•First long-term OS data of erlotinib + bevacizumab vs erlotinib in this population.•Both treatment arms showed a similar median OS of approximately 4 years.•Results of EGFR and VEGF inhibitor ...combination therapies are eagerly awaited.
The JO25567 randomized Phase II study demonstrated a statistically significant progression-free survival (PFS) benefit with erlotinib plus bevacizumab compared with erlotinib monotherapy in chemotherapy-naïve Japanese patients with epidermal growth factor receptor mutation-positive (EGFR+) non-small-cell lung cancer (NSCLC). Here we present updated PFS and final overall survival (OS) data after a median follow-up of 34.7 months.
Patients with stage IIIB/IV or postoperative recurrent NSCLC were randomized to receive oral erlotinib 150 mg once daily (n = 77) or erlotinib in combination with intravenous bevacizumab 15 mg/kg every 21 days (n = 75) until disease progression or unacceptable toxicity. OS was analyzed using an unstratified Cox proportional hazards model.
Consistent with the primary analysis, addition of bevacizumab to erlotinib was associated with a significant improvement in PFS (hazard ratio HR 0.52; 95 % confidence interval CI: 0.35–0.76; log-rank two-sided P = 0.0005; median 16.4 months vs 9.8 months, respectively). In contrast, a significant improvement in OS was not seen (HR 0.81; 95 % CI, 0.53–1.23; P = 0.3267; median 47.0 months vs 47.4 months, respectively). Post-study therapy was similar between the treatment arms and EGFR mutation type did not affect OS outcomes. The 5-year OS rate was numerically higher with erlotinib plus bevacizumab vs erlotinib monotherapy (41 % vs 35 %). Updated safety analyses confirmed the previously reported manageable tolerability profile, with no new safety issues.
Addition of bevacizumab to first-line erlotinib did not show significant improvement in OS in Japanese patients with stage IIIB/IV or postoperative recurrent EGFR+ NSCLC. Both treatment arms showed a similar median OS benefit (as long as 4 years), irrespective of individual patient characteristics. Results from ongoing studies evaluating the combination of EGFR and VEGF signaling inhibitors are eagerly awaited.
JapicCTI-111390 and JapicCTI-142569.
Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of ...anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM.
We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan–Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies.
In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group 6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03).
Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.
•Acral melanoma is a distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma.•We retrospectively examined advanced-stage acral melanoma patients treated with an anti-PD-1 antibody.•Anti-PD-1 antibodies have limited efficacy in Japanese acral melanoma patients.•Patients with nail apparatus melanoma had poorer response and survival than patients with palm and sole melanoma.
Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety ...and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody.
Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25–75 mg p.o. twice a day; continuous or intermittent), savolitinib (600–800 mg p.o. once a day), or durvalumab (3–10 mg/kg intravenous every 2 weeks).
At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm—diarrhea (75%), rash (58%), nausea (47%); savolitinib arm—nausea (67%), rash (56%), vomiting (50%); durvalumab arm—rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively.
Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated.
NCT02143466.
•Patients with advanced EGFR-mutant NSCLC received osimertinib 80 mg combined with selumetinib, savolitinib or durvalumab.•Feasible dosing strategies were identified for osimertinib plus selumetinib or savolitinib.•Osimertinib plus durvalumab was not feasible due to increased reporting of interstitial lung disease.•Responses were seen in all treatment arms, warranting further analysis of the feasible combinations identified.•Osimertinib-based combinations represent a compelling approach now being investigated broadly to further improve outcomes.
It is beneficial to evaluate changes in neuroscience research field regarding research directions and topics over a defined period. Such information enables stakeholders to quickly identify the most ...influential research and incorporate latest evidence into research-informed education. To our knowledge, no study reported changes in neuroscience literature over the last decade. Therefore, the current study determined research terms with highest citation scores, compared publication shares of research areas and contributing countries in this field from 2006 to 2015 and identified the most productive journals.
Data were extracted from Web of Science and Journal Citation Reports (JCR). Only articles and reviews published in journals classified under the JCR "Neurosciences" category over the period of interest were included. Title and abstract fields of each included publication were extracted and analyzed via VOSviewer to identify recurring terms with high relative citation scores. Two term maps were produced for publications over the study period to illustrate the extent of co-occurrence, and the impact of terms was evaluated based on their relative citation scores. To further describe the recent research priority or "hot spots," 10 terms with the highest relative citation scores were identified annually. In addition, by applying Bradford's law, we identified 10 journals being the most productive journals per annum over the survey period and evaluated their bilbiometric performances.
