Clinical and immunologic responses in melanoma patients vaccinated with MAGE-A3-genetically modified lymphocytes.

Cancer vaccines have recently been shown to induce some clinical benefits. The relationship between clinical activity and anti-vaccine T cell responses is somewhat controversial. Indeed, in many trials it has been documented that the induction of vaccine-specific T cells exceeds the clinical responses observed. Here, we evaluate immunological and clinical responses in 23 MAGE-A3(+) melanoma patients treated with autologous lymphocytes genetically engineered to express the tumor antigen MAGE-A3 and the viral gene product thymidine kinase of the herpes simplex virus (HSV-TK). HSV-TK was used as safety system in case of adverse events and as tracer antigen to monitor the immune competence of treated patients. The increase of anti-TK and anti-MAGE-A3 T-cells after vaccination was observed in 90 and 27% of patients, respectively. Among 19 patients with measurable disease, we observed a disease control rate of 26.3%, with one objective clinical response, and four durable, stable diseases. Three patients out of five with no evidence of disease (NED) at the time of vaccination remained NED after 73+, 70+ and 50+ months. Notably, we report that only patients experiencing MAGE-A3-specific immune responses showed a clinical benefit. Additionally, we report that responder and non-responder patients activate and expand T cells against the tracer antigen TK in a similar way, suggesting that local rather than systemic immune suppression might be involved in limiting clinically relevant antitumor immune responses.

Non-peptide NK1 receptor ligands based on the 4-phenylpyridine moiety.

The quinoline nucleus of the previously described 4-phenylquinoline-3-carboxamides NK(1) receptor ligands 7 has been transformed into either substituted or azole-(i.e., triazole or tetrazole) fused pyridine moieties of compounds 9 and 10, respectively, in order to obtain NK(1) receptor ligands showing lower molecular weight or higher hydrophilicity. The program of molecular manipulations produced NK(1) receptor ligands showing affinity in the nanomolar range. In particular, 4-methyl-1-piperazinyl derivative 9j showed an IC(50) value of 4.8 nM and was proved to behave as a NK(1) antagonist blocking Sar(9)-SP-sulfone induced proliferation and migration of microvascular endothelial cells. Therefore, compound 9j has been labeled with [(11)C]CH(3)I (t(1/2)=20.4 min, ß(+)=99.8%) starting from the corresponding des-methyl precursor 9i using with a radiochemical yield of about 10% (not decay corrected) and a specific radioactivity>1 Ci/µmol in order to be used as a radiotracer in next PET studies.

A modified damped Richardson-Lucy algorithm to reduce isotropic background effects in spherical deconvolution.

Spherical deconvolution methods have been applied to diffusion MRI to improve diffusion tensor tractography results in brain regions with multiple fibre crossing. Recent developments, such as the introduction of non-negative constraints on the solution, allow a more accurate estimation of fibre orientations by reducing instability effects due to noise robustness. Standard convolution methods do not, however, adequately model the effects of partial volume from isotropic tissue, such as gray matter, or cerebrospinal fluid, which may degrade spherical deconvolution results. Here we use a newly developed spherical deconvolution algorithm based on an adaptive regularization (damped version of the Richardson-Lucy algorithm) to reduce isotropic partial volume effects. Results from both simulated and in vivo datasets show that, compared to a standard non-negative constrained algorithm, the damped Richardson-Lucy algorithm reduces spurious fibre orientations and preserves angular resolution of the main fibre orientations. These findings suggest that, in some brain regions, non-negative constraints alone may not be sufficient to reduce spurious fibre orientations. Considering both the speed of processing and the scan time required, this new method has the potential for better characterizing white matter anatomy and the integrity of pathological tissue.

Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy.

