Immunogenicity of constitutively active V599EBRaf

Activating BRAF somatic missense mutations within the kinase domain are present in 60-66% of melanomas. The vast majority of these represent a single substitution of glutamate for valine (V599E). Here, we demonstrate spontaneous HLA-B*2705-restricted cytotoxic T-cell responses against an epitope derived from (V599E)BRaf. These T-cell responses were mutation specific as the corresponding epitope derived from wild-type BRaf was not recognized. The loss of the (V599E)BRAF genotype during progression from primary to metastatic melanoma in patients with (V599E)BRaf specific T-cell responses suggests an active immune selection of nonmutated melanoma clones by the tumor-bearing host.     

A comparison of reproductive risk factors for CIS lesions and invasive breast cancer

A differential effect of reproductive factors on the incidence of carcinoma in situ of the breast (CIS) and invasive cancer may indicate that hormonal factors related to reproductive history not only influence the initial steps towards breast cancer but also preinvasive malignant lesions. A comparison of reproductive factors was performed using a population-based cohort of 1.5 million Danish women born between 1935 and 1978. Between 1983 and 1998, 15,590 cases of invasive breast cancer and 871 cases of CIS were identified using a database with extensive clinical information. Number of births and age at first birth were similarly associated with the risk of being diagnosed with ductal carcinoma in situ (DCIS) compared to invasive breast cancer [RR(DCIS)(per birth)/RR(invasive)(per birth) = 1.03(0.93-1.14), RR(DCIS)(per 5yr) /RR(invasive)(per 5yr) = 1.06(0.96-1.17)]. Also, the short-term risk the first 10 years after birth was similar for DCIS and invasive cancer [RR(DCIS) /RR(invasive) = 0.90 (0.74-1.09)]. Additional analyses were performed according to characteristics of the DCIS lesion (size, malignancy grade, noncomedo or comedo type). In conclusion, our observations do not support the theory that reproductive history is associated with progression from noninvasive to invasive breast cancer.     

Alcohol intake and risk of non-Hodgkin lymphoma in men and women

Objective: The effect of alcohol intake on risk of NHL is unclear. We therefore conducted a population-based case-control study to examine the association between alcohol and NHL risk. Methods: 613 NHL cases and 480 population controls in Sweden reported their average consumption of beer, wine, and liquor 2years before the study. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (CI) for associations between alcohol intake and NHL risk. Results: Intake of total alcohol, beer, wine, or liquor was not associated with risk of overall NHL. There was no difference in risk of NHL among those who habitually consumed above 19.1g of ethanol per day, compared to those who consumed on average 0–2.2g of ethanol per day (OR = 1.2 (95% CI: 0.8, 1.7); p _trend = 0.29). However, the association was significantly positive among males (OR = 1.8 (95% CI: 1.1, 2.9); p _trend = 0.06). Total alcohol, beer, wine, or liquor intake was not associated with any major histopathologic subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia. Conclusions: Alcohol does not appear to be a major etiologic factor for overall NHL, nor its common subtypes.     

Pre- and inter-hospital transport of severely head-injured patients in rural Northern Norway

The purpose of this study was to survey the time consumed during the pre- and inter-hospital transport of severely head injured patients in Northern Norway. All patients (n = 85) operated for an intracranial mass lesions within 48 h after injury during the 10-year period 1986-1995 were included in this retrospective analysis. Ambulance records, transfer notes, and hospital records were reviewed. The transport of patients was classified as either direct from the trauma scene to the University Hospital (direct admission group) or as an inter-hospital transfer (transfer group). Forty-seven (55%) patients were in the direct admission group, and 38 (45%) were transferred through another hospital. The majority of patients (81%) were transported by air ambulance. Median time from injury to arrival in the emergency room was 5 (1-44) h. Time necessary for transport was significantly (p < 0.001) shorter in the direct admission group (median 3 h) compared to the transfer group (median 8 h). The inter-hospital transfer time was < or = 3 h in 17%. Clearly, the advanced air ambulance service in Northern Norway makes rapid inter-hospital transfer possible despite extremely long geographical distances. Our findings indicate that this possibility is not always utilized.     

