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Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in Cushing's disease
Purpose
Cushing’s disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during osilodrostat (potent oral 11β-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC).
Methods
LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing’s disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study.
Results
At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control.
Conclusions
Improvements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing’s disease occurred alongside decreases in mUFC.
Trial registration
NCT02180217 (first posted July 2014).
Journal Article
A global cloud map of the nearest known brown dwarf
A map of the surface of a brown dwarf reveals features that suggest patchy clouds, providing the mechanism for the dispersal of atmospheric dust as brown dwarfs cool with age.
Casting a weather eye on a nearby brown dwarf
The recently discovered system known as Luhman 16AB is a binary consisting of two brown dwarfs — objects much bigger than planets but not big enough to become stars — and is a mere six light years from us. Only Alpha Centauri and Barnard's star are closer. Ian Crossfield
et al
. have now mapped the surface of brown dwarf Luhman 16B in the infrared and find large-scale surface patterns indicative of patchy clouds. Monitoring suggests that the characteristic timescale for the evolution of global weather patterns is about one day. Further observations of the evolution of weather patterns on brown dwarfs could provide a new benchmark for understanding how global circulation conditions affect dusty atmospheres on brown dwarfs and giant extrasolar planets.
Brown dwarfs—substellar bodies more massive than planets but not massive enough to initiate the sustained hydrogen fusion that powers self-luminous stars
1
,
2
—are born hot and slowly cool as they age. As they cool below about 2,300 kelvin, liquid or crystalline particles composed of calcium aluminates, silicates and iron condense into atmospheric ‘dust’
3
,
4
, which disappears at still cooler temperatures (around 1,300 kelvin)
5
,
6
. Models to explain this dust dispersal include both an abrupt sinking of the entire cloud deck into the deep, unobservable atmosphere
5
,
7
and breakup of the cloud into scattered patches
6
,
8
(as seen on Jupiter and Saturn
9
). However, hitherto observations of brown dwarfs have been limited to globally integrated measurements
10
, which can reveal surface inhomogeneities but cannot unambiguously resolve surface features
11
. Here we report a two-dimensional map of a brown dwarf’s surface that allows identification of large-scale bright and dark features, indicative of patchy clouds. Monitoring suggests that the characteristic timescale for the evolution of global weather patterns is approximately one day.
Journal Article
Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study
In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing’s disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing’s disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing’s disease.
Journal Article
Clinical and Immunomodulatory Effects of Toceranib Combined with Low‐Dose Cyclophosphamide in Dogs with Cancer
Background Tyrosine kinase inhibitors (TKIs) and metronomic dosing of cyclophosphamide (CYC) can improve tumor control by suppression of regulatory T cells (Treg) and restoration of T cell‐mediated immune responses in mice and humans. The immunomodulatory effects of the TKI toceranib, as a single agent or in combination with metronomic CYC, have not been previously investigated in dogs. Hypothesis The primary objectives of this study were to determine the effects of toceranib and metronomic CYC treatment on lymphocyte subsets including Treg and on interferon‐gamma (IFN‐γ) secretion in dogs with cancer. We hypothesized that toceranib would selectively decrease Treg numbers and increase IFN‐γ production and that addition of CYC would further enhance these effects. Animals Fifteen client‐owned dogs with advanced tumors were entered into a prospective clinical trial. Methods Dogs received toceranib at 2.75 mg/kg once every other day. After 2 weeks, oral CYC was added at 15 mg/m2 daily. Numbers of Treg and lymphocyte subsets were measured in blood by flow cytometry during the 8‐week study period. Serum concentrations of IFN‐γ were measured by ELISA. Results Administration of toceranib significantly decreased the number and percentage of Treg in the peripheral blood of dogs with cancer. Dogs receiving toceranib and CYC demonstrated a significant increase in serum concentrations of IFN‐γ, which was inversely correlated with Treg numbers after 6 weeks of combination treatment. Conclusions In addition to antitumor effects, these data support further investigations into the immunomodulatory effects of toceranib, administered alone or in combination with CYC in dogs with cancer.
Journal Article
Intensity-Modulated and Image-Guided Radiation Therapy for Treatment of Genitourinary Carcinomas in Dogs
Abstract
Background
External beam radiation therapy can be used to treat pelvic tumors in dogs, but its utility is limited by lack of efficacy data and associated late complications.
Hypothesis/Objectives
The objective of this study was to assess local tumor control, overall survival, and toxicosis after intensity-modulated and image-guided radiation therapy (IM/IGRT) for treatment of genitourinary carcinomas (CGUC) in dogs.
Animals
21 client-owned dogs.
Methods
A retrospective study was performed. Medical records of dogs for which there was intent to treat with a course of definitive-intent IM/IGRT for CGUC between 2008 and 2011 were reviewed. Descriptive and actuarial statistics comprised the data analysis.
Results
Primary tumors were located in the prostate (10), urinary bladder (9), or urethra (2). The total radiation dose ranged from 54–58 Gy, delivered in 20 daily fractions. Grade 1 and 2 acute gastrointestinal toxicoses developed in 33 and 5% of dogs, respectively. Grade 1 and 2 acute genitourinary and grade 1 acute integumentary toxicoses were documented in 5, 5, and 20% of dogs, respectively. Four dogs experienced late grade 3 gastrointestinal or genitourinary toxicosis. The subjective response rate was 60%. The median event-free survival was 317 days; the overall median survival time was 654 days. Neither local tumor control nor overall survival was statistically dependent upon location of the primary tumor.
