Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice.

In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤ 500 ms) of radiation delivered at ultrahigh dose rate (≥ 40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤ 0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc(+) orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor-β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor-α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.

Cataractogenesis after total body irradiation.

PURPOSE: To evaluate the prognostic factors and the ophthalmologic follow-up on cataract formation following total body irradiation (TBI) prior to bone marrow transplantation (BMT). METHODS AND MATERIALS: Between 1980 and 1992, 494 patients were referred to our department for TBI prior to BMT. The mean age was 32 +/- 11 (median: 32, range: 2-63) years and the male to female ratio was 1.6 (304:190). The majority of patients were treated for acute leukemia (lymphoblastic, n = 177, 36%; or nonlymphoblastic , n = 139, 28%); 80 (16%) for chronic myeloid leukemia, 60 (12%) for non-Hodgkin's lymphoma, 23 (5%) for multiple myeloma, and 15 (3%) for other malignancies. Two hundred and fifty-four (51%) patients were grafted in the first complete remission (CR), 118 (24%) in second CR. Allogenic BMT was performed in 210 (43%) patients, and autologous BMT in 284 (57%). Methotrexate combined to steroids (n = 47, 22%) or to cyclosporine (n = 163, 78%) was administered for graft-versus-host disease (GvHD) prophylaxis. In 188 patients (38%), heparin was used in the prevention of veno-occlusive disease (VOD) of the liver. Furthermore, steroid administration was registered in 223 (45%). The conditioning chemotherapy consisted of cyclophosphamide (Cy) alone in 332 (67%) patients. Total-body irradiation was administered either in single dose (STBI; 10 Gy in 1 day, n = 291) or in six fractions (FTBI; 12 Gy over 3 consecutive days, n = 203) before BMT. The mean instantaneous dose rate was 0.0574 +/- 0.0289 Gy/min (0.024-0.1783). It was < 0.048 Gy/min in 157 patients (LOW group), > or = 0.048 Gy/min and <0.09 Gy/min in 301 patients (MEDIUM group), and > or = 0.09 Gy/min in 36 patients (HIGH group). RESULTS: When considering all patients, 42 (8.5%) patients developed cataracts after 13 to 72 months (median: 42 months) with a 5-year estimated cataract incidence (ECI) of 23%. Thirty-three (11.3%) out of 291 patients in the STBI group, and 9 (4.4%) out of 203 patients in the FTBI group developed cataracts with 5-year estimated incidences of 34 and 11%, respectively (p = 0.0004). Seven (19.4%) out of 36 patients in the HIGH group, 33 (10.9%) out of 301 in the MEDIUM group, and 2 (1.2%) out of 157 in the LOW group developed cataracts with respective 5-year cataract incidences of 54%, 30%, and 3.5% (HIGH vs. MEDIUM, p = 0.07; MEDIUM vs. LOW, p = 0.0001; HIGH vs. LOW, p < 0.0001). On the other hand, patients who received heparin as prophylactic treatment against VOD of the liver had less cataracts than those who did not receive (5-year ECI of 16% vs. 28%, respectively; p = 0.01). There was no statistically significant difference in terms of 5-year ECI according to age, sex, administration of steroids, GvHD prophylaxis, type of BMT, or previous cranial radiotherapy in children. Multivariate analysis revealed that the instantaneous dose rate (p = 0.001), and the administration of heparin against VOD (p = 0.05) were the two independent factors influencing the cataract incidence, while age, fractionation, and use of steroids were not. Among the 42 patients who developed cataracts, 38 had bilateral extracapsular cataract extraction and intraocular lens implantation, and only 4 (10%) developed secondary cataracts in a median follow-up period of 39 months. CONCLUSION: Among the abovementioned TBI parameters, high instantaneous dose rate seems to be the main risk factor of cataract formation, and the administration of heparin appears to have a protective role in cataractogenesis. On the other hand, ionizing radiation seems to have a protective effect on posterior capsule opacification following extracapsular cataract extraction and intraocular lens implantation.

