We investigated circulatory dynamics in patients with vasodepressor type neurally mediated syncope (VT-NMS) by performing high-resolution Holter electrocardiography and a correlation analysis of ...changes in adenylate cyclase activity, blood pressure, and pulse during the head-up tilt test. Holter electrocardiography was performed for 30 patients. Adenylate cyclase activity was evaluated in lymphocytes from blood samples taken at rest and during the head-up tilt test. There was no change in autonomic nerve fluctuation during electrocardiography in VT-NMS patients, but our results showed a significant difference in blood pressure and adenylate cyclase activity between VT-NMS patients and healthy volunteers; the systolic blood pressure of VT-NMS patients decreased after 5 min, while at 10 min, the adenylate cyclase activity was the highest (0.53%) and the systolic blood pressure was the lowest (111.8 mm Hg). Pulse rates increased after 10 min. VT-NMS patients showed higher blood pressure, pulse rate, and adenylate cyclase activity during the tilt test than did healthy volunteers. In patients with syncope, standing for longer than 10 minutes may increase the risk of VT-NMS. From our results, we consider it likely that high systolic blood pressure and adenylate cyclase activity at rest cause fainting in VT-NMS patients. Our findings may be helpful for identifying individuals with a high risk of developing NMS in the healthy population.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Thyroid dysfunction is frequently caused by treatment with antiprogrammed cell death-1 ligand 1 antibodies (PD-L1-Abs) and anticancer drugs, including ramucirumab (RAM) and multitargeted tyrosine ...kinase inhibitors (multi-TKIs), which are often used prior to PD-L1-Ab treatment in cancer patients.
A total of 148 patients treated with PD-L1-Abs were evaluated for antithyroid antibodies at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation and then were observed until the visits stopped.
Of the 148 patients, 15 (10.1%) developed thyroid dysfunction after PD-L1-Ab treatment (destructive thyroiditis in 8 and hypothyroidism without preceding thyrotoxicosis in 7). The prevalence of an elevated thyroid-stimulating hormone (TSH) level at baseline (3/15 20.0% vs 4/133 3.0%, P < .05), positive antithyroglobulin antibodies (TgAbs) at baseline (4/15 26.7% vs 5/133 3.8%, P < .05) and prior treatment with RAM or multi-TKIs (3/15 20.0% vs 5/133 3.8%, P < .05) were significantly higher in patients with vs without thyroid dysfunction. In a multivariate analysis, elevated TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs were significantly associated with the development of thyroid dysfunction, with ORs of 7.098 (95% CI 1.154-43.638), 11.927 (95% CI 2.526-56.316), and 8.476 (95% CI 1.592-45.115), respectively.
The results of this real-world study suggest that the risk of thyroid dysfunction induced by PD-L1-Abs can be predicted by the TSH level at baseline, TgAb positivity at baseline, and prior treatment with RAM or multi-TKIs.
Lorlatinib is a potent, brain‐penetrant, third‐generation anaplastic lymphoma kinase (ALK)/ROS proto‐oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance ...mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK‐rearranged/ROS1‐rearranged advanced non–small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC‐ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK‐rearranged/ROS1‐rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty‐one ALK‐rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC‐ORR. The ORR and the IC‐ORR for Japanese patients in EXP2‐5 were 54.8% (95% confidence interval CI: 36.0‐72.7) and 46.7% (95% CI: 21.3‐73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9‐81.6). The most common treatment‐related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single‐dose and multiple‐dose pharmacokinetic profiles among Japanese patients were similar to those in non–Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK‐rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
Lorlatinib showed clinically meaningful responses (54.8%; 95% CI: 36.0‐72.7) and intracranial responses (46.7%; 95% CI: 21.3‐73.4) among ALK‐rearranged Japanese patients with non–small cell lung cancer who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only (42.9%; 95% CI: 9.9‐81.6). Lorlatinib was generally well tolerated, with a similar adverse event profile among Japanese patients to that among the overall population.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Squamous cell carcinoma (SCC) transformation has been identified as a mechanism of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or ...erlotinib, in EGFR-mutated lung cancer. However, whether second- or third-generation TKIs can overcome resistance due to SCC transformation remains unclear. We herein report an EGFR-mutated lung adenocarcinoma undergoing transformation into SCC that exhibited a durable response to afatinib, which is a second-generation irreversible EGFR-TKI. We suggest that afatinib can be considered as a treatment option for EGFR-mutated tumor undergoing SCC transformation, particularly in the absence of a T790M mutation.