Arthroscopic knee surgery does not modify hyperalgesic responses to heat injury

BACKGROUND: Experimental studies suggest that surgical injury may up- or down-regulate nociceptive function. Therefore, the aim of this clinical study was to evaluate the effect of elective arthroscopically assisted knee surgery on nociceptive responses to a heat injury. METHODS: Seventeen patients scheduled to undergo repair of the anterior cruciate ligament and 16 healthy controls were studied. The first burn injury was induced 6 days before surgery, and the second burn was induced 1 day after surgery with a contact thermode (12.5 cm2, 47 degrees C for 7 min) placed on the medial aspect of the calf contralateral to the surgical side. Ibuprofen and acetaminophen were given for 2 days before the first burn injury and again from the time of surgery. In the controls, the two burn injuries were separated by 7 days. Sensory variables included cumulated pain score during induction of the burn (visual analog scale), secondary hyperalgesia area, and mechanical and thermal pain perception and pain thresholds assessed before and 1 h after the burn injury. RESULTS: The heat injuries induced significant increases in pain perception (P < 0.001) and decreases in pain thresholds (P < 0.02). Baseline heat pain thresholds were higher during the second burn injury in patients (P < 0.001) and controls (P < 0.01). However, there were no significant differences in pain to heat injury (P > 0.8), secondary hyperalgesia areas (P > 0.1), mechanical and thermal pain perception (P > 0.1), or mechanical and thermal pain thresholds (P > 0.08) in the burn area before surgery compared to after surgery. CONCLUSION: Arthroscopic knee surgery did not modify nociceptive responses to a contralaterally applied experimental burn injury.     

Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies

Evidence has emerged that childhood leukemia is initiated in utero. High birth weight is one of the few birth-related factors that has been associated with childhood leukemia, albeit not consistently. The authors conducted a meta-analysis of studies of the association between birth weight and childhood leukemia risk. Study-specific odds ratios for leukemia were calculated, using a cutoff at 4,000 g of birth weight. The authors also evaluated whether the association between birth weight and leukemia followed a log-linear dose-response-like pattern. They calculated summary estimates using weighted averages of study-specific odds ratios from dichotomous and trend analyses. Eighteen studies (published between 1962 and 2002) were included, encompassing 10,282 children with leukemia. Children weighing 4,000 g or more at birth were at higher risk of acute lymphoblastic leukemia than children weighing less (odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.17, 1.37). Furthermore, data were consistent with a dose-response-like effect (OR = 1.14/1,000-g birth weight increase, 95% CI: 1.08, 1.20). Studies of acute myeloid leukemia indicated a similar increase in risk for children weighing 4,000 g or more at birth (OR = 1.27, 95% CI: 0.73, 2.20) and a dose-response-like effect (OR = 1.29/1,000 g, 95% CI: 0.80, 2.06), but results varied across studies. Our findings support a relation between birth weight and childhood acute lymphoblastic leukemia risk and emphasize the need for additional studies of the biologic mechanisms underlying this association.     

Influence of a Microemulsion Vehicle on Cutaneous Bioequivalence of a Lipophilic Model Drug Assessed by Microdialysis and Pharmacodynamics

Purpose. The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil–in–water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method. Methods. Dermal delivery of lidocaine was estimated by microdialysis in 8 volunteers. Absorption coefficients and lag times were determined by pharmacokinetic modelling of the microdialysis data. Subsequently, the anaesthetic effect of the treatments was assessed by mechanical stimuli using von Frey hairs in 12 volunteers. Results. The microemulsion formulation increased the cutaneous absorption coefficient of lidocaine 2.9 times (95% confidence interval: 1.9/4.6) compared with the O/W emulsion–based cream. Also, lag time decreased from 110 ± 43 min to 87 ± 32 min (P = 0.02). The compartmental pharmacokinetic model provided an excellent fit of the concentration–time curves with reliable estimation of absorption coefficient and lag time. A significant anaesthetic effect was found for both active treatments compared to placebo (P < 0.02), but the effect did not diverge significantly between the two formulations. Conclusions. The microemulsion vehicle can be applied to increase dermal drug delivery of lipophilic drugs in humans. The microdialysis technique combined with an appropriate pharmacokinetic model provides a high sensitivity in bioequivalence studies of topically applied substances.     

Scattered brain infarct pattern on diffusion-weighted magnetic resonance imaging in patients with acute ischemic stroke

BACKGROUND AND PURPOSE: Infarct patterns on brain imaging contribute to the etiologic classification of ischemic stroke. However, the association of specific subtypes of infarcts and etiologic mechanisms is often weak, and acute lesions are frequently missed on initial computed tomography (CT). Diffusion-weighted imaging (DWI) is superior in visualizing acute ischemic lesions as compared to CT and conventional magnetic resonance imaging (MRI). In our prospective study, we addressed the question whether a distinct pattern of infarction on DWI is associated with infarct etiology and clinical outcome. METHODS: Sixty-two patients with clinical signs of acute ischemic stroke and negative acute CT upon admission underwent DWI within 10 days after the ictus. Neurological status was documented using the NIH stroke scale. A scattered lesion pattern was defined by at least 2 separate hyperintense DWI lesions within the territory of one of the major cerebral arteries. Ischemic lesions were defined as acute if the region was demarcated strongly hyperintense in all DW images, and if the apparent diffusion coefficient was below normal. RESULTS: In 32 patients, DWI revealed a scattered lesion pattern, while in 30 patients a single acute lesion was detected. In patients with scattered lesions, potential arterial or cardiac embolic sources were detected in 26 patients (81.3%), as compared to 5 patients (16.6%) in the group with single lesions (chi(2) test, p < 0.0001). The neurological status of patients with scattered lesions improved significantly more than among patients with single lesions (Mann-Whitney test, p < 0.0003). CONCLUSION: A scattered lesion pattern on DWI in patients with acute brain infarction and negative initial CT scan is associated with an embolic etiology and may indicate a favorable clinical outcome.     

