Early clinical experience of boron neutron capture therapy for glioblastoma multiforme

Boron neutron capture therapy (BNCT) is a binary treatment modality that can selectively irradiate tumor tissue. BNCT uses drugs containing a stable isotope of boron. {sup 10}B, to sensitize tumor cells to irradiation by low energy (thermal) neutrons. The interaction of the {sup 10}B with a thermal neutron (neutron capture) causes the {sup 10}B nucleus to split, releasing an alpha particle and a lithium nucleus. These products of the {sup 10}B(n, {alpha}){sup 7}Li reaction are very damaging to cells but have a combined path length in tissue of approximately 14 {mu}m, or roughly the diameter of one or two cells. Thus, most of the ionizing energy imparted to tissue is localized to {sup 10}B-loaded cells

A treatment planning comparison of BPA- or BSH-based BNCT of malignant gliomas

Accurate delivery of the prescribed dose during clinical BNCT requires knowledge (or reasonably valid assumptions) about the boron concentrations in tumor and normal tissues. For conversion of physical dose (Gy) into photon-equivalent dose (Gy-Eq), relative biological effectiveness (RBE) and/or compound-adjusted biological effectiveness (CBE) factors are required for each tissue. The BNCT treatment planning software requires input of the following values: the boron concentration in blood and tumor, RBEs in brain, tumor and skin for the high-LET beam components, the CBE factors for brain, tumor, and skin, and the RBE for the gamma component

Some recent developments in treatment planning software and methodology for BNCT

Over the past several years/the Idaho National Engineering Laboratory (INEL) has led the development of a unique, internationally-recognized set of software modules (BNCT rtpe) for computational dosimetry and treatment planning for Boron Neutron Capture Therapy (BNCT). The computational capability represented by this software is essential to the proper administration of all forms of radiotherapy for cancer. Such software addresses the need to perform pretreatment computation and optimization of the radiation dose distribution in the target volume. This permits the achievement of the optimal therapeutic ratio (tumor dose relative to critical normal tissue dose) for each individual patient via a systematic procedure for specifying the appropriate irradiation parameters to be employed for a given treatment. These parameters include angle of therapy beam incidence, beam aperture and shape,and beam intensity as a function of position across the beam front. The INEL software is used for treatment planning in the current series of human glioma trials at Brookhaven National Laboratory (BNL) and has also been licensed for research and developmental purposes to several other BNCT research centers in the US and in Europe

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer.

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients

In Vivo Fluorescence Lifetime Imaging Monitors Binding of Specific Probes to Cancer Biomarkers

One of the most important factors in choosing a treatment strategy for cancer is characterization of biomarkers in cancer cells. Particularly, recent advances in Monoclonal Antibodies (MAB) as primary-specific drugs targeting tumor receptors show that their efficacy depends strongly on characterization of tumor biomarkers. Assessment of their status in individual patients would facilitate selection of an optimal treatment strategy, and the continuous monitoring of those biomarkers and their binding process to the therapy would provide a means for early evaluation of the efficacy of therapeutic intervention. In this study we have demonstrated for the first time in live animals that the fluorescence lifetime can be used to detect the binding of targeted optical probes to the extracellular receptors on tumor cells in vivo. The rationale was that fluorescence lifetime of a specific probe is sensitive to local environment and/or affinity to other molecules. We attached Near-InfraRed (NIR) fluorescent probes to Human Epidermal Growth Factor 2 (HER2/neu)-specific Affibody molecules and used our time-resolved optical system to compare the fluorescence lifetime of the optical probes that were bound and unbound to tumor cells in live mice. Our results show that the fluorescence lifetime changes in our model system delineate HER2 receptor bound from the unbound probe in vivo. Thus, this method is useful as a specific marker of the receptor binding process, which can open a new paradigm in the “image and treat” concept, especially for early evaluation of the efficacy of the therapy

Epidemiological impact of waning immunization on a vaccinated population

This is an epidemiological SIRV model based study that is de- signed to analyze the impact of vaccination in containing infection spread, in a 4-tiered population compartment comprised of susceptible, infected, recov- ered and vaccinated agents. While many models assume a lifelong protection through vaccination, we focus on the impact of waning immunization due to conversion of vaccinated and recovered agents back to susceptible ones. Two asymptotic states exist, the \disease-free equilibrium" and the \endemic equi- librium" and we express the transitions between these states as function of the vaccination and conversion rates and using the basic reproduction number. We nd that the vaccination of newborns and adults have dierent consequences on controlling an epidemic. Also, a decaying disease protection within the re- covered sub-population is not sucient to trigger an epidemic on the linear level. We perform simulations for a parameter set modelling a disease with waning immunization like pertussis. For a diusively coupled population, a transition to the endemic state can proceed via the propagation of a traveling infection wave, described successfully within a Fisher-Kolmogorov framework