Adjuvant chemotherapy after surgery improves survival of patients with stage II–III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, ...suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II–III gastric cancer.
In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II–III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival.
We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2–92·0), 74·8% (69·9–80·1), and 66·0% (60·1–72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% 95% CI 73·5–87·1 vs 64·5% 56·8–73·3; univariate hazard ratio 0·47 95% CI 0·30–0·75, p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% 66·5–79·9 in patients who received chemotherapy plus surgery vs 72·5% 65·8–79·9 in patients who only had surgery; 0·93 0·62–1·38, p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (pinteraction=0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort.
The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II–III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted.
Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.
It is unclear whether laparoscopic distal gastrectomy for locally advanced gastric cancer is oncologically equivalent to open distal gastrectomy. The noninferiority of laparoscopic subtotal ...gastrectomy with D2 lymphadenectomy for locally advanced gastric cancer compared with open surgery in terms of 3-year relapse-free survival rate was evaluated.
A phase III, open-label, randomized controlled trial was conducted for patients with histologically proven locally advanced gastric adenocarcinoma suitable for distal subtotal gastrectomy. The primary end point was the 3-year relapse-free survival rate; the upper limit of the hazard ratio (HR) for noninferiority was 1.43 between the laparoscopic and open distal gastrectomy groups.
From November 2011 to April 2015, 1,050 patients were randomly assigned to laparoscopy (n = 524) or open surgery (n = 526). After exclusions, 492 patients underwent laparoscopic surgery and 482 underwent open surgery and were included in the analysis. The laparoscopy group, compared with the open surgery group, suffered fewer early complications (15.7%
23.4%, respectively;
= .0027) and late complications (4.7%
9.5%, respectively;
= .0038), particularly intestinal obstruction (2.0%
4.4%, respectively;
= .0447). The 3-year relapse-free survival rate was 80.3% (95% CI, 76.0% to 85.0%) for the laparoscopy group and 81.3% (95% CI, 77.0% to 85.0%; log-rank
= .726) for the open group. Cox regression analysis after stratification by the surgeon revealed an HR of 1.035 (95% CI, 0.762 to 1.406; log-rank
= .827;
for noninferiority = .039). When stratified by pathologic stage, the HR was 1.020 (95% CI, 0.751 to 1.385; log-rank
= .900;
for noninferiority = .030).
Laparoscopic distal gastrectomy with D2 lymphadenectomy was comparable to open surgery in terms of relapse-free survival for patients with locally advanced gastric cancer. Laparoscopic distal gastrectomy with D2 lymphadenectomy could be a potential standard treatment option for locally advanced gastric cancer.
Circulating tumor DNA (ctDNA) has emerged as a candidate biomarker for cancer screening. However, studies on the usefulness of ctDNA for postoperative recurrence monitoring are limited. The present ...study monitored ctDNA in postoperative blood by employing cancer-specific rearrangements. Personalized cancer-specific rearrangements in 25 gastric cancers were analyzed by whole-genome sequencing (WGS) and were employed for ctDNA monitoring with blood up to 12 months after surgery. Personalized cancer-specific rearrangements were identified in 19 samples. The median lead time, which is the median duration between a positive ctDNA detection and recurrence, was 4.05 months. The presence of postoperative ctDNA prior to clinical recurrence was significantly correlated with cancer recurrence within 12 months of surgery (P = 0.029); in contrast, no correlation was found between cancer recurrence and the presence of preoperative ctDNA, suggesting the clinical usefulness of postoperative ctDNA monitoring for cancer recurrence in gastric cancer patients. However, the clinical application of ctDNA can be limited by the presence of ctDNA non-shedders (42.1%, 8/19) and by inconsistent postoperative ctDNA positivity.
Alkaline water electrolysis (AWE) systems offer a cost‐effective and scalable approach for large‐scale hydrogen production using renewable energy sources. However, their susceptibility to load ...fluctuations, particularly the reverse‐current (RC) phenomenon during shutdown events, poses a significant challenge to the long‐term stability and scalability of these systems. Herein, a catalytic approach for enhancing the RC tolerance in AWE systems by using Pb‐decorated Ni cathode catalysts (Pb/Ni) is introduced. The oxidation of Pb/Ni by repeated RC lowers the electromotive force for the reverse current operation, and consequently, imparts RC tolerance. Intriguingly, contrary to the expectation that the decoration with lead, an inert material for the hydrogen evolution reaction (HER), will interfere with the hydrogen generation of the Ni catalyst, the presence of Pb on the Ni cathode after the RC flow promotes both the proton desorption and water‐dissociation steps, improving the HER activity. Furthermore, the AWE stack testing with Pb/Ni catalysts is perfectly operated, demonstrating remarkably enhanced RC tolerance during startup/shut‐down (SU/SD) testing protocol. This paper presents a new strategy for mitigating the AWE performance degradation induced by RC flow and for achieving Pb/Ni catalysts with improved operational durability against RC flow in AWE systems.