From 2006 to 2015, there were 47 terms involved in the annual lists of top 10 terms with highest relative citation scores. The most frequently recurring terms were autism (8), meta-analysis (7), functional connectivity (6), default mode network (4) and neuroimaging (4). Neuroscience research related to psychology and behavioral sciences showed an increase in publication share over the survey period, and China has become one of the major contributors to neuroscience research. Ten journals were frequently identified (≥8 years) as core journals within the survey period.
The landscape of neuroscience research has changed recently, and this paper provides contemporary overview for researchers and health care workers interested in this field's research and developments. Brain imaging and brain connectivity terms had high relative citation scores.
Epidermal growth factor receptor (EGFR) mutation is predictive for the efficacy of EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC) treatment. We evaluated the ...performance, sensitivity, and concordance between five EGFR tests.
DNA admixtures (n = 34; 1%–50% mutant plasmid DNA) and samples from NSCLC patients 116 formalin-fixed paraffin-embedded (FFPE) tissue, 29 matched bronchofiberscopic brushing (BB) cytology, and 20 additional pleural effusion (PE) cytology samples were analyzed. EGFR mutation tests were PCR-Invader®, peptide nucleic acid-locked nucleic acid PCR clamp, direct sequencing, Cycleave™, and Scorpion Amplification Refractory Mutation System (ARMS)®. Analysis success, mutation status, and concordance rates were assessed.
All tests except direct sequencing detected four mutation types at ≥1% mutant DNA. Analysis success rates were 91.4%–100% (FFPE) and 100% (BB and PE cytology), respectively. Inter-assay concordance rates of successfully analyzed samples were 94.3%–100% (FFPE; kappa coefficients: 0.88–1.00), 93.1%–100% (BB cytology; 0.86–1.00), and 85.0%–100% (PE cytology; 0.70–1.00), and 93.1%–96.6% (0.86–0.93) between BB cytology and matched FFPE.
All EGFR assays carried out comparably in the analysis of FFPE and cytology samples. Cytology-derived DNA is a viable alternative to FFPE samples for analyzing EGFR mutations.
Protein tandem repeats (TRs) are motifs comprised of near-identical contiguous sequence duplications. They are found in approximately 14% of all proteins and are implicated in diverse biological ...functions facilitating both structured and disordered protein-protein and protein-DNA interactions. These functionalities make protein TR domains an attractive component for the modular design of protein constructs. However, the repetitive nature of DNA sequences encoding TR motifs complicates their synthesis and mutagenesis by traditional molecular biology workflows commonly employed by protein engineers and synthetic biologists. To address this challenge, we developed a computational protocol to significantly reduce the complementarity of DNA sequences encoding TRs called TReSR (for Tandem Repeat DNA Sequence Redesign). The utility of TReSR was demonstrated by constructing a novel constitutive repressor synthesized by duplicating the LacI DNA binding domain into a single-chain TR construct by assembly PCR. Repressor function was evaluated by expression of a fluorescent reporter delivered on a single plasmid encoding a three-component genetic circuit. The successful application of TReSR to construct a novel TR-containing repressor with a DNA sequence that is amenable to PCR-based construction and manipulation will enable the incorporation of a wide range of TR-containing proteins for protein engineering and synthetic biology applications.
We present a new common stratigraphic timescale for the North Greenland Ice Core Project (NGRIP) and GRIP ice cores. The timescale covers the period 7.9–14.8 kyr before present and includes the ...Bølling, Allerød, Younger Dryas, and early Holocene periods. We use a combination of new and previously published data, the most prominent being new high‐resolution Continuous Flow Analysis (CFA) impurity records from the NGRIP ice core. Several investigators have identified and counted annual layers using a multiparameter approach, and the maximum counting error is estimated to be up to 2% in the Holocene part and about 3% for the older parts. These counting error estimates reflect the number of annual layers that were hard to interpret, but not a possible bias in the set of rules used for annual layer identification. As the GRIP and NGRIP ice cores are not optimal for annual layer counting in the middle and late Holocene, the timescale is tied to a prominent volcanic event inside the 8.2 kyr cold event, recently dated in the DYE‐3 ice core to 8236 years before A. D. 2000 (b2k) with a maximum counting error of 47 years. The new timescale dates the Younger Dryas‐Preboreal transition to 11,703 b2k, which is 100–150 years older than according to the present GRIP and NGRIP timescales. The age of the transition matches the GISP2 timescale within a few years, but viewed over the entire 7.9–14.8 kyr section, there are significant differences between the new timescale and the GISP2 timescale. The transition from the glacial into the Bølling interstadial is dated to 14,692 b2k. The presented timescale is a part of a new Greenland ice core chronology common to the DYE‐3, GRIP, and NGRIP ice cores, named the Greenland Ice Core Chronology 2005 (GICC05). The annual layer thicknesses are observed to be log‐normally distributed with good approximation, and compared to the early Holocene, the mean accumulation rates in the Younger Dryas and Bølling periods are found to be 47 ± 2% and 88 ± 2%, respectively.
