A novel agent SL-401 induces anti-myeloma activity by targeting plasmacytoid dendritic cells, osteoclastogenesis and cancer stem-like cells.

Novel therapies for multiple myeloma (MM) can target mechanism(s) in the host-MM bone marrow (BM) microenvironment mediating MM progression and chemoresistance. Our studies showed increased numbers of tumor-promoting, immunosuppressive and drug-resistant plasmacytoid dendritic cells (pDCs) in the MM BM microenvironment. pDC-MM cell interactions upregulate interleukin-3 (IL-3), which stimulates both pDC survival and MM cell growth. Since IL-3 R is highly expressed on pDCs in the MM BM milieu, we here targeted pDCs using a novel IL-3 R-targeted therapeutic SL-401. In both in vitro and in vivo models of MM in its BM milieu, SL-401 decreases viability of pDCs, blocks pDC-induced MM cell growth, and synergistically enhances anti-MM activity of bortezomib and pomalidomide. Besides promoting pDC survival and MM cell growth, IL-3 also mediates progression of osteolytic bone disease in MM. Osteoclast (OCL) progenitor cells express IL-3 R, and we show that SL-401 abrogates monocyte-derived OCL formation and bone resorption. Finally, we show that SL-401 also decreases the viability of IL-3 R-expressing cancer stem-like cells in MM. Overall, our study provides the preclinical basis for clinical trials of SL-401 to block pDC-induced MM cell growth, inhibit osteoclastogenesis and target MM stem-like cell subpopulations to improve patient outcome in MM.

Genetic sonography after first-trimester Down syndrome screening.

OBJECTIVE: Approximately 90% of Down syndrome cases are detected during first-trimester screening. We aimed to determine the potential effectiveness of second-trimester genetic sonography as a sequential screen for Down syndrome. METHODS: In this simulation study, published statistical parameters for first-trimester free beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A and nuchal translucency thickness, and second-trimester ultrasound markers (nuchal fold, hyperechoic bowel, short humerus, short femur, echogenic intracardiac focus, pyelectasis and major abnormality) were used to model the effectiveness of second-trimester genetic sonography combined with first-trimester screening. RESULTS: First-trimester combined screening alone resulted in a detection rate of 88.5% with a 4.2% false-positive rate. A follow-up genetic ultrasound examination in which only one sonographic marker was found and previous results were not taken into account would detect an additional 8% of Down syndrome cases for an additional false-positive rate of 13.2%. Using individual marker likelihood ratios to modify the first-trimester risk for screen-negative patients, genetic sonography detected an additional 6.1% of Down syndrome cases for an additional 1.2% false-positive rate, giving a total detection rate of 94.6% and a total false-positive rate of 5.4%. In a contingent protocol, in which genetic sonography would be performed only for patients with a first-trimester risk of between 1/300 and 1/2500, the detection rate was 4.8% and the false-positive rate was 0.7%, giving a total detection rate of 93.3% and a total false-positive rate of 4.9%. CONCLUSION: Second-trimester genetic sonography, if used properly, can be an effective sequential screen following first-trimester Down syndrome screening. Further studies on the role of the genetic sonogram as a follow-up to first-trimester combined screening are warranted.

First-trimester maternal dried blood Down syndrome screening marker levels in early pregnancy loss.

OBJECTIVE: To determine the association of free beta hCG and PAPP-A measured during first-trimester Down syndrome risk assessment with early pregnancy loss when blood is drawn prior to scheduled ultrasound. METHODS: Maternal dried blood samples were collected prior to the ultrasound exam for Down syndrome risk assessment. Free beta hCG and PAPP-A levels in 55 patients who experienced loss of pregnancy prior to their scheduled ultrasound appointment were compared to 6464 control pregnancies using logistic regression. RESULTS: Low levels of free beta hCG and PAPP-A were associated with increased risk of early pregnancy loss. The detection rate of early pregnancy loss for a fixed 5% false-positive rate using free beta alone, PAPP-A alone and a combination of the two were 47, 36 and 49%, respectively. CONCLUSION: Free beta hCG and PAPP-A can identify pregnancies at increased risk for early pregnancy loss. More studies are needed to determine whether further evaluation of these pregnancies prior to the scheduled ultrasound is warranted.

Geometric morphometric analysis of shape outlines of the normal and abnormal fetal skull using three-dimensional sonographic multiplanar display.