Conclusions and Clinical Importance
IM/IGRT is generally well-tolerated and provides an effective option for locoregional control of CGUC. As compared with previous reports in the veterinary literature, inclusion of IM/IGRT in multimodal treatment protocols for CGUC can result in superior survival times; controlled prospective evaluation is warranted.
Journal Article
Low-Dose Cyclophosphamide Selectively Decreases Regulatory T Cells and Inhibits Angiogenesis in Dogs with Soft Tissue Sarcoma
Background: Low‐dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angiogenesis and suppressing regulatory T cells (Treg) in mice and humans. The effects of metronomic chemotherapy on Treg and tumor angiogenesis in dogs has not been investigated previously. Objective: To determine whether metronomic cyclophosphamide (CYC) therapy decreases Treg or exhibits antiangiogenic activity or both in dogs with soft tissue sarcoma (STS). We hypothesized that Treg numbers would be increased in dogs with STS and that continuous dosing of CYC would decrease Treg in a dose‐dependent manner, as well as exhibit antiangiogenic activity. Animals: Eleven client‐owned dogs with grade I or II STS. Twenty‐one healthy dogs were used as controls. Methods: Prospective, open, clinical trial. Dogs with STS were enrolled in 2 dose cohorts and administered CYC at 12.5 or 15 mg/m2 PO once daily for 28 days. Whole blood and tumor biopsy specimens were obtained on days 0, 14, and 28 to assess changes in T lymphocyte subsets by flow cytometry and tumor microvessel density (MVD), respectively. Results: Administration of CYC at 12.5 mg/m2/d significantly decreased the number of Treg from days 0 to 28, but there was no change in the percentage of Treg or tumor MVD. In dogs that received CYC at 15.0 mg/m2/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. Conclusions: CYC administered at 15 mg/m2/d should be used in further studies examining the antitumor properties of low‐dose CYC in dogs.
Journal Article
Decreased ratio of CD8+ T cells to regulatory T cells associated with decreased survival in dogs with osteosarcoma
Background: Increased numbers of regulatory T cells (Treg) and decreased ratios of CD8+ T cells to Treg have been shown to correlate with decreased survival times (ST) in humans with certain malignancies. A possible connection between Treg and ST in dogs with cancer has not been investigated previously. Hypothesis: The purpose of this study was to compare numbers of Treg and T lymphocyte subsets in dogs with osteosarcoma (OSA) to those of healthy dogs and to determine whether pretreatment values were associated with disease-free interval or with ST. We hypothesized that Treg numbers would be increased in dogs with cancer and that dogs with a high percentage of Treg would have a poorer prognosis. Animals: Twelve client-owned dogs with appendicular OSA were entered into a prospective clinical trial. Twenty-two healthy dogs were used as controls. Methods: The percentages and numbers of Treg and CD4+ and CD8+ T cells in blood, lymph nodes, and tumors were determined with flow cytometry and compared between dogs with OSA and control dogs. Results: Dogs with OSA had significantly fewer circulating CD8+ T cells and significantly more Treg compared with healthy dogs. The CD8/Treg ratio also was significantly lower in dogs with OSA compared with control dogs. In dogs with OSA, a decreased CD8/Treg ratio was associated with significantly shorter STs. Conclusions: These data support a role for Treg in the immune control of canine OSA and suggest that determination of the CD8/Treg ratio may be useful for assessing outcomes.
Journal Article
Changes in Regulatory T Cells in Dogs with Cancer and Associations with Tumor Type
Abstract
Background
Regulatory T cells (Treg) have been shown to suppress antitumor immunity and often are increased in humans and rodents with cancer. However, Tregs have not been well studied in dogs with cancer and it is not known if certain tumor types are associated with increased Tregs.
Hypothesis
We hypothesized that Treg percentages would be increased in dogs with cancer and that Treg percentages would be higher in dogs with certain types of cancer.
Animals
The percentages and numbers of Tregs and nonregulatory T cells and B cells were assessed in 34 dogs with cancer and 9 age-matched control dogs. Dogs evaluated included 14 dogs with sarcoma, 7 dogs with carcinoma, 7 dogs with lymphoma, and 6 dogs with mast cell tumor.
Methods
Numbers and percentages of Tregs, CD4+, and CD8+ T cells and B cells were determined using flow cytometry and compared between control dogs and dogs with cancer.
Results
The percentage of Tregs was significantly increased overall in dogs with cancer compared with control dogs. When tumor types were compared, Treg percentages were significantly increased in dogs with carcinoma. The Treg/CD8 T cell ratio was significantly higher in dogs with cancer compared with control dogs and was also significantly increased in 2 dogs with T-cell lymphoma.
Conclusions
Treg percentages in blood were increased in dogs with cancer, particularly in dogs with carcinoma. The Treg/CD8 ratio also identified tumor-specific abnormalities in dogs with cancer. These findings indicate that tumor-specific factors may affect Tregs in dogs.
Journal Article
Genomic Testing, Unexpected Consanguinity, and Adolescent Parents
This case study about an infant with epidermolysis bullosa and his fourteen-year-old mother involves pediatric genomic testing and concerns about the adolescent parent’s decision-making capacity. Four commentaries explore ethics issues in the case, including the following challenges: The current ethics guidelines regarding informed decision-making for genomic testing and return of results have been relatively silent on how to involve parents who are minors in decision-making on behalf of their children. This lack of guidance can be particularly difficult for physicians when genetic test results revealing consanguinity raise concerns about sexual abuse of a minor, provoking questions about mandatory reporting requirements. Finally, medical teams may find themselves having to evaluate an adolescent parent’s capacity in making medical decisions for her child while questioning the role and relationship of her support person.
Journal Article