PURPOSE: Detection of recurrence in prostate cancer patients with biochemical failure after radical prostatectomy by [(11)C]choline PET/CT depends on the prostate-specific antigen (PSA) level. The role of other clinical and pathological variables has not been explored. METHODS: A total of 2,124 prostate cancer patients referred to our Institution for [(11)C]choline PET/CT from December 2004 to January 2007 for restaging of disease were retrospectively considered for this study. Inclusion criteria were: previous treatment by radical prostatectomy, and biochemical failure, defined as at least two consecutive PSA measurements of >0.2 ng/ml. These criteria were met for 358 patients. Binary logistic analysis was used to investigate the predictive factors of [(11)C]choline PET/CT. PET/CT findings were validated using criteria based on histological analysis, and follow-up clinical and imaging data. Receiver operating characteristic (ROC) analysis was used to assess the performance of [(11)C]choline PET/CT in relation to PSA levels. RESULTS: The mean PSA level was 3.77 +/- 6.94 ng/ml (range 0.23-45 ng/ml; median 1.27 ng/ml). PET/CT was positive for recurrence in 161 of 358 patients (45%). On an anatomical region basis, [(11)C]choline pathological uptake was observed in lymph nodes (107/161 patients, 66%), prostatectomy bed (55/161 patients, 34%), and in the skeleton (46/161 patients, 29%). PET/CT findings were validated using histological criteria (46/358, 13%), and follow-up clinical and imaging criteria (312/358, 87%). Sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were, respectively, 85%, 93%, 91%, 87%, and 89%. In multivariate analysis, high PSA levels, advanced pathological stage, previous biochemical failure and older age were significantly (P < 0.05) associated with an increased risk of positive PET/CT findings. The percentage of positive scans was 19% in those with a PSA level between 0.2 and 1 ng/ml, 46% in those with a PSA level between 1 and 3 ng/ml, and 82% in those with a PSA level higher than 3 ng/ml. ROC analysis showed that PET/CT-positive and PET/CT-negative patients could be best distinguished using a PSA cut-off value of 1.4 ng/ml. CONCLUSIONS: In addition to PSA levels, pathological stage, previous biochemical failure and age should be considered by physicians when referring prostate cancer patients with biochemical failure after radical prostatectomy to [(11)C]choline PET/CT.

Monitoring disease evolution and treatment response in lysosomal disorders by the peripheral benzodiazepine receptor ligand PK11195.

Microglia activation and neuroinflammation play a pivotal role in the pathogenesis of lysosomal storage disorders (LSD) affecting the central nervous system (CNS), which are amenable to treatment by hematopoietic stem cell transplantation (HSCT). HSCT efficacy relies on replacing the intra- and extra-vascular hematopoietic cell compartments, including CNS microglia, with a cell population expressing the functional enzyme. Non-invasive and quantitative assessment of microglia activation and of its reduction upon HSCT might allow for evaluation of disease evolution and response to treatment in LSD. We here demonstrate that microglia activation can be quantified ex vivo and in vivo by PET using the peripheral benzodiazepine receptor ligand PK11195 in two models of LSD. Furthermore, we show a differential PBR binding following microglia replacement by donor cells in mice undergoing HSCT. Our data indicates that PBR ligands constitute valuable tools for monitoring the evolution and the response to treatment of LSD with CNS involvement, and enable us to evaluate whether the turnover between endogenous and donor microglia following HSCT could be adequate enough to delay disease progression.

Lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: a [18F]-fluoro-2-deoxy-D-glucose PET/CT study.

OBJECTIVE: Neutrophilic inflammation plays a key role in the pathogenesis of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Positron emission tomography (PET) with [F]-fluoro-2-deoxy-D-glucose (FDG) can be used to image cellular metabolism that, during lung inflammatory processes, likely reflects neutrophils activity. The aim of this study was to assess the magnitude and regional distribution of inflammatory metabolic activity in the lungs of patients with ALI/ARDS by PET with FDG. DESIGN: Prospective clinical investigation. PATIENTS: Ten patients with ALI/ARDS; four spontaneously breathing and two mechanically ventilated subjects, without known lung disease, served as controls. INTERVENTIONS: In each individual we performed an FDG PET/computed tomography of the thorax. MEASUREMENTS AND MAIN RESULTS: FDG cellular influx rate constant (Ki) was computed for the imaged lung field and for regions of interest, grouping voxels with similar density. In all patients with ALI/ARDS, Ki was higher than in controls, also after accounting for the increased lung density. Ki values differed greatly among patients, but in all patients Ki of the normally aerated regions was much higher (2- to 24-fold) than in controls. Whereas in some patients the highest Ki values corresponded to regions with the lowest aeration, in others these regions had lower Ki than normally and mildly hypoaerated regions. CONCLUSION: In patients with ALI/ARDS, undergoing mechanical ventilation since days, the metabolic activity of the lungs is markedly increased across the entire lung density spectrum. The intensity of this activation and its regional distribution, however, vary widely within and between patients.

