Justin Lee

Tumor radiation response enhancement by acoustical stimulation of the vasculature

We have discovered that ultrasound-mediated microbubble vascular disruption can enhance tumor responses to radiation in vivo. We demonstrate this effect using a human PC3 prostate cancer xenograft model. Results indicate a synergistic effect in vivo with combined single treatments of ultrasound-stimulated microbubble vascular perturbation and radiation inducing an over 10-fold greater cell kill with combined treatments. We further demonstrate with experiments in vivo that induction of ceramide-related endothelial cell apoptosis, leading to vascular disruption, is a causative mechanism. In vivo experiments with ultrasound and bubbles permit radiation doses to be decreased significantly for comparable effect. We envisage this unique combined ultrasound-based vascular perturbation and radiation treatment method being used to enhance the effects of radiation in a tumor, leading to greater tumor eradication.

Quantitative Ultrasound Evaluation of Tumor Cell Death Response in Locally Advanced Breast Cancer Patients Receiving Chemotherapy

Purpose: Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivo models. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods. Experimental Design: Patients (n = 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients. Results: Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Such differences between clinically and pathologically determined responding and nonresponding patients were statistically significant (P < 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell death with, on average, an increase in mid-band fit and 0-MHz intercept of 9.1 ± 1.2 dBr and 8.9 ± 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months. Conclusion: This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment. Clin Cancer Res; 19(8); 2163–74. ©2013 AACR.

Low-frequency quantitative ultrasound imaging of cell death in vivo.

PURPOSE Currently, no clinical imaging modality is used routinely to assess tumor response to cancer therapies within hours to days of the delivery of treatment. Here, the authors demonstrate the efficacy of ultrasound at a clinically relevant frequency to quantitatively detect changes in tumors in response to cancer therapies using preclinical mouse models. METHODS Conventional low-frequency and corresponding high-frequency ultrasound (ranging from 4 to 28 MHz) were used along with quantitative spectroscopic and signal envelope statistical analyses on data obtained from xenograft tumors treated with chemotherapy, x-ray radiation, as well as a novel vascular targeting microbubble therapy. RESULTS Ultrasound-based spectroscopic biomarkers indicated significant changes in cell-death associated parameters in responsive tumors. Specifically changes in the midband fit, spectral slope, and 0-MHz intercept biomarkers were investigated for different types of treatment and demonstrated cell-death related changes. The midband fit and 0-MHz intercept biomarker derived from low-frequency data demonstrated increases ranging approximately from 0 to 6 dBr and 0 to 8 dBr, respectively, depending on treatments administrated. These data paralleled results observed for high-frequency ultrasound data. Statistical analysis of ultrasound signal envelope was performed as an alternative method to obtain histogram-based biomarkers and provided confirmatory results. Histological analysis of tumor specimens indicated up to 61% cell death present in the tumors depending on treatments administered, consistent with quantitative ultrasound findings indicating cell death. Ultrasound-based spectroscopic biomarkers demonstrated a good correlation with histological morphological findings indicative of cell death (r2=0.71, 0.82; p<0.001). CONCLUSIONS In summary, the results provide preclinical evidence, for the first time, that quantitative ultrasound used at a clinically relevant frequency, in addition to high-frequency ultrasound, can detect tissue changes associated with cell death in vivo in response to cancer treatments.

Volumetric changes of the anterolateral thigh free flap following adjuvant radiotherapy in total parotidectomy reconstruction

The aim of this study was to prospectively evaluate volume change in anterolateral thigh free flaps pre‐ and postradiotherapy and to compare computed tomography (CT) volumetric analysis with intraoperative water displacement calculation.

