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Background: CyberKnife ® stereotactic radiotherapy allows for minimally invasive treatment with satisfactory results in patients with inoperable primary or metastatic lung cancer. The objective of this study was to identify factors influencing the probability of local control., Methods: Ninety-five patients (100 lung tumors) treated between January and December 2013 at our department by SBRT (stereotactic body radiation therapy) using CyberKnife ® were included in the study. There were 71 stage T1 or T2 primary tumors and 29 secondary tumors. The tracking methods were as follow: fiducial markers with Synchrony ® in 50 cases (gold seeds in 35, coils in 15 cases), spine with 4D-CT and Xsight ® Spine in 43 cases, and direct viewing by Xsight ® Lung in 7 cases. The methods were allocated according to the characteristics of each target., Results: With a median follow-up of 24 months, the probability of local control at 24 months was 88%. The probability of local control differed according to the size of the target (92% for tumors ≤35 mm and 54% for tumors >35 mm: P=0.013) and according to the distance of the fiducial markers in relation to the target (95% when <50 mm and 69% when ≥50 mm: P=0.011)., Conclusions: The best results were obtained with small lesions. With Synchrony ® , the distance of the target relative to the fiducial markers should be less than 50 mm. Gold seeds are recommended, although coils may be used instead of gold seeds. The number of fiducial markers did not have a significant impact on the probability of local control. With an appropriate tracking method, stereotactic radiotherapy is an efficient treatment for stage I lung cancer and lung oligometastases., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Many age-related human diseases have inflammatory components of uncertain causes. It has been proposed that some may be initiated or sustained by doubly mutated immune cells that have both inappropriately activated inflammasomes and enhanced replicative potential. Genes of cells that express mutant TERT and NLRP3 proteins are presumed to be at increased risk for mutagenesis because they reside in subtelomeric regions of chromatin that are deficient in DNA repair mechanisms. Expanded clones of proinflammatory cells can occur throughout one's lifetime and could represent an alternative explanation for some forms of pathologic scarring that are now attributed to truncated telomeres.-Marchesi, V. T. De novo digenic mutations of telomere-associated proteins and inflammasomes initiate many chronic human diseases: a hypothesis., (© FASEB.)

Objective: To report grade ≥2 overall late rectal and urinary toxicities in patients (pts) with prostate cancer treated by intensity-modulated radiotherapy (IMRT) at 3 dose-levels. Identify predictors of radiation toxicity and report biochemical progression free survival (bPFS)., Methods: A total of 277 pts were treated with 70Gy (10.8%), 74Gy (63.9%) and 80 Gy (25.3%) using IMRT without pelvic irradiation were analyzed. Short or long-course androgen deprivation therapy (ADT) was allowed in 46.1% of pts. The toxicity was described using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 scale. Cox regression models addressed demographics, disease and dosimetry characteristics as potential predictors of late grade ≥2 toxicity after adjusting for other modifying factors., Results: The median follow-up was 77 months (range 15; 150). There was no grade ≥4 toxicity. The 5-year cumulative rate of grade ≥2 late rectal and urinary toxicities was 6.3% (95% CI = 3.8%; 10.3%) and 25.3% (95% CI = 19.8%; 31.8%) respectively. In multivariate analysis, only the dose (80Gy vs 74 and 70Gy) was found to increase the risk of rectal toxicity (HR = 2.96 [1.07; 8.20]). For pts receiving 74 Gy, International Prostate Symptom Score (IPSS) at baseline ≥8 (HR = 2.40 [1.08; 5.35]) and dose ≥73Gy delivered in more than 2% of bladder (D2%) were found to be predictors of bladder toxicity (HR = 3.29 [1.36; 7.98]). The 5-year biochemical relapse free survival was 81.0% [74.5%; 86.0%] in the entire population, 97.5% [83.5%; 99.6%] in the low risk group, 84.9% [76.7%; 90.3%] in the intermediate risk group and 66.4% [51.8%; 77.4%] in the high-risk group. D'Amico low (HR = 0.09 [0.01; 0.69]) and intermediate risk groups (HR = 0.50 [0.28; 0.88]) as well as PSA nadir ≥0.2 ng/ml (HR = 1.79 [1.01; 3.21]) were predictive of biochemical relapse., Conclusions: The rate of late rectal toxicity increased with higher doses, while Dmax ≥74Gy, D2% ≥ 73Gy for bladder wall and baseline IPSS ≥8 increased late urinary toxicity.