Enhanced cytotoxicity and decreased CD8 dependence of human cancer-specific cytotoxic T lymphocytes after vaccination with low peptide dose.

In mice, vaccination with high peptide doses generates higher frequencies of specific CD8+ T cells, but with lower avidity compared to vaccination with lower peptide doses. To investigate the impact of peptide dose on CD8+ T cell responses in humans, melanoma patients were vaccinated with 0.1 or 0.5 mg Melan-A/MART-1 peptide, mixed with CpG 7909 and Incomplete Freund's adjuvant. Neither the kinetics nor the amplitude of the Melan-A-specific CD8+ T cell responses differed between the two vaccination groups. Also, CD8+ T cell differentiation and cytokine production ex vivo were similar in the two groups. Interestingly, after low peptide dose vaccination, Melan-A-specific CD8+ T cells showed enhanced degranulation upon peptide stimulation, as assessed by CD107a upregulation and perforin release ex vivo. In accordance, CD8+ T cell clones derived from low peptide dose-vaccinated patients showed significantly increased degranulation and stronger cytotoxicity. In parallel, Melan-A-specific CD8+ T cells and clones from low peptide dose-vaccinated patients expressed lower CD8 levels, despite similar or even stronger binding to tetramers. Furthermore, CD8+ T cell clones from low peptide dose-vaccinated patients bound CD8 binding-deficient tetramers more efficiently, suggesting that they may express higher affinity TCRs. We conclude that low peptide dose vaccination generated CD8+ T cell responses with stronger cytotoxicity and lower CD8 dependence.

Radiothérapie « flash » à très haut débit de dose : un moyen d'augmenter l'indice thérapeutique par minimisation des dommages aux tissus sains [Ultrahigh dose-rate, "flash" irradiation minimizes the side-effects of radiotherapy].

PURPOSE: Pencil beam scanning and filter free techniques may involve dose-rates considerably higher than those used in conventional external-beam radiotherapy. Our purpose was to investigate normal tissue and tumour responses in vivo to short pulses of radiation. MATERIAL AND METHODS: C57BL/6J mice were exposed to bilateral thorax irradiation using pulsed (at least 40Gy/s, flash) or conventional dose-rate irradiation (0.03Gy/s or less) in single dose. Immunohistochemical and histological methods were used to compare early radio-induced apoptosis and the development of lung fibrosis in the two situations. The response of two human (HBCx-12A, HEp-2) tumour xenografts in nude mice and one syngeneic, orthotopic lung carcinoma in C57BL/6J mice (TC-1 Luc+), was monitored in both radiation modes. RESULTS: A 17Gy conventional irradiation induced pulmonary fibrosis and activation of the TGF-beta cascade in 100% of the animals 24-36 weeks post-treatment, as expected, whereas no animal developed complications below 23Gy flash irradiation, and a 30Gy flash irradiation was required to induce the same extent of fibrosis as 17Gy conventional irradiation. Cutaneous lesions were also reduced in severity. Flash irradiation protected vascular and bronchial smooth muscle cells as well as epithelial cells of bronchi against acute apoptosis as shown by analysis of caspase-3 activation and TUNEL staining. In contrast, the antitumour effectiveness of flash irradiation was maintained and not different from that of conventional irradiation. CONCLUSION: Flash irradiation shifted by a large factor the threshold dose required to initiate lung fibrosis without loss of the antitumour efficiency, suggesting that the method might be used to advantage to minimize the complications of radiotherapy.

Low-frequency drug-resistant HIV-1 and risk of virological failure to first-line NNRTI-based ART: a multicohort European case-control study using centralized ultrasensitive 454 pyrosequencing.

