Nivolumab is approved as an option for third- or later-line treatment of advanced gastric/gastroesophageal junction (G/GEJ) cancer in several countries after ATTRACTION-2. To further improve the ...therapeutic efficacy of first-line therapy, exploration of a nivolumab-chemotherapy combination is warranted. In part 1 (phase II) of ATTRACTION-4, the safety and efficacy of nivolumab combined with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (CapeOX) as first-line therapy for unresectable advanced or recurrent human epidermal growth factor receptor 2 (HER2)-negative G/GEJ cancer were evaluated.
Patients were randomized (1 : 1) to receive nivolumab (360 mg intravenously every 3 weeks) plus SOX (S-1, 40 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) or CapeOX (capecitabine, 1000 mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130 mg/m2 intravenously on day 1 every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal.
Of 40 randomized patients, 39 (nivolumab plus SOX, 21; nivolumab plus CapeOX, 18) and 38 (21 and 17, respectively) comprised the safety and efficacy populations, respectively. Most frequent (>10%) grade 3/4 treatment-related adverse events were neutropenia (14.3%) in the nivolumab plus SOX group, and neutropenia (16.7%), anemia, peripheral sensory neuropathy, decreased appetite, type 1 diabetes mellitus, and nausea (11.1% each) in the nivolumab plus CapeOX group. No treatment-related death occurred. Objective response rate was 57.1% (95% confidence interval 34.0–78.2) with nivolumab plus SOX and 76.5% (50.1–93.2) with nivolumab plus CapeOX. Median overall survival was not reached (NR) in both groups. Median progression-free survival was 9.7 months (5.8–NR) and 10.6 months (5.6–12.5), respectively.
Nivolumab combined with SOX/CapeOX was well tolerated and demonstrated encouraging efficacy for unresectable advanced or recurrent HER2-negative G/GEJ cancer. ATTRACTION-4 has proceeded to part 2 (phase III) to compare nivolumab plus SOX/CapeOX versus placebo plus SOX/CapeOX.
NCT02746796.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) ...reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS).
We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0−1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea.
Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC median OS: 13.4months with GC and 15.1months with GS, HR, 0.945; 90% confidence interval (CI), 0.78–1.15; P=0.046 for non-inferiority. The median PFS was 5.8months with GC and 6.8months with GS (HR 0.86; 95% CI 0.70–1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm.
GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC.
This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Introduction
There is a continuing worldwide shortage of organs from deceased human donors for transplantation into patients with end-stage organ failure. Genetically engineered pigs could ...resolve this problem, and could also provide tissues and cells for the treatment of conditions such as diabetes, Parkinson’s disease and corneal blindness.
Sources of data
The current literature has been reviewed.
Areas of agreement
The pathobiologic barriers are now largely defined. Research progress has advanced through the increasing availability of genetically engineered pigs and novel immunosuppressive agents. Life-supporting pig kidneys and islets have functioned for months or years in nonhuman primates.
Areas of controversy
The potential risk of transfer of a pig infectious microorganism to the recipient continues to be debated.
Growing points
Increased attention is being paid to selection of patients for initial clinical trials.
Areas timely for developing research
Most of the advances required to justify a clinical trial have now been met.
Background and Purpose
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no effective treatment. Fasudil hydrochloride (fasudil), a potent rho kinase (ROCK) inhibitor, is ...useful for the treatment of ischaemic diseases. In previous reports, fasudil improved pathology in mouse models of Alzheimer's disease and spinal muscular atrophy, but there is no evidence in that it can affect ALS. We therefore investigated its effects on experimental models of ALS.
Experimental Approach
In mice motor neuron (NSC34) cells, the neuroprotective effect of hydroxyfasudil (M3), an active metabolite of fasudil, and its mechanism were evaluated. Moreover, the effects of fasudil, 30 and 100 mg·kg−1, administered via drinking water to mutant superoxide dismutase 1 (SOD1G93A) mice were tested by measuring motor performance, survival time and histological changes, and its mechanism investigated.
Key Results
M3 prevented motor neuron cell death induced by SOD1G93A. Furthermore, M3 suppressed both the increase in ROCK activity and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and the reduction in phosphorylated Akt induced by SOD1G93A. These effects of M3 were attenuated by treatment with a PI3K inhibitor (LY294002). Moreover, fasudil slowed disease progression, increased survival time and reduced motor neuron loss, in SOD1G93A mice. Fasudil also attenuated the increase in ROCK activity and PTEN, and the reduction in Akt in SOD1G93A mice.