OBJECTIVES: Geometric morphometric analysis has been used to quantify differences in biological shapes. Cranial irregularities are described in anomalous fetuses but are qualitative and ill-defined. Our goal was to apply geometric morphometric statistical analysis using three-dimensional (3D) multiplanar display to quantify shape differences in normal and abnormal fetal skulls. METHODS: This was a retrospective pilot study of mid-trimester patients undergoing ultrasonography. 3D multiplanar display using spatial rotation was used to identify landmarks in coronal and transverse planes to establish a consistent fetal facial profile. Outline coordinates of the brow were determined by blinded examiners using computer software. Elliptical Fourier analysis (EFA) was used to obtain sets of functional coefficients. An atypicality index (AI) was determined from retained principal component (PC) scores. An AI > 95(th) percentile of the expected distribution defined outliers. RESULTS: Outlines were successfully identified in 38 patients (six abnormal). Using the AI, there were three outliers, all from abnormal fetuses (trisomy 18, trisomy 21, and campomelic dysplasia). Two fetuses with trisomy 21 and one with an unbalanced translocation had normal atypicality indices. CONCLUSIONS: 3D multiplanar display and geometric morphometric analysis enable quantification of fetal skull shape. An abnormal skull shape was identified in two of four aneuploid fetuses and no normal ones. Geometric morphometric analysis represents a promising new quantitative modality which, when applied with 3D sonographic multiplanar display, may be used to more objectively analyze fetal malformation. Larger prospective trials are needed to refine the technique and improve reproducibility.

Maternal weight and ethnic adjustment within a first-trimester Down syndrome and trisomy 18 screening program.

OBJECTIVE(S): To estimate weight and ethnic group correction factors for first-trimester screening markers. METHODS: Ethnic-specific median MoM free beta hCG and pregnancy associated plasma protein A (PAPP-A) and delta nuchal translucency values were calculated for cohorts of maternal weight (20 lb each) using data from 51,206 patients undergoing first-trimester screening. False-positive rates for Down syndrome and trisomy 18 were evaluated both prior to and after weight and ethnicity adjustment. RESULTS: Free beta hCG and PAPP-A significantly decreased with increasing maternal weight while nuchal translucency increased by a clinically insignificant amount. For free beta hCG the regression formula indicated that after accounting for maternal weight MoM values were 16% higher for African Americans, 6% higher for Asians and 9% lower for Hispanics compared to Caucasians (p < 0.001, p = 0.001, p < 0.001, respectively) but there was no significant difference for Asian Indians. For PAPP-A, MoM values were 35% higher for African Americans (p < 0.001) but were not significantly different for the other ethnic groups compared to Caucasians. Down syndrome false-positive rates did not vary with maternal weight prior to (p = 0.291) or after weight adjustment of biochemistry (p = 0.054). Trisomy 18 false-positive rates varied significantly with weight both before (OR = 1.455 per 20-pound increase, p < 0.001) and after (OR = 1.066 per 20-pound increase, p = 0.01) weight adjustment of biochemistry; however, the odds ratio was greatly reduced after weight adjustment. CONCLUSION(S): The first-trimester screening markers, free beta hCG, PAPP-A and nuchal translucency vary with maternal weight and ethnicity. Adjustment of free beta hCG and PAPP-A is indicated but adjustment of nuchal translucency results may not be necessary.

First-trimester screening for trisomy-21 using a simplified method to assess the presence or absence of the fetal nasal bone.

OBJECTIVE: To determine the benefit of including nasal bone assessment in addition to standard first-trimester markers (nuchal translucency, free beta human chorionic gonadotropin and pregnancy-associated plasma protein A) as a screening test for Down syndrome, using a strict criterion for classification of nasal bone absence. STUDY DESIGN: Nasal bone assessment was conducted in 2411 patients with crown-rump length between 45 and 84 mm, including 15 patients with Down syndrome. A patient was considered to have an absent nasal bone only if there was no evidence of present nasal bone. Unlike other studies, nasal bone was classified as present when there was evidence of a thin echogenic line under the skin. Simulation studies were conducted to assess the detection rate and false-positive rate of a combined first-trimester screening protocol including nasal bone assessment. RESULTS: There were 9 of 2396 (0.4%) unaffected cases with absent nasal bone (95% confidence interval 0.2%, 0.7%) and 8 of 15 (53.3%) Down syndrome cases (95% confidence interval 26.6%, 78.7%). Using a 1 in 250 risk cut-off, the detection rate of standard first-trimester screening was 87%, with a false-positive rate of 4.3%. Incorporating nasal bone measurement improved the detection rate of Down syndrome to 90% and reduced the false-positive rate to 2.5%. CONCLUSION: The use of a strict criterion to determine nasal bone absence leads to fewer cases classified as absent and may simplify the implementation of nasal bone as a marker for first-trimester screening, resulting in lower false-positives and higher detection, compared with other current screening protocols.