OBJECTIVES: It is still debated if pre-existing minority drug-resistant HIV-1 variants (MVs) affect the virological outcomes of first-line NNRTI-containing ART. METHODS: This Europe-wide case-control study included ART-naive subjects infected with drug-susceptible HIV-1 as revealed by population sequencing, who achieved virological suppression on first-line ART including one NNRTI. Cases experienced virological failure and controls were subjects from the same cohort whose viraemia remained suppressed at a matched time since initiation of ART. Blinded, centralized 454 pyrosequencing with parallel bioinformatic analysis in two laboratories was used to identify MVs in the 1%-25% frequency range. ORs of virological failure according to MV detection were estimated by logistic regression. RESULTS: Two hundred and sixty samples (76 cases and 184 controls), mostly subtype B (73.5%), were used for the analysis. Identical MVs were detected in the two laboratories. 31.6% of cases and 16.8% of controls harboured pre-existing MVs. Detection of at least one MV versus no MVs was associated with an increased risk of virological failure (OR = 2.75, 95% CI = 1.35-5.60, P = 0.005); similar associations were observed for at least one MV versus no NRTI MVs (OR = 2.27, 95% CI = 0.76-6.77, P = 0.140) and at least one MV versus no NNRTI MVs (OR = 2.41, 95% CI = 1.12-5.18, P = 0.024). A dose-effect relationship between virological failure and mutational load was found. CONCLUSIONS: Pre-existing MVs more than double the risk of virological failure to first-line NNRTI-based ART.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Large-scale imatinib dose-concentration-effect study in CML patients under routine care conditions.

This observational study analyzed imatinib pharmacokinetics and response in 2478 chronic myeloid leukemia (CML) patients. Data were obtained through centralized therapeutic drug monitoring (TDM) at median treatment duration of ≥2 years. First, individual initial trough concentrations under 400mg/day imatinib starting dose were estimated. Second, their correlation (C^min(400mg)) with reported treatment response was verified. Low imatinib levels were predicted in young male patients and those receiving P-gp/CYP3A4 inducers. These patients had also lower response rates (7% lower 18-months MMR in male, 17% lower 1-year CCyR in young patients, Kaplan-Meier estimates). Time-point independent multivariate regression confirmed a correlation of individual C^min(400mg) with response and adverse events. Possibly due to confounding factors (e.g. dose modifications, patient selection bias), the relationship seemed however flatter than previously reported from prospective controlled studies. Nonetheless, these observational results strongly suggest that a subgroup of patients could benefit from early dosage optimization assisted by TDM, because of lower imatinib concentrations and lower response rates.

A peripheral dose calculation model for estimating second cancer risk after breast radiotherapy