The transient stability of the catalyst caused by the reverse‐current phenomenon during the shutdown of the AWE system by load fluctuations is one of the most challenging limitations to address. This study introduces a catalytic approach for enhancing the RC by decorating lead on Ni catalysts. The surface decoration of the Ni catalyst with Pb (Pb/Ni) catalyst exhibits improved HER activity as well as remarkable RC‐flow resistance.
Organic solar cells based on bulk heterojunctions (BHJs) are attractive energy‐conversion devices that can generate electricity from absorbed sunlight by dissociating excitons and collecting charge ...carriers. Recent breakthroughs attained by development of nonfullerene acceptors result in significant enhancement in power conversion efficiency (PCEs) exceeding 17%. However, most of researches have focused on pursuing high efficiency of small‐area (<1 cm2) unit cells fabricated usually with spin coating. For practical application of organic photovoltaics (OPVs) from lab‐scale unit cells to industrial products, it is essential to develop efficient technologies that can extend active area of devices with minimized loss of performance and ensured operational stability. In this progress report, an overview of recent advancements in materials and processing technologies is provided for transitioning from small‐area laboratory‐scale devices to large‐area industrial scale modules. First, development of materials that satisfy requirements of high tolerability in active layer thickness and large‐area adaptability is introduced. Second, morphology control using various coating techniques in a large active area is discussed. Third, the recent research progress is also underlined for understanding mechanisms of OPV degradation and studies for improving device long‐term stability along with reliable evaluation procedures.
Recent advances in organic photovoltaic (OPV) materials and processing technologies are promising for transitioning of OPV devices from laboratory‐scale to large‐area industrial scale modules. Recent breakthroughs attained by development of nonfullerene acceptors have led to significant enhancement in power conversion efficiency. It is essential to elucidate degradation mechanisms of OPV devices for improving device long‐term stability.
To compare short-term surgical outcomes including financial cost of robotic and laparoscopic gastrectomy.
Despite a lack of supporting evidence, robotic surgery has been increasingly adopted as a ...minimally invasive modality for the treatment of gastric cancer because of its assumed technical superiority over conventional laparoscopy.
A prospective, multicenter comparative study was conducted. Patients were matched according to the surgeon, extent of gastric resection, and sex. The primary endpoint was morbidity and mortality. Outcomes were analyzed on an intention-to-treat and per-protocol basis.
A total of 434 patients were enrolled for treatment with either robotic (n = 223) or laparoscopic (n = 211) gastrectomy for intention-to-treat analysis, and a total of 370 patients (n = 185 per treatment) were compared in per-protocol analysis. Results were similar between both analyses. In per-protocol analysis, both groups showed similar overall complication rates (robotic = 11.9% vs laparoscopic = 10.3%) and major complication rates (robotic = 1.1% vs laparoscopic = 1.1%) with no operative mortality in either group. Patients treated with robotic surgery showed significantly longer operative time (robotic = 221 minutes vs laparoscopic = 178 minutes; P < 0.001) and significantly higher total costs (robotic = US$13,432 vs laparoscopic = US$8090; P < 0.001), compared with those who underwent laparoscopic gastrectomy. No significant differences between groups were noted in estimated blood loss, rates of open conversion, diet build-up, or length of hospital stay.
The use of robotic systems is assumed to provide a technically superior operative environment for minimally invasive surgery. However, our analysis of perioperative surgical outcomes indicated that robotic gastrectomy is not superior to laparoscopic gastrectomy. Clinical trials identification: NCT01309256.
