1. |
- Glasbey, JC, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
2. |
|
|
3. |
|
|
4. |
|
|
5. |
|
|
6. |
|
|
7. |
- Musher, Benjamin L., et al.
(författare)
-
LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001) results from arm 1 of a non-randomised, single-centre, phase 1/2 study
- 2024
-
Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 25:4, s. 488-500
-
Tidskriftsartikel (refereegranskat)abstract
- Background Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. Methods LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m 2 plus gemcitabine 1000 mg/m 2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 mu L of LOAd703 at 5 x 10 10 (dose 1), 1 x 10 11 (dose 2), or 5 x 10 11 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants. Findings Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8 + effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response. Interpretation Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing.
|
|
8. |
|
|
9. |
- Nijs, Jo, et al.
(författare)
-
Nociceptive, neuropathic, or nociplastic low back pain? : The low back pain phenotyping (BACPAP) consortium's international and multidisciplinary consensus recommendations
- 2024
-
Ingår i: The Lancet Rheumatology. - : Elsevier. - 2665-9913. ; 6:3, s. e178-e188
-
Tidskriftsartikel (refereegranskat)abstract
- The potential to classify low back pain as being characterised by dominant nociceptive, neuropathic, or nociplastic mechanisms is a clinically relevant issue. Preliminary evidence suggests that these low back pain phenotypes might respond differently to treatments; however, more research must be done before making specific recommendations. Accordingly, the low back pain phenotyping (BACPAP) consortium was established as a group of 36 clinicians and researchers from 13 countries (five continents) and 29 institutions, to apply a modified Nominal Group Technique methodology to develop international and multidisciplinary consensus recommendations to provide guidance for identifying the dominant pain phenotype in patients with low back pain, and potentially adapt pain management strategies. The BACPAP consortium's recommendations are also intended to provide direction for future clinical research by building on the established clinical criteria for neuropathic and nociplastic pain. The BACPAP consortium's consensus recommendations are a necessary early step in the process to determine if personalised pain medicine based on pain phenotypes is feasible for low back pain management. Therefore, these recommendations are not ready to be implemented in clinical practice until additional evidence is generated that is specific to these low back pain phenotypes.
|
|
10. |
- Topuz, G, et al.
(författare)
-
Silurian anorogenic basic and acidic magmatism in Northwest Turkey: Implications for the opening of the Paleo-Tethys
- 2020
-
Ingår i: Lithos. - : Elsevier BV. - 0024-4937. ; 356-357
-
Tidskriftsartikel (refereegranskat)abstract
- © 2019 Elsevier B.V. The Sakarya Zone (northern Turkey) is a Gondwana-derived continental block accreted to northern Laurussia during the Carboniferous, and is regarded as the eastward extension of Armorica. Timing of its detachment from the northern margin of Gondwana, thus opening of the Paleo-Tethys, is poorly known. Here, we report on metagranite and amphibolite with Silurian igneous crystallization ages from the Early Carboniferous high-temperature/middle to low-pressure amphibolite-facies metamorphic rocks of the Sarıcakaya Massif within the Sakarya Zone (NW Turkey). The metagranite-amphibolite complex is exposed mainly along the southern margin of the Sarıcakaya Massif over an area of ca. 12 km by 1.5 km. The metagranite contains preserved domains of porphyric texture, indicative of derivation from a former granite porphyry. The amphibolite is devoid of any relict igneous texture. Both the metagranite and amphibolite are crosscut by late up to 50 cm thick felsic veins. Uranium-Pb dating on igneous zircons from both metagranite and amphibolite yielded Silurian ages of ca. 419 ± 6 to 434 ± 7 Ma (2σ), and on those from a felsic vein an age of 319 ± 5 Ma (2σ) (Late Carboniferous). Geochemically, amphibolite displays anorogenic transitional tholeiitic to alkaline signatures. Initial εHf values of the igneous zircons from both metagranite and amphibolite show a large variation with medial values of −16 to −9 and + 3 to +6, respectively. Thus, the protoliths of amphibolite were derived from melts of depleted mantle, and those of the metagranite, on the other hand, from melts of reworked crustal material. We suggest that the Silurian anorogenic magmatism is related to a rifting event at the northern margin of Gondwana leading to the detachment of the Sakarya Zone and hence placing an age on the initial opening of the Paleo-Tethys. This interpretation is based on (i) the presence of Late Silurian to Devonian deep-sea sedimentary blocks in the Paleo-Tethyan accretionary complexes, and (ii) the resemblance of the U[sbnd]Pb age spectra of detrital zircons in the metaclastic sequence of the Sarıcakaya Massif to those of Cambro-Ordovician sandstones in Jordan (Gondwana), and (iii) the local occurrence of anorogenic A-type granites of Late Ordovician-Silurian age in the Anatolide-Tauride Block, a continental block which rifted from Gondwana during the Early Triassic. Wholly anorogenic nature of the Late Ordovician to Silurian igneous rocks in the Sarıcakaya Massif and reported in literature does not support the opening of the Paleo-Tethys as back-arc ocean, as suggested in most paleogeographic reconstructions.
|
|