Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma.

Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911-17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line (n = 7) or ≥ third-line (n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours.

BACKGROUND: LY3039478 is an orally bioavailable selective Notch inhibitor. This phase 1a/b trial evaluated the safety, pharmacokinetics and antitumour activity of LY3039478 in patients with soft tissue sarcoma (STS) and gastrointestinal stromal tumour (GIST). METHODS: This multipart, phase 1 trial enrolled patients with refractory advanced/metastatic STS and GIST, measurable disease, Eastern Cooperative Oncology Group ≤1 and baseline tumour tissue. Eligible patients received LY3039478 50mg/75 mg three times per week, for 28-day cycle until disease progression. Safety assessments were based on Common Terminology Criteria for Adverse Events, V4.0. Tumour responses were assessed using Response Evaluation Criteria in Solid Tumours (RECIST 1.1) and Choi criteria. Primary objectives were to confirm the recommended phase 2 dose of LY3039478 and document the antitumour activity. Secondary objectives were safety and toxicity, pharmacokinetics (PK), progression-free survival (PFS) and overall survival (OS). RESULTS: Sixty-nine patients were enrolled and received LY3039478 (27 males, 42 females; median age 58, range 31-78). 16/37 (43%) patients with evaluable samples were positive for Notch 1 immunohistochemistry. Per RECIST 1.1, in leiomyosarcoma (LMS) group (n = 29), ten (36%) had stable disease (SD) and one (4%) had unconfirmed partial response (PR). In GIST group (n = 13), four (31%) had SD. Among other STS subtypes (n = 27), one patient with angiosarcoma had unconfirmed PR, six (21%) had SD. Median PFS was 1.9 months (95% confidence interval:1.6-3.3) for LMS, 1.9 months (0.3-6.1) for GIST and 1.7 months (1.4-2.2) for other STS groups. Median OS was 7.4 months (4.3-non-evaluable [NE]) for LMS, 16.5 months (3.9-16.5) for GIST and 5.6 months (3.4-NE) for other STS groups. Most common adverse events were diarrhoea, nausea, vomiting and decreased appetite. CONCLUSION: LY3039478 suggested a modest clinical activity in patients with STS and GIST and had a manageable safety profile.

Multimodal optical, X-ray CT, and SPECT imaging of a mouse model of breast cancer lung metastasis.

Tumor heterogeneity is recognized as a major issue within clinical oncology, and the concept of personalized molecular medicine is emerging as a means to mitigate this problem. Given the vast number of cancer types and subtypes, robust pre-clinical models of cancer must be studied to interrogate the molecular mechanisms involved in each scenario. In particular, mouse models of tumor metastasis are of critical importance for pre-clinical cancer research at the cancer cell molecular level. In many of these experimental systems, tumor cells are injected intravenously, and the distribution and proliferation of these cells are subsequently analyzed via ex vivo methods. These techniques require large numbers of animals coupled with time-consuming histological preparation and analysis. Herein, we demonstrate the use of two facile and noninvasive imaging techniques to enhance the study of a pre-clinical model of breast cancer metastasis in the lung. Breast cancer cells were labeled with a near-infrared fluorophore that enables their visualization. Upon injection into a living mouse, the distribution of the cells in the body was detected and measured using whole animal fluorescence imaging. X-ray computed tomography (CT) was subsequently used to provide a quantitative measure of longitudinal tumor cell accumulation in the lungs over six weeks. A nuclear probe for lung perfusion, 99mTc-MAA, was also imaged and tested during the time course using single photon emission computed tomography (SPECT). Our results demonstrate that optical fluorescence methods are useful to visualize cancer cell distribution patterns that occur immediately after injection. Longitudinal imaging with X-ray CT provides a convenient and quantitative avenue to measure tumor growth within the lung space over several weeks. Results with nuclear imaging did not show a correlation between lung perfusion (SPECT) and segmented lung volume (CT). Nevertheless, the combination of animal models and noninvasive optical and CT imaging methods provides better research tools to study cancer cell differences at the molecular level. Ultimately, the knowledge gleaned from these improved studies will aid researchers in uncovering the mechanisms mediating breast cancer metastasis, and eventually improve the treatments of patients in the clinic.

[The influence of cardiopulmonary bypass operation on the biodistribution of 99mTc-HMPAO-labelled granulocytes - Evaluation in pigs by planar scintigraphy and section-analyses]. / Einfluss der extrakorporalen Perfusion auf die Biodistribution 99mTc-HMPAO-markierter Granulozyten. Evaluierung im Schwein mittels planarer Szintigraphie und Sektionsanalytik.

