Breast irradiation with three conformal photon fields for patients with high lung involvement

Since 2001, 50 breast cancer patients, for whom extensive lung/heart involvement was expected from the use of conventional tangential 2-field technique (2F) owing to complex anatomies, were irradiated using a 3-field conformal technique (3F). Dose plans were designed for both 3F and 2F and a dose volume histogram analysis on ipsilateral lung, heart, and target was conducted. The 3F technique allowed a significant reduction in ipsilateral lung irradiation: mean dose dropped from 16.0±3.8 (2F) to 12.0±2.7 Gy (3F) and V_45Gy from 20.7±6.8 (2F) to 3.2±2.9% (3F). Similarly, in patients irradiated to the left breast, heart mean dose was reduced from 8.1 Gy (2F) to 6.8 Gy (3F) and D_15% from 19.0 Gy to 14.0 Gy. All differences reached a high degree of significance. The target coverage was not clinically compromised since the slight reduction using 3F compared with 2F is limited to V_95% while V_90% difference, even if statistically significant, is small: 98.2±1.8% (3F) and 98.8±1.6 (2F). A preliminary report on clinical follow up is also included; with a mean follow up of 15.8 months, no pulmonary or cardiac complications were observed.     

Diagnostic applications of cardiac multislice CT with sixteen-row scanner: state of the art

Coronary angiography is nowadays the diagnostic standard in the evaluation of coronary artery anatomy, in the identification of stenoses and in the follow-up of revascularization procedures (PTCA-stenting, bypass). The limitations of such technique in terms of invasivity and high cost has targeted research efforts towards the development of non invasive diagnostic tools. Technological evolution in the field of helical CT has provided 2, 4, 8 and 16 detector-row multislice scanners characterized by progressive improvements in terms of spatial and temporal resolution that have made them increasingly suitable for the analysis of moving structures with high quality anatomic detail. The main cardiologic applications of multislice CT include coronary calcium scoring, the evaluation of coronary vascular anatomy and disease, follow-up of revascularization procedures (stenting, bypass), and the evaluation of cardiac walls and chambers. The aim of this paper is to describe the applications of sixteen detector-row multisclice CT in non invasive evaluation of cardiac and coronary diseases.     

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1) is an autosomal dominant disorder characterised by progressive degeneration of right ventricular myocardium, arrhythmias and risk of sudden death. By linkage analysis, we previously mapped the involved gene to chromosome 14q24.3. In the present study we report on linkage analysis of one additional and unrelated family, which enabled to confirm previous locus assignment. Another family is reported, in which genetic and clinical data suggest linkage to the same locus. Direct sequencing of DNA from individuals belonging to established ARVD1 families failed to detect causative mutations in exonic sequences of four genes (POMT2, TGFbeta3, KIAAA1036 and KIAA0759) expressed in the heart and which defects could possibly induce plasma membrane instability or apoptosis, key features of ARVD pathogenesis.     

Medicinal chemistry of A2A adenosine receptor antagonists

Due to the clearly demonstrated receptor-receptor interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and development of potent and selective A(2A)adenosine receptor antagonists became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been deeply investigated as A(2A) adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A(2A) adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002), which have been used as pharmacological tools for studying this receptor subtype. However, those compounds showed some problems that do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385). In the last few years great efforts have been made to overcome these problems, trying to optimize not only the pharmacological profile but also the pharmacokinetic character of this class of compounds. The aim of this report is to briefly summarize the recent progress made in this attractive field of research.     

