Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.     

IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.     

The effect of calcium fluoride (CaF(2)) on the chemical solubility of an apatite-mullite glass-ceramic material.

OBJECTIVE: To assess the effect of varying CaF(2) on the chemical solubility of apatite-mullite glass-ceramic (G-C) materials in both the glassy and crystallized states. METHODS: Apatite-mullite forming glasses used in this study are ionomer cement derivatives based on the general formula (4.5SiO(2)-3Al(2)O(3)-1.5P(2)O(5)-3CaO-XCaF(2)). Six glass formulations were produced where X=0.5, 1, 1.5, 2, 2.5 and 3, and called HG1-6, respectively. Batches were melted in covered silliminite crucibles in a furnace overnight at 1050 degrees C, then at 1450 degrees C for 2h, before quenching in water. The six glass compositions were analyzed using differential thermal analysis (DTA), X-ray diffraction (XRD) and X-ray fluorescence spectrometry (XRF). Thirty discs (2mm thick and 12 mm diameter) were produced per glass using the lost wax casting technique. Ten were left as cast and 10 heat treated to either apatite or apatite-mullite. Solubility testing was carried out according to International Standard BS EN ISO 6872 1999 and the mass difference in solubility calculated as mug/cm(2). A lithium disilicate G-C system was used as a control material. RESULTS: All compositions formed glasses and on heat treatment could form apatite and apatite-mullite. The as-cast glass samples were the most soluble followed by the apatite samples. The apatite-mullite G-C was significantly less soluble than the other two phases (p<0.05) for all six compositions. The control material was significantly less soluble than all the HG glass-ceramic compositions for every phase (p<0.05). Decreasing the CaF(2) content (3-0.5 mol%) led to a decrease in solubility, without affecting the ability of the material to form apatite and apatite-mullite phases. SIGNIFICANCE: Increasing the CaF(2) content increases the chemical solubility for the glass, apatite G-C and apatite-mullite G-C phases. The solubility values obtained show that all the compositions, as cast and heat treated would be suitable for use as core ceramics.     

The effect of different surface treatments on bond strength between leucite reinforced feldspathic ceramic and composite resin

Objectives

The aim of this study was to evaluate the effect of different surface treatments on the microtensile bond strength between a leucite reinforced glass–ceramic and composite resin.

Methods

Leucite reinforced ceramic blocks (n = 24) were constructed using the hot pressing technique. The blocks were assigned to 4 groups, which received the following surface treatments: G1: hydrofluoric (HF) acid and silane; G2: silane alone; G3: HF acid and silane then dried with warm air (100 °C); G4: silane alone then dried with warm air (100 °C). Unfilled resin was applied, followed by composite resin. Specimens were prepared and loaded in tension to determine the microtensile bond strength. Failure modes were classified by stereo- and scanning electron microscopy (SEM). Data was analysed using Kruskal–Wallis test followed by the Dunn's multiple range test.

Results

The groups including the warm air step (G3 and G4) achieved a significantly stronger adhesion than G1 and G2. Pre-treatment of the surface with hydrofluoric acid in G1 resulted in significantly higher bond strength than G2. Failures were mostly cohesive in the luting resin for G1, G3 and G4 and mainly adhesive at the ceramic–resin interface in G2.

Conclusions

The method of application of silane to the ceramic surface can have a significant influence on the adhesion between the ceramic restoration and the resin cement. Enhancing the condensation reaction by drying the silane with a 100 ?C warm air stream significantly improved the microtensile bond strength, possibly eliminating the need for the hydrofluoric acid etching step.     

