Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials ...evidence is meager.
A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms and Standard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (N=504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (N=1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all P<0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios ≥4 and ≤1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, P<0.001) with PG guidance.
These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862.
•Interobserver agreement for DLL3 expression is substantial among thoracic pathologists.•High DLL3 expression (≥ 50% of tumor cells) is observed in almost 80% of small cell lung ...carcinomas.•Approximately one third of atypical and typical carcinoid tumors show high DLL3 expression.•High DLL3 expression is associated with better overall survival in small cell lung carcinomas.
Delta-like protein 3 (DLL3), an inhibitory Notch ligand, is the target for rovalpituzumab tesirine in development for the treatment of small cell lung cancer (SCLC). We studied the expression of DLL3, its reproducibility and prognostic role in pulmonary neuroendocrine tumors.
Institutional pathology files were searched for resected pulmonary neuroendocrine tumors (1995–2017). Expression of DLL3 (clone SP347) was categorized as high (≥50% of tumor cells) or low (<50%). Interobserver agreement among 5 thoracic pathologists was measured by Krippendorff’s α coefficient. Staging (N = 148) was performed according to the 8th AJCC.
Our study included 157 patients with a median age of 62.2 years (range 23.2–88.1) including 59 men (37.6%). Tumors included 44 (28.0%) SCLC, 46 (29.3%) atypical and 67 (42.7%) typical carcinoid tumors at stages I (N = 83, 56.1%), II (N = 28, 18.9%), and III/IV (N = 37, 25.0%). Interobserver agreement for high vs low DLL3 expression (N = 70) was 82.9% (α = 0.79, substantial). High DLL3 expression was observed in 35 (79.5%) SCLC, 17 (37.0%) atypical and 22 (32.8%) typical carcinoid tumors. High DLL3 was associated with SCLC morphology (p < 0.0001). During a median follow-up of 4.2 years (range, 2 days–20.3 years), 70 patients died; 19 died from disease. High DLL3 expression was associated with better overall survival in SCLC (p = 0.049) but not after adjusting for age, tumor size and stage.
DLL3 expression is reliably quantifiable by pathologists and is highly expressed in the majority of SCLC and a subset of carcinoid tumors, making it an attractive target for anti-DLL3 treatment.
Oncogenic alterations in RET have been identified in multiple tumour types, including 1–2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour ...activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC.
ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis.
Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50–71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50–86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients 18%), hypertension (26 11%), and anaemia (24 10%); there were no treatment-related deaths in this population.
Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC.
Blueprint Medicines.
Rearranged during transfection (
) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and ...manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic
-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up.
Adult patients with advanced/metastatic
-mutant medullary thyroid cancer (MTC) or
fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with
-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with
-mutant MTC, and patients with previously treated
fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint.
As of October 18, 2021, the measurable disease population comprised of 61 patients with
-mutant MTC and prior C/V, 62 treatment-naïve patients with
-mutant MTC, and 22 patients with
fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% confidence interval; 95% CI: 42.4-68.5 in patients with
-mutant MTC and prior C/V, 77.4% 95% CI: 65.0-87.1 in treatment-naïve patients with
-mutant MTC, and 90.9% 95% CI: 70.8-98.9 in patients with previously treated
fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with
-mutant MTC and prior C/V, not reached in treatment-naïve patients with
-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated
fusion-positive thyroid cancer. In the
-altered thyroid cancer safety population (
= 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment.
In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic
altered thyroid cancer. Clinical Trial Registration: NCT03037385.
This is a summary of a research study called ARROW, which tested a medicine called pralsetinib in patients with non-small cell lung cancer (NSCLC), thyroid cancer, and other advanced solid tumours ...caused by a change in a gene called
. For the purposes of this summary, only patients with NSCLC with a change in
called fusion (
fusion+) are highlighted.
In total, 281 patients with
fusion+ NSCLC had taken part in this study across the USA, Europe, and Asia. Patients were asked to take four pills (adding up to 400 mg) of pralsetinib each day and were checked for any changes in their tumours, as well as for any side effects. After an average of 8 months of treatment with pralsetinib, 72% of previously untreated patients and 59% of patients who had previously received chemotherapy had considerable shrinkage of their tumours. Among 10 patients with tumours which had spread to the brain (all of whom had received previous treatments), 70% had their tumours shrink greatly in the brain after treatment with pralsetinib. On average, patients lived with little to no tumour growth for 16 months. In previously untreated patients, the most common severe side effects that were considered related to pralsetinib treatment were decreased white blood cells (neutrophils and lymphocytes), increased blood pressure, and an increase in a blood protein called creatine phosphokinase. In previously treated patients, the severe side effects were decreased white blood cells (neutrophils, lymphocytes, and leukocytes), increased blood pressure, and low levels of red blood cells. In both untreated and previously treated patients, the most common severe side effects that required hospital attention were lung inflammation/swelling causing shortness of breath (pneumonitis) and lung infection (pneumonia).
Overall, the ARROW study showed that pralsetinib was effective in shrinking tumours in patients with
fusion+ NSCLC regardless of previous treatment history. The recorded side effects were expected in patients receiving this type of medicine.
: NCT03037385 (ARROW) (ClinicalTrials.gov).
