Vector-apodizing phase plate coronagraph: design, current performance, and future development [Invited].

Over the last decade, the vector-apodizing phase plate (vAPP) coronagraph has been developed from concept to on-sky application in many high-contrast imaging systems on 8 m class telescopes. The vAPP is a geometric-phase patterned coronagraph that is inherently broadband, and its manufacturing is enabled only by direct-write technology for liquid-crystal patterns. The vAPP generates two coronagraphic point spread functions (PSFs) that cancel starlight on opposite sides of the PSF and have opposite circular polarization states. The efficiency, that is, the amount of light in these PSFs, depends on the retardance offset from a half-wave of the liquid-crystal retarder. Using different liquid-crystal recipes to tune the retardance, different vAPPs operate with high efficiencies (${\gt}96\%$) in the visible and thermal infrared (0.55 µm to 5 µm). Since 2015, seven vAPPs have been installed in a total of six different instruments, including Magellan/MagAO, Magellan/MagAO-X, Subaru/SCExAO, and LBT/LMIRcam. Using two integral field spectrographs installed on the latter two instruments, these vAPPs can provide low-resolution spectra (${\rm{R}} \sim 30$) between 1 µm and 5 µm. We review the design process, development, commissioning, on-sky performance, and first scientific results of all commissioned vAPPs. We report on the lessons learned and conclude with perspectives for future developments and applications.

Imaging low-mass planets within the habitable zone of α Centauri.

Giant exoplanets on wide orbits have been directly imaged around young stars. If the thermal background in the mid-infrared can be mitigated, then exoplanets with lower masses can also be imaged. Here we present a ground-based mid-infrared observing approach that enables imaging low-mass temperate exoplanets around nearby stars, and in particular within the closest stellar system, α Centauri. Based on 75-80% of the best quality images from 100 h of cumulative observations, we demonstrate sensitivity to warm sub-Neptune-sized planets throughout much of the habitable zone of α Centauri A. This is an order of magnitude more sensitive than state-of-the-art exoplanet imaging mass detection limits. We also discuss a possible exoplanet or exozodiacal disk detection around α Centauri A. However, an instrumental artifact of unknown origin cannot be ruled out. These results demonstrate the feasibility of imaging rocky habitable-zone exoplanets with current and upcoming telescopes.

Combined-modality 125J-seed-brachytherapy, external beam radiation and androgen deprivation therapy of unfavorable-risk prostate cancer: report of outcomes and side-effects.

PURPOSE: To analyze outcomes and complication rates in an unselected cohort of men with unfavorable (NCCN intermediate and high-risk) PCa receiving combined-modality radiation treatment (CRT). METHODS: Patients received androgen deprivation therapy for 1 year and combined-modality radiation treatment (CRT) consisting of external-beam radiotherapy (EBRT, 59.4 Gy, 33 fractions) and 125J seed-brachytherapy (S-BT, 100 Gy). Subgroups, including WHO group 3-5, and initial PSA (iPSA) < 20 and > 20 ng/ml were identified. Biochemical recurrence-free (BRFS), metastasis-free (MFS), cancer-specific (CSS) and overall survival (OS) were calculated at 5 and 10 years using the Kaplan-Meier method. Subgroups were compared using log-rank test and Cox proportional hazards regression. Urogenital and gastrointestinal side-effects were reported according to the CTCAE classification. RESULTS: After a median of 6.9 years (range 2-13) calculated 5- and 10-year rates for the whole cohort of 425 men were 92.8% and 82.5% for BRFS, 95.1%, and 88.8% for MFS, 98.2%, and 95.1 for CSS, and 95.4%, and 80.1% for OS, respectively. Univariate (UVA) and multivariate analysis (MV) identified a group with unfavorable outcome with iPSA > 20 ng/ml, comprising 24% of all patients, in which 55% of recurrences, 54% of metastases and 71% of cancer-specific deaths occurred. Side-effects were limited, with < 5% of patients complaining of genitourinary and 0.5% of gastrointestinal AEs after 5 years. CONCLUSION: CRT is an excellent treatment option for men with unfavorable PCa. In a subgroup of patients with iPSA > 20 ng/ml further, possibly systemic, treatment options should be identified.

