Enamel Caries Lesion Depth Obtained by Optical Coherence Tomography and Transverse Microradiography: A Comparative Study.

INTRODUCTION: Visual imaging of subsurface caries lesions is of vital interest in dentistry, which can be obtained by invasive radiography technique as well as by available non-destructive imaging approaches. Thus, as a first step toward the development of a new innovative approach, Spectral-domain optical coherence tomography (SD-OCT) was applied to detect the lesion depth in comparison to the established reference technique (transverse microradiography [TMR]). METHODS: Bovine enamel specimens were demineralized for 5 days, following previous studies. For OCT, the resulting artificial lesions were scanned three-dimensionally (SD-OCT) and semi-automated measured (CarLQuant). For TMR, specimens were sectioned and the lesion depth was manually determined (Inspektor Research System). RESULTS: The range of lesion depth detected with OCT was 24.0-174.0 µm (mouth rinse study), 18.0-178.0 µm (toothpastes study) and with TMR 59.2-198.0 µm (mouth rinse study), 33.2-133.4 µm (toothpastes study). We found a strong correlation between both methods in terms of lesion depth (Spearman rankwith outlierp < 0.001, Rho = 0.75, Spearman rankwithout outlierp = 0.001, Rho = 0.79). The two methods produce similar results (Passing-Bablok regression, 1.16). As deeper is the lesion, the smallest is the difference between both methods as indicated by Bland-Altman-plots. CONCLUSION: Especially in the case of deep lesions, the values obtained by both methods are in agreement, and OCT can potentially substitute TMR to detect and assess lesion depth with the benefit of being non-destructive.

Combining Solid and Liquid Biopsy for Therapy Monitoring in Esophageal Cancer.

Esophageal cancer (EC) has one of the highest mortality rates among cancers, making it imperative that therapies are optimized and dynamically adapted to individuals. In this regard, liquid biopsy is an increasingly important method for residual disease monitoring. However, conflicting detection rates (14% versus 60%) and varying cell-free circulating tumor DNA (ctDNA) levels (0.07% versus 0.5%) have been observed in previous studies. Here, we aim to resolve this discrepancy. For 19 EC patients, a complete set of cell-free DNA (cfDNA), formalin-fixed paraffin-embedded tumor tissue (TT) DNA and leukocyte DNA was sequenced (139 libraries). cfDNA was examined in biological duplicates and/or longitudinally, and TT DNA was examined in technical duplicates. In baseline cfDNA, mutations were detected in 12 out of 19 patients (63%); the median ctDNA level was 0.4%. Longitudinal ctDNA changes were consistent with clinical presentation. Considerable mutational diversity was observed in TT, with fewer mutations in cfDNA. The most recurrently mutated genes in TT were TP53, SMAD4, TSHZ3, and SETBP1, with SETBP1 being reported for the first time. ctDNA in blood can be used for therapy monitoring of EC patients. However, a combination of solid and liquid samples should be used to help guide individualized EC therapy.

Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors.

BACKGROUND: Phase I trial to determine the safety and efficacy of paclitaxel, sapanisertib, and serabelisib. PATIENTS AND METHODS: Patients with previously treated advanced solid tumors were eligible for this open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) with weekly paclitaxel. A traditional 3 + 3 dose escalation design with 5 dosing cohorts was used. Patient reported outcomes were also evaluated. RESULTS: 19 heavily pretreated patients were enrolled (10 ovarian, 3 breast, and 6 endometrial cancers). All patients received comprehensive genomic profiling prior to enrollment. RP2D is sapanisertib 3 or 4 mg, serabelisib 200 mg on days 2-4, 9-11, 16-18 and 23-25 with paclitaxel 80 mg/m2 on days 1, 8 and 15 every 28 days. All patients in Cohort 5 required dose reductions and one patient experienced a DLT. The most frequent grade 3 or 4 adverse events were decreased WBCs (20%), nonfebrile neutropenia (12%), anemia (9%), elevated liver enzymes (4%), and hyperglycemia (11%). 3 patients had a CR, 4 had a PR, and 4 patients had SD > six months. ORR was 47% and CBR was 73% in 15 evaluable patients. Including all 19 enrolled patients, the PFS was 11 months and OS is still ongoing at 17 months. CONCLUSIONS: The combination of sapanisertib, serabelisib, and paclitaxel was safe and generally well tolerated. Preliminary efficacy was remarkable in an area of unmet need, especially for patient with PI3K/AKT/mTOR pathway aberrations. Positive effects and sustained clinical benefit were even seen in patients that were refractory to platinum and had failed taxane, everolimus, or temsirolimus. CLINICAL TRIAL NUMBER: ClinicalTrials.gov, NCT03154294.