Conclusions and Implications
These findings indicate that fasudil may be effective at suppressing motor neuron degeneration and symptom progression in ALS. Hence, fasudil may have potential as a therapeutic agent for ALS treatment.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
The purpose of this paper is to report on the relationship between lymphoscintigraphic findings and the operative results of lymphaticovenous anastomosis (LVA) as well as the resection of genital ...acquired lymphangiectasia (GAL). Seventeen patients with GAL who underwent lymphoscintigraphy between April 2012 and June 2016 were included in this retrospective study. LVA and GAL resections were performed for 14 patients. The GALs were resected in a spindle shape to the full thickness of the genital skin, and the wounds were closed primarily. Following the procedure, we investigated the recurrence rate and compared the results with the lymphoscintigraphic findings. The average follow-up period was 19.2 months. Six patients were without recurrence, and eight patients experienced a small recurrence of GAL. The average period from operation to recurrence was 16.8 months (range: 1–41 months). Of the six patients who had genital accumulation in lymphoscintigraphy, two patients experienced recurrence (33.3%), whereas six of the eight patients without genital accumulation experienced recurrence (75.0%). The frequency of cellulitis was observed to be reduced postoperatively in all patients, and recurrence was observed in one patient at 11 months postoperatively. In conclusion, lower limb LVA combined with genital skin tumor resection was effective for preventing the recurrence of GAL in patients who demonstrated communication between the lymphatic vessels in the lower limb and genitals. This procedure also had the benefit of reducing the frequency of cellulitis for an average of 19.2 months of follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Fusion reactions of size-selected linear polyyne molecules, C10H2, in the ultrathin one-dimensional (1D) nanospace of double wall carbon nanotubes (DWCNTs) have been observed, leading to the ...formation of very long linear carbon chains. The formation and growth of long linear carbon chains is investigated by Raman spectroscopy and density-functional tight-binding-based molecular dynamics simulations. The high-resolution transmission electron microscope images of C10H2@DWCNTs show that the encapsulated linear C10H2 molecules have a length of 1.2–1.3 nm. After the high temperature annealing at 1073–1273 K under high vacuum conditions, new Raman bands appear at 1800–1850 cm–1, and the Raman bands arising from encapsulated pristine polyyne molecules at 2000–2200 cm–1 completely disappear. This is clear evidence that a fusion reaction occurs to form long linear carbon chains inside the 1D nanospace of DWCNTs.
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IJS, KILJ, NUK, PNG, UL, UM
We analyze solar elemental abundances in coronal post-flare loops of an X8.3 flare (SOL2017-09-10T16:06) observed on the west limb on 2017 September 10 near 18 UT using spectra recorded by the ...Extreme-ultraviolet Imaging Spectrometer (EIS) on the Hinode spacecraft. The abundances in the corona can differ from photospheric abundances due to the first ionization potential (FIP) effect. In some loops of this flare, we find that the abundances appear to be coronal at the loop apices or cusps, but steadily transform from coronal to photospheric as the loop footpoint is approached. This result is found from the intensity ratio of a low-FIP ion spectral line (Ca xiv) to a high-FIP ion spectral line (Ar xiv) formed at about the same temperature (4-5 MK). Both lines are observed close in wavelength. Temperature, which could alter the interpretation, does not appear to be a factor based on intensity ratios of Ca xv lines to a Ca xiv line. We discuss the abundance result in terms of the Laming model of the FIP effect, which is explained by the action of the ponderomotive force in magnetohydrodynamic (MHD) waves in coronal loops and in the underlying chromosphere.
Abstract Toll-like receptors (TLRs) are signaling receptors in the innate immune system that is a specific immunologic response to systemic bacterial infection. We investigated whether cerebral ...ischemia induced by the middle cerebral artery occlusion (MCAO) for 2 h differed in mice that lack a functional TLR3, TLR4, or TLR9 signaling pathway. TLR4, but not TLR3 or TLR9, knock-out (KO) mice had significantly smaller infarct area and volume at 24 h after ischemia-reperfusion (I/R) compared with wild-type mice. In addition, TLR4 KO mice improved in neurological deficits after I/R compared with wild-type mice. Moreover, we investigated the expression of TLR4 in the ischemic brain with immunohistochemistry. The number of TLR4-positive cells gradually increased from 1 h after MCAO to 22 h after I/R. We also examined the localization of TLR4 in the ischemic area. TLR4 was localized with CD11b-positive microglial cells in the ischemic striatum and the number of CD11b-positive microglial cells was smaller in TLR4 KO mice than in wild-type mice. In addition, we investigated the translocation of NF-κB among TLR3, 4, and 9 KO mice after I/R injury using western blotting. NF-κB's p65 subunit was decreased in TLR4 KO mice compared to wild-type mice, but not TLR3 or 9 KO mice. These data suggest that TLR4 knockout, but not TLR3 or TLR9 knockout, may play a neuroprotective role in ischemic brain injury induced by MCAO in mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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