Radiobiological quantities in proton-therapy: Estimation and validation using Geant4-based Monte Carlo simulations.

PURPOSE: The Geant4 Monte Carlo simulation toolkit was used to reproduce radiobiological parameters measured by irradiating three different cancerous cell lines with monochromatic and clinical proton beams. METHODS: The experimental set-up adopted for irradiations was fully simulated with a dedicated open-source Geant4 application. Cells survival fractions was calculated coupling the Geant4 simulations with two analytical radiobiological models: one based on the LEM (Local Effect Model) approach and the other on a semi-empirical parameterisation. Results was evaluated and compared with experimental data. RESULTS AND CONCLUSIONS: The results demonstrated the Geant4 ability to reproduce radiobiological quantities for different cell lines.

Raman spectroscopy for the evaluation of the radiobiological sensitivity of normal human breast cells at different time points after irradiation by a clinical proton beam.

Among different radiotherapy techniques, proton irradiation is an established and effective method for treatment of several types of cancer, because less healthy tissue is exposed with respect to conventional radiotherapy by photons/electrons. Recently, proton therapy has been proposed for the treatment of breast cancer. In vitro studies of proton irradiated normal human breast cells can provide information about cellular radioresponse, particularly as far as healthy tissue is concerned. In this paper, a study of the effects at different time points, following proton irradiation at different doses, of human normal MCF10A breast cells is performed by Raman spectroscopy. The aim of this investigation is to detect the unwanted effects of proton treatment and to investigate the possibility of monitoring them and of making an assessment of the cellular sensitivity by means of such a technique. The obtained results seem to indicate a rather significant sensitivity of MCF10A cells to proton irradiation. In fact, even at doses as low as 0.5 Gy, biological effects are clearly detectable in Raman spectra. In particular, ratiometric analysis of the Raman spectra measured from the nucleoplasm compartment showed that DNA/RNA damage increases with time, suggesting that most cells are unable to repair DNA/RNA broken bonds. The results obtained by the Raman spectroscopy analysis exhibit a similar trend with regard to dose to those obtained by commonly used radiobiological assays (i.e. MTT, clonogenic assay, senescence, apoptosis and necrosis). The results of this study strongly suggest the possibility that the Raman technique can be used to identify molecular markers predicting radiation response.

Monte Carlo GEANT4-based application for in vivo RBE study using small animals at LNS-INFN preclinical hadrontherapy facility.

Preclinical studies represent an important step towards a deep understanding of the biological response to ionizing radiations. The effectiveness of proton therapy is higher than photons and, for clinical purposes, a fixed value of 1.1 is used for the relative biological effectiveness (RBE) of protons considered 1.1. Recent in vitro studies have reported that the RBE along the spread-out Bragg peak (SOBP) is not constant and, in particular, the RBE value increases on the distal part of SOBP. The present work has been carried-out in the perspective of a preclinical hadrontherapy facility at LNS-INFN and was focused on the experimental preparation of an in vivo study concerning the RBE variation along the SOBP. The main purpose of this work was to determine, using GEANT4-based Monte Carlo simulations, the best configuration for small animal treatments. The developed GEANT4 application simulates the proton-therapy beam line of LNS-INFN (CATANA facility) and allows to import the DICOM-CT images as targets. The RBE will be evaluated using a deterministic radiation damage like myelopathy as end-point. In fact, the dose at which the 50% of animals will show the myelopathy is supposed to be LET-dependent. In this work, we studied different treatment configurations in order to choose the best two that maximize the LET difference reducing as much as possible the dose released to healthy tissue. The results will be useful to plan hadrontherapy treatments for preclinical in vivo studies and, in particular, for the future in vivo RBE studies.

First experimental proof of Proton Boron Capture Therapy (PBCT) to enhance protontherapy effectiveness.

Protontherapy is hadrontherapy's fastest-growing modality and a pillar in the battle against cancer. Hadrontherapy's superiority lies in its inverted depth-dose profile, hence tumour-confined irradiation. Protons, however, lack distinct radiobiological advantages over photons or electrons. Higher LET (Linear Energy Transfer) 12C-ions can overcome cancer radioresistance: DNA lesion complexity increases with LET, resulting in efficient cell killing, i.e. higher Relative Biological Effectiveness (RBE). However, economic and radiobiological issues hamper 12C-ion clinical amenability. Thus, enhancing proton RBE is desirable. To this end, we exploited the p + 11B → 3α reaction to generate high-LET alpha particles with a clinical proton beam. To maximize the reaction rate, we used sodium borocaptate (BSH) with natural boron content. Boron-Neutron Capture Therapy (BNCT) uses 10B-enriched BSH for neutron irradiation-triggered alpha particles. We recorded significantly increased cellular lethality and chromosome aberration complexity. A strategy combining protontherapy's ballistic precision with the higher RBE promised by BNCT and 12C-ion therapy is thus demonstrated.

Glucose starvation induces cell death in K-ras-transformed cells by interfering with the hexosamine biosynthesis pathway and activating the unfolded protein response.