Characterization of preclinical models of prostate cancer using PET-based molecular imaging.

PURPOSE: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice spontaneously develop hormone-dependent and hormone-independent prostate cancer (PC) that potentially resembles the human pathological condition. The aim of the study was to validate PET imaging as a reliable tool for in vivo assessment of disease biology and progression in TRAMP mice using radioligands routinely applied in clinical practice: [(18)F]FDG and [(11)C]choline. METHODS: Six TRAMP mice were longitudinally evaluated starting at week 11 of age to visualize PC development and progression. The time frame and imaging pattern of PC lesions were subsequently confirmed on an additional group of five mice. RESULTS: PET and [(18)F]FDG allowed detection of PC lesions starting from 23 weeks of age. [(11)C]Choline was clearly taken up only by TRAMP mice carrying neuroendocrine lesions, as revealed by post-mortem histological evaluation. CONCLUSION: PET-based molecular imaging represents a state-of-the-art tool for the in vivo monitoring and metabolic characterization of PC development, progression and differentiation in the TRAMP model.

Syntax without language: neurobiological evidence for cross-domain syntactic computations.

Not all conceivable grammars are realized within human languages. Rules based on rigid distances, in which a certain word must occur at a fixed distance from another word, are never found in grammars of human languages. Distances between words are specified in terms of relative, non-rigid positions. The left inferior frontal gyrus (IFG) (Broca's area) has been found to be involved in the computation of non-rigid but not of rigid syntax in the language domain. A fundamental question is therefore whether the neural activity underlying this non-rigid architecture is language-specific, given that analogous structural properties can be found in other cognitive domains. Using event-related functional magnetic resonance imaging (fMRI) in sixteen healthy native speakers of Italian, we measured brain activity for the acquisition of rigid and non-rigid syntax in the visuo-spatial domain. The data of the present experiment were formally compared with those of a previous experiment, in which there was a symmetrical distinction between rigid and non-rigid syntax in the language domain. Both in the visuo-spatial and in the language domain, the acquisition of non-rigid syntax, but not the acquisition of rigid syntax, activated Brodmann Area 44 of the left IFG. This domain-independent effect was specifically modulated by performance improvement. Thus, in the human brain, one single "grammar without words" serves different higher cognitive functions.

Changes in glucose metabolism during and after radiotherapy in non-small cell lung cancer.

AIMS AND BACKGROUND: Evaluation of the metabolic response to radiotherapy in nonsmall cell lung cancer patients is commonly performed about three months after the end of radiotherapy. The aim of the present study was to assess with positron emission tomography/computed tomography (PET/CT) and [18F]fluorodeoxyglucose changes in glucose metabolism during and after radiotherapy in non-small cell lung cancer patients. METHODS AND STUDY DESIGN: In 6 patients, PET/CT scans with [18F]fluorodeoxyglucose were performed before (PET0), during (PET1; at a median of 14 days before the end of radiotherapy) and after the end of radiotherapy (PET2 and PET3, at a median of 28 and 93 days, respectively). The metabolic response was scored according to visual and semiquantitative criteria. RESULTS: Standardize maximum uptake at PET1 (7.9 +/- 4.8), PET2 (5.1 +/- 4.1) and PET3 (2.7 +/- 3.1) were all significantly (P < 0.05; ANOVA repeated measures) lower than at PET0 (16.1 +/- 10.1). Standardized maximum uptake at PET1 was significantly higher than at both PET2 and PET3. There were no significant differences in SUV(max) between PET2 and PET3. PET3 identified 4 complete and 2 partial metabolic responses, whereas PET1 identified 6 partial metabolic responses. Radiotherapy-induced increased [l8F]fluorodeoxyglucose uptake could be visually distinguished from tumor uptake based on PET/CT integration and was less frequent at PET1 (n = 2) than at PET3 (n = 6). CONCLUSION: In non-small cell lung cancer, radiotherapy induces a progressive decrease in glucose metabolism that is greater 3 months after the end of treatment but can be detected during the treatment itself. Glucose avid, radiotherapy-induced inflammation is more evident after the end of radiotherapy than during radiotherapy and does not preclude the interpretation of [18F]fluorodeoxyglucose images, particularly when using PET/CT.

