Bevacizumab enhances the therapeutic efficacy of Irinotecan against human head and neck squamous cell carcinoma xenografts

Combining antiangiogenic agents with traditional cytotoxic chemotherapy offers the potential to target both vascular and cellular components of a growing tumor mass. Here, we examined the antitumor activity of the vascular endothelial growth factor antibody, Bevacizumab (Avastin?) in combination with the topoisomerase I inhibitor, Irinotecan (CPT-11) against human head and neck squamous cell carcinoma (HNSCC) xenografts. Bevacizumab was administered daily (at 5 or 20mg/kg) to nude mice bearing FaDu HNSCC xenografts for 28days with the first dose beginning seven days prior to Irinotecan (100mg/kg, weekly × 4). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and immunohistochemical (IHC) methods were employed to study the antiangiogenic effects of Bevacizumab in vivo. Kinetics of tumor response to treatment was studied by monitoring tumor volume over a 60-day period. DCE-MRI detected a significant reduction in vascular permeability following treatment with Bevacizumab (5mg/kg) while high dose Bevacizumab (20mg/kg) induced significant microvascular damage and tumor necrosis, confirmed by immunohistochemistry (IHC). Irinotecan alone resulted in complete tumor regression (cures) in ～40% of animals while Bevacizumab alone did not result in any cures. Treatment with Bevacizumab (5mg/kg/day×28days) in combination with Irinotecan (100mg/kg, weekly × 4) was highly effective in inhibiting FaDu tumor growth and resulted in complete tumor regression in 80% of animals. These results demonstrate that long term administration of Bevacizumab effectively modulates chemotherapeutic efficacy against HNSCC xenografts. Further investigation into the therapeutic potential of this combination strategy against HNSCC is warranted.     

Targeting the oncogenic protein beta-catenin to enhance chemotherapy outcome against solid human cancers

Background  

Beta-catenin is a multifunctional oncogenic protein that contributes fundamentally to cell development and biology. Elevation in expression and activity of β-catenin has been implicated in many cancers and associated with poor prognosis. Beta-catenin is degraded in the cytoplasm by glycogen synthase kinase 3 beta (GSK-3β) through phosphorylation. Cell growth and proliferation is associated with β-catenin translocation from the cytoplasm into the nucleus.     

Leukocytosis and Circulating Blasts in Older Adults With Newly Diagnosed Acute Myeloid Leukemia: Are They Valuable Factors for Therapeutic Decision-Making?

BackgroundThe treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of response and overall survival. Identification of valuable factors that can facilitate therapeutic decision-making between intensive chemotherapy and investigational treatment strategies is warranted.MethodsAnalysis of proliferative (white blood cell [WBC] count) and invasive (percentage of blast cells in peripheral blood) characteristics of leukemic blasts at diagnosis is presented in a population of 432 promyelocytic leukemia AML patients who are older than than 60 years and have been selected for entering onto five successive clinical trials combining an anthracycline and cytarabine.ResultsFive groups of patients were defined according to these two relevant parameters used in clinical practice. Response rates were lower for the hyperproliferative groups (47% and 46%, respectively) and the nonproliferative groups displaying circulating blasts (56% and 59%, respectively) compared with those for the nonproliferative and noninvasive group (77%) (P = .0003). Median overall survivals were shorter for the hyperproliferative groups (5.7 and 5.8 months, respectively) compared with those observed for the nonproliferative groups (8.9 and12.6 months, respectively).ConclusionsThis combination of basic characteristics helps estimate the outcome of elderly AML patients who are usually selected for intensive chemotherapy. Although these factors remain valuable for identifying leukemia behavior, our study demonstrated that results of intensive chemotherapy in elderly patients remained poor, whatever the prognostic group. Comparison with recent data from the literature requires investigators to study results differently and to consider investigational therapy as being the most appropriate treatment even for this highly selected population.     

Molecular characterization of methicillin-resistant Staphylococcus aureus isolated in Tunisia

Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections are an emerging problem, especially related to the production of staphylococcal toxins. In this study we investigate the phenotypic and genotypic characteristics of 72 Tunisian MRSA. Our results revealed that these strains are multiresistant. Using multiplex polymerase chain reaction, we detected staphylococcal cassette chromosome mec (SCCmec) type IV and IVA in 66 isolates. The latter are Panton-Valentine leukocidin positive. The leukotoxin genes lukE-lukD were found in most strains (92.4%). The amplification of gamma-hemolysin gene was detected only in 2 MRSA isolates. Among all strains, only 1 expressed the exfoliatin A. fnbA gene was detected in 12 strains, fnbB gene in 2 strains, and both fnbA and fnbB genes in 2 other strains. The most predominant accessory gene regulator group identified was group III. Full characterization of these MRSA strains requires the association of SCCmec typing with other molecular methods such as pulsed-field gel electrophoresis, multilocus-sequence typing, and spa typing.     