AbstractBreast cancer is one of the most common cancers affecting one in eight women during their lives. Survival rates have increased steadily thanks to early diagnosis with mammography screening and more efficient treatment strategies. Post-operative radiation therapy is a standard of care in the management of breast cancer and has been shown to reduce efficiently both local recurrence rate and breast cancer mortality. Radiation therapy is however associated with some late effects for long-term survivors. Radiation-induced secondary cancer is a relatively rare but severe late effect of radiation therapy. Currently, radiotherapy plans are essentially optimized to maximize tumor control and minimize late deterministic effects (tissue reactions) that are mainly associated with high doses (» 1 Gy). With improved cure rates and new radiation therapy technologies, it is also important to evaluate and minimize secondary cancer risks for different treatment techniques. This is a particularly challenging task due to the large uncertainties in the dose-response relationship.In contrast with late deterministic effects, secondary cancers may be associated with much lower doses and therefore out-of-field doses (also called peripheral doses) that are typically inferior to 1 Gy need to be determined accurately. Out-of-field doses result from patient scatter and head scatter from the treatment unit. These doses are particularly challenging to compute and we characterized it by Monte Carlo (MC) calculation. A detailed MC model of the Siemens Primus linear accelerator has been thoroughly validated with measurements. We investigated the accuracy of such a model for retrospective dosimetry in epidemiological studies on secondary cancers. Considering that patients in such large studies could be treated on a variety of machines, we assessed the uncertainty in reconstructed peripheral dose due to the variability of peripheral dose among various linac geometries. For large open fields (> 10x10 cm2), the uncertainty would be less than 50%, but for small fields and wedged fields the uncertainty in reconstructed dose could rise up to a factor of 10. It was concluded that such a model could be used for conventional treatments using large open fields only.The MC model of the Siemens Primus linac was then used to compare out-of-field doses for different treatment techniques in a female whole-body CT-based phantom. Current techniques such as conformai wedged-based radiotherapy and hybrid IMRT were investigated and compared to older two-dimensional radiotherapy techniques. MC doses were also compared to those of a commercial Treatment Planning System (TPS). While the TPS is routinely used to determine the dose to the contralateral breast and the ipsilateral lung which are mostly out of the treatment fields, we have shown that these doses may be highly inaccurate depending on the treatment technique investigated. MC shows that hybrid IMRT is dosimetrically similar to three-dimensional wedge-based radiotherapy within the field, but offers substantially reduced doses to out-of-field healthy organs.Finally, many different approaches to risk estimations extracted from the literature were applied to the calculated MC dose distribution. Absolute risks varied substantially as did the ratio of risk between two treatment techniques, reflecting the large uncertainties involved with current risk models. Despite all these uncertainties, the hybrid IMRT investigated resulted in systematically lower cancer risks than any of the other treatment techniques. More epidemiological studies with accurate dosimetry are required in the future to construct robust risk models. In the meantime, any treatment strategy that reduces out-of-field doses to healthy organs should be investigated. Electron radiotherapy might offer interesting possibilities with this regard.RésuméLe cancer du sein affecte une femme sur huit au cours de sa vie. Grâce au dépistage précoce et à des thérapies de plus en plus efficaces, le taux de guérison a augmenté au cours du temps. La radiothérapie postopératoire joue un rôle important dans le traitement du cancer du sein en réduisant le taux de récidive et la mortalité. Malheureusement, la radiothérapie peut aussi induire des toxicités tardives chez les patients guéris. En particulier, les cancers secondaires radio-induits sont une complication rare mais sévère de la radiothérapie. En routine clinique, les plans de radiothérapie sont essentiellement optimisées pour un contrôle local le plus élevé possible tout en minimisant les réactions tissulaires tardives qui sont essentiellement associées avec des hautes doses (» 1 Gy). Toutefois, avec l'introduction de différentes nouvelles techniques et avec l'augmentation des taux de survie, il devient impératif d'évaluer et de minimiser les risques de cancer secondaire pour différentes techniques de traitement. Une telle évaluation du risque est une tâche ardue étant donné les nombreuses incertitudes liées à la relation dose-risque.Contrairement aux effets tissulaires, les cancers secondaires peuvent aussi être induits par des basses doses dans des organes qui se trouvent hors des champs d'irradiation. Ces organes reçoivent des doses périphériques typiquement inférieures à 1 Gy qui résultent du diffusé du patient et du diffusé de l'accélérateur. Ces doses sont difficiles à calculer précisément, mais les algorithmes Monte Carlo (MC) permettent de les estimer avec une bonne précision. Un modèle MC détaillé de l'accélérateur Primus de Siemens a été élaboré et validé avec des mesures. La précision de ce modèle a également été déterminée pour la reconstruction de dose en épidémiologie. Si on considère que les patients inclus dans de larges cohortes sont traités sur une variété de machines, l'incertitude dans la reconstruction de dose périphérique a été étudiée en fonction de la variabilité de la dose périphérique pour différents types d'accélérateurs. Pour de grands champs (> 10x10 cm ), l'incertitude est inférieure à 50%, mais pour de petits champs et des champs filtrés, l'incertitude de la dose peut monter jusqu'à un facteur 10. En conclusion, un tel modèle ne peut être utilisé que pour les traitements conventionnels utilisant des grands champs.Le modèle MC de l'accélérateur Primus a été utilisé ensuite pour déterminer la dose périphérique pour différentes techniques dans un fantôme corps entier basé sur des coupes CT d'une patiente. Les techniques actuelles utilisant des champs filtrés ou encore l'IMRT hybride ont été étudiées et comparées par rapport aux techniques plus anciennes. Les doses calculées par MC ont été comparées à celles obtenues d'un logiciel de planification commercial (TPS). Alors que le TPS est utilisé en routine pour déterminer la dose au sein contralatéral et au poumon ipsilatéral qui sont principalement hors des faisceaux, nous avons montré que ces doses peuvent être plus ou moins précises selon la technTque étudiée. Les calculs MC montrent que la technique IMRT est dosimétriquement équivalente à celle basée sur des champs filtrés à l'intérieur des champs de traitement, mais offre une réduction importante de la dose aux organes périphériques.Finalement différents modèles de risque ont été étudiés sur la base des distributions de dose calculées par MC. Les risques absolus et le rapport des risques entre deux techniques de traitement varient grandement, ce qui reflète les grandes incertitudes liées aux différents modèles de risque. Malgré ces incertitudes, on a pu montrer que la technique IMRT offrait une réduction du risque systématique par rapport aux autres techniques. En attendant des données épidémiologiques supplémentaires sur la relation dose-risque, toute technique offrant une réduction des doses périphériques aux organes sains mérite d'être étudiée. La radiothérapie avec des électrons offre à ce titre des possibilités intéressantes.