Testing General Relativity with Stellar Orbits around the Supermassive Black Hole in Our Galactic Center.

We demonstrate that short-period stars orbiting around the supermassive black hole in our Galactic center can successfully be used to probe the gravitational theory in a strong regime. We use 19 years of observations of the two best measured short-period stars orbiting our Galactic center to constrain a hypothetical fifth force that arises in various scenarios motivated by the development of a unification theory or in some models of dark matter and dark energy. No deviation from general relativity is reported and the fifth force strength is restricted to an upper 95% confidence limit of |α|<0.016 at a length scale of λ=150 astronomical units. We also derive a 95% confidence upper limit on a linear drift of the argument of periastron of the short-period star S0-2 of |ω[over ˙]_{S0-2}|<1.6×10^{-3} rad/yr, which can be used to constrain various gravitational and astrophysical theories. This analysis provides the first fully self-consistent test of the gravitational theory using orbital dynamic in a strong gravitational regime, that of a supermassive black hole. A sensitivity analysis for future measurements is also presented.

The shortest-known-period star orbiting our Galaxy's supermassive black hole.

Stars with short orbital periods at the center of our Galaxy offer a powerful probe of a supermassive black hole. Over the past 17 years, the W. M. Keck Observatory has been used to image the galactic center at the highest angular resolution possible today. By adding to this data set and advancing methodologies, we have detected S0-102, a star orbiting our Galaxy's supermassive black hole with a period of just 11.5 years. S0-102 doubles the number of known stars with full phase coverage and periods of less than 20 years. It thereby provides the opportunity, with future measurements, to resolve degeneracies in the parameters describing the central gravitational potential and to test Einstein's theory of general relativity in an unexplored regime.

Guía clínica para el diagnóstico y tratamiento de los carcinomas de las células uroteliales de las vías urinarias superiores: actualización de 2011 / European Guidelines for the Diagnosis and Management of Upper Urinary Tract Urothelial Cell Carcinomas: 2011 Update

Contexto: El Grupo de Guías Clínicas sobre el carcinoma de células uroteliales de las vías urinarias superiores (CCU-VUS) de La Asociación Europea de Urología (EAU) ha elaborado una nueva guía clínica para ayudar a los médicos a evaluar el tratamiento del CCU-VUS basado en los datos científicos, y a incorporar las presentes recomendaciones a la práctica clínica diaria. Objetivo: Este documento ofrece una breve visión general de la guía clínica de la EAU sobre el CCU-VUS como una ayuda para los médicos en su práctica diaria. Adquisición de datos científicos: Las recomendaciones proporcionadas en la guía actual se basan en una meticulosa revisión de las guías y documentos sobre CCU-VUS disponibles, identificados mediante una búsqueda sistemática en Medline. Los datos sobre neoplasias uroteliales malignas y CCU-VUS en la literatura se buscaron mediante Medline con las siguientes palabras clave: cáncer del tracto urinario, carcinomas uroteliales, tracto urinario superior, carcinoma, células de transición, pelvis renal, uréter, cáncer vesical, quimioterapia, nefroureterectomía, tratamiento adyuvante, tratamiento neoadyuvante, recidiva, factores de riesgo y supervivencia. Un equipo de expertos sopesó las referencias Síntesis de los datos científicos: Hay una falta de datos en la literatura actual para proporcionar recomendaciones consistentes, debido a la rareza de la enfermedad. Una serie de recientes estudios multicéntricos ya están disponibles, mientras que las publicaciones anteriores se basaban solo en poblaciones limitadas. Sin embargo, la mayoría de estos estudios han sido análisis retrospectivos. Se recomienda la clasificación TNM2009. Se hacen recomendaciones para el diagnóstico, así como para el tratamiento radical y conservador; también se tratan los factores pronósticos. Se proporcionan recomendaciones para el seguimiento del paciente después de diferentes opciones terapéuticas. Conclusiones: Esta guía contiene información para el diagnóstico y tratamiento de los pacientes individuales de acuerdo a un enfoque estándar actual. Al determinar el régimen de tratamiento óptimo, los médicos deben tener en cuenta las características clínicas específicas de cada paciente con respecto a la función renal, incluyendo comorbilidades médicas, localización del tumor, grado y estadio y el estado de los marcadores moleculares (AU)