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor antagonists. Influence of the N5 substituent on the affinity at the human A 3 and A 2B adenosine receptor subtypes: a molecular modeling investigation

A new series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines bearing various substituents at both the N5-pyrimidinyl and N8-pyrazolyl positions have been synthesized, and their binding affinities at the four human adenosine receptor subtypes (hA(1), hA(2A), hA(2B), and hA(3)) have been evaluated. All the described compounds contain arylacetyl moieties at the N5 position and arylalkyl substituents at the N8 position. Surprisingly, all the compounds present their most potent affinities at the hA(2B) adenosine receptor with a range of selectivities against the other subtypes. When bulky groups are present simultaneously at the N5 and N8 positions (e.g., compound 9), the best selectivity for the hA(2B) receptor was observed (K(i)(hA(1)) = 1100 nM; K(i)(hA(2A)) = 800 nM; K(i)(hA(2B)) = 20 nM; K(i)(hA(3)) = 300 nM, K(i)(hA(1)/A(2B)) = 55, K(i)(hA(2A)/A(2B)) = 40, K(i)(hA(3)/hA(2B)) = 15). To understand the molecular significance of these results, we compared the putative TM (transmembrane) binding motif of compound 9 on both hA(2B) and hA(3) receptors. From our docking studies, compound 9 fits neatly inside the TM region of the hA(2B) receptor but not in the corresponding hA(3) region, illustrating significant differences between the two subtypes. The study herein presented permits an understanding of why the bioisosteric replacement of an -NH, present in previously reported hA(3) receptor antagonists, with a -CH(2) group at the N5 position induces such large differences in hA(2B)/hA(3) affinity. In the molecular structure of the hA(3) receptor, two residues, Ser243 (TM6) and Ser271 (TM7), create a hydrophilic region, which seems to permit a better accommodation of the phenylurea series into this putative hA(3) binding site than the phenylacetyl series.     

Peri-operative outcomes of patients with stage IV endometriosis undergoing robotic-assisted laparoscopic surgery

We analyzed peri-operative outcomes of 80 patients who underwent robotic-assisted laparoscopic surgery and were diagnosed with stage IV endometriosis (revised American Society for Reproductive Medicine) between January 2007 and December 2010 at a tertiary gynecologic oncology referral center with a fellowship training program. Eligible women had a combination of one or more factors: pelvic mass, sub-acute or chronic pelvic pain, dysmenorrhea, dyspareunia, elevated serum CA-125, diagnosed with stage IV endometriosis at surgery with robotic-assisted gynecologic procedures using the da Vinci^? Surgical System. The mean age was 43.7?±?7.0?years, body mass index 27.5?±?7.4?kg/m², and 23 (28.9%) patients had prior endometriosis surgery. Presenting symptoms included: chronic pelvic pain (48.8%), dysmenorrhea (40.3%), and dyspareunia (33.8%). Sixty-nine (86%) patients had pelvic masses (43 unilateral and 26 bilateral). Thirty-seven (46.3%) had elevated CA-125 levels (mean 97.9?±?71.6 U/ml). Forty-eight (60%) underwent robotic-assisted laparoscopic hysterectomy (RALH)/bilateral salpingo-oophorectomy (BSO), 9 (11.3%) RALH/unilateral salpingo-oophorectomy (USO), 5 (6.3%) modified radical hysterectomy, and 10 (13%) USO or BSO only. Four (5%) had ovarian cystectomies with excision of endometriotic implants. Three (3.8%) underwent appendectomy and no patient required bowel resection. Four (5%) patients required conversion to laparotomy during the first 15 cases of this series [dense adhesions (3) and ureteral injury (1)]. Mean operative time was 115?±?46?min, blood loss 88?±?67?ml, and length of stay 1.0?±?0.4?days. There were four (5%) complications (ureteral injury, cuff abscess, cuff hematoma, re-admission for nausea and vomiting secondary to narcotics) and no transfusions. One (1.3%) patient underwent a second surgery for pain (dyspareunia). Robotic-assisted surgery for stage IV endometriosis resulted in excellent pain relief, with few laparotomy conversions or complications during a robotic learning-curve experience.     

Elevated levels of the acute‐phase serum amyloid are associated with heightened lung cancer risk

BACKGROUND:

The authors investigated whether early stage lung cancer could be identified by proteomic analyses of plasma.