Evaluation of exposure biomarkers in offshore workers exposed to low benzene and toluene concentrations.

Characterize ethylbenzene and xylene air concentrations, and explore the biological exposure markers (urinary t,t-muconic acid (t,t-MA) and unmetabolized toluene) among petroleum workers offshore. Offshore workers have increased health risks due to simultaneous exposures to several hydrocarbons present in crude oil. We discuss the pooled benzene exposure results from our previous and current studies and possible co-exposure interactions. BTEX air concentrations were measured during three consecutive 12-h work shifts among 10 tank workers, 15 process operators, and 18 controls. Biological samples were collected pre-shift on the first day of study and post-shift on the third day of the study. The geometric mean exposure over the three work shifts were 0.02 ppm benzene, 0.05 ppm toluene, 0.03 ppm ethylbenzene, and 0.06 ppm xylene. Benzene in air was significantly correlated with unmetabolized benzene in blood (r = 0.69, p < 0.001) and urine (r = 0.64, p < 0.001), but not with urinary t,t-MA (r = 0.27, p = 0.20). Toluene in air was highly correlated with the internal dose of toluene in both blood (r = 0.70, p < 0.001) and urine (r = 0.73, p < 0.001). Co-exposures were present; however, an interaction of metabolism was not likely at these low benzene and toluene exposures. Urinary benzene, but not t,t-MA, was a reliable biomarker for benzene at low exposure levels. Urinary toluene was a useful biomarker for toluene exposure. Xylene and ethylbenzene air levels were low. Dermal exposure assessment needs to be performed in future studies among these workers.

Oxygen-sensing reporter strain of Pseudomonas fluorescens for monitoring the distribution of low-oxygen habitats in soil.