In vivo optimisation study for multi-baseline MR-based thermometry in the context of hyperthermia using MR-guided high intensity focused ultrasound for head and neck applications

Abstract Purpose: In this in vivo study, the feasibility to perform hyperthermia treatments in the head and neck using magnetic resonance image-guided high intensity focused ultrasound (MRgHIFU) was established using a porcine acute model. Materials and methods: Porcine specimens with a weight between 17 and 18 kg were treated in the omohyoid muscle in the neck. Hyperthermia was applied with a target temperature of 41 °C for 30 min using a Sonalleve MRgHIFU system. MR-based thermometry was calculated using water-proton resonance frequency shift and multi-baseline look-up tables indexed by peak-to-peak displacement (Dpp) measurements using a pencil-beam navigator. Three hyperthermia experiments were conducted at different Dpp values of 0.2, 1.0 and 3.0 mm. An optimisation study was carried out to establish the optimal parameters controlling the multi-baseline method that ensured a minimisation of spatial-average peak-to-peak temperature (TSA-pp) and temperature direct current bias (TSA-DC). Results: The multi-baseline technique reduced considerably the noise on both TSA-pp and TSA-DC. The reduction of noise was more important when Dpp was higher. For Dpp = 3 mm the average (±standard deviation (SD)) of TSA-pp and TSA-DC was reduced from 4.5 (± 2.5) and 2.5 (±0.6) °C, respectively, to 0.8 (± 0.7) and 0.09 (± 0.2) °C. Conclusions: This in vivo study showed the level of noise in PRFS-based thermometry introduced by respiratory motion in the context of MRgHIFU hyperthermia treatment for head and neck and the feasibility of reducing this noise using a multi-baseline technique.

A Review of Radiotherapy for Merkel Cell Carcinoma of the Head and Neck

Merkel cell carcinoma of the head and neck (MCCHN) presents a clinical challenge due to its aggressive natural history, unpredictable lymphatic drainage, and high degree of treatment related morbidity. Histological examination of the regional lymph nodes is very important in determining the optimal treatment and is usually achieved by sentinel lymph node biopsy. Radiotherapy plays a critical role in the treatment of most patients with MCCHN. Surgery with adjuvant radiotherapy to the primary tumour site is associated with high local control rates. If lymph nodes are clinically or microscopically positive, adjuvant radiotherapy is indicated to decrease the risk of regional recurrence. The majority of locoregional recurrences occur at the edge or just outside of the radiation field, reflecting both the inherent radiosensitivity of MCC and the importance of relatively large volumes to include “in-transit” dermal lymphatic pathways. When surgical excision of the primary or nodal disease is not feasible, primary radiotherapy alone should be considered as a potentially curative modality and confers good loco-regional control. Concurrent chemoradiotherapy is well tolerated and may further improve outcomes.

Magnetic resonance-guided high-intensity focused ultrasound combined with radiotherapy for palliation of head and neck cancer-a pilot study.

BackgroundRadiotherapy is a critical component of the multidisciplinary management of cancers of the head and neck. It may comprise the primary curative treatment modality or is used in an adjuvant setting to improve local control and survival by preventing seeding and reseeding of distant metastases from persistent reservoirs of locoregional disease. Although considerable advances have been made recently in the fields of radiotherapy, systemic treatment and surgery for head and neck tumours, locoregional recurrence rates remain high and treatment side effects may have severe impact on patients’ quality of life.Magnetic resonance-guided high-intensity focused ultrasound (MRg-HIFU) is a novel technique in the treatment of cancer that has the potential to improve tumour cure rates and decrease treatment-related toxicity. Clinical applications of HIFU are being used increasingly for the treatment of several tumour sites, for example uterine leiomyomas and prostate cancer.Methods/DesignThe pilot study presented here is an initial step toward utilizing MRg-HIFU for head and neck cancer treatment. The rationale for novel treatment options in head and neck cancer is reviewed as well as emerging evidence that support the increasing clinical utilization of MRg-HIFU.DiscussionThis pilot study aims to assess safety, toxicity and feasibility of MRg-HIFU treatments to the head and neck region and to evaluate changes caused by MRg-HIFU within the treated tumour regions based on post-treatment MRI.