The aim of radiotherapy is to deliver enough radiation to the tumor in order to achieve maximum tumour control in the irradiated volume with as few serious complications as possible with an irradiation dose as low as possible to normal tissue. The quality of radiotherapy is essential for optimal treatment and quality control is to reduce the bias in clinical trials avoiding possible major deviations. The assurance and quality control programs have been developed in large european (EORTC, GORTEC) and american cooperative groups (RTOG) of radiation oncology since the 1980s. We insist here on the importance of quality assurance in radiotherapy and the current status in this domain and the criteria for quality control especially for current clinical trials within GORTEC are discussed here.

This essay explores an alternative pathway to Alzheimer's dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.

Alzheimer's disease threatens to become the scourge of the 21st century. Hundreds of millions of aging people throughout the world are at risk, but it is clear that the disease encompasses more than just the natural aging process. Deposits of amyloid β peptides in the brains of demented individuals are a defining feature of the disease, yet two decades of intensive investigation, focusing on reducing or removing amyloid deposits, have failed to produce any meaningful therapeutic interventions. Some researchers question whether amyloid is the appropriate target. Others maintain that early, presymptomatic intervention would be a more informative test, and propose large-scale clinical trials in patients who are believed to be in the earliest, and potentially reversible, stages of the disease. This review explores the wisdom of that approach., (Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Cytolytic CD8(+) T cells (CTLs) kill virally infected cells, tumor cells, or other potentially autoreactive T cells in a calcium-dependent manner. To date, the molecular mechanism that leads to calcium intake during CTL differentiation and function has remained unresolved. We demonstrate that desmoyokin (AHNAK1) is expressed in mature CTLs, but not in naive CD8(+) T cells, and is critical for calcium entry required for their proper function during immune response. We show that mature AHNAK1-deficient CTLs exhibit reduced Ca(v)1.1 alpha1 subunit expression (also referred to as L-type calcium channels or alpha1S pore-forming subunits), which recently were suggested to play a role in calcium entry into CD4(+) T cells. AHNAK1-deficient CTLs show marked reduction in granzyme-B production, cytolytic activity, and IFN-gamma secretion after T cell receptor stimulation. Our results demonstrate an AHNAK1-dependent mechanism controlling calcium entry during CTL effector function.

The aim of this study is to introduce tools to improve the security of each IMRT patient treatment by determining action levels for the dose delivery process. To achieve this, the patient-specific quality control results performed with an ionization chamber--and which characterize the dose delivery process--have been retrospectively analyzed using a method borrowed from industry: Statistical process control (SPC). The latter consisted in fulfilling four principal well-structured steps. The authors first quantified the short-term variability of ionization chamber measurements regarding the clinical tolerances used in the cancer center (+/- 4% of deviation between the calculated and measured doses) by calculating a control process capability (C(pc)) index. The C(pc) index was found superior to 4, which implies that the observed variability of the dose delivery process is not biased by the short-term variability of the measurement. Then, the authors demonstrated using a normality test that the quality control results could be approximated by a normal distribution with two parameters (mean and standard deviation). Finally, the authors used two complementary tools--control charts and performance indices--to thoroughly analyze the IMRT dose delivery process. Control charts aim at monitoring the process over time using statistical control limits to distinguish random (natural) variations from significant changes in the process, whereas performance indices aim at quantifying the ability of the process to produce data that are within the clinical tolerances, at a precise moment. The authors retrospectively showed that the analysis of three selected control charts (individual value, moving-range, and EWMA control charts) allowed efficient drift detection of the dose delivery process for prostate and head-and-neck treatments before the quality controls were outside the clinical tolerances. Therefore, when analyzed in real time, during quality controls, they should improve the security of treatments. They also showed that the dose delivery processes in the cancer center were in control for prostate and head-and-neck treatments. In parallel, long-term process performance indices (P(p), P(pk), and P(pm)) have been analyzed. Their analysis helped defining which actions should be undertaken in order to improve the performance of the process. The prostate dose delivery process has been shown statistically capable (0.08% of the results is expected to be outside the clinical tolerances) contrary to the head-and-neck dose delivery process (5.76% of the results are expected to be outside the clinical tolerances).