The root-colonizing bacterium Pseudomonas fluorescens CHA0 was used to construct an oxygen-responsive biosensor. An anaerobically inducible promoter of Pseudomonas aeruginosa, which depends on the FNR (fumarate and nitrate reductase regulation)-like transcriptional regulator ANR (anaerobic regulation of arginine deiminase and nitrate reductase pathways), was fused to the structural lacZ gene of Escherichia coli. By inserting the reporter fusion into the chromosomal attTn7 site of P. fluorescens CHA0 by using a mini-Tn7 transposon, the reporter strain, CHA900, was obtained. Grown in glutamate-yeast extract medium in an oxystat at defined oxygen levels, the biosensor CHA900 responded to a decrease in oxygen concentration from 210 x 10(2) Pa to 2 x 10(2) Pa of O(2) by a nearly 100-fold increase in beta-galactosidase activity. Half-maximal induction of the reporter occurred at about 5 x 10(2) Pa. This dose response closely resembles that found for E. coli promoters which are activated by the FNR protein. In a carbon-free buffer or in bulk soil, the biosensor CHA900 still responded to a decrease in oxygen concentration, although here induction was about 10 times lower and the low oxygen response was gradually lost within 3 days. Introduced into a barley-soil microcosm, the biosensor could report decreasing oxygen concentrations in the rhizosphere for a 6-day period. When the water content in the microcosm was raised from 60% to 85% of field capacity, expression of the reporter gene was elevated about twofold above a basal level after 2 days of incubation, suggesting that a water content of 85% caused mild anoxia. Increased compaction of the soil was shown to have a faster and more dramatic effect on the expression of the oxygen reporter than soil water content alone, indicating that factors other than the water-filled pore space influenced the oxygen status of the soil. These experiments illustrate the utility of the biosensor for detecting low oxygen concentrations in the rhizosphere and other soil habitats.

Germline mutations in retinoma patients: relevance to low-penetrance and low-expressivity molecular basis.

PURPOSE: To study phenotype-genotype correlation in patients who have retinoma, which is a benign tumor resembling the post irradiation regression pattern of retinoblastoma (RB). METHODS: We selected patients who had retinoma and positive family history for RB and patients who had retinoma in one eye and either retinoma or RB in the other eye. The study included 22 patients with available DNA: 18 from 11 families and four sporadic cases. DNA was extracted from peripheral blood leukocytes. The RB1 gene was screened by DHPLC and direct sequencing of the promoter and all the exons. RESULTS: We identified 17 occurrences of 11 distinct germline mutations in two sporadic and in 15 familial cases (nine families). The 11 identified mutations were located in exons 1, 10,11,13,14, and 19 to 23. Four of the identified mutations were not previously reported, including g.64407delT, g.153236A>T, g.156743delTCTG, and g.162078delA. Eight out the 11 mutations were truncating and three were nontruncating (missense). There was no correlation between the type of mutation and the number of tumor foci per eye (RB or retinomas). Highly heterogeneous intrafamilial expressivity was observed. CONCLUSIONS: To our knowledge, this study is the largest series of mutations of consecutive retinoma patients. The present data suggest that the type of inherited mutations underlying retinoma is undistinguishable from RB related ones, i.e., largely dominated by truncating mutants. This finding is in contrast with the RB1 genotypic spectrum of mutations associated with low-penetrance RB, i.e., nontruncating mutants. The molecular mechanism underlying low-penetrance and attenuated expressivity (retinomas) appeared to be distinct.

Calculation of correction factors for ionization chamber measurements with small fields in low-density media.

The quantity of interest for high-energy photon beam therapy recommended by most dosimetric protocols is the absorbed dose to water. Thus, ionization chambers are calibrated in absorbed dose to water, which is the same quantity as what is calculated by most treatment planning systems (TPS). However, when measurements are performed in a low-density medium, the presence of the ionization chamber generates a perturbation at the level of the secondary particle range. Therefore, the measured quantity is close to the absorbed dose to a volume of water equivalent to the chamber volume. This quantity is not equivalent to the dose calculated by a TPS, which is the absorbed dose to an infinitesimally small volume of water. This phenomenon can lead to an overestimation of the absorbed dose measured with an ionization chamber of up to 40% in extreme cases. In this paper, we propose a method to calculate correction factors based on the Monte Carlo simulations. These correction factors are obtained by the ratio of the absorbed dose to water in a low-density medium □D(w,Q,V1)(low) averaged over a scoring volume V₁ for a geometry where V₁ is filled with the low-density medium and the absorbed dose to water □D(w,QV2)(low) averaged over a volume V₂ for a geometry where V₂ is filled with water. In the Monte Carlo simulations, □D(w,QV2)(low) is obtained by replacing the volume of the ionization chamber by an equivalent volume of water, according to the definition of the absorbed dose to water. The method is validated in two different configurations which allowed us to study the behavior of this correction factor as a function of depth in phantom, photon beam energy, phantom density and field size.