The Effect of Solutions Containing Extracts of Vochysia tucanorum Mart., Myrcia bellaCambess., Matricaria chamomilla L. and Malva sylvestris L. on Cariogenic Bacterial Species and Enamel Caries Development.

This study evaluated the effect of experimental solutions containing plant extracts on bacterial species and enamel caries prevention. Microcosm biofilm was produced from human saliva mixed with McBain saliva (0.2% sucrose) on bovine enamel for 5 days (3 days under anaerobiosis and 2 days under aerobiosis) at 37°C. From the 2nd day, the following treatments were applied (1 × 60 s/day): Vochysia tucanorum (10 mg/mL); Myrcia bella (5 mg/mL); Matricaria chamomilla (80 mg/mL); Malva sylvestris, fluoride, and xylitol (Malvatricin Plus®); 0.12% chlorhexidine (CHX, PerioGard®); and PBS (negative control). The medium pH was measured. Quantitative polymerase chain reaction was performed for the detection of Streptococcus mutans and Lactobacillus spp. Enamel demineralization was measured by spectral-domain optical coherence tomography. The data were compared by means of the Kruskal-Wallis/Dunn, two-way ANOVA/Bonferroni, and ANOVA/Tukey tests (p < 0.05). The pH decreased after sucrose exposure; only CHX reestablished pH >5.5 by the last day. CHX also eliminated Lactobacillusspp., but the other treatments did not differ significantly from PBS. Malvatricin Plus® and CHX eliminated S. mutans, but the other treatments did not differ from PBS. Similar results were seen concerning the reduction of lesion depth and reflectivity. The experimental natural-extract solutions were ineffective against cariogenic bacteria and in preventing the development of enamel caries.

Prolonged functional development of the parahippocampal place area and occipital place area.

Successful navigation of our surroundings is of high environmental relevance and involves processing of the visual scenery. Scene-processing undergoes a major behavioral improvement during childhood. However, possible neural changes that underlie this cognitive development in scene perception are understudied in comparison to other stimulus categories. We used a functional magnetic resonance imaging (fMRI) scene localizer and behavioral recognition and memory tasks in 7-8-year-olds, 11-12-year-olds, and adults to test whether scene-selective areas-the parahippocampal place area (PPA), the retrosplenial cortex (RSC), and the occipital place area (OPA)-show a change in volume and selectivity with age, and whether this change is correlated with behavioral perception and memory performance. We find that children have a smaller PPA and OPA than adults, while the size of RSC does not differ. Furthermore, selectivity for scenes in the PPA and the OPA, but not in the RSC, increases with age. This increase seems to be driven by both increasing responses to preferred stimuli and decreasing responses to non-preferred stimuli. Our findings extend previous knowledge about visual cortex development by unveiling the underlying mechanisms of age-related volume and selectivity increases in the scene network especially elucidating the poorly understood development of the OPA.

Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma.

18F-Fluorodeoxyglucose (FDG)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging with background signal suppression (DWIBS) are 2 powerful functional imaging modalities in the evaluation of malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET false-negative"). The aim of this study was to describe the proportion of PET false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET false-negativity to be 11%. Neither tumor load-associated parameters, such as degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P < .001) which provides a mechanistic explanation for this feature. In conclusion, we demonstrate a relevant number of patients with FDG-PET false-negative MM and a strong association between hexokinase-2 expression and this negativity: a finding which may also be relevant for clinical imaging of other hematological cancers.

Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.

To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.

Branch: an interactive, web-based tool for testing hypotheses and developing predictive models.

UNLABELLED: Branch is a web application that provides users with the ability to interact directly with large biomedical datasets. The interaction is mediated through a collaborative graphical user interface for building and evaluating decision trees. These trees can be used to compose and test sophisticated hypotheses and to develop predictive models. Decision trees are built and evaluated based on a library of imported datasets and can be stored in a collective area for sharing and re-use. AVAILABILITY AND IMPLEMENTATION: Branch is hosted at http://biobranch.org/ and the open source code is available at http://bitbucket.org/sulab/biobranch/ CONTACTS: asu@scripps.edu or bgood@scripps.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Omics Pipe: a community-based framework for reproducible multi-omics data analysis.