Engagement of the T cell antigen receptor (TCR) during antigen presentation initiates a coordinated action of a large number of signaling proteins and ion channels. AHNAK1 is a scaffold protein, highly expressed by CD4+ T cells, and is a critical component for calcium signaling. We showed that AHNAK1-deficient mice were highly susceptible to Leishmania major infection. AHNAK1-deficient CD4+ T cells responded poorly to TCR stimulation in vitro with low proliferation and low Interleukin-2 production. Furthermore, AHNAK1 deficiency resulted in a reduced calcium influx upon TCR crosslinking and subsequent poor activation of the transcription factor NFAT. AHNAK1 was required for plasma membrane expression of L-type calcium channels alpha 1S (Cav1.1), probably through its interaction with the beta regulatory subunit. Thus, AHNAK1 plays an essential role in T cell Ca2+ signaling through Cav1 channels, triggered via TCR activation; therefore, AHNAK1 is a potential target for therapeutic intervention.

In an attempt to have better targeting of the prostate during radiotherapy it is necessary to understand the mechanical interactions between bladder, rectum, and prostate and estimate their consequences on prostate motion. For this, the volumes of bladder, rectum, and lungs were modified concomitantly on a deceased person. A CT acquisition was performed for each of these different pelvic configurations (36 acquisitions). An increase in the volume of the bladder or lungs induces a compression of tissues of the pelvic area from its supero-anterior (S-A) to infero-posterior (I-P) side. Conversely, an increase of rectum volume induces a compression from the I-P to the S-A side of the pelvic region. These compressive actions can be added or subtracted from each other, depending on their amplitudes and directions. Prostate motion occurs when a movement of the rectum is observed (this movement depends, itself, on lungs and bladder volume). The maximum movement of prostate is 9 mm considering maximal bladder or rectal action, and 11 mm considering maximum lung action. In some other cases, opposition of compressive effects can lead to stasis of the prostate. Based on the volumes of bladder, rectum, and lungs, it is possible to qualitatively estimate the movement of organs of the pelvic area. The best way to reduce prostate movement is to recommend the patient to have an empty rectum, with either full bladder and/or full lungs.

Alzheimer's disease is a complex neurodegenerative process that is believed to be due to the accumulation of short, hydrophobic peptides derived from amyloid precursor proteins by proteolytic cleavage. It is widely believed that these Abeta peptides are secreted into the extracellular spaces of the CNS, where they assemble into toxic oligomers that kill neurons and eventually form deposits of senile plaques. This essay explores the possibility that a fraction of these Abeta peptides never leave the membrane lipid bilayer after they are generated, but instead exert their toxic effects by competing with and compromising the functions of intramembranous segments of membrane-bound proteins that serve many critical functions. Based on the presence of shared amino acid sequences containing GxxG motifs, I speculate that accumulations of intramembranous Abeta peptides might affect the functions of amyloid precursor protein itself and the assembly of the PS1, Aph1, Pen 2, Nicastrin complex.

To explore the function of the giant AHNAK molecule, first described in 1992 [Shtivelman, E., Cohen, F. E. & Bishop, J. M. (1992) Proc. Natl. Acad. Sci. USA 89, 5472-5476], we created AHNAK null mice by homologous recombination. Homozygous knockouts showed no obvious phenotype, but revealed instead a second AHNAK-like molecule, provisionally designated AHNAK2. Like the original AHNAK, AHNAK2 is a 600-kDa protein composed of a large number of highly conserved repeat segments. Structural predictions suggest that the repeat segments of both AHNAKs may have as their basic framework a series of linked, antiparallel beta-strands similar to those found in beta-propeller proteins. Both AHNAKs appear to localize to Z-band regions of mouse cardiomyocytes and cosediment with membrane vesicles containing the dihydropyridine receptor, which is consistent with earlier reports that the AHNAKs are linked to L-type calcium channels and can be phosphorylated by protein kinase A. The localization of the AHNAKs in close proximity to transverse tubule membranes and Z-band regions of cardiac sarcomeres raise the possibility that they might be involved in regulating excitation/contraction coupling of cardiomyocytes, but other studies indicate that the association of AHNAKs with calcium channel proteins is more widespread. AHNAK2 is predicted to have a PDZ domain within its N-terminal, nonrepeating domain, which may mediate these interactions.