Cancer cells, which use more glucose than normal cells and accumulate extracellular lactate even under normoxic conditions (Warburg effect), have been reported to undergo cell death under glucose deprivation, whereas normal cells remain viable. As it may be relevant to exploit the molecular mechanisms underlying this biological response to achieve new cancer therapies, in this paper we sought to identify them by using transcriptome and proteome analysis applied to an established glucose-addicted cellular model of transformation, namely, murine NIH-3T3 fibroblasts harboring an oncogenic K-RAS gene, compared with parental cells. Noteworthy is that the analyses performed in high- and low-glucose cultures indicate that reduction of glucose availability induces, especially in transformed cells, a significant increase in the expression of several unfolded protein response (UPR) hallmark genes. We show that this response is strictly associated with transformed cell death, given that its attenuation, by reducing protein translation or by increasing cell protein folding capacity, preserves the survival of transformed cells. Such an effect is also observed by inhibiting c-Jun NH2-terminal kinase, a pro-apoptotic signaling mediator set downstream of UPR. Strikingly, addition of N-acetyl-D-glucosamine, a specific substrate for the hexosamine biosynthesis pathway (HBP), to glucose-depleted cells completely prevents transformed cell death, stressing the important role of glucose in HBP fuelling to ensure UPR attenuation and increased cell survival. Interestingly, these results have been fully recognized in a human model of breast cancer, MDA-MB-231 cells. In conclusion, we show that glucose deprivation, leading to harmful accumulation of unfolded proteins in consequence of a reduction of protein glycosylation, induces a UPR-dependent cell death mechanism. These findings may open the way for new therapeutic strategies to specifically kill glycolytic cancer cells.

Effect of pharmacists on health care outcomes in hospitalized patients.

The cost-effectiveness of pharmacists and their effect on inpatient health care outcomes were evaluated. For one year, data were collected on all patients receiving care from general medicine and general surgery teams at Walter Reed Army Medical Center, Washington, D.C. Two of five medicine teams and one of three surgery teams included a pharmacist. Teams that included a pharmacist were compared with teams that did not, in terms of patients' length of stay (LOS), mortality, and drug cost per admission. Data were compared for 3081 patients and collected for another 557 who were not included in the comparative study design. Health care teams that included a pharmacist had a shorter log LOS and lower log drug cost per admission but no difference in mortality. The average cost savings for teams that included a pharmacist was $377 per inpatient admission, and the benefit-to-cost ratio was 6.03:1. The inclusion of pharmacists on health care teams was cost-effective and provided a favorable benefit-to-cost ratio.

Impact of HIV infection on pharmaceutical services at Walter Reed Army Medical Center.

Services developed by the pharmacy department at Walter Reed Army Medical Center (WRAMC) relating to the treatment and study of patients infected with the human immunodeficiency virus (HIV) are described. The WRAMC pharmacy department closely monitored use of azidothymidine (renamed zidovudine) before and after its approval by FDA. It has also done pharmaceutical cost studies for HIV-infected patients by disease stage according to the Walter Reed Classification System. An Army pharmacist at the U.S. Army Centralized Allergen Extract Laboratory is involved with the development and distribution of delayed hypersensitivity skin tests used to determine the progression of the disease; the current test battery correlates with the CD4 T-lymphocyte count, low numbers of which indicate disease progression. The Walter Reed Retrovirus Research Group includes an Army pharmacist who not only is involved with the traditional distributive and clinical aspects of the position but also is involved in clinical pharmacy, pharmacoepidemiology, and social and behavioral research. This pharmacist is the principal investigator on protocols studying the relationship of various factors to the frequency and distribution of both beneficial and adverse pharmaceutical outcomes in this patient population. The pharmacy department at WRAMC has taken an active role in both the treatment of HIV-infected patients and HIV-associated research, as part of an aggressive overall Army effort to develop effective treatment and chemoprophylaxis or immunoprophylaxis for this disease.

Pharmacy practice in the United States Army.

The current status of pharmaceutical services in the United States Army Medical Department is described. The mission of the Army Medical Department is to ensure the health of the soldier during times of peace and war. Of the 225 commissioned pharmacy officers currently on active duty, 156 are assigned to U.S. Army medical centers and community hospitals in the United States, and 29 are stationed at hospitals in Europe, Korea, Panama, and Japan. Army pharmacy officers are supported by 879 Army-trained pharmacy technicians and 319 civilian pharmacists employed by the Army. Army Medical Department hospital pharmacies provide inpatient and ambulatory-care services as well as specialized nuclear pharmacy, oncology, investigational drug, and materials development services. Pharmacy officers assigned to the Pharmacy Branch of the U.S. Army Academy of Health Sciences conduct 17-week technician training programs six times a year and provide other pharmacy courses and continuing education programs. The U.S. Army Allergen Extract Laboratory dispenses diagnostic and immunotherapy agents by mail in response to prescriptions submitted by military allergy clinics. Pharmacy officers may be deployed with field hospitals during times of combat or for extended training exercises in places such as Egypt, Grenada, and Honduras. Pharmacy officers may also be assigned to three- or four-year tours of duty in Army hospitals located in Europe. In the future, the emphasis of Army pharmacy practice will be on the expansion of clinical pharmaceutical services and the development of advanced interactive communication systems, quality assurance programs, and peer-review programs.