An overview of the current status of national reporting systems for adverse reactions to dental materials

OBJECTIVES: Since all dental materials pose a potential risk to patients and members of the dental team, the post-market monitoring of adverse reactions caused by dental materials should be considered essential. This article reviews the current status of post-market monitoring of adverse reactions to dental materials and highlights some of the issues that arise in trying to establish an evidence base on the characteristics of adverse reactions to dental materials. METHODS: Norway, Sweden and more recently the UK have sought to monitor adverse reactions to dental materials systematically and proactively in an effort to add to the evidence base on the safety of dental materials. Their experiences in undertaking post-market surveillance have been combined in preparing this article. RESULTS: To date the Norwegian, Swedish and the UK projects has received 1268 reports over 11 years, 848 reports over 5.5 years and 1117 reports over 3 years, respectively, relating to adverse reactions seen or experienced by dental personnel and patients. Presently, there are no harmonized criteria for what can be classified as an adverse reaction related to dental materials. Under reporting is a recognised problem and lack of awareness and lack of clarity as to what constitutes an adverse reaction may be contributory factors. A pro-active reporting system takes a considerable time to become established, but can generate a lot of potentially useful information. CONCLUSIONS: There is a need to raise the awareness among dental professionals of the potential for adverse reactions due to dental materials and to develop an internationally accepted system of data gathering that can produce the evidence that reflect the extent, severity and incidence of adverse reactions to dental materials.     

Spectral reflectance and color of dentin ceramics for all-ceramic restorations

OBJECTIVE: The study was conducted to observe the spectral reflectance curves, and evaluate the color coordinates (CIELAB) of VM7 dentin ceramics (VITA, Germany) across the whole 3D-MASTER shade system. METHODS: Three disc samples, 13 mm in diameter and 1.4mm in thickness, were produced for each shade by firing following the manufacturer's instructions. Each fired disc was ground to a thickness of 1.0 mm and both faces were polished. Spectral reflectance data in the visible spectrum under the standard illuminant D65 were collected at 1 nm intervals by using a computer-controlled spectrophotometer. Color coordinates, L*, a*, b*, C*, h, in the three-dimensional CIELAB color space were obtained. RESULTS: (1) Spectral reflectance in the short-wavelength range systematically decreased with increasing chroma number (M1, M2, and M3) when compared within the same value (lightness) group (1M, 2M, 3M, 4M, and 5M). (2) Spectral reflectance decreased systematically across the whole visible spectrum with increasing value group when compared within the same chroma group. (3) A negative relationship was recognized between lightness (L*) and chromaticity index a* (red-green direction). That is, a* coordinate increases from approximately 1 for the 1M1 sample to approximately 13 for the 5M3 sample, the corresponding lightness systematically decreased from 87 to 69. (4) With increasing a* coordinate, hue angle (h) significantly decreased from 85 degrees for the 1M1 sample to 69 degrees for the 5M3 sample. (5) Lightness apparently increased with increasing hue angle (h) throughout the whole range of the 3D-MASTER shade system. (6) A strong positive relationship between chroma (C*) and chromaticity index b* (yellow-blue direction) was found, demonstrating that the chroma of the present ceramic is mainly controlled by the b* coordinate. SIGNIFICANCE: Systematic variations in spectral reflectance and color coordinates of VM7 dentin were observed throughout the 3D-MASTER shade system and were suggested to be caused by the fine structure of the sample which can interfere with shorter wavelengths in the visible spectrum.     

The effect of casting conditions on the biaxial flexural strength of glass–ceramic materials

OBJECTIVE: To assess the effect of mould and glass casting temperatures on the biaxial flexural strength (BFS) of two different types of castable glass-ceramic, using existing laboratory equipment and techniques. METHODS: Two castable glass-ceramic materials were evaluated. One glass (LG3) is based on SiO2-Al2O3-P2O5-CaO-CaF2, and is similar in composition to glasses used in the manufacture of glass-ionomer cements. The other glass (SG3) is based on SiO2-K2O-Na2O-CaO-CaF2, and is a canasite-based material. Both materials were used to produce discs of 12 mm diameter and 2 mm thickness using the same lost-wax casting process as used for metal castings. Mould temperatures of between 500 degrees C and 1000 degrees C and glass casting temperatures of between 1100 degrees C and 1450 degrees C were evaluated. The cast discs were cerammed and the biaxial flexural strength determined with a Lloyd 2000 R tester. RESULTS: A significant difference was found for the BFS in the range of mould temperatures evaluated, with the optimum investment mould temperature being 590 degrees C for LG3 and 610 degrees C for SG3 (p = 0.0002 and p = 0.019, respectively). No significant differences were seen between any of the glass casting temperatures evaluated. SIGNIFICANCE: The mould temperature for castable glass-ceramic materials produced using the lost-wax casting process can have a significant effect on BFS. The optimum mould temperature may differ slightly depending on the type of material being used. The glass casting temperature of these materials does not appear to have a significant effect on BFS.     

