Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the ...relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies.
Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing.
A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients.
Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.
Recently, MLS (Mobile Laser Scanning) has been successfully used in a road maintenance. In this paper, we present the application of MLS for the inspection of clearance along railway tracks of West ...Japan Railway Company. Point clouds around the track are captured by MLS mounted on a bogie and rail position can be determined by matching the shape of the ideal rail head with respect to the point cloud by ICP algorithm. A clearance check is executed automatically with virtual clearance model laid along the extracted rail. As a result of evaluation, the accuracy of extracting rail positions is less than 3 mm. With respect to the automatic clearance check, the objects inside the clearance and the ones related to a contact line is successfully detected by visual confirmation.
Endovascular therapy (EVT) utilizing percutaneous transluminal angioplasty has become a standard technique to re-establish sufficient blood flow in ischemic limbs of patients with peripheral arterial ...disease (PAD). Long chronic total occlusion (CTO) of the superficial femoral artery (SFA) remains one of the challenging lesions in the field of EVT for PAD patients, despite the recent introduction of many dedicated interventional devices such as high-performance guidewires. In this article, we report a novel interventional technique, trans-collateral angioplasty (TCA), to improve the initial success rate of EVT for long SFA-CTO lesions. We present one representative case, and describe the technical tips and appropriate device selection criteria for the TCA procedure. The outcomes of TCA for long SFA-CTO performed last year at our institution are also summarized and discussed.
: Pruritus is an important symptom in atopic dermatitis (AD), but the major pruritogen have not been identified. NC/Nga mice, spontaneously develop an eczematous AD‐like skin lesion when kept under ...conventional conditions, but not under specific pathogen‐free (SPF) conditions, have been thought to be an animal model for AD. In this study, to determine whether newly identified cytokine, IL‐31, may be involved in pruritus of AD, we examined the IL‐31 expression in spontaneous dermatitis model which showed itch‐associated long‐lasting (over 1.5 s duration) scratching behavior and compared with that of hapten‐induced contact dermatitis model without itch‐associated long‐lasting scratching behavior, using NC/Nga mice. In NC/Nga mice cohabited with NC/Nga mice which developed severe dermatitis for 2 weeks (conventional NC/Nga mice), the numbers of long‐lasting scratching counts were significantly increased. Yet in 2,4,6‐trinitrochlorobenzene (TNCB)‐sensitized and challenged mice (TNCB‐applied NC/Nga mice), no significant increase in long‐lasting scratching counts was observed. In conventional NC/Nga mice with long‐lasting scratching behavior, expression of IL‐31 mRNA was increased, while in TNCB‐applied NC/Nga mice without long‐lasting scratching behavior, the expression of IL‐31 mRNA were unchanged. There was a good correlation between the scratching counts and expression of IL‐31 mRNA in conventional NC/Nga mice, but not so in TNCB‐applied NC/Nga mice. These results suggest that IL‐31 causes the itch‐associated scratching behavior in conventional NC/Nga mice, an experimental animal model for AD.
Some regulators of plant growth and differentiation have been shown to induce the differentiation of several human myeloid leukemia cells, and might be effective as differentiation inducers to ...control acute myelogenous leukemia cells. In this study, the growth-inhibiting and differentiation-inducing effects of jasmonates on human myeloid leukemia cells were examined. Several myeloid leukemia cells were cultured with methyl jasmonate (MJ) and its derivatives. Cell differentiation was determined by nitroblue tetrazolium-reducing activity, morphological changes, alpha-naphthyl acetate esterase activity and expression of differentiation-associated surface antigens. MJ induced both monocytic and granulocytic differentiation of HL-60 cells. MJ activated mitogen-activated protein kinase (MAPK) in the cells before causing myelomonocytic differentiation. MAPK activation was necessary for MJ-induced differentiation, since PD98059, an inhibitor of MAPK kinase, suppressed the differentiation induced by MJ. MJ also induced the differentiation of other human leukemia cell lines. Introduction of a double bond at the 4,5-position greatly enhanced the differentiation-inducing activity of MJ. MJ and its derivatives potently induce the differentiation of some myelomonocytic leukemia cells. One novel derivative is a particularly promising therapeutic agent for the treatment of leukemia.
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