A dosimetric study of cardiac dose sparing using the reverse semi-decubitus technique for left breast and internal mammary chain irradiation

BACKGROUND AND PURPOSE Breath-hold techniques can reduce cardiac dose in breast radiotherapy. The reverse semi-decubitus (RSD) technique is an alternative free-breathing method used at our centre. This study compares the dosimetry of free-breathing supine, RSD and moderate deep inspiration breath-hold (mDIBH) techniques. MATERIALS AND METHODS Twelve patients with left-sided breast cancer who were simulated using standard supine, RSD and mDIBH techniques were identified retrospectively. New plans using standard breast tangents and techniques for internal mammary chain (IMC) nodal coverage were assessed. RESULTS Using standard tangents, mean heart dose, heart V25Gy and mean left anterior descending artery (LAD) dose were found to be significantly lower for RSD and mDIBH when compared to free-breathing supine (p ⩽ 0.03). Using wide-tangents, the maximum LAD point dose was also lower for RSD and mDIBH (p ⩽ 0.02). There were no statistically significant dosimetric differences found between the RSD and mDIBH simulation techniques for standard breast-tangent plans, though organ-at-risk doses were lower for mDIBH in wide-tangent plans. There was no improvement in cardiac dosimetry between RSD and free-breathing supine when using an electron field IMC plan. CONCLUSIONS For patients unable to tolerate breath-hold, the RSD technique is an alternative approach that can reduce cardiac dose.

Prospective Study of Breast Radiation Dermatitis

Background Despite clear benefits of radiotherapy (RT) for breast cancer, there are numerous side effects. Radiation dermatitis has a significant impact on quality of life and can result in treatment interruptions or cessation. The purpose of this study was to prospectively follow breast radiation dermatitis and determine trends including peak toxicity. Patients and Methods Upon initiation of RT treatment, to assess skin reaction, each patient was seen weekly by the healthcare team, or contacted via telephone to assess patient‐reported symptoms. Weekly progression of radiation dermatitis was assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Patients were stratified for analysis of radiation dermatitis based on RT technique and dosage. Results A total of 148 patients with 2 or more skin assessments were analyzed. The majority of patients received 2‐field tangential RT (64.2%) with a dose of 5000 cGy in 25 fractions. Overall, patients experienced the most Grade 2 CTCAE toxicity (61.9%) 2 weeks after completion of RT; Grade 3 toxicity also peaked at this time (8.3%). Regardless of stratification by RT technique or by dosage of RT, Grade 2 and 3 toxicities consistently peaked at 1 or 2 weeks after RT. Conclusions Breast radiation dermatitis appears to peak approximately 2 weeks after RT. Treatment factors such as technique or dosing regimen do not appear to have a substantial effect on radiation dermatitis, but our study was limited by small sample size. This study provides additional evidence that radiation dermatitis should continue to be followed closely, especially in the 2 weeks following RT. Micro‐Abstract Radiation dermatitis is a common distressing side effect of breast radiotherapy. This study of 148 patients aimed to determine the trend of radiation dermatitis. Radiation dermatitis appears to peak at 2 weeks after radiotherapy; treatment factors such as technique or dosing regimen do not appear to have a substantial effect, but our study was limited by small sample size. Radiation dermatitis should continue to be followed closely, especially in the 2 weeks following RT.

Emergency department visits and unplanned hospitalizations in the treatment period for head and neck cancer patients treated with curative intent: A population-based analysis

BACKGROUND Mucosal head and neck squamous cell cancers are often managed with multimodality treatment which can be associated with significant toxicity. The objective of this study was to assess emergency department visits and unplanned hospitalizations for these patients during and immediately after their treatment. METHODS A cohort of patients treated for head and neck squamous cell carcinoma was developed using administrative data. Emergency department visits and hospitalizations in the 90-day post-treatment period was determined. If a second treatment was initiated prior to the completion of 90 days, the attributable risk period was changed to the second treatment. RESULTS Cohort of 3898 patients (1312 larynx/hypopharynx; 2586 oral cavity/oropharynx) from 2008 to 2012. The number of unplanned hospitalizations or ED visits (per 100 patient days) were 0.69 for surgery, 0.78 for surgery followed by concurrent chemoradiotherapy (CCRT), 0.55 for surgery followed by radiotherapy, 0.86 for CCRT, and 0.50 for radiation. Patients receiving CCRT had a statistically higher likelihood of treatment period events. The larynx/hypopharynx cancer subsite, higher comorbidity and more advanced stage of disease were all independent predictors of events. CONCLUSIONS Patients undergoing treatment for head and neck cancer have significant unplanned hospitalizations and visits to the emergency department in the treatment period. Rates are higher in patients receiving CCRT. Quality improvement interventions should be used to improve these rates.