4D-PET data sorting into different number of phases: a NEMA IQ phantom study.

This study aims at evaluating the dependence of 4D-PET data sorting on the number of phases in which the respiratory cycle can be divided. The issue is to find the best compromise to reduce the conflicting effects induced by increasing the number of phases: lesion motion on each set of images decreases, but on the other hand image noise increases. The IQ NEMA 2001 IEC body phantom was used to simulate the movement of neoplastic lesions in the thorax and abdomen, investigating the effect of target size (10-37 mm), lesion to background activity concentrations ratio (4-to-1 and 8-to-1), total acquisition time (3, 6, 12, 20 min) and number of phase partition (1, 2, 4, 6, 8, 10, 13). The phantom was moved in a cranial-caudal direction with an excursion of 25 mm and with a period of 4.0 s. Five parameters associated to lesion volume and activity concentration were considered to assess the capability of the 4D-PET technique to "freeze" the phantom motion. The results for all the parameters showed the capability of the 4D-PET acquisition technique to "freeze" the lesion motion. The division into 6 phases was found to be the best compromise between temporal resolution and image noise for the phase where the "lesions" move faster, whereas the partition into 4 phases could be used if a stable breathing phase is considered.

In vivo PET study of 5HT(2A) serotonin and D(2) dopamine dysfunction in drug-naive obsessive-compulsive disorder.

There are several lines of evidence, the majority indirect, suggesting that changes in serotonergic or dopaminergic neurotransmission may contribute to the pathogenesis of obsessive-compulsive disorder (OCD). We evaluated the co-occurrence of serotonergic and dopaminergic dysfunctions in OCD subjects, all drug-naive, with no co-morbidity and homogeneous for symptoms. Each subject underwent two positron emission tomography (PET) scans to measure in vivo both serotonin (5-HT(2A)) and dopamine (D(2)) receptor distribution. For this, we used [11C]MDL and [11C]Raclopride, highly selective antagonists of 5-HT(2A) and D(2) receptors, respectively. The comparison with a control group was carried out using both voxel-wise (SPM2) and regions of interest (ROI) approaches. There was a significant reduction of 5-HT(2A) receptor availability in frontal polar, dorsolateral, and medial frontal cortex, as well as in parietal and temporal associative cortex of OCD patients. We also found a significant correlation between 5-HT(2A) receptor availability in orbitofrontal and dorsolateral frontal cortex and clinical severity, suggesting a specific role for serotonin in determining the OCD symptoms. There was also a significant reduction of [11C]Raclopride uptake in the whole striatum, particularly in the ventral portion, possibly reflecting endogenous dopaminergic hyperactivity. The co-existence of serotonergic and dopaminergic dysfunction in the same homogeneous group of drug-naive OCD patients provides in vivo evidence for the complex molecular mechanisms of OCD, and represents the basis for further studies on the effect of therapeutic agents with specific modulatory effects on these neurotransmission systems.

A voxel-based PET study of dopamine transporters in Parkinson's disease: relevance of age at onset.

We used positron emission tomography (PET) and the dopamine transporter (DAT) ligand [(11)C]FECIT to measure loss of nigrostriatal dopaminergic neurons in early phase of early onset (EOPD) and late onset Parkinson's disease (LOPD). The analysis was carried out with both regions of interest and voxelwise method (SPM2), at group and single subject levels. Genetic analysis tested for the mutations occurring most frequently in Caucasian population. A significant, bilateral, asymmetric DAT reduction was observed in both EOPD and LOPD. Noteworthy, the side and severity of DAT binding reduction significantly correlated with the severity and asymmetry of motor clinical scores. The two EOPD patients carrying mutations in the PARK2 and PARK6 genes, respectively, displayed the lowest values, bilaterally. This work demonstrates that severity of nigrostriatal damage in early disease phase of sporadic PD is not dependent on age at onset. Genetically determined PD is associated with more severe and widespread dopaminergic impairment.

Evidence of limited motion of the prostate by carefully emptying the rectum as assessed by daily MVCT image guidance with helical tomotherapy.

