Summary Background Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small ...molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles. Methods In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov , number NCT00406809. Findings 55 patients were enrolled (median age 59 years, IQR 51–67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40–218). Interpretation Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study. Funding Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.
Patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) following autologous stem cell transplant (ASCT) remain a management challenge with few reliably effective treatments. ...Lenalidomide, an immunomodulatory drug approved for patients with myelodysplastic syndrome with del(5q), multiple myeloma, and mantle cell lymphoma, has demonstrated some activity in patients with R/R cHL, though the toxicity of traditional doses and schedules has been a barrier to consistent use. Low dose continuous (LDC) schedules have emerged as promising, with a more favorable safety profile. We report herein that LDC schedules are associated with a far more tolerable toxicity profile, and exhibit at least equivalent efficacy in this patient population. We report that patients diagnosed with R/R cHL who previously underwent, or were not candidates for, ASCT and/or clinical trials, were administered daily LDC lenalidomide (20 mg orally with dose reduction for toxicity). Among the 19 patients included in this analysis, 11% of patients achieved a partial response (PR), with no documented complete responses (CR). A total of 12 (63%) patients maintained stable disease (SD), with 7 patients (37%) remaining in SD for more than 6 months. The clinical benefit rate (comprised of CR, PR, and SD for greater than 6 months) was 47% (7 out of 19 patients). The median progression-free survival and overall survival of all patients were 9.4 months (range, 4.6–14.4 months) and 90 months (range, 63.6–166.8 months), respectively. In general, the treatment was well tolerated, with grade 3 or 4 adverse events consisting of neutropenia (n = 4), and one case each of thrombocytopenia, fatigue, rash, creatinine elevation, aspartate transaminase/alanine transaminase elevation, and treatment related secondary malignancy. In a heavily treated R/R cHL patient population, daily LDC lenalidomide was associated with a high disease control rate with a favorable toxicity profile.
Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in ...chromatin proteins, for example, histones. The structure of chromatin may be altered by post-translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses.
Cutaneous T-cell lymphomas (CTCLs) are rare lymphomas that arise primarily in the skin and are treated with skin-directed therapies in early-stage disease. Systemic therapy is indicated once ...skin-directed therapy is ineffective or for advanced-stage disease. CTCLs tend to be poorly responsive to chemotherapy and are incurable except for allogeneic stem cell transplantation. Recently, a new class of agents called histone deacetyalse inhibitors (HDACis) have shown remarkable activity in T-cell lymphomas in general and CTCLs in particular. Oral vorinostat and intravenous romidepsin are two HDACis that are now approved by the US FDA for use in patients with relapsed CTCLs. Several other HDACis are currently in clinical trials for CTCLs and other diseases and, although these agents vary by chemical structure and potency, the results of the ongoing clinical trials will eventually reveal if there are differences in clinical activity as well. The exact mechanism of action of these agents is unknown, but they are thought to affect the acetylation status of histones and other proteins in the cell and epigentically modulate transcription and other cellular activities. This leads to a myriad of downstream effects on cell cycle, apoptosis and differentiation. The following review summarizes the known biological mechanisms and clinical activity of various HDACis in the treatment of CTCLs and tries to define their role in the treatment paradigm of these unusual disorders.
Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, ...bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.
Assess the effect of filtered back projection (FBP) and hybrid (adaptive statistical iterative reconstruction ASIR) and pure (model-based iterative reconstruction MBIR) iterative reconstructions on ...abdominal computed tomography (CT) acquired with 75% radiation dose reduction.
In an institutional review board-approved prospective study, 10 patients (mean standard deviation age, 60 (8) years; 4 men and 6 women) gave informed consent for acquisition of additional abdominal images on 64-slice multidetector-row CT (GE 750HD, GE Healthcare). Scanning was repeated over a 10-cm scan length at 200 and 50 milliampere second (mA s), with remaining parameters held constant at 120 kilovolt (peak), 0.984:1 pitch, and standard reconstruction kernel. Projection data were deidentified, exported, and reconstructed to obtain 4 data sets (200-mA s FBP, 50-mA s FBP, 50-mA s ASIR, 50-mA s MBIR), which were evaluated by 2 abdominal radiologists for lesions and subjective image quality. Objective noise and noise spectral density were measured for each image series.
Among the 10 patients, the maximum weight recorded was 123 kg, with maximum transverse diameter measured as 43.7 cm. Lesion conspicuity at 50-mA s MBIR was better than on 50-mA s FBP and ASIR images (P < 0.01). Image noise was rated as suboptimal on low-dose FBP and ASIR but deemed acceptable in MBIR images. Objective noise with 50-mA s MBIR was 2 to 3 folds lower compared to 50-mA s ASIR, 50-mA s FBP, and 200-mA s FBP (P < 0.0001). Noise spectral density analyses demonstrated that ASIR retains the noise spectrum signature of FBP, whereas MBIR has much lower noise with a more regularized noise spectrum pattern.