Conversion to reverse shoulder arthroplasty fifty-one years after shoulder arthrodesis: A case report

BACKGROUND Patients with a shoulder arthrodesis generally experience restriction in range of motion and limitations in activities of daily living. In addition, up to one-third of the patients deals with serious peri scapular pain. The conversion of a shoulder arthrodesis in a reverse shoulder arthroplasty(RSA) has been described as an effective treatment to achieve better function and decreased pain, although literature is sparse. We present the case of a conversion from a painful shoulder arthrodesis to RSA, after a 51 years interval.CASE SUMMARY A 71-year-old male presented with severe peri scapular pain and limited function 51 years after shoulder arthrodesis. Preoperative workup showed a normal bone stock of the glenoid and an intact axillary nerve, but atrophic posterior part of the deltoid muscle. The shoulder arthrodesis was successfully converted to RSA. Twelve months postoperative the patient was very satisfied. He has no pain at rest, nor with exercise and experienced definite improvements in activities of daily living, despite his limited range of motion.CONCLUSION Conversion from shoulder arthrodesis to a RSA can be performed safely, with a high chance of peri scapular pain relief; even after a longstanding arthrodesis.     

Cognitive performance in children with acute early-onset anorexia nervosa

When anorexia nervosa (AN) occurs in children below the age of 14 years, it is referred to as early-onset AN (EO-AN). Over the last years, there has been an increased focus on the role of cognitive functioning in the development and maintenance of AN. Adults with AN show inefficiencies in cognitive functions such as flexibility and central coherence. Systematic neuropsychological examinations of patients with EO-AN are missing. Thirty children with EO-AN and 30 adolescents with AN, as well as 60 healthy controls (HC) underwent an extensive neuropsychological examination. ANOVAs with post hoc tests and explorative regression analyses were conducted. Patients with EO-AN (mean age = 2.17 ± 1.57 years) showed no significant differences in flexibility, inhibition, planning, central coherence, visuospatial short- and long-term memory or recognition in comparison to HC (mean age = 11.62 ± 1.29 years). Performance of adolescents with AN (mean age = 15.93 ± 0.70 years) was not significantly different compared to HC (mean age = 16.20 ± 1.26 years). Explorative regression analyses revealed a significant interaction of age and group for flexibility (adjusted R ²  = 0.30, F = 17.85, p = 0.013, η _p ²  = 0.32). Contrary to expectations, the current study could not confirm the presence of inefficient cognitive processing in children with EO-AN compared to HC. Nonetheless, the expected age-related improvement of flexibility might be disrupted in children and adolescents with AN. Longitudinal neuropsychological examinations are necessary to provide more information about the role of cognitive functioning in the development and maintenance of AN.     

An RNA virus hijacks an incognito function of a DNA repair enzyme

A previously described mammalian cell activity, called VPg unlinkase, specifically cleaves a unique protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection. For over three decades, the identity of this cellular activity and its normal role in the uninfected cell had remained elusive. Here we report the purification and identification of VPg unlinkase as the DNA repair enzyme, 5'-tyrosyl-DNA phosphodiesterase-2 (TDP2). Our data show that VPg unlinkase activity in different mammalian cell lines correlates with their differential expression of TDP2. Furthermore, we show that recombinant TDP2 can cleave the protein-RNA linkage generated by different picornaviruses without impairing the integrity of viral RNA. Our results reveal a unique RNA repair-like function for TDP2 and suggest an unusual role in host-pathogen interactions for this cellular enzyme. On the basis of the identification of TDP2 as a potential antiviral target, our findings may lead to the development of universal therapeutics to treat the millions of individuals afflicted annually with diseases caused by picornaviruses, including myocarditis, aseptic meningitis, encephalitis, hepatitis, and the common cold.