PURPOSE: To assess setup and organ motion error by means of analysis of daily megavoltage computed tomography (MVCT) of patients treated with hypofractionated helical tomotherapy (71.4-74.2 Gy in 28 fractions). METHODS AND MATERIALS: Data from 21 patients were analyzed. Patients were instructed to empty the rectum carefully before planning CT and every morning before therapy by means of a self-applied rectal enema. The position of the prostate was assessed by means of automatic bone matching (BM) with the planning kilovoltage CT (BM, setup error) followed by a direct visualization (DV) match on the prostate. Deviations between planning and therapy positions referred to BM and BM + DV were registered for the three main axes. In case of a full rectum at MVCT with evident shift of the prostate, treatment was postponed until after additional rectal emptying procedures; in this case, additional MVCT was performed before delivering the treatment. Data for 522 fractions were available; the impact of post-MVCT procedure was investigated for 17 of 21 patients (410 fractions). RESULTS: Prostate motion relative to bony anatomy was limited. Concerning posterior-anterior shifts, only 4.9% and 2.7% of fractions showed deviation of 3 mm or greater of the prostate relative to BM without and with consideration of post-MVCT procedures, respectively. Interobserver variability for BM + DV match was within 0.8 mm (1 SD). CONCLUSIONS: Daily MVCT-based correction is feasible. The BM + DV matching was found to be consistent between operators. Rectal emptying using a daily enema is an efficient tool to minimize prostate motion, even for centers that have not yet implemented image-guided radiotherapy.

Intensity-modulated proton therapy versus helical tomotherapy in nasopharynx cancer: planning comparison and NTCP evaluation.

PURPOSE: To compare intensity-modulated proton therapy (IMPT) and helical tomotherapy (HT) treatment plans for nasopharynx cancer using a simultaneous integrated boost approach. METHODS AND MATERIALS: The data from 6 patients who had previously been treated with HT were used. A three-beam IMPT technique was optimized in the Hyperion treatment planning system, simulating a "beam scanning" technique. HT was planned using the tomotherapy treatment planning system. Both techniques were optimized to simultaneously deliver 66 Gy in 30 fractions to planning target volume (PTV1; GTV and enlarged nodes) and 54 Gy to PTV2 subclinical, electively treated nodes. Normal tissue complication probability calculation was performed for the parotids and larynx. RESULTS: Very similar PTVs coverage and homogeneity of the target dose distribution for IMPT and HT were found. The conformity index was significantly lower for protons than for photons (1.19 vs. 1.42, respectively). The mean dose to the ipsilateral and contralateral parotid glands decreased by 6.4 Gy and 5.6 Gy, respectively, with IMPT. The volume of mucosa and esophagus receiving > or =20 Gy and > or =30 Gy with IMPT was significantly lower than with HT. The average volume of larynx receiving > or =50 Gy was significantly lower with HT, while for thyroid, it was comparable. The volume receiving > or =30, > or =20, and > or =10 Gy in total body volume decreased with IMPT by 14.5%, 19.4%, and 23.1%, respectively. The normal tissue complication probability for the parotid glands was significantly lower with IMPT for all sets of parameters; however, we also estimated an almost full recovery of the contralateral parotid with HT. The normal tissue complication probability for the larynx was not significantly different between the two irradiation techniques. CONCLUSION: Excellent target coverage, homogeneity within the PTVs, and sparing of the organs at risk were reached with both modalities. IMPT allows for better sparing of most organs at risk at medium-to-low doses.

Dose-volume and biological-model based comparison between helical tomotherapy and (inverse-planned) IMAT for prostate tumours.