MOTIVATION: Omics Pipe (http://sulab.scripps.edu/omicspipe) is a computational framework that automates multi-omics data analysis pipelines on high performance compute clusters and in the cloud. It supports best practice published pipelines for RNA-seq, miRNA-seq, Exome-seq, Whole-Genome sequencing, ChIP-seq analyses and automatic processing of data from The Cancer Genome Atlas (TCGA). Omics Pipe provides researchers with a tool for reproducible, open source and extensible next generation sequencing analysis. The goal of Omics Pipe is to democratize next-generation sequencing analysis by dramatically increasing the accessibility and reproducibility of best practice computational pipelines, which will enable researchers to generate biologically meaningful and interpretable results. RESULTS: Using Omics Pipe, we analyzed 100 TCGA breast invasive carcinoma paired tumor-normal datasets based on the latest UCSC hg19 RefSeq annotation. Omics Pipe automatically downloaded and processed the desired TCGA samples on a high throughput compute cluster to produce a results report for each sample. We aggregated the individual sample results and compared them to the analysis in the original publications. This comparison revealed high overlap between the analyses, as well as novel findings due to the use of updated annotations and methods. AVAILABILITY AND IMPLEMENTATION: Source code for Omics Pipe is freely available on the web (https://bitbucket.org/sulab/omics_pipe). Omics Pipe is distributed as a standalone Python package for installation (https://pypi.python.org/pypi/omics_pipe) and as an Amazon Machine Image in Amazon Web Services Elastic Compute Cloud that contains all necessary third-party software dependencies and databases (https://pythonhosted.org/omics_pipe/AWS_installation.html).

Tumor cells in multiple myeloma patients inhibit myeloma-reactive T cells through carcinoembryonic antigen-related cell adhesion molecule-6.

Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.

Towards sensible toxicity testing for nanomaterials: proposal for the specification of test design.

During the last decade, nanomaterials (NM) were extensively tested for potential harmful effects towards humans and environmental organisms. However, a sound hazard assessment was so far hampered by uncertainties and a low comparability of test results. The reason for the low comparability is a high variation in the (1) type of NM tested with regard to raw material, size and shape and (2) procedures before and during the toxicity testing. This calls for tailored, nanomaterial-specific protocols. Here, a structured approach is proposed, intended to lead to test protocols not only tailored to specific types of nanomaterials, but also to respective test system for toxicity testing. There are existing standards on single procedures involving nanomaterials, however, not all relevant procedures are covered by standards. Hence, our approach offers a detailed way of weighting several plausible alternatives for e.g. sample preparation, in order to decide on the procedure most meaningful for a specific nanomaterial and toxicity test. A framework of several decision trees (DT) and flow charts to support testing of NM is proposed as a basis for further refinement and in-depth elaboration. DT and flow charts were drafted for (1) general procedure-physicochemical characterisation, (2) choice of test media, (3) decision on test scenario and application of NM to liquid media, (4) application of NM to the gas phase, (5) application of NM to soil and sediments, (6) dose metrics, (S1) definition of a nanomaterial, and (S2) dissolution. The applicability of the proposed approach was surveyed by using experimental data retrieved from studies on nanoscale CuO. This survey demonstrated the DT and flow charts to be a convenient tool to systematically decide upon test procedures and processes, and hence pose an important step towards harmonisation of NM testing.

Clinical and prognostic role of annexin A2 in multiple myeloma.

Annexin A2 (ANXA2) promotes myeloma cell growth, reduces apoptosis in myeloma cell lines, and increases osteoclast formation. ANXA2 has been described in small cohorts of samples as expressed by myeloma cells and cells of the BM microenvironment. To investigate its clinical role, we assessed 1148 samples including independent cohorts of 332 and 701 CD138-purified myeloma cell samples from previously untreated patients together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores, along with expression of ANXA2 in whole BM samples, stromal cells, osteoblasts, osteoclasts, and BM sera. ANXA2 is expressed in all normal and malignant plasma cell samples. Higher ANXA2 expression in myeloma cells is associated with significantly inferior event-free and overall survival independently of conventional prognostic factors and is associated with gene expression-determined high risk and high proliferation. Within the BM, all cell populations, including osteoblasts, osteoclasts, and stromal cells, express ANXA2. ANXA2 expression is increased significantly in myelomatous versus normal BM serum. ANXA2 exemplifies an interesting class of targetable bone-remodeling factors expressed by normal and malignant plasma cells and the BM microenvironment that have a significant impact on survival of myeloma patients.

