In addition to advanced non-small cell lung cancer, nanoparticle albumin-bound paclitaxel (nab-PTX) may also harbor potential benefit for patients with relapsed small cell lung cancer (SCLC), since ...weekly paclitaxel (PTX) shows modest activity for relapsed SCLC. We evaluated the efficacy and safety of both weekly nab-PTX and PTX for relapsed SCLC.We retrospectively reviewed 52 consecutive relapsed SCLC patients who were treated with weekly nab-PTX or PTX at our hospital.The response rate, median progression-free survival and overall survival with nab-PTX and PTX were 5.6 vs 8.8%, 3.2 vs 1.7 months, and 5.4 vs 4.5 months, respectively. No statistically significant differences were observed. There was no statistical difference between the 2 groups for ≥Grade 3 adverse events.Weekly nab-PTX and PTX showed similar activity for relapsed SCLC. The toxicity profile of nab-PTX was equally tolerable to that of PTX.
3150 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. ...Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . Table: see text
Crizotinib, approved in Japan (2017) for
-positive NSCLC, has limited real-world data.
Crizotinib monotherapy real-world effectiveness and treatment status were analyzed from claims data (June ...2017-March 2021; Japanese Medical Data Vision; 58 patients tested for
-NSCLC).
Median duration of treatment (DoT; primary end point), any line: 12.9 months; 22 patients on crizotinib, 23 discontinued, 13 receiving post-crizotinib treatment. 1L (n = 27) median DoT: 13.0 months (95% CI, 4.4-32.0 months); 13 patients on crizotinib; seven discontinued; seven receiving post-crizotinib treatment. 2L (n = 13) median DoT: 14.0 months (95% CI, 4.6-22.2 months); 2L+ (n = 31): nine patients on crizotinib; 16 discontinued; six receiving post-crizotinib treatment. Post-crizotinib treatments (chemotherapy, cancer immunotherapy, anti-VEGF/R) did not affect crizotinib DoT.
Data supplement crizotinib's effectiveness in
-positive NSCLC previously seen in clinical trials/real-world.
We analyzed the mechanisms underlying the ion transport induced by tert-butyl hydroperoxide (t-BOOH), a membrane-permeant oxidant that has been widely used as a model of oxidative stress, in human ...airway epithelial cells (Calu-3). We found that t-BOOH induced a short-circuit current that was composed of two distinct components, a peaked component (PC) and a sustained component (SC). Both components were reduced by the presence of H-89 (N-2-(4-bromocinnamylamino)ethyl-5-isoquinoline) 10 microM, a protein kinase A (PKA) inhibitor and clofilium (100 microM, a cAMP-dependent K+ channel inhibitor) but not by charybdotoxin (50 nM, a human intermediate conductance Ca2+-activated K+ channel inhibitor), suggesting that both PC and SC were generated through a common PKA-dependent/Ca2+-independent pathway. Notwithstanding, analyses of the physiological properties revealed that PC and SC were attributable to different pathways. PC, but not SC, was correlated with apical membrane Cl- conductance and was inhibited by the cyclooxygenase (COX)-2 inhibitor NS-398 (N-2-(cyclohexyloxyl)-4-nitrophenyl-methane sulfonamide; 10 microM). In contrast, SC, but not PC, was composed of a component sensitive to bumetanide (50 microM), an inhibitor of the basolateral Na+-K+-2Cl- cotransporter (NKCC1), and was abolished by the cytoskeleton dysfunction induced by cytochalasin D (10 microM) and (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane carboxamide (Y-27632; 20 microM). Collectively, t-BOOH induces PKA-related anion secretion through two independent pathways: rapid activation of apical anion efflux through a COX-2-dependent/cytoskeleton-independent pathway and relatively delayed activation of NKCC1 for basolateral anion uptake through a COX-2-independent/cytoskeleton-dependent pathway.
Purpose
The feasibility and safety of cavotricuspid isthmus (CTI) ablation with contiguous lesions using ablation index (AI) under the guidance of fluoroscopy integrated 3D mapping (CARTO UNIVU/CU) ...in typical atrial flutter (AFL) remains uncertain. This study aimed to determine the efficacy of AI-guided CTI ablation with contiguous lesions in patients with AFL.
Methods
In this single-center, prospective, non-randomized, single-arm, observational study, procedural outcomes were determined in 151 patients undergoing AI-guided CTI ablation (AI group) with a target AI value of 450 and an interlesion distance of ≤ 4 mm under CU guidance. These outcomes were compared with those of 30 patients undergoing non-AI-guided ablation (non-AI group).
Results
Among 151 patients, first-pass conduction block was achieved in 120 (80%) patients in the AI group (67% in the non-AI group,
P
= 0.152) with a shorter fluoroscopy time of 0.2 ± 0.4 min (1.7 ± 2.0 min in the non-AI group,
P
< 0.001). Conduction gaps were located at the atrial aspects near the inferior vena cava in 24 of 31 (78%) patients without first-pass conduction block. The AI group received 11 ± 5 (12 ± 4 in the non-AI group,
P
= 0.098) radiofrequency (RF) applications, and the RF time was 4.2 ± 2.4 (5.1 ± 2.5 min in the non-AI group,
P
= 0.011). Despite the occurrence of steam pop in 3 (2%) patients, none of them developed cardiac tamponade. No patients had recurrence within 6 months of follow-up.
Conclusions
AI-guided CTI ablation in combination with CU was feasible and effective in reducing radiation exposure in patients with AFL.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Certain oncogenes, including mutant RAS and BRAF, induce a type of senescence known as oncogene-induced senescence (OIS) in normal cells in a cell-type-specific manner. OIS serves as a barrier to ...transformation by activated oncogenes. Our previous studies showed that mutant KRAS
did not efficiently induce OIS in an hTERT/Cdk4-immortalized normal human bronchial epithelial cell line (HBEC3), but it did enhance both anchorage-dependent and anchorage-independent growth. In this study, we investigated whether mutant BRAF, a well-known inducer of OIS, could trigger OIS in HBEC3 cells. We also assessed the impact of mutant BRAF on the growth of HBEC3 cells, as no previous studies have examined this using a normal bronchial epithelial cell line model. We established an HBEC3 cell line, designated as HBEC3-BIN, that expresses mutant BRAF
in a doxycycline-regulated manner. Unlike our previous finding that KRAS
upregulated both pERK and pAKT, mutant BRAF
upregulated pERK but not pAKT in HBEC3-BIN cells. Similar to KRAS
, BRAF
did not efficiently induce OIS. Interestingly, while BRAF
inhibited colony formation in anchorage-dependent conditions, it dramatically enhanced colony formation in anchorage-independent conditions in HBEC3-BIN. In HBEC3 cells without BRAF
or KRAS
expression, p21 was only detected in the cytoplasm, and its localization was not altered by the expression of BRAF
or KRAS
. Next-generation sequencing analysis revealed an enrichment of gene sets known to be involved in carcinogenesis, including IL3/JAK/STAT3, IL2, STAT5, and the EMT pathway. Our results indicate that, unlike KRAS
, which promoted both, BRAF
enhances anchorage-independent growth but inhibits anchorage-dependent growth of HBEC3. This contrast may result from differences in activation signaling in the downstream pathways. Furthermore, HBEC3 cells appear to be inherently resistant to OIS, which may be partly due to the fact that p21 remains localized in the cytoplasm upon expression of BRAF
or KRAS
.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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