The primary dimensions of taste are affective value, intensity and quality. Numerous studies have reported the role of the insula in evaluating these dimensions of taste; however, the results were ...inconsistent. Therefore, in the current study, we performed meta-analyses of published data to identify locations consistently activated across studies and evaluate whether different regions of the human brain could be responsible for processing different dimensions of taste. Meta-analyses were performed on 39 experiments, with 846 total healthy subjects (without psychiatric/neurological disorders) in 34 studies reporting whole-brain results. The aim was to establish the activation likelihood estimation (ALE) of taste-mediated regional activation across the whole brain. Apart from one meta-analysis for all studies in general, three analyses were performed to reveal the clusters of activation that were attributable to processing the affective value (data from 323 foci), intensity (data from 43 foci) and quality (data from 45 foci) of taste. The ALE revealed eight clusters of activation outside the insula for processing affective value, covering the middle and posterior cingulate, pre-/post-central gyrus, caudate and thalamus. The affective value had four clusters of activation (two in each hemisphere) in the insula. The intensity and quality activated only the insula, each with one cluster on the right. The concurrence between studies was moderate; at best, 53% of the experiments contributed to the significant clusters attributable to the affective value, 60% to intensity and 50% to quality. The affective value was processed bilaterally in the anterior to middle insula, whereas intensity was processed in the right antero-middle insula, and quality was processed in the right middle insula. The right middle dorsal insula was responsible for processing both the affective value and quality of taste. The exploratory analysis on taste quality did not have a significant result if the studies using liquid food stimuli were excluded. Results from the meta-analyses on studies involving the oral delivery of liquid tastants or liquid food stimuli confirmed that the insula is involved in processing all three dimensions of taste. More experimental studies are required to investigate whether brain activations differ between liquid tastants and food. The coordinates of activated brain areas and brain maps are provided to serve as references for future taste/food studies.
•Data was pooled from 34 whole-brain taste fMRI papers (39 experiments, 846 subjects).•Affective value of taste appeared to be processed by bilateral anterior and middle insula, cingulate cortex, striatum and orbitofrontal cortex•Intensity of taste was processed in right antero-middle insula.•Quality of taste was processed in right middle dorsal insula.•This study provided brain maps and coordinates for future taste/food studies.
There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing ...chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC).
Patients with a malignant solid tumor who would receive HEC containing 50 mg/m2 or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2–4) and aprepitant (125 mg on day 1 and 80 mg on days 2–3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0–120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea).
Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0–120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0–24 h) period, while at the delayed (24–120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0–120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369).
The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point.
UMIN000004863.
Abstract This study estimated the cumulative incidence and risk ratio for osteonecrosis of the jaw (ONJ) after tooth extraction in patients with and without administration of bisphosphonates (BP) and ...identified potential risk factors for bisphosphonate-induced osteonecrosis of the jaw (BIONJ). A cohort study was conducted in all patients undergoing tooth extraction at a university hospital in Japan from April 2006 to June 2009. Of 3216 patients, 126 had BP administration, of whom 5 (3.9%, 95% confidence interval (CI): 1.2–9.2) developed ONJ, versus 1 (0.032%, 95% CI: 0.00081–0.18) among 3090 patients without BP administration. BP administration was associated with the development of ONJ after tooth extraction, with an unadjusted risk ratio of 122.6 (95% CI: 14.4–1041.8). When stratified by age and route of BP administration, the risk ratio for ONJ patients aged 65 years or older with intravenous BP administration compared to those without was 200.2 (95% CI: 23.8–1679.4, P < 0.001). Patients receiving BP showed a significant association between the incidence of BIONJ and alveolar bone loss score. The risk of ONJ is higher in patients with than without BP administration, particularly intravenous administration. Severe periodontitis might be a risk factor for BIONJ.
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