A single high dose of oral vitamin D3 is insufficient to correct a deficiency in a rheumatologic population

Introduction Vitamin D plays a major role in bone metabolismand neuromuscular function. Supplementation with vitamin D iseffective to reduce the risk of fall and of fracture. However adherenceto oral daily vitamin D is low. Screening and correcting vitamin Dinsufficiency in a rheumatologic population could improve bothmorbidity and quality of life. After determining the prevalence ofvitamin D deficiency in this population, we evaluated if supplementationwith a single high dose of oral 25-OH vitamin D3 wassufficient to correct this abnormality.Methods During one month (November 2009), levels of 25-OHvitamin D were systematically determined in our rheumatology outpatientclinic and classified in: vitamin D deficiency (< 10 μg/l),vitamin D insufficiency (10 to 30 μg/l) or normal vitamin D (> 30 μg/l).Patients with insufficiency or deficiency received respectively a singlehigh dose of 300'000 IU or 600'000 IU oral vitamin D3. In addition,all patients with osteoporosis were prescribed daily supplement ofcalcium (1 g) and vitamin D (800 IU). 25-OH vitamin D levels werereevaluated after 3 months.Results Vitamin D levels were initially determined in 292 patients(mean age 53, 211 women, 87 % Caucasian). 77 % had inflammatoryrheumatologic disease (IRD), 20 % osteoporosis (OP) and 12 %degenerative disease (DD). Vitamin D deficiency was present in 20(6.8 %), while 225 (77.1 %) had insufficiency. Of the 245 patientswith levels < 30μg/l, a new determination of vitamin D level wasavailable in 173 (71 %) at 3 months.Conclusion Vitamin D insufficiency is highly prevalent in ourrheumatologic population (84 %), and is not adequately correctedby a single high dose of oral vitamin D3 in > 50 % of the patientswith IRD and DD. In patients with OP, despite association of asingle high dose with daily oral vitamin D supplementation, 40 %of patients are still deficient when reevaluated at 3 months.

Gefitinib in Combination With Irradiation With or Without Cisplatin in Patients With Inoperable Stage III Non-Small Cell Lung Cancer: A Phase I Trial.

Purpose : To establish the feasibility and tolerability of gefitinib (ZD1839, Iressa) with radiation (RT) or concurrent chemoradiation (CRT) with cisplatin (CDDP) in patients with advanced non small cell lung cancer (NSCLC).Patients and Methods : In this multicenter Phase I study, 5 patients with unresectable NSCLC received 250 mg gefitinib daily starting 1 week before RT at a dose of 63 Gy (Step 1). After a first safety analysis, 9 patients were treated daily with 250 mg gefitinib plus CRT in the form of RT and weekly CDDP 35 mg/m(2) (Step 2). Gefitinib was maintained for up to 2 years until disease progression or toxicity.Results : Fourteen patients were assessed in the two steps. In Step 1 (five patients were administered only gefitinib and RT), no lung toxicities were seen, and there was no dose-limiting toxicity (DLT). Adverse events were skin and subcutaneous tissue reactions, limited to Grade 1-2. In Step 2, two of nine patients (22.2%) had DLT. One patient suffered from dyspnea and dehydration associated with neutropenic pneumonia, and another showed elevated liver enzymes. In both steps combined, 5 of 14 patients (35.7%) experienced one or more treatment interruptions.Conclusions : Gefitinib (250 mg daily) in combination with RT and CDDP in patients with Stage HI NSCLC is feasible, but CDDP likely enhances toxicity. The impact of gefitinib on survival and disease control as a first-line treatment in combination with RT remains to be determined. (C) 2011 Elsevier Inc.