AIM: of the study was to evaluate the influence of an extra corporal perfusion (cardiopulmonary bypass operation - cpb) on activation and biodistribution of (99m)Tc labelled granulocytes in pigs with and without inhibition of the granulocytes by a leukocyte inhibition module (LIM). The cpb is often related to an activation of granulocytes resulting in an inflammatory answer. The biological mechanisms are unsolved yet. First trials of our group showed that LIM may inhibit the activation of neutrophils and therefore antagonize a cpb-caused impairment of cardiac function. This study is the continuation of these experiments with a higher number of animals and the focus on scintigraphic imaging. ANIMALS, MATERIAL, METHODS: 39 German landrace pigs were subdivided into three groups: group A (control) median sternotomy without cpb, group B with cpb, group C with LIM in addition to cpb. After labelling with (99m)Tc-HMPAO autologues granulocytes were reinjected. Subsequently to cpb, the animals underwent scintigraphic imaging. Quantification was performed with ROI evaluation and with tissue samples (section analysis) examined in a well counter. RESULTS: A high uptake of (99m)Tc-HMPAO was found in the liver. The count rates in brain, heart, lung, spleen and kidneys were far below. The amount of 99mTc-activity in the organ related to the half life corrected administered activity [%] was for the tissue samples (group A/B/C): brain 0.01/0.02/0.03; lung 12.1/8.3/11.5; heart 0.35/0.54/0.42; kidney 1.24/0.87/1.02; spleen 4.0/4.0/4.5, liver 16.8/20.9/19.6. The count rates determined by ROI-evaluation of the scintigraphic images related to the total count rate in the image [%] were (group A/B/C): brain 1.1/0.9/1.0; lung 15.6/10.4/12.2; heart 4.0/3.5/3.4; kidney 4.0/2.9/3.2; spleen 7.6/7.7/9.5, liver 23.1/36.7/31.4. A significant difference in the tracer uptake between the groups could neither be detected by scintigraphic imaging nor evaluation of tissue samples. CONCLUSION: Scintigraphic imaging as well as section analysis showed a comparable biodistribution of the tracer. Therefore, the initial results of our group were not confirmed with a considerably higher number of animals. Neither cpb nor the use of the LIM influenced distribution of 99mTc-labelled granulocytes in pigs significantly.

[The population-based mammography screening programme in Germany: uptake and first experiences of women in 10 federal states]. / Das populationsbezogene Mammografie-Screening-Programm in Deutschland: Inanspruchnahme und erste Erfahrungen von Frauen in 10 Bundesländern.

PURPOSE: Within the statutory health insurance (SHI) cancer early detection programme (KFU) an organised, population-based, quality-assured mammographic screening programme in Germany was initiated for women aged 50-69 years in 2004. The aim of the study was to evaluate uptake and first experiences of participants with this new screening approach and to evaluate the background of knowledge, attitudes and intention to address a needs-assessed communication strategy. MATERIALS AND METHODS: A representative, explorative survey within the female population was conducted in 10 federal states. A telephone survey of randomly selected 68,188 contacts was performed, 9,004 women gave informed consent to evaluate rates of invitation and uptake followed by a mailed questionnaire. Of these, 3,469 were returned and 3,226 were analysed. RESULTS: The invitation rate of the programme was 56.6%, the uptake of mammographic screening was 66%, and the screening coverage rate was 37.3%. 90% of the participants were insured by SHI, women with lower socio-economic strata were attracted in accordance with the data of the general population. 61% of all women did not know that the risk of breast cancer increases with age and 56% believed that screening prevents breast cancer. 62.1% judged their own risk to be low. A physician's recommendation to participate was significantly associated with attendance (p<0.05). 90% of the participants would follow the next invitation. CONCLUSION: The KFU targeted group of women was reached and the organised mammography screening programme was well perceived by invited women. For developing a lasting communication strategy information deficits have to be considered along with beliefs and attitudes of elegible women.

Real-time elastography and contrast-enhanced ultrasound for the assessment of thyroid nodules.