Model-based iterative reconstruction renders acceptable image quality and diagnostic confidence in 50- mA s abdominal CT images, whereas FBP and ASIR images are associated with suboptimal image quality at this radiation dose level.
Objectives
To assess the diagnostic accuracy of fast acquisition MRI in suspected cases of paediatric appendicitis presenting to a tertiary referral hospital.
Materials and methods
A prospective ...study was undertaken between May and October 2017 of 52 children who presented with suspected appendicitis and were referred for an abdominal ultrasound. All patients included in this study received both an abdominal ultrasound and five-sequence MRI consisting of axial and coronal gradient echo T2 scans, fat-saturated SSFSE and a diffusion-weighted scan. Participants were randomised into groups of MRI with breath-holds or MRI with free breathing. A patient satisfaction survey was also carried out. Histopathology findings, where available, were used as a gold standard for the purposes of data analysis. Statistical analysis was performed, and
p
values < 0.05 were considered statistically significant.
Results
Ultrasound had a sensitivity and specificity of 25% and 92.9%, respectively. MRI with breath-hold had a sensitivity and specificity of 81.8% and 66.7%, respectively, whilst MRI with free breathing was superior with sensitivity and specificity of 92.3% and 84.2%, respectively. MRI with free breathing was also more time efficient (
p
< 0.0001). Group statistics were comparable (
p
< 0.05).
Conclusions
The use of fast acquisition MRI protocols, particularly free breathing sequences, for patients admitted with suspected appendicitis can result in faster diagnosis, treatment and discharge. It also has a statistically significant diagnostic advantage over ultrasound. Additionally, the higher specificity of MR can reduce the number of negative appendectomies performed in tertiary centres.
Radiological imaging has a crucial role in pulmonary evaluation in cystic fibrosis (CF), having been shown to be more sensitive than pulmonary function testing at detecting structural lung changes. ...The present review summarizes the latest published information on established and evolving pulmonary imaging techniques for assessing people with this potentially life-limiting disorder.
Chest computed tomography (CT) has taken over the predominant role of chest radiography in many centres for the initial assessment and surveillance of CF lung disease. However, several emerging techniques offer a promising means of pulmonary imaging using less ionizing radiation. This is of particular importance given these patients tend to require repeated imaging throughout their lives from a young age. Such techniques include ultra-low-dose CT, tomosynthesis, dynamic radiography and magnetic resonance imaging. In addition, deep-learning algorithms are anticipated to improve diagnostic accuracy.
The recent introduction of triple-combination CF transmembrane regulator therapy has put further emphasis on the need for sensitive methods of monitoring treatment response to allow for early adaptation of treatment regimens in order to limit irreversible lung damage. Further research is needed to establish how emerging imaging techniques can contribute to this safely and effectively.
Tablet devices have recently been used in radiological image interpretation because they have a display resolution comparable to desktop LCD monitors. We identified a need to examine tablet display ...performance prior to their use in preliminary interpretation of radiological images. We compared the spatial and contrast resolution of a commercially available tablet display with a diagnostic grade 2 megapixel monochrome LCD using a contrast detail phantom. We also recorded reporting discrepancies, using the ACR RADPEER system, between preliminary interpretation of 100 emergency CT brain examinations on the tablet display and formal review on a diagnostic LCD. The iPad display performed inferiorly to the diagnostic monochrome display without the ability to zoom. When the software zoom function was enabled on the tablet device, comparable contrast detail phantom scores of 163 vs 165 points were achieved. No reporting discrepancies were encountered during the interpretation of 43 normal examinations and five cases of acute intracranial hemorrhage. There were seven RADPEER2 (understandable) misses when using the iPad display and 12 with the diagnostic LCD. Use of software zoom in the tablet device improved its contrast detail phantom score. The tablet allowed satisfactory identification of acute CT brain findings, but additional research will be required to examine the cause of “understandable” reporting discrepancies that occur when using tablet devices.
Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic ...lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1–359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1–359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5–4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1–359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice.
Background: FUS inclusions are hallmarks of certain neurodegenerative diseases.
Results: Expression of a highly aggregate prone FUS variant in transgenic mice causes proteinopathy and severe motor phenotype.
Conclusion: Aggregation of FUS is sufficient to recapitulate motor pathology typical for amyotrophic lateral sclerosis.
Significance: Understanding the role of protein aggregation in the development of human neurodegenerative diseases is crucial for designing efficient therapeutic approaches.
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