Electrically active constructs can have a beneficial effect on electroresponsive tissues, such as the brain, heart, and nervous system. Conducting polymers (CPs) are being considered as components of ...these constructs because of their intrinsic electroactive and flexible nature. However, their clinical application has been largely hampered by their short operational time due to a decrease in their electronic properties. We show that, by immobilizing the dopant in the conductive scaffold, we can prevent its electric deterioration. We grew polyaniline (PANI) doped with phytic acid on the surface of a chitosan film. The strong chelation between phytic acid and chitosan led to a conductive patch with retained electroactivity, low surface resistivity (35.85 ± 9.40 kilohms per square), and oxidized form after 2 weeks of incubation in physiological medium. Ex vivo experiments revealed that the conductive nature of the patch has an immediate effect on the electrophysiology of the heart. Preliminary in vivo experiments showed that the conductive patch does not induce proarrhythmogenic activities in the heart. Our findings set the foundation for the design of electronically stable CP-based scaffolds. This provides a robust conductive system that could be used at the interface with electroresponsive tissue to better understand the interaction and effect of these materials on the electrophysiology of these tissues.
Calorie restriction (CR) retards aging and increases longevity in many animal models. However, it is unclear whether CR can be implemented in humans without adverse effects on body composition.
We ...evaluated the effect of a 2-y CR regimen on body composition including the influence of sex and body mass index (BMI; in kg/m
) among participants enrolled in CALERIE-2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a multicenter, randomized controlled trial.
Participants were 218 nonobese (BMI: 21.9-28.0) adults aged 21-51 y who were randomly assigned to 25% CR (CR,
= 143) or ad libitum control (AL,
= 75) in a 2:1 ratio. Measures at baseline and 12 and 24 mo included body weight, waist circumference, fat mass (FM), fat-free mass (FFM), and appendicular mass by dual-energy X-ray absorptiometry; activity-related energy expenditure (AREE) by doubly labeled water; and dietary protein intake by self-report. Values are expressed as means ± SDs.
The CR group achieved 11.9% ± 0.7% CR over 2-y and had significant decreases in weight (-7.6 ± 0.3 compared with 0.4 ± 0.5 kg), waist circumference (-6.2 ± 0.4 compared with 0.9 ± 0.5 cm), FM (-5.4 ± 0.3 compared with 0.5 ± 0.4 kg), and FFM (-2.0 ± 0.2 compared with -0.0 ± 0.2 kg) at 24 mo relative to the AL group (all between-group
< 0.001). Moreover, FFM as a percentage of body weight at 24 mo was higher, and percentage of FM was lower in the CR group than in the AL. AREE, but not protein intake, predicted preservation of FFM during CR (
< 0.01). Men in the CR group lost significantly more trunk fat (
= 0.03) and FFM expressed as a percentage of weight loss (
< 0.001) than women in the CR group.
Two years of CR had broadly favorable effects on both whole-body and regional adiposity that could facilitate health span in humans. The decrements in FFM were commensurate with the reduced body mass; although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline. CALERIE was registered at clinicaltrials.gov as NCT00427193.
In this direct replication of Mueller and Oppenheimer’s (2014) Study 1, participants watched a lecture while taking notes with a laptop (n = 74) or longhand (n = 68). After a brief distraction and ...without the opportunity to study, they took a quiz. As in the original study, laptop participants took notes containing more words spoken verbatim by the lecturer and more words overall than did longhand participants. However, laptop participants did not perform better than longhand participants on the quiz. Exploratory meta-analyses of eight similar studies echoed this pattern. In addition, in both the original study and our replication, higher word count was associated with better quiz performance, and higher verbatim overlap was associated with worse quiz performance, but the latter finding was not robust in our replication. Overall, results do not support the idea that longhand note taking improves immediate learning via better encoding of information.
The hrp gene clusters of plant pathogenic bacteria control pathogenicity on their host plants and ability to elicit the hypersensitive reaction in resistant plants. Some hrp gene products constitute ...elements of the type III secretion system, by which effector proteins are exported and delivered into plant cells. Here, we show that the hrpZ gene product from the bean halo-blight pathogen, Pseudomonas syringae pv. phaseolicola (HrpZ Psph ), is secreted in an hrp -dependent manner in P. syringae pv. phaseolicola and exported by the type III secretion system in the mammalian pathogen Yersinia enterocolitica . HrpZ Psph was found to associate stably with liposomes and synthetic bilayer membranes. Under symmetric ionic conditions, addition of 2 nM of purified recombinant HrpZ Psph to the cis compartment of planar lipid bilayers provoked an ion current with a large unitary conductivity of 207 pS. HrpZ Psph -related proteins from P. syringae pv. tomato or syringae triggered ion currents similar to those stimulated by HrpZ Psph . The HrpZ Psph -mediated ion-conducting pore was permeable for cations but did not mediate fluxes of Cl − . Such pore-forming activity may allow nutrient release and/or delivery of virulence factors during bacterial colonization of host plants.
Neural fibrolipoma of the foot Ly, Justin Q; Bui-Mansfield, Liem T; SanDiego, Jerry W ...
Journal of computer assisted tomography,
07/2003, Volume:
27, Issue:
4
Journal Article
Peer reviewed
Neural fibrolipoma is a benign tumor comprised of hypertrophied fibrofatty tissue with intermixed nerve tissue. We present the case of a neural fibrolipoma of the foot that underwent above-ankle ...amputation and review the characteristic features of this unique form of localized gigantism.
PDF