OBJECTIVE: Work-up of thyroid nodules remains challenging. Recent technologies enable determination of tissue elasticity and perfusion using ultrasound devices. The aim of the present study was to evaluate real-time elastography (RTE) and contrast-enhanced ultrasound with Sonovue (CEUS) for the differentiation of benign and malignant thyroid nodules. MATERIALS AND METHODS: Inclusion criteria were: nodules ≥1 cm, non-functioning or hypo-functioning on radionuclide scanning, and cytological/histological assessment. All patients received conventional ultrasound, RTE and CEUS. RTE was classified as: Elasticity-Score (ES)1 = soft, ES2 = predominantly soft, ES3 = predominantly hard, ES4 = hard nodule. CEUS-video clips were digitally recorded and analyzed using time-intensity-curves within selected regions-of-interest. RESULTS: Fifty-three nodules in 50 patients were available for analysis. Forty-six nodules were benign on cytology/histology, 6 nodules were papillary carcinoma and one nodule was a follicular carcinoma. Nodule margin irregularity was the ultrasound pattern most predictive of malignancy with sensitivity 57% (95% confidence interval: 18-90%) and specificity 85% (71-94% p<0.05). When using ES3&4 for the diagnosis of malignant nodules sensitivity and specificity were 86% (42-99.7%) and 87% (75-95%), respectively (p = 0.0003). The only malignant nodule missed with RTE was a follicular carcinoma. Sensitivity for the diagnosis of papillary carcinoma therefore was 100%. No specific CEUS pattern could be identified to differentiate between benign and malignant nodules. CONCLUSIONS: RTE seems to be a useful tool in the work-up of thyroid nodules to exclude papillary thyroid cancer. However, follicular carcinoma remains a challenging problem. CEUS did not improve the characterization of thyroid nodules in this preliminary study.

18F-FDG PET for detecting metastases and synchronous primary malignancies in patients with oral and oropharyngeal cancer.

AIM: Assessment of the efficiency of 18F-FDG-PET (PET) for the detection of distant metastases and synchronous primary malignancies in patients with oral and oropharyngeal squamous cell cancer (OOSCC). PATIENTS, METHODS: Retrospective evaluation of PET studies of 422 patients with histologically confirmed OOSCC. 99 patients (23.5%) demonstrated a suspect distant finding of whom 84 could be interdisciplinary evaluated and consecutively confirmed or refuted by other diagnostic modalities or biopsy. RESULTS: In 74 of 80 evaluable cases, PET showed the primary tumour (92.5%). 26/84 suspect distant lesions (31%) showed by means of PET were confirmed to be malignancies (mean SUV 3.96; range 1.4-9.37). Main sites were the lung, the upper aerodigestive tract, and the gastrointestinal system. In the other 58 cases (69%), where the suspect lesions were confirmed as benign, mean SUV was 2.65 (range 0.7-6.5) (difference statistically significant). The SUV above which every suspect finding was proven to be of malignant condition was 6.5 (specificity 100%, sensitivity 38%, accuracy 81%). CONCLUSION: PET may have an important role in initial staging and the detection of distant metastases and synchronous primary malignancies. Setting a SUV threshold for determining malignancies can support interpretation. In borderline cases, however, interdisciplinary evaluation by means of other diagnostic modalities remains crucial.

Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779.

BACKGROUND: von Willebrand factor (VWF) has a role in both hemostasis and thrombosis. Platelets adhere to damaged arteries by interactions between the VWF A1-domain and glycoprotein Ib receptors under conditions of high shear. This initial platelet binding event stimulates platelet activation, recruitment, and activation of the clotting cascade, promoting thrombus formation. OBJECTIVE: To characterize the inhibitory activity of a VWF inhibitory aptamer. METHODS: Using in vitro selection, aptamer stabilization, and conjugation to a 20-kDa poly(ethylene glycol), we generated a nuclease-resistant aptamer, ARC1779, that binds to the VWF A1-domain with high affinity (K(D) approximately 2 nM). The aptamer was assessed for inhibition of VWF-induced platelet aggregation. In vitro inhibition of platelet adhesion was assessed on collagen-coated slides and injured pig aortic segments. In vivo activity was assessed in a cynomolgus monkey carotid electrical injury thrombosis model. RESULTS AND CONCLUSION: ARC1779 inhibited botrocetin-induced platelet aggregation (IC90 approximately 300 nM) and shear force-induced platelet aggregation (IC95 approximately 400 nM). It reduced adhesion of platelets to collagen-coated matrices and formation of platelet thrombi on denuded porcine arteries. ARC1779 also inhibited the formation of occlusive thrombi in cynomolgus monkeys. We have discovered a novel anti-VWF aptamer that could have therapeutic use as an anti-VWF agent in the setting of VWF-mediated thrombosis.

Thyroid sonomorphology, thyroid peroxidase antibodies and thyroid function: new epidemiological data in unselected German employees.