Context: The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice. Objective: This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice. Evidence acquisition: The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched sing Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references. Evidence synthesis: There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options. Conclusions: These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patient’s specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status (AU)

[European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. European Association of Urology Guideline Group for urothelial cell carcinoma of the upper urinary tract]. / Guía clínica para el diagnóstico y tratamiento de los carcinomas de las células uroteliales de las vías urinarias superiores: actualización de 2011.

CONTEXT: The European Association of Urology (EAU) Guideline Group for urothelial cell carcinoma of the upper urinary tract (UUT-UCC) has prepared new guidelines to aid clinicians in assessing the current evidence-based management of UUT-UCC and to incorporate present recommendations into daily clinical practice. OBJECTIVE: This paper provides a brief overview of the EAU guidelines on UUT-UCC as an aid to clinicians in their daily practice. EVIDENCE ACQUISITION: The recommendations provided in the current guidelines are based on a thorough review of available UUT-UCC guidelines and papers identified using a systematic search of Medline. Data on urothelial malignancies and UUT-UCCs in the literature were searched using Medline with the following keywords: urinary tract cancer, urothelial carcinomas, upper urinary tract, carcinoma, transitional cell, renal pelvis, ureter, bladder cancer, chemotherapy, nephroureterectomy, adjuvant treatment, neoadjuvant treatment, recurrence, risk factors, and survival. A panel of experts weighted the references. EVIDENCE SYNTHESIS: There is a lack of data in the current literature to provide strong recommendations due to the rarity of the disease. A number of recent multicentre studies are now available, whereas earlier publications were based only on limited populations. However, most of these studies have been retrospective analyses. The TNM classification 2009 is recommended. Recommendations are given for diagnosis as well as for radical and conservative treatment; prognostic factors are also discussed. Recommendations are provided for patient follow-up after different therapeutic options. CONCLUSIONS: These guidelines contain information for the diagnosis and treatment of individual patients according to a current standardised approach. When determining the optimal treatment regimen, physicians must take into account each individual patient's specific clinical characteristics with regard to renal function including medical comorbidities; tumour location, grade and stage; and molecular marker status.

Apoptosis by gemcitabine in non-small cell lung cancer cell line KNS62 is induced downstream of caspase 8 and is profoundly blocked by Bcl-xL over-expression.