Abstract
Background
MET exon 14 skipping is an oncogenic driver occurring in 3–4% of non-small cell lung cancer (NSCLC). The MET inhibitor tepotinib has demonstrated clinical efficacy in patients ...with MET exon 14 skipping NSCLC. Here, we present data from Japanese patients in the Phase II VISION study, evaluating the efficacy and safety of tepotinib.
Methods
In the open-label, single-arm, Phase II VISION study, patients with advanced/metastatic NSCLC with MET exon 14 skipping received oral tepotinib 500 mg once daily. The primary endpoint was objective response by independent review. Subgroup analyses of Japanese patients were preplanned.
Results
As of 1 January 2020, 19 Japanese patients received tepotinib and were evaluated for safety, 15 of whom had ≥9 months’ follow-up and were also analysed for efficacy. By independent review, objective response rate (ORR) was 60.0% (95% confidence interval CI: 32.3, 83.7), median duration of response was not reached (95% CI: 6.9, not estimable ne), and progression-free survival was 11.0 months (95% CI: 1.4, ne). ORR in patients with MET exon 14 skipping identified by liquid biopsy (n = 8) was 87.5% (95% CI: 47.3, 99.7), and by tissue biopsy (n = 12) was 50.0% (95% CI: 21.1, 78.9). Patients’ quality of life was maintained with tepotinib treatment. Among patients evaluated for safety, the most common treatment-related adverse events (any grade) were blood creatinine increase and peripheral oedema (12 and nine patients, respectively).
Conclusions
Tepotinib demonstrated robust and durable clinical efficacy in Japanese patients with advanced NSCLC harbouring MET exon 14 skipping, identified by either liquid or tissue biopsy. The main adverse events, blood creatinine increase and peripheral oedema, were manageable.
In VISION, tepotinib demonstrated robust efficacy in Japanese patients with MET exon 14 skipping NSCLC. The safety profile was tolerable, with mostly mild–moderate adverse events and few treatment discontinuations.
The “bud” of an aortic aneurysm Yamaguchi, Tetsuo; Morise, Masahiro; Sato, Atsuhiko ...
Clinical case reports,
October 2021, Volume:
9, Issue:
10
Journal Article
Peer reviewed
Open access
An overlooked “bud” of an aortic aneurysm on a chest radiography resulted in a saccular aortic aneurysm 9 years later. This eye‐catching image showed us the importance of not only documenting ...abnormalities in regular radiography but also further imaging evaluation for definitive diagnosis and continuous image follow‐up.
A chest radiography plays an important role to detect an early sign of critical diseases. In this case, thoracic aortic aneurysm “buds” in the chest radiography was overlooked and it enlarged later. It is important for physicians not only to document abnormal findings but also make close inspection.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Carboplatin (CBDCA)-induced emetic risk is currently classified on the basis of CBDCA-area under the curve (CBDCA-AUC). We investigated the utility of three CBDCA dosage parameters for predicting ...emesis by CBDCA. Patients with thoracic cancer treated with CBDCA were included. The endpoints were complete response (CR) and total control (TC). CR was defined as no vomiting and no use of rescue medication during the overall assessment period, whereas TC was defined as no vomiting, nausea, nor use of rescue medication during the overall assessment period. The parameters of CBDCA were defined as follows: (1) CBDCA-AUC; (2) CBDCA/body surface area (BSA): the administered dose of CBDCA per body surface area (mg/m
); and (3) total CBDCA/body: the total administered dose of CBDCA (mg). Eighty-five patients were evaluated. The median CBDCA/BSA but not CBDCA-AUC was higher in patients with non-CR compared to those with CR. Receiver operating characteristic curve analysis revealed that the AUC of CBDCA/BSA for predicting non-CR was higher than that of CBDCA-AUC. CBDCA/BSA shows greater potential for predicting CBDCA-induced emetic risk compared with CBDCA-AUC, which is the parameter in current antiemetic guidelines.
To identify potential therapeutic targets for lung cancer, we performed semi‐genome‐wide shRNA screening combined with the utilization of genome‐wide expression and copy number data. shRNA screening ...targeting 5043 genes in NCI‐H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer.
By doing an integrative analysis we have identified PSMA6, a subunit of the proteasome complex, as one of the most promising targets for lung cancer. We showed that PSMA6 knockdown suppressed the viability of cancer cells through the induction of apoptosis or cell cycle arrest at G2/M, with only a minimal effect on normal lung epithelial cells. Our data suggested that targeting PSMA6 for lung cancer may be an attractive novel therapeutic strategy.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