What is the association between MRI and conventional radiography in measuring femoral head migration?

Background and purpose — Pelvic radiographs are traditionally used for assessing femoral head migration in residual acetabular dysplasia (RAD). Knowledge of the heightened importance of cartilaginous structures in this condition has led to increased use of MRI in assessing both osseous and cartilaginous structures of the pediatric hip. Therefore, we assessed the relationship between migration percentages (MP) found on MRI and conventional radiographs. Second, we analyzed the reliability of MP in MRI and radiographs.Patients and methods — We retrospectively identified 16 patients (mean age 5 years [2–8], 14 girls), examined for RAD during a period of 2½ years. 4 raters performed blinded repeated measurements of osseous migration percentage (MP) and cartilaginous migration percentage (CMP) in MRI and radiographs. Pelvic rotation and tilt indices were measured in radiographs. Bland–Altman (B–A) plots and intraclass correlation coefficients (ICC) were calculated for agreement and reliability.Results — B–A plots for MP_R and MP_MRI produced a mean difference of 6.4 with limits of agreement –11 to 24, with higher disagreements at low average MP values. Mean MP_R differed from mean MP_MRI (17% versus 23%, p < 0.001). MP_R had the best interrater reliability with an ICC of 0.92 (0.86–0.96), compared with MP_MRI and CMP with ICC values of 0.61 (0.45–0.70) and 0.52 (0.26–0.69), respectively. Intrarater reliability for MP_R, MP_MRI and CMP all had ICC values above 0.75 and did not differ statistically significantly. Differences inMP_MRI and MP_R showed no correlation to pelvic rotation index, pelvic tilt index, or interval between radiograph and MRI exams.Interpretation — Pelvic radiographs underestimated MP when compared with pelvic MRI. We propose CMP as a new imaging measurement, and conclude that it has good intrarater reliability but moderate interrater reliability. Measurement of MP in radiographs and MRI had mediocre to excellent reliability.

MRI scans have been used in the diagnosis and prognostication of developmental dysplasia of the hip (DDH) for the last 30 years (Bos et al. 1988). MRI scans permit the examiner complete control over orientation of the examined pelvis, allowing for more accurate measurements and visualization of non-bony structures. However, conventional pelvic radiographs are still the preferred method of examination for children over the age of 6 months due to financial considerations and challenges in scanning children, such as anxiety of the child and the need for sedation.Residual acetabular dysplasia (RAD) occurs in 3.5–17% of treated cases of DDH (Tucci et al. 1991, Alexiev et al. 2006) and is a known risk factor for secondary osteoarthritis (Malvitz and Weinstein 1994). Indications for corrective surgery for this condition remain controversial, as seen in the tendency of surgeons to undertreat RAD patients who need surgery, rather than overtreat those who do not (Ömeroǧlu et al. 2012).Many radiographic measurements have been proposed to indicate the severity and prognosis of DDH and many are used when deciding which patients should receive corrective surgery. The most commonly used are the osseous acetabular index (OAI) and acetabular head coverage (Ömeroǧlu et al. 2012). None of these measurements, on their own or in combination, have been shown to predict DDH prognosis accurately in all cases, and are therefore most commonly used in various combinations at the discretion of the surgeon. Acetabular head coverage, both cartilaginous and osseous, is of importance for the stability of the hip joint (Bos et al. 1991, Domenech et al. 2001) and is commonly estimated by the osseous migration percentage (MP), first proposed by Reimers (Reimers 1980), and has been shown to be predictive of later osteoarthritis (Terjesen 2011). MP estimates the percentage of the osseous femoral head that is covered by the osseous acetabulum. In this study we emulated the method developed by Reimers, in measuring the percentage of the cartilaginous femoral head covered by the cartilaginous acetabulum, and propose the name: cartilaginous migration percentage (CMP).Currently, there are no studies comparing reliability, agreement, and correlation of MP in radiographs and MRI or between MP and CMP.We compared agreement and correlation of MP measurements in pelvic radiographs and coronal MRI sequences. We assessed values and inter- and intrarater reliability when measuring CMP on pelvic MRI, and evaluated inter- and intrarater reliability when measuring MP on pelvic radiographs and MRI in hips evaluated for RAD corrective surgery.