Reliability of landmark recording on film and digital lateral cephalograms.

The aims of this study were: (a) to evaluate reliability of landmark location in digital processed images of film cephalograms of varying quality with that obtained in the films, and (b) to evaluate the pattern of error in landmark location with the two techniques. The sample consisted of 20 original cephalograms (OQ), 10 'high' quality images (Q1), and 10 'average' quality images (Q2). Measurements on films were performed using a digitizer connected to a PC and controlled by a cephalometric program, while measurements on digital images were obtained using a mouse and a cephalometric program for landmark sampling. To assess the digital images (DQ), the films were video recorded (B/W video camera), digitized (matrix = 512 x 512 x 8), stored in a PC, and displayed on a quality monitor. Fifteen cephalometric landmarks were recorded by three observers twice on each of the 20 images by the two methods. Mean x- and y-values were calculated for each landmark to obtain the best estimate of each landmark position. Comparisons between the OQ and DQ group, and between the subgroups of different film quality were performed (Wilcoxon's rank sum test). In general, measurements from the OQ images were more reliable than from the DQ images (P < 0.02). The pattern of recording error also differed between the two techniques, OQ images being more reliable along the x-axis (P < 0.01), while along the y-axis, reliability was not significantly different between the two groups. Q1 and Q2 images did not differ significantly in either group (P > 0.05). A difference was, however, observed between OQ2 and DQ2 images (P < 0.02), while this was not the case for OQ1 and DQ1 images. The generally lower reliability for measurements on the digital images could be ascribed to the much larger error, especially in the y-axis, for the Q2 images.

Treatment of Class II high angle malocclusions with the Herbst appliance: a cephalometric investigation.

The purpose of this study was to examine the results of treatment of Class II malocclusions by using two different designs of the Herbst appliance. Cephalometric records from lateral headplates of 19 consecutively treated Class II cases were evaluated. The headplates were taken before and after the treatment stage in which the Herbst appliance was used. The patients were divided into two groups: the first group, normohypodivergent, was treated with the Herbst appliance attached to bands; the second group, hyperdivergent, was treated with the Herbst appliance attached to acrylic splints in which a high-pull headgear was also used. The results were compared between these groups and with a control group age-matched from Bolton standards to match the changes in the Herbst samples against what might be expected in case of normal growth during similar periods of time. The results of the investigation revealed the following: (1) 9 months of treatment resulted in Class I dental arch relationships in all 19 cases; (2) the Herbst appliance attached to bands did not significantly modify the vertical growth pattern of the normohypodivergent patients; and (3) in hyperdivergent patients, the use of a Herbst appliance attached to acrylic splints in conjunction with the use of a high-pull headgear allowed a better control of the vertical dimension, as assessed by the cephalometric parameters (FA, FMA, Go-Gn-SN). The clinician should be aware of the different dentofacial changes induced in the vertical plane by different designs of the Herbst appliance to better program treatment strategy.

Thermographic findings in cranio-facial pain.

This work assesses the differences in the thermographic findings in the craniofacial and neck areas between normal individuals and patients with craniofacial pain or headache, and investigates the influence of muscle contraction on such findings. Thermographic records were taken in 10 healthy subjects and 47 patients suffering from craniofacial pain or headache of different kinds. In the patients with painful episodes the record was taken between attacks. In all the normal subjects and in 19 patients lateral thermograms were also taken during and after maximal tooth clenching for three minutes. The majority of the patients, as compared to the normal group, showed some thermal alterations and asymmetry. Such alterations seem to be due both to vascular instability and muscle contraction: these two factors may be variably superimposed in the different conditions. In patients with cluster headache or chronic paroxysmal hemicrania the presence on the symptomatic side of a cold spot along the supraorbital area and/or the inner orbital canthus, was a constant finding. We conclude that thermography is useful as an additional diagnostic means in patients with head and face pain, and that the clenching test may increase the amount of information provided.

Variations of skin temperature in patients with craniofacial pain. A thermographic evaluation.

Thermography of craniofacial region was taken in 33 patients with different types of craniofacial pain. In 26 patients (78%) a thermal asymmetry was found which corresponded to the painful area in 19 patients (57%). It can be concluded that temperature alterations in different areas of the face are common in such patients and are probably the consequence of functional alterations of the sympathetic system.