Clinical implications of the overshoot effect for treatment plan delivery and patient-specific quality assurance for step-and-shoot IMRT

In this work, overshoot and undershoot effects associated with step-and-shoot IMRT (SSIMRT) delivery on a Varian Clinac 21iX are investigated, and their impact on patient-specific QA point dose measurements and treatment plan delivery are evaluated. Pinnacle(3) SSIMRT plans consisting of 5, 10, and 15 identical 5 x 5 cm(2) MLC defined segments and MU/segment values of 5 MU, 10 MU, and 20 MU were utilized and delivered at 600/300 MU/min. Independent of the number of segments the overshoot and undershoot at 600 MU/min were approximately +/- 10%, +/- 5%, and +/- 2.5% for 5 MU/segment, 10 MU/segment, and 20 MU/segment, respectively. At 300 MU/min, each of these values is approximately halved. Interfractional variation of these effects (10 fractions), as well as dosimetric variations for intermediate segments, are reduced at the lower dose rate. QA point-dose measurements for a sample (n = 29) of head and neck SSIMRT beams were on average 2.9% (600 MU/min) and 1.7% (300 MU/min) higher than Pinnacle3 planned doses. In comparison for prostate beams (n = 46), measured point doses were 0.8% (600 MU/min) and 0.4% (300 MU/min) higher. The reduction in planned-measured point-dose discrepancies at 300 MU/min can be attributed in part to the inclusion of the first segment (overshoot) in the admixture of segments that deliver measured dose. Pinnacle(3) plans for 10/9 head and neck/prostate treatments were adjusted by +/- 0.5 MU to include the effects of overshoot and undershoot at 600 MU/min. Comparing original and adjusted plans for each site indicated that the original plan was preferred in 70% and 89% of head and neck and prostate cases, respectively. The disparity between planned and delivered treatment that this suggests can potentially be mitigated by treating SSIMRT at a dose rate below 600 MU/min

A Multicenter, Randomized, Placebo‐Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis

Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients. Methods: A randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P 50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety. Results: A total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar. Conclusion: Atorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

In response to Fogarty et al. and why adjuvant whole brain radiotherapy is not recommended routinely

The routine use of adjuvant whole brain radiotherapy (AWBRT) after surgery or stereotactic radiosurgery is now discouraged by a number of international expert panels. Three decades of randomised studies have shown that, although AWBRT improves radiological measures of intracranial disease control, the clinical benefit is unclear and it is also associated with inferior quality of life and neurocognitive function. The number of patients with melanoma in these trials was low, but data suggesting that treatment-related side effects should vary according to histology of the primary malignancy are lacking. For metastatic melanoma, the role of AWBRT to control microscopic disease in the brain is also a less relevant concern because systemic therapies with intracranial activity are now available. Whether AWBRT is useful in select patients deemed at high risk of neurologic death remains undefined

Beta-Adrenoceptor Activation Reduces Both Dermal Microvascular Endothelial Cell Migration Via a cAMP-Dependent Mechanism and Wound Angiogenesis.

Angiogenesis is an essential process during tissue regeneration; however, the amount of angiogenesis directly correlates with the level of wound scarring. Angiogenesis is lower in scar-free fetal wounds while angiogenesis is raised and abnormal in pathophysiological scarring such as hypertrophic scars and keloids. Delineating the mechanisms that modulate angiogenesis and could reduce scarring would be clinically useful. Beta-adrenoceptors (β-AR) are G protein-coupled receptors expressed on all skin cell-types. They play a role in wound repair but their specific role in angiogenesis is unknown. In this study, a range of in vitro assays (single cell migration, scratch wound healing, ELISAs for angiogenic growth factors and tubule formation) were performed with human dermal microvascular endothelial cells (HDMEC) to investigate and dissect mechanisms underpinning β-AR-mediated modulation of angiogenesis in chick chorioallantoic membranes (CAM) and murine excisional skin wounds. β-AR activation reduced HDMEC migration via cAMP-dependent and PKA-independent mechanisms as demonstrated through use of an EPAC agonist that auto-inhibited the cAMP-mediated β-AR transduced reduction in HDMEC motility; a PKA inhibitor was, conversely, ineffective. ELISA studies demonstrated that β-AR activation reduced pro-angiogenic growth factor secretion from HDMECs (fibroblast growth factor 2) and keratinocytes (vascular endothelial growth factor A) revealing possible β-AR-mediated autocrine and paracrine anti-angiogenic mechanisms. In more complex environments, β-AR activation delayed HDMEC tubule formation and decreased angiogenesis both in the CAM assay and in murine excisional skin wounds in vivo. β-AR activation reduced HDMEC function in vitro and angiogenesis in vivo; therefore, β-AR agonists could be promising anti-angiogenic modulators in skin

β2AR antagonists and Β2AR gene deletion both promote skin wound repair processes

Skin wound healing is a complex process requiring the coordinated, temporal orchestration of numerous cell types and biological processes to regenerate damaged tissue. Previous work has demonstrated that a functional β-adrenergic receptor autocrine/paracrine network exists in skin, but the role of β2-adrenergic receptor (β2AR) in wound healing is unknown. A range of in vitro (single-cell migration, immunoblotting, ELISA, enzyme immunoassay), ex vivo (rat aortic ring assay), and in vivo (chick chorioallantoic membrane assay, zebrafish, murine wild-type, and β2AR knockout excisional skin wound models) models were used to demonstrate that blockade or loss of β2AR gene deletion promoted wound repair, a finding that is, to our knowledge, previously unreported. Compared with vehicle-only controls, β2AR antagonism increased angiogenesis, dermal fibroblast function, and re-epithelialization, but had no effect on wound inflammation in vivo. Skin wounds in β2AR knockout mice contracted and re-epithelialized faster in the first few days of wound repair in vivo. β2AR antagonism enhanced cell motility through distinct intracellular signalling mechanisms and increased vascular endothelial growth factor secretion from keratinocytes. β2AR antagonism promoted wound repair processes in the early stages of wound repair, revealing a possible new avenue for therapeutic intervention

In response to Fogarty et al. and why adjuvant whole brain radiotherapy is not recommended routinely

Abstract The routine use of adjuvant whole brain radiotherapy (AWBRT) after surgery or stereotactic radiosurgery is now discouraged by a number of international expert panels. Three decades of randomised studies have shown that, although AWBRT improves radiological measures of intracranial disease control, the clinical benefit is unclear and it is also associated with inferior quality of life and neurocognitive function. The number of patients with melanoma in these trials was low, but data suggesting that treatment-related side effects should vary according to histology of the primary malignancy are lacking. For metastatic melanoma, the role of AWBRT to control microscopic disease in the brain is also a less relevant concern because systemic therapies with intracranial activity are now available. Whether AWBRT is useful in select patients deemed at high risk of neurologic death remains undefined