AIM: Employees of Sanofi-Aventis Deutschland GmbH underwent thyroid screening in 2006 to assess new data about the prevalence of irregular sonomorphological pattern, elevated thyroid peroxidase antibodies (TPO AB) and thyroid function in an unselected adult German population. PARTICIPANTS, METHODS: The examination included 700 unselected employees. Blood samples were analyzed for serum TSH and TPO AB, and ultrasound of the thyroid was performed. RESULTS: In 40.7% of the participants (n = 285) an irregular sonomorphological pattern was detected: goiter in 13.7%, nodules in 35.6%, nodular goiter in 8.6% and a hypoechogenic pattern of the thyroid gland in 20.4%. Serum TSH was increased in 3.9% and decreased in 0.6%. Elevated TPO AB values were observed in 13%. Only 1.4% (n = 10) showed elevated TPO AB combined with a TSH increase. Sonomorphological abnormalities were associated with increased TPO AB in 7.1%. Elevated TPO AB was observed significantly more often in combination with sonomorphological pathology (54.9%) than without (45.1%) (p = 0.003). CONCLUSIONS: Sonomorphological disorders are still very common in Germany and our results are comparable with previous screening examinations. Elevated TPO AB correlated significantly with the sonomorphological pattern of nodules and goiter. This may reflect an improved iodine supply or a hypertrophic stage of autoimmune thyroiditis in some cases.

Planar silicon-based light polarizers.

Silicon-based thin-film polarizers operating in the visible and near-infraed spectral range are fabricated by electrochemical etching of bulk silicon wafers. Anisotropically etched (110) porous silicon layers exhibit a strong in-plane anisotropy of the refractive index. Stackes of alternating layers with different mean refractive indices and thicknesses act as dichroic Bragg reflectors or microcavities, respectively. Both structures have two distinct reflection and transmission bands depending on the polarization of the incident linearly polarized light. Planar polarizers are realized through the combination, in one structure, of a dichroic reflector with either a second reflector or a microcavity with different spectral responses.

Subclinical hyperthyroidism in dementia and correlation of the metabolic index in FDG-PET.

AIM: Thyroid hormone status and thyroid antibodies were evaluated in patients suffering from dementia for further study of an association of hyperthyroidism with AD and vascular dementia (VD), respectively. PATIENTS: In 77 patients with dementia, and 42 controls, thyrotropin (TSH) and thyroid antibodies were correlated with the different types of dementia and the metabolic index (MI) based on imaging with F-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). RESULTS: Twenty-two of all patients with dementia (29%) had borderline (TSH 0.3-0.5 mU/l) or decreased TSH levels (TSH < 0.3 mU/L). TSH values were significantly lower in patients suffering from AD (median: 1.1 mU/l) and VD (0.5 mU/l) than in the control group (1.5 mU/l) (p < 0.01). Decreased or borderline TSH levels were present in 52% of the patients with VD, but in only 10% of the controls, and in 23% of the patients with AD. Antibodies to thyroid peroxidase were positive in 16% of all patients with dementia. The MI in patients suffering from AD with borderline TSH levels was 0.81 (0.70, 0.94). In contrast, patients suffering from AD with normal TSH values showed a slightly higher MI of 0.84 (0.76, 0.89) (p = n.s.). CONCLUSION: Decreased or borderline TSH values are associated with an increased probability of having dementia, especially VD.

Stimulated light emission in dense fog confined inside a porous glass matrix.

We report on light amplification through stimulated emission in a dielectrically disordered medium. Liquid fragments confined in the solid matrix of porous quartz layers result in a random fluctuation of the dielectric function, and dye molecules embedded in the voids yield optical gain. The level of opacity is tunable by the ambient vapor pressure of the dielectric substance. In the multiple scattering regime, a strong intensity enhancement of the dye emission accompanied by significant spectral narrowing is observed above the threshold for a layer being in the opalescence state.

Giant birefringence in anisotropically nanostructured silicon.

We performed a study of the in-plane birefringence of anisotropically nanostructured Si layers, which exhibit a greater difference in the main value of the anisotropic refractive index than that of natural birefringent crystals. The anisotropy parameters were found to be strongly dependent on the typical size of the Si nanowires used to assemble the layers. This finding opens the possibility of an application of birefringent Si retarders to a wide spectral range for control of the polarization state of light.

Ordering and self-organization in nanocrystalline silicon

The spontaneous formation of organized nanocrystals in semiconductors has been observed during heteroepitaxial growth and chemical synthesis. The ability to fabricate size-controlled silicon nanocrystals encapsulated by insulating SiO2 would be of significant interest to the microelectronics industry. But reproducible manufacture of such crystals is hampered by the amorphous nature of SiO2 and the differing thermal expansion coefficients of the two materials. Previous attempts to fabricate Si nanocrystals failed to achieve control over their shape and crystallographic orientation, the latter property being important in systems such as Si quantum dots. Here we report the self-organization of Si nanocrystals larger than 80 A into brick-shaped crystallites oriented along the (111) crystallographic direction. The nanocrystals are formed by the solid-phase crystallization of nanometre-thick layers of amorphous Si confined between SiO2 layers. The shape and orientation of the crystallites results in relatively narrow photoluminescence, whereas isotropic particles produce qualitatively different, broad light emission. Our results should aid the development of maskless, reproducible Si nanofabrication techniques.