Genomic Considerations in the Treatment of Thyroid Carcinoma.

Highlighting genomically driven targeted therapies to improve outcomes in advanced thyroid carcinoma.

Assessment of the axial resolution of a compact gamma camera with coded aperture collimator.

PURPOSE: Handheld gamma cameras with coded aperture collimators are under investigation for intraoperative imaging in nuclear medicine. Coded apertures are a promising collimation technique for applications such as lymph node localization due to their high sensitivity and the possibility of 3D imaging. We evaluated the axial resolution and computational performance of two reconstruction methods. METHODS: An experimental gamma camera was set up consisting of the pixelated semiconductor detector Timepix3 and MURA mask of rank 31 with round holes of 0.08 mm in diameter in a 0.11 mm thick Tungsten sheet. A set of measurements was taken where a point-like gamma source was placed centrally at 21 different positions within the range of 12-100 mm. For each source position, the detector image was reconstructed in 0.5 mm steps around the true source position, resulting in an image stack. The axial resolution was assessed by the full width at half maximum (FWHM) of the contrast-to-noise ratio (CNR) profile along the z-axis of the stack. Two reconstruction methods were compared: MURA Decoding and a 3D maximum likelihood expectation maximization algorithm (3D-MLEM). RESULTS: While taking 4400 times longer in computation, 3D-MLEM yielded a smaller axial FWHM and a higher CNR. The axial resolution degraded from 5.3 mm and 1.8 mm at 12 mm to 42.2 mm and 13.5 mm at 100 mm for MURA Decoding and 3D-MLEM respectively. CONCLUSION: Our results show that the coded aperture enables the depth estimation of single point-like sources in the near field. Here, 3D-MLEM offered a better axial resolution but was computationally much slower than MURA Decoding, whose reconstruction time is compatible with real-time imaging.

Tooth-composite bond failure with a universal and an etch-and-rinse adhesive depending on mode and frequency of application.

OBJECTIVES: To evaluate the effect of an additional layer of universal adhesive on the interfacial enamel/dentin-composite gap formation in relation to application mode and aging, via spectral domain optical coherence tomography (SD-OCT) and scanning electron microscopy (SEM). METHODS: In vitro class V cavities in 114 caries-free premolars were restored by applying one or two layers of a universal adhesive (Scotchbond Universal, SBU) in self-etch (se) and etch-and-rinse (er) mode or the reference adhesive OptiBond FL (OFL-er). The restorations were imaged by SD-OCT (six groups, n = 8) and SEM (n = 3) directly after filling (t1), water storage (t2, 24 h), embedding (t3), and thermo-mechanical loading (t4, TCML). The interfacial gaps were quantified using 26 parameters and analyzed using principal component analysis and linear mixed effect models. RESULTS: Gap formation at enamel and dentin was significantly influenced by the adhesive, the application mode and number of layers (p < 0.001). This was due to the influence of the SBU-er mode (p < 1e-05), which showed significantly more gap formation and a greater range of variation with double application when compared to SBU-se and OFL. The fewest interfacial gaps occurred with one or two applications of OFL-er and one layer of SBU-er. SIGNIFICANCE: Adhesive application mode and the number of adhesive layers are relevant factors in the tooth-composite bond failure. Double application worsened the adaptation of SBU to freshly prepared dentin conditioned with phosphoric acid.

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.

OBJECTIVES: Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies. RESULTS: Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff. CONCLUSIONS: The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.

Evaluation of anti-Xa levels in patients with venous thromboembolism within the first 48 h of anticoagulation with unfractionated heparin.