METHODS:

For the first case‐control study, plasma samples from 52 patients with lung cancer and from a group of 51 controls were analyzed by surface‐enhanced laser desorption/ionization time‐of‐flight mass spectrometry. In a second case‐control study, a classifier of 4 markers (mass‐to‐charge ratio, 11,681, 6843, 5607, and 8762) also was tested for validation on plasma from 16 consecutive patients with screen‐detected cancer versus 406 healthy individuals. The most relevant marker was identified, and an enzyme‐linked immunosorbent assay‐based analysis revealed that signal intensity was correlated with concentration.

RESULTS:

The classifier had a sensitivity of 94.23% and a specificity of 76.47% in the first study but lost predictive value in the second study. Nevertheless, the 11,681 cluster, which was identified as serum amyloid protein A (SAA), resulted in a multiple logistic regression model that indicated a strong association with lung cancer. When both studies were considered as a together, the odds ratio (OR) for an SAA intensity ≥0.5 was 10.27 (95% confidence interval [CI], 4.64‐22.74), whereas an analysis restricted to stage I cancers (TNM classification) revealed an OR of 8.45 (95% CI, 2.76‐25.83) for T1 lung cancer and 21.22 (95% CI, 5.62‐80.14) for T2 lung cancer.

CONCLUSIONS:

SAA levels were predictive of an elevated risk of lung cancer, supporting the general view that inflammation is implicated in lung cancer development. Cancer 2010. © 2010 American Cancer Society.     

Search superiority in autism within, but not outside the crowding regime

Visual cognition of observers with autism spectrum disorder (ASD) seems to show an unbalance between the complementary functions of integration and segregation. This study uses visual search and crowding paradigms to probe the relative ability of children with autism, compared to normal developments children, to extract individual targets from cluttered backgrounds both within and outside the crowding regime. The data show that standard search follows the same pattern in the ASD and control groups with a strong effect of the set size that is substantially weakened by cueing the target location with a synchronous spatial cue. On the other hand, the crowding effect of eight flankers surrounding a small peripheral target is virtually absent in the clinical sample, indicating a superior ability to segregate cluttered visual items. This data, along with evidence of an impairment to the neural system for binding contours in ASD, bring additional support to the general idea of a shift of the trade-off between integration and segregation toward the latter. More specifically, they show that when discriminability is balanced across conditions, an advantage in odd-man out tasks is evident in ASD observers only within the crowding regime, when binding mechanism might get compulsorily triggered in normal observers.     

Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivo production and functional evaluation as a potential therapeutic tool for lowering plasma LDL cholesterol

A soluble form of human low-density lipoprotein receptor (LDL-R) fused in frame with rabbit transferrin (LDL-Rs(hu)/Tf(rab)) is assessed in vivo as a therapeutic tool for lowering plasma LDL cholesterol. The cDNA encoding LDL-Rs(hu)/Tf(rab) is expressed in mice, using a hydrodynamics-based gene transfer procedure. The transgene is transcribed in the liver of transduced animals and the corresponding protein is secreted into the bloodstream. Circulating LDL-Rs(hu)/Tf(rab) binds LDL specifically, thus indicating that it is correctly processed through the cellular compartments in vivo. More importantly, the expression of LDL-Rs(hu)/Tf(rab) allows the removal of injected human (125)I-labeled LDL ((123)I-LDL) from the bloodstream of transduced CD1 mice, which show faster LDL plasma clearance, anticipating by approximately 90 min the same clearance value observed in control animals. A similar effect is observed in transduced LDL-R(-/-) mice, in which the clearance of injected human LDL depends solely on the presence of circulating LDL-Rs(hu) /Tf(rab). In these animals the extent of plasma LDL clearance is directly related to the concentration of LDL-Rs(hu)/Tf(rab) in the blood. Finally, LDL-Rs(hu)/Tf(rab) does not alter the pattern of LDL organ distribution: in transduced animals, as well as in control animals, liver and bladder are the predominantly labeled organs after (123)I-LDL injection. However, LDL-Rs(hu)/Tf(rab) has a quantitative effect on LDL tissue deposition: in treated animals LDL-Rs(hu)/Tf(rab) determines an increase in radioactivity in the liver at early times after (123)I-LDL injection and a progressive labeling of the bladder, starting 20 min after injection.