Segmented crystalline scintillators: empirical and theoretical investigation of a high quantum efficiency EPID based on an initial engineering prototype CsI(TI) detector

Modern-day radiotherapy relies on highly sophisticated forms of image guidance in order to implement increasingly conformal treatment plans and achieve precise dose delivery. One of the most important goals of such image guidance is to delineate the clinical target volume from surrounding normal tissue during patient setup and dose delivery, thereby avoiding dependence on surrogates such as bony landmarks. In order to achieve this goal, it is necessary to integrate highly efficient imaging technology, capable of resolving soft-tissue contrast at very low doses, within the treatment setup. In this paper we report on the development of one such modality, which comprises a nonoptimized, prototype electronic portal imaging device (EPID) based on a 40 mm thick, segmented crystalline CsI(Tl) detector incorporated into an indirect-detection active matrix flat panel imager (AMFPI). The segmented detector consists of a matrix of 160 x 160 optically isolated, crystalline CsI(Tl) elements spaced at 1016 microm pitch. The detector was coupled to an indirect detection-based active matrix array having a pixel pitch of 508 microm, with each detector element registered to 2 x 2 array pixels. The performance of the prototype imager was evaluated under very low-dose radiotherapy conditions and compared to that of a conventional megavoltage AMFPI based on a Lanex Fast-B phosphor screen. Detailed quantitative measurements were performed in order to determine the x-ray sensitivity, modulation transfer function, noise power spectrum, and detective quantum efficiency (DQE). In addition, images of a contrast-detail phantom and an anthropomorphic head phantom were also acquired. The prototype imager exhibited approximately 22 times higher zero-frequency DQE (approximately 22%) compared to that of the conventional AMFPI (approximately 1%). The measured zero-frequency DQE was found to be lower than theoretical upper limits (approximately 27%) calculated from Monte Carlo simulations, which were based solely on the x-ray energy absorbed in the detector-indicating the presence of optical Swank noise. Moreover, due to the nonoptimized nature of this prototype, the spatial resolution was observed to be significantly lower than theoretical expectations. Nevertheless, due to its high quantum efficiency (approximately 55%), the prototype imager exhibited significantly higher DQE than that of the conventional AMFPI across all spatial frequencies. In addition, the frequency-dependent DQE was observed to be relatively invariant with respect to the amount of incident radiation, indicating x-ray quantum limited behavior. Images of the contrast-detail phantom and the head phantom obtained using the prototype system exhibit good visualization of relatively large, low-contrast features, and appear significantly less noisy compared to similar images from a conventional AMFPI. Finally, Monte Carlo-based theoretical calculations indicate that, with proper optimization, further, significant improvements in the DQE performance of such imagers could be achieved. It is strongly anticipated that the realization of optimized versions of such very high-DQE EPIDs would enable megavoltage projection imaging at very low doses, and tomographic imaging from a "beam's eye view" at clinically acceptable doses.     

Monte Carlo investigations of megavoltage cone-beam CT using thick, segmented scintillating detectors for soft tissue visualization

Megavoltage cone-beam computed tomography (MV CBCT) is a highly promising technique for providing volumetric patient position information in the radiation treatment room. Such information has the potential to greatly assist in registering the patient to the planned treatment position, helping to ensure accurate delivery of the high energy therapy beam to the tumor volume while sparing the surrounding normal tissues. Presently, CBCT systems using conventional MV active matrix flat-panel imagers (AMFPIs), which are commonly used in portal imaging, require a relatively large amount of dose to create images that are clinically useful. This is due to the fact that the phosphor screen detector employed in conventional MV AMFPIs utilizes only approximately 2% of the incident radiation (for a 6 MV x-ray spectrum). Fortunately, thick segmented scintillating detectors can overcome this limitation, and the first prototype imager has demonstrated highly promising performance for projection imaging at low doses. It is therefore of definite interest to examine the potential performance of such thick, segmented scintillating detectors for MV CBCT. In this study, Monte Carlo simulations of radiation energy deposition were used to examine reconstructed images of cylindrical CT contrast phantoms, embedded with tissue-equivalent objects. The phantoms were scanned at 6 MV using segmented detectors having various design parameters (i.e., detector thickness as well as scintillator and septal wall materials). Due to constraints imposed by the nature of this study, the size of the phantoms was limited to approximately 6 cm. For such phantoms, the simulation results suggest that a 40 mm thick, segmented CsI detector with low density septal walls can delineate electron density differences of approximately 2.3% and 1.3% at doses of 1.54 and 3.08 cGy, respectively. In addition, it was found that segmented detectors with greater thickness, higher density scintillator material, or lower density septal walls exhibit higher contrast-to-noise performance. Finally, the performance of various segmented detectors obtained at a relatively low dose (1.54 cGy) was compared with that of a phosphor screen similar to that employed in conventional MV AMFPIs. This comparison indicates that for a phosphor screen to achieve the same contrast-to-noise performance as the segmented detectors approximately 18 to 59 times more dose is required, depending on the configuration of the segmented detectors.     

Cigarette smoking and acute leukemia

Recent cohort and case-control studies have suggested that cigarette smoking may be involved in the etiology of leukemia. Rising trends have been observed for all leukemias when the amount of cigarettes smoked increased. However, the magnitude of the trend was strongest for myeloid leukemia. Although no detailed biological mechanism has been proposed, a causal link is made plausible by evidence of systemic effects of cigarette smoke and the presence in cigarette smoke of chemicals (benzene) and radioactive substances that have been associated with leukemia risk. Cigarette smoking has a deleterious effect on survival in leukemia by shortening complete remission duration and subsequent survival. The data reported in this review are derived from the medical literature and from the experience of the authors.