of PAI and the therapeutic US has potential for image-guided vascular therapy for HCC.