Role of SRP19 in assembly of the Archaeoglobus fulgidus signal recognition particle.

Previous studies have shown that SRP19 promotes association of the highly conserved signal peptide-binding protein, SRP54, with the signal recognition particle (SRP) RNA in both archaeal and eukaryotic model systems. In vitro characterization of this process is now reported using recombinantly expressed components of SRP from the hyperthermophilic, sulfate-reducing archaeon Archaeoglobus fulgidis. A combination of native gel mobility shift, filter binding, and Ni-NTA agarose bead binding assays were used to determine the binding constants for binary and ternary complexes of SRP proteins and SRP RNA. Archaeal SRP54, unlike eukaryotic homologues, has significant intrinsic affinity for 7S RNA (K(D) approximately 15 nM), making it possible to directly compare particles formed in the presence and absence of SRP19 and thereby assess the precise role of SRP19 in the assembly process. Chemical modification studies using hydroxyl radicals and DEPC identify nonoverlapping primary binding sites for SRP19 and SRP54 corresponding to the tips of helix 6 and helix 8 (SRP19) and the distal loop and asymmetric bulge of helix 8 (SRP54). SRP19 additionally induces conformational changes concentrated in the proximal asymmetric bulge of helix 8. Selected nucleotides in this bulge become modified as a result of SRP19 binding but are subsequently protected from modification by formation of the complete complex with SRP54. Together these results suggest a model for assembly in which bridging the ends of helix 6 and helix 8 by SRP19 induces a long-range structural change to present the proximal bulge in a conformation compatible with high-affinity SRP54 binding.

Solution structure of a substrate for the archaeal pre-tRNA splicing endonucleases: the bulge-helix-bulge motif.

The structure of the bulge-helix-bulge motif that constitutes the intron/exon splice site in H. volcanii pre-tRNATrp has been determined by NMR spectroscopy. The conformations of the two 3 nt bulges, where the pre-tRNA is cleaved, are stabilized by stacking interactions between bulge nucleotides and bases in the adjacent Watson-Crick helices and by a network of backbone hydrogen bonds. Both bulges are presented on the same minor groove face of the central 4 bp helix, and the overall structure has approximate two-fold symmetry, which makes it well-suited for attack by archaeal splicing endonucleases, which are symmetric dimers.

Infecçöes relacionadas ao cateter venoso central em terapia intensiva / Central venous catheter-related infections in critically-ill-patients

OBJETIVO. Determinar a incidência, a etiologia e os fatores de risco das infecçoes relacionadas ao cateter venoso central em terapia intensiva. METODOLOGIA. Estudo observacional de coorte, prospectivo, em pacientes criticamente enfermos submetidos à cateterizaçao venosa profunda por punçao percutânea. Realizadas culturas quantitativa da pele, semiquantitativa da ponta e quantitativa do canhao do cateter, e hemocultura periférica. Os possíveis fatores de risco foram submetidos à análise univariada e multivariada. RESULTADOS. Foram estudados 57 períodos de cateterizaçao em 51 pacientes. A incidência de infecçao local foi de 21,1 por cento (33,8/1.000 dias-cateter), e de bacteremia, 8,7 por cento (l4,1/1.000 dias-cateter). A pele no local de inserçao estava colonizada em 32,7 por cento dos pacientes e o canhao, em 29,1 por cento. A origem dos microrganismos causadores de infecçao foi a pele em 41,2 por cento, o canhao em 29,4 por cento, infecçao a distância em 5,9 por cento, e nao ficou esclarecida em 23,5 por cento dos casos. Estafilococos coagulase-negativa foram os agentes etiológicos predominantes. Identificou-se, como variáveis independentemente associadas à infecçao local, a purulência no orifício de inserçao e a utilizaçao de outro dispositivo intravascular. As variáveis independentemente associadas à bacteremia foram a inserçao na veia jugular interna e a colonizaçao do canhao do cateter. CONCLUSOES. A bacteremia é uma complicaçao importante do cateterismo venoso central em terapia intensiva. Os estafilococos coagulase-negativa predominam nesta modalidade de infecçao hospitalar. A inserçao do cateter na veia jugular interna e a colonizaçao do canhao aumentam o risco de bacteremia relacionada à linha venosa central.