BACKGROUND: This study assesses the chemotherapeutic drug gemcitabine in the human non-small cell lung cancer (NSCLC) cell line KNS62 in relation to the CD95-induced apoptotic pathway, and the role of the anti-apoptotic protein Bcl-xL in vitro and in vivo. MATERIALS AND METHODS: Apoptosis was determined by JAM assay and DAPI staining analysis. Activation of key apoptotic proteins, including caspases 3, 8 and 9 and BID, as well as cytochrome c release and mitochondrial transmembrane potential (MTP), were measured. The impact of the caspase inhibitor zVAD on gemcitabine-induced apoptosis was quantified. The in vitro results were verified in vivo in an orthotopic murine xenotransplantation model. RESULTS: Gemcitabine treatment, as well as stimulation of CD95, resulted in cleavage of effector caspase 3 as well as its substrate PARP and caspase 9, followed by DNA fragmentation. Cleavage of caspase 8 was demonstrated after CD95 activation but not after the application of gemcitabine. In KNS62-Bcl-xL clones, release of cytochrome c and loss of mitochondrial transmembrane potential were suppressed. Consequently, apoptosis after gemcitabine therapy, as well as CD95-induced apoptosis, were significantly inhibited. Caspase inhibitor zVAD only partly reversed gemcitabine-induced DNA fragmentation. In vivo, there was a significant reduction in tumour volume under gemcitabine therapy. Bcl-xL over-expressing tumours were completely resistant to gemcitabine therapy. CONCLUSIONS: In NSCLC cell line KNS62 gemcitabine activated the mitochondrial apoptotic pathway downstream of mitochondria without activation of initiator caspases. Bcl-xL over-expression induced significant resistance to gemcitabine. In vivo, the anti-apoptotic effect of Bcl-xL was more pronounced than in vitro. Gemcitabine also induced caspase-independent DNA fragmentation in KNS62 cells.

Human endostatin inhibits growth of human non-small-cell lung cancer in a murine xenotransplant model.

Overall prognosis in human NSCLC remains poor. Antiangiogenic treatment has become a promising concept for the treatment of solid malignancies. Our purpose was to evaluate the efficacy of recombinant HSENDO for the treatment of human NSCLC in an orthotopic murine xenotransplantation model. The efficacy of HSENDO was tested in vitro in cell-proliferation, cell-migration and tube-formation assays. In vivo, the effect of HSENDO on tumor growth was tested in s.c. xenotransplanted human NSCLC and on intrapulmonary induced human NSCLC. In vitro, HSENDO inhibited both human and rodent endothelial cell proliferation in a time- and dose-dependent fashion. Endothelial cell migration was inhibited by 97%. Tube formation of murine endothelial cells was inhibited and preexisting tubes degenerated after HSENDO exposure. In vivo, HSENDO delayed growth of s.c. xenotransplanted tumors. Immunohistochemic staining demonstrated no change in microvessel density but a significant reduction of proliferating tumor cells and an increase in bFGF and VEGF expression, reflecting the antiangiogenic effect of HSENDO. Intrapulmonary tumor induction caused death subsequent to metastatic disease. Systemic HSENDO application extended survival significantly. HSENDO was demonstrated to inhibit endothelial cell proliferation, migration and tube formation effectively. In vivo growth of s.c. transplanted tumors was delayed and survival extended by 32% and 69%, respectively, after intrapulmonary NSCLC induction.

Effective treatment of malignant pleural effusion by minimal invasive thoracic surgery: thoracoscopic talc pleurodesis and pleuroperitoneal shunts in 101 patients.

BACKGROUND: For effective palliation of patients with malignant pleural effusion due to advanced neoplastic disease, any proposed treatment should have low procedure-related mortality and morbidity. METHODS: The clinical outcome of 119 thoracoscopies in 101 patients (56 women, 45 men), from 42 to 91 years of age (mean, 68 +/- 9 years) with malignant pleural effusions was evaluated in a retrospective study. Video-assisted thoracoscopy (VATS) talc pleurodesis was done in 105 instances, and a pleuroperitoneal shunt was performed 14 times as an alternative when complete expansion of the lung could not be achieved due to tumor implants on the visceral pleura. RESULTS: The VATS talc pleurodesis resulted in clinically significant improvement of dyspnea in 92.2% of the patients. Thirty-day mortality was 2.8% and morbidity was 2.8%. The mean duration of postoperative survival was 6.7 months. Recurrent pleural effusion occurred in 5.7% of patients after a mean interval of 6 months. Clinical relief of dyspnea was obtained in 73% of the patients treated with pleuroperitoneal shunts. Thirty-day mortality in this group was 21% and morbidity was 14.3%. The mean duration of survival was 4.2 months. CONCLUSIONS: The VATS talc pleurodesis is appropriate for palliation of patients with malignant pleural effusions and should be performed once the diagnosis has been confirmed. Patients with lungs trapped by visceral carcinomatosis may benefit from placement of a pleuroperitoneal shunt as an alternative.