BACKGROUND AND PURPOSE: Helical tomotherapy (HT) and intensity-modulated arc therapy (IMAT) are two arc-based approaches to the delivery of intensity-modulated radiotherapy (IMRT). Through plan comparisons we have investigated the potential of IMAT, both with constant (conventional or IMAT-C) and variable (non-conventional or IMAT-NC, a theoretical exercise) dose-rate, to serve as an alternative to helical tomotherapy. MATERIALS AND METHODS: Six patients with prostate tumours treated by HT with a moderately hypo-fractionated protocol, involving a simultaneous integrated boost, were re-planned as IMAT treatments. A method for IMAT inverse-planning using a commercial module for static IMRT combined with a multi-leaf collimator (MLC) arc-sequencing was developed. IMAT plans were compared to HT plans in terms of dose statistics and radiobiological indices. RESULTS: Concerning the planning target volume (PTV), the mean doses for all PTVs were similar for HT and IMAT-C plans with minimum dose, target coverage, equivalent uniform dose (EUD) and tumour control probability (TCP) values being generally higher for HT; maximum dose and degree of heterogeneity were instead higher for IMAT-C. In relation to organs at risk, mean doses and normal tissue complication probability (NTCP) values were similar between the two modalities, except for the penile bulb where IMAT was significantly better. Re-normalizing all plans to the same rectal toxicity (NTCP=5%), the HT modality yielded higher TCP than IMAT-C but there was no significant difference between HT and IMAT-NC. The integral dose with HT was higher than that for IMAT. CONCLUSIONS: with regards to the plan analysis, the HT is superior to IMAT-C in terms of target coverage and dose homogeneity within the PTV. Introducing dose-rate variation during arc-rotation, not deliverable with current linac technology, the simulations result in comparable plan indices between (IMAT-NC) and HT.

Contrast enhanced 4D-CT imaging for target volume definition in pancreatic ductal adenocarcinoma.

A procedure to improve target volume definition in pancreatic ductal adenocarcinoma by contrast enhanced 4D-CT imaging has been implemented for radiotherapy planning. The procedure allows good quality images to be obtained over the whole patient's breathing cycle in terms of anatomical details, pancreatic enhancement and vessel definition.

Hypofractionated adjuvant radiotherapy with helical tomotherapy after radical prostatectomy: planning data and toxicity results of a Phase I-II study.

PURPOSE: To report on planning and toxicity findings of hypofractionated adjuvant radiotherapy with helical Tomotherapy (HTT) after radical prostatectomy (RP) for prostate carcinoma (pCa). METHODS AND MATERIALS: Fifty consecutive patients submitted to RP for pT2R1/pT3a/pT3b-pN0 pCa were enrolled in a Phase I-II trial to receive 58Gy/20 fractions (5/week) on tumoral bed. Endpoint was to verify a risk of toxicity and biochemical failure not exceeding that observed in our Institutional 3DCRT, conventionally fractionated series (153 patients). Toxicities were graded according the RTOG scoring system. RESULTS: Excellent coverage of PTV and high homogeneity of dose distribution were always achieved. Median follow-up was 25 months. Acute G2-3 RTOG genitourinary (GU) and acute G2 intestinal toxicities were similar (12% vs 15.6% and 4% vs 7%, respectively), while acute G2 proctitis was 0% vs 9% in HTT and 3DCRT group, respectively. Similarly, late Grade 2 gastrointestinal sequelae were 0% vs 8.5%. The incidence of late urethral stricture, 8% and 9% in HTT and 3DCRT group, respectively, is comparable to that of RP-only series. CONCLUSIONS: Acute toxicity and early late toxicity outcomes of a moderately hypofractionated regimen with HTT post-RP are excellent. A longer follow-up is needed to fully assess the validity of this approach.

Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC.

BACKGROUND AND PURPOSE: To investigate the impact of Helical Tomotherapy (HT) upon the dose distribution when compared to our routinely delivered 3D conformal radiotherapy (CRT) in the case of patients affected by stage III non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: Thirteen stage III inoperable NSCLC patients were scheduled to receive 61.2-70.2Gy, 1.8Gy/fraction. Two treatment techniques (HT and CRT) were considered, and in the case of CRT the dose calculation was performed using both the pencil beam (PB) and Anisotropic Analytical Algorithm (AAA) available on the Varian Eclipse planning system. Dose volume constraints for PTV coverage and OAR sparing were assessed for the HT inverse planning with the highest priority upon PTV coverage and spinal cord sparing. The three plans were compared in terms of dose-volume histograms (DVHs) and normal tissue complication probability (NTCP). A statistical analysis was performed using non-parametric Wilcoxon matched pairs tests. RESULTS: In CRT the use of a less accurate algorithm (PB) decreased the monitor unit number by 2.4%. HT significantly improved dose homogeneity within PTV compared with CRT_AAA. For lung parenchyma V20-V40 were lower with HT, corresponding to a decrease of 7% in the risk of radiation pneumonitis. The volume of the heart and esophagus irradiated to >45-60Gy were reduced using HT plans. For eight PTs with an esophagus-PTV overlap >5%, HT significantly reduced both late and acute esophageal complication probability. CONCLUSIONS: Our findings obtained in stage III NSCLC patients underline that HT guarantees an important sparing of lungs and esophagus, thus HT has the potential to improve therapeutic ratio, when compared with CRT, by means of dose escalation and/or combined treatment strategy. In CRT of locally advanced lung cancers, the use of a more advanced algorithm would give significantly better modeling of target dose and coverage.