Background: A 2019 study by Prucnal and colleagues found that the majority of patients treated with unfractionated heparin for pulmonary embolism did not maintain therapeutic activated partial thromboplastin time levels during the first 48 h of therapy. Objective: The purpose of this study was to evaluate the ability of an institution's unfractionated heparin dosing protocol to achieve and maintain therapeutic anti-Xa levels within the first 48 h of therapy in patients with venous thromboembolism. Methods: This retrospective study included 205 patients from May 2016 through September 2020. Patients were divided into two cohorts: bolus plus infusion (N = 89) and infusion only (N = 116). The primary objective was to determine the number of patients who achieved at least one therapeutic level. Results: Overall, 200 patients (97.6%) had at least one therapeutic level with no statistically significant difference between cohorts (p = 0.65). No more than 60% of patients achieved a therapeutic level at any of the 6-h intervals throughout the timeframe. The median time to the first therapeutic level in the overall group was 12.8 h with no statistically significant difference between the bolus plus infusion and infusion-only cohorts (13.3 h versus 12.7 h, respectively, p = 0.48). Conclusions: Most patients were able to achieve at least one therapeutic level within the first 48 h, but fewer were able to maintain therapeutic levels. Further studies are warranted to determine whether alternative dosing strategies would yield consistent achievement of therapeutic levels and affect patient-oriented outcomes.

The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor.

A plethora of myeloma growth factors (MGFs) has been identified, but their relative importance and cooperation have not been determined. We investigated 5 MGFs (interleukin-6 [IL-6], insulin-like growth factor type 1 [IGF-1], hepatocyte growth factor [HGF], HB-epidermal growth factor [HB-EGF], and a proliferation-inducing ligand [APRIL]) in serum-free cultures of human myeloma cell lines (HMCLs). In CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival whereas CD45(+) HMCLs could not survive without addition of MGFs, mainly IGF-1 and IL-6. IGF-1 was the major one: its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF, or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression without t(4;14) can also have a poor prognosis. Thus, IGF-1-targeted therapy, eventually in combination with anti-IL-6 therapy, could be promising in a subset of patients with MMCs expressing IGF-1R.

Induction of angiogenesis by normal and malignant plasma cells.

Abundant bone marrow angiogenesis is present in almost all myeloma patients requiring therapy and correlated to treatment response and survival. We assessed the expression of 402 angiogenesis-associated genes by Affymetrix DNA microarrays in 466 samples, including CD138-purified myeloma cells (MMCs) from 300 previously untreated patients, in vivo microcirculation by dynamic contrast-enhanced magnetic resonance imaging, and in vitro angiogenesis (AngioKit-assay). Normal bone marrow plasma cells (BMPCs) express a median of 39 proangiogenic (eg, VEGFA, ADM, IGF-1) and 28 antiangiogenic genes (eg, TIMP1, TIMP2). Supernatants of BMPCs unlike those of memory B cells induce angiogenesis in vitro. MMCs do not show a significantly higher median number of expressed proangiogenic (45) or antiangiogenic (31) genes, but 97% of MMC samples aberrantly express at least one of the angiogenic factors HGF, IL-15, ANG, APRIL, CTGF, or TGFA. Supernatants of MMCs and human myeloma cell lines induce significantly higher in vitro angiogenesis compared with BMPCs. In conclusion, BMPCs express a surplus of proangiogenic over antiangiogenic genes transmitting to the ability to induce in vitro angiogenesis. Aberrant expression of proangiogenic and down-regulation of antiangiogenic genes by MMCs further increases the angiogenic stimulus, together leading to bone marrow angiogenesis at various degrees in all myeloma patients.

Inhibition of aurora kinases for tailored risk-adapted treatment of multiple myeloma.

Genetic instability and cellular proliferation have been associated with aurora kinase expression in several cancer entities, including multiple myeloma. Therefore, the expression of aurora-A, -B, and -C was determined by Affymetrix DNA microarrays in 784 samples including 2 independent sets of 233 and 345 CD138-purified myeloma cells from previously untreated patients. Chromosomal aberrations were assessed by comprehensive interphase fluorescence in situ hybridization and proliferation of primary myeloma cells by propidium iodine staining. We found aurora-A and -B to be expressed at varying frequencies in primary myeloma cells of different patient cohorts, but aurora-C in testis cell samples only. Myeloma cell samples with detectable versus absent aurora-A expression show a significantly higher proliferation rate, but neither a higher absolute number of chromosomal aberrations (aneuploidy), nor of subclonal aberrations (chromosomal instability). The clinical aurora kinase inhibitor VX680 induced apoptosis in 20 of 20 myeloma cell lines and 5 of 5 primary myeloma cell samples. Presence of aurora-A expression delineates significantly inferior event-free and overall survival in 2 independent cohorts of patients undergoing high-dose chemotherapy, independent from conventional prognostic factors. Using gene expression profiling, aurora kinase inhibitors as a promising therapeutic option in myeloma can be tailoredly given to patients expressing aurora-A, who in turn have an adverse prognosis.