Combretastatin A-4 prodrug inhibits growth of human non-small cell lung cancer in a murine xenotransplant model.

BACKGROUND: Combretastatin A-4 prodrug (CA-4PD) has been identified as a potent antivascular agent in various rodent tumor models. The aim of this study was to investigate the effect of CA-4PD on human non-small cell lung cancer (NSCLC). METHODS: Cytostatic and cytotoxic effects of CA-4PD on selected NSCLC cells, Colo-699 and KNS-62, were studied in vitro. After subcutaneous xenotransplantation the effect of systemically administrated CA-4PD on tumor growth was investigated in vivo. A newly established orthotopic xenotransplant model was employed to estimate prolongation of survival after intrapulmonary tumor induction with secondary metastatic disease. RESULTS: In vitro, CA-4PD displayed a time and dose dependent antiproliferative effect on human lung cancer cells. In vivo, CA-4PD significantly delayed growth of subcutaneously induced lung cancer. This growth delay was translated into a prolongation of survival in the metastasizing orthotopic xenotransplant model. CONCLUSIONS: In vitro CA-4PD inhibits proliferation of NSCLC cells, most likely by disruption of microtubule assembly. In vivo, systemic treatment inhibits growth of subcutaneously xenotransplanted tumors by an antivascular effect. In the case of metastasizing human lung cancer this translated into a prolongation of survival.

An improved orthotopic xenotransplant procedure for human lung cancer in SCID bg mice.

BACKGROUND: Overall prognosis in human lung cancer is still poor. A highly reproducible, easy to perform in vivo model, which closely resembles the clinical features of advanced human lung cancer, is required for the evaluation of novel therapies. METHODS: Tumor cells, originated from a human adenocarcinoma, a squamous cell carcinoma, and an undifferentiated large cell carcinoma, were xenotransplanted heterotopically by subcutaneous and intravenous injection and compared with orthotopic intrapleural and intrapulmonary xenotransplantation by a facilitated engraftment procedure into SCID bg mice. RESULTS: Subcutaneous injection of tumor cells resulted in a 100% engraftment rate with establishment of solid tumors without clinically relevant metastases. Intravenous injection had poor engraftment rates by hematogenous spread. Depending on the cell line, a 80% to 100% engraftment rate in orthotopic xenotransplantation was achieved, resulting in a consistent pattern of mediastinal and bilateral pulmonary metastases. CONCLUSIONS: The facilitated orthotopic xenotransplantation of human lung cancer is easy to perform and results in a reproducible in vivo model that closely resembles the clinical features of advanced human lung cancer. Consequently, this model appears suitable for in vivo evaluation of novel cancer therapies in preclinical tests.

Differences of glycoconjugates exposed on hypernephroma and normal kidney cells.

We analyzed the outer cell membranes of normal kidney cells, hypernephroma cells, nude mouse transplants of hypernephroma tissue, and cell lines derived from hypernephroma using horseradish peroxidase-coupled lectins of different specificity, in order to investigate their binding to cryostat sections or the cell surfaces of suspended single cells. We showed that hypernephroma cells express higher amounts of receptors for Robinia pseudoacacia lectin, soy bean lectin and Phaseolus vulgaris lectin compared to those prepared from normal kidneys. In contrast, Helix pomatia lectin is bound to connective tissue elements of both malignant and non-malignant tissue exclusively. L-fucose and D-galactose residues are detectable on malignant cells, but not on their non-malignant counterparts. However, the expression of the latter varies considerably among cells from different hypernephromas. No significant difference could be demonstrated between hypernephroma, hypernephroma cell lines and hypernephroma transplants in regard to the carbohydrate profile on the cell surfaces.