Results of a two-year quality control program for a helical tomotherapy unit.

BACKGROUND AND PURPOSE: Image-guided helical tomotherapy (HT) is a new modality for delivering intensity modulated radiation therapy (IMRT) with helical irradiation: the slip ring continuously rotates while the couch moves into the bore. The radiation source (Linac, 6 MV) is collimated into a fan beam and modulated by means of a binary multileaf collimator (MLC). A xenon detector array, opposite the radiation source, allows a megavoltage-CT (MVCT) acquisition of patient images for set-up verification. The aim of this paper is to report the results of a two-year quality control (QC) program for the physical and dosimetric characterization of an HT unit installed at our Institute and clinically activated in November 2004, in order to monitor and verify the stability and the reliability of this promising radiation treatment unit. MATERIALS AND METHODS: Conventional Linac acceptance protocols (ATP) and QC protocols were adapted to HT with the addition of specific items reflecting important differences between the two irradiation modalities. QC tests can be summarized as: (a) mechanical and geometrical characterization of the system's components: evaluation of alignment among radiation source-gantry rotation plan-jaws-MLC-MVCT; (b) treatment beam configuration in static condition: depth dose curves (PDD) and profiles, output factors, output reproducibility and linearity; (c) dynamic component characterization: accuracy and reproducibility of MLC positioning; rotational output reproducibility and linearity, leaf latency, couch movement constancy; (d) gantry-couch and MLC-gantry synchronization; and (e) MVCT image quality. Peculiar periodicity specific tolerance and action levels were defined. Ionization chambers (Exradin A1SL 0.056 cc), films (XOmat-V/EDR2), water and solid water phantoms were used to perform quality assurance measurements. RESULTS: Over a two-year period the final average output variation after possible beam output adjustment was -0.2+/-1% for the static condition and equal to 0+/-1% for the rotational condition: around 98% of the collected output data was within the action level compared to 94% if no beam output adjustment was considered. An average energy variation of -0.4+/-0.4% was found. The daily absolute dose verification of IMRT plans showed a dose reproducibility of -0.5+/-1.2% and -0.4+/-2.2%, for low and high dose gradient regions, respectively. Source-jaws-MLC and MVCT alignment results and jaw and leaf positioning accuracy were +/-1mm. Couch-gantry-MLC synchrony tests showed good stability level (

Synthesis and biological characterization of novel 2-quinolinecarboxamide ligands of the peripheral benzodiazepine receptors bearing technetium-99m or rhenium.

Potential receptor imaging agents based on Tc-99m for the in vivo visualization of the peripheral benzodiazepine receptor (PBR) have been designed on the basis of the information provided by the previously published structure-affinity relationship studies, which suggested the existence of tolerance to voluminous substituents in the receptor area interacting with 3-position of the quinoline nucleus of 2-quinolinecarboxamides 5. In the first step of the investigation, the stereoelectronic features of the above-indicated receptor area were also probed by means of 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide derivatives bearing different substituents on the terminal piperazine nitrogen atom (compounds 6a-f). The structure-affinity relationship data confirmed the existence of a tolerance to bulky lipophilic substituents and stimulated the design of bifunctional ligands based on the 4-phenyl-3-[(1-piperazinyl)methyl]-2-quinolinecarboxamide moiety (compounds 6h,j,k,m). The submicromolar PBR affinity of rhenium complexes 6j,m suggests that the presence of their metal-ligand moieties with encaged rhenium is fairly compatible with the interaction with the PBR binding site. Thus, in order to obtain information on the in vivo behavior of these bifunctional ligands, (99m)Tc-labeled compounds 6h,k were synthesized and evaluated in preliminary biodistribution and single photon emission tomography (SPET) studies. The results suggest that both tracers do not present a clear preferential distribution in tissues rich in PBR, probably because of their molecular dimensions, which may hamper both the intracellular diffusion toward PBR and the interaction with the binding site.