First‐in‐human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor,in patients with advanced solid tumors

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first‐in‐human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1‐3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1‐180 mg) was carried out to assess dose‐limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25‐(OH)₂‐vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140‐mg dose; one patient in the 180‐mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose‐dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose‐dependent increases were observed in all pharmacodynamic markers and plateaued at 100‐140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow‐up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.     

Human papillomavirus genotype contribution to cervical cancer and precancer: Implications for screening and vaccination in Japan

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012‐2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2‐3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type‐specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type‐specific RCs between CIN1 and CIN2‐3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type‐specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2‐3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2‐3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01‐4.98), followed by HPV31 (2.51, 1.54‐5.24), HPV18 (2.43, 1.59‐4.32), HPV35 (1.56, 0.43‐8.36), HPV33 (1.01, 0.49‐3.31), HPV52 (0.99, 0.76‐1.33), and HPV58 (0.97, 0.75‐1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71‐2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14‐0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9‐valent vaccine contributed to 89.7% (95% CI, 88.7‐90.7) of CIN2‐3/AIS and 93.8% (95% CI, 92.4‐95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9‐valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women.     

Intracellular claudin‐1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis

Claudins are the major component of tight junctions, which form a primary barrier to paracellular diffusion and maintain cell polarity in normal epithelia and endothelia. In cancer cells, claudins play additional roles besides serving as components of the tight junctions, and participate in anoikis or invasion. Among the claudin family proteins, claudin‐1 has the most promising potential, both diagnostically and prognostically, in many types of cancers, including oral, gastric, liver, and colon cancers. However, conflicting results have been reported in relation to the degree of claudin‐1 expression and the prognosis, suggesting that the expression level of claudin‐1 alone is not sufficient to analyze the relationship between claudin‐1 and cancer progression. As endocytic trafficking of claudin‐1 has been reported in several epithelial cell types in vitro, we aimed to determine whether intracellular localization of claudin‐1 is the missing aspect between claudin‐1 and cancer. We investigated the expression of claudin‐1 in 83 tongue squamous cell carcinoma (TSCC) pathological specimens. Although the expression level of claudin‐1 based on immunohistochemistry was not associated with TSCC progression, within the high claudin‐1 expression group, the incidence of intracellular localization of claudin‐1 was correlated with cervical lymph node metastasis. In an in vitro experiment, claudin‐1 was constitutively internalized in TSCC‐derived cells. Motility of TSCC‐derived cells was increased by deficiency of claudin‐1, suggesting that the decrease in cell‐surface claudin‐1 promoted the cell migration. Therefore, intracellular localization of claudin‐1 at the invasion front may represent a promising diagnostic marker of TSCC.     

The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model

Cancer Chemotherapy and Pharmacology - Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of...     

Predictive value of the coronary artery calcium score and advanced plaque characteristics: Post hoc analysis of the PREDICT registry

BackgroundWhether coronary plaque characteristics assessed in coronary computed tomography angiography (CCTA) in association with the coronary artery calcium score (CACS) have predictive value for coronary events is unclear. We aimed to examine the predictive value of the CACS and plaque characteristics for the occurrence of coronary events.MethodsAmong 2802 patients who were analyzed in the PREDICT registry, 2083 with suspected coronary artery disease (CAD) were studied using post hoc analysis. High-risk plaques were defined as having ≥2 adverse characteristics, such as low computed tomographic attenuation, positive remodeling, spotty calcification, and napkin-ring sign. An adjudicative composite of coronary events (cardiac death, nonfatal acute coronary syndrome, and coronary revascularization ≥3 months after indexed CCTA) were analyzed.ResultsSeventy-three (3.5%) patients had coronary events and 313 (15.0%) had high-risk plaques. Multivariate Cox proportional hazard analysis showed that high-risk plaques remained an independent predictor of coronary events (adjusted hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.13–3.34, P ?= ?0.0154), as well as the log-transformed CACS (adjusted HR 1.24, 95% CI 1.11–1.39, P ?= ?0.0002) and the presence of obstructive stenosis (adjusted HR 5.63, 95% CI 3.22–10.12, P 0.0001). In subgroup analyses, high-risk plaques were independently predictive only in the low CACS class (<100).ConclusionThis study shows that assessment of adverse features by coronary plaque imaging independently predicts coronary events in patients with suspected CAD and a low CACS. Our findings suggest that the clinical value of high-risk plaques to CACS and stenosis assessment appears marginal.