We run self-consistent simulations of Milky Way-sized, isolated disk galaxies to study the formation and evolution of a stellar bar as well as a nuclear ring in the presence of gas. We consider two ...sets of models with cold or warm disks that differ in the radial velocity dispersions, and vary the gas fraction by fixing the total disk mass. A bar forms earlier and more strongly in the cold disks with larger , while gas progressively delays the bar formation in the warm disks. The bar formation enhances a central mass concentration, which in turn causes the bar to decay temporarily, after which it regrows in size and strength, eventually becoming stronger in models with smaller . Although all bars rotate fast in the beginning, they rapidly turn to slow rotators. In our models, only the gas-free, warm disk undergoes rapid buckling instability, while other disks thicken more gradually via vertical heating. The gas driven inward by the bar potential readily forms a star-forming nuclear ring. The ring is very small when it first forms and grows in size over time. The ring star formation rate is episodic and bursty due to feedback, and is well correlated with the mass inflow rate to the ring. Some expanding shells produced by star formation feedback are sheared out in the bar regions and collide with dust lanes to appear as filamentary interbar spurs. The bars and nuclear rings formed in our simulations have properties similar to those in the Milky Way.
An exciton is the bosonic quasiparticle of electron-hole pairs bound by the Coulomb interaction1. Bose-Einstein condensation of this exciton state has long been the subject of speculation in various ...model systems2,3, and examples have been found more recently in optical lattices and two-dimensional materials4-9. Unlike these conventional excitons formed from extended Bloch states4-9, excitonic bound states from intrinsically many-body localized states are rare. Here we show that a spin-orbit-entangled exciton state appears below the Néel temperature of 150 kelvin in NiPS3, an antiferromagnetic van der Waals material. It arises intrinsically from the archetypal many-body states ofthe Zhang-Rice singlet10,11, and reaches a coherent state assisted by the antiferromagnetic order. Using configuration-interaction theory, we determine the origin of the coherent excitonic excitation to be a transition from a Zhang-Rice triplet to a Zhang-Rice singlet. We combine three spectroscopic tools-resonant inelastic X-ray scattering, photoluminescence and optical absorption-to characterize the exciton and to demonstrate an extremely narrow excitonic linewidth below 50 kelvin. The discovery of the spin-orbit-entangled exciton in antiferromagnetic NiPS3 introduces van der Waals magnets as a platform to study coherent many-body excitons.
Arabidopsis thaliana homeobox 12 (ATHB12), a homeodomain‐leucine zipper class I (HD‐Zip I) gene, is highly expressed in leaves and stems, and induced by abiotic stresses, but its role in development ...remains obscure. To understand its function during plant development, we studied the effects of loss and gain of function. Expression of ATHB12 fused to the EAR‐motif repression domain (SRDX) – P₃₅S::ATHB12SRDX (A12SRDX) and PATHB₁₂::ATHB12SRDX – slowed both leaf and root growth, while the growth of ATHB12‐overexpressing seedlings (A12OX) was accelerated. Microscopic examination revealed changes in the size and number of leaf cells. Ploidy was reduced in A12SRDX plants, accompanied by decreased cell expansion and increased cell numbers. By contrast, cell size was increased in A12OX plants, along with increased ploidy and elevated expression of cell cycle switch 52s (CCS52s), which are positive regulators of endoreduplication, indicating that ATHB12 promotes leaf cell expansion and endoreduplication. Overexpression of ATHB12 led to decreased phosphorylation of Arabidopsis thaliana ribosomal protein S6 (AtRPS6), a regulator of cell growth. In addition, induction of ATHB12 in the presence of cycloheximide increased the expression of several genes related to cell expansion, such as EXPANSIN A10 (EXPA10) and DWARF4 (DWF4). Our findings strongly suggest that ATHB12 acts as a positive regulator of endoreduplication and cell growth during leaf development.
We investigated microsatellite instability (MSI) status and programed cell death ligand 1 (PD-L1) expression as predictors of prognosis and responsiveness to chemotherapy for stage II/III gastric ...cancer.
The clinical implications of MSI status and PD-L1 expression in gastric cancer have not been well-elucidated.
Tumor specimens and clinical information were collected from patients enrolled in the CLASSIC trial-a randomized controlled study of capecitabine plus oxaliplatin-based adjuvant chemotherapy. Five quasi-monomorphic mononucleotide markers were used to assess tumor MSI status. PD-L1 expressions of tumor and stromal immune cells were evaluated using immunohistochemistry.
Of 592 patients, 40 (6.8%) had MSI-high (MSI-H) tumors. Among 582 patients available for immunohistochemistry evaluation, PD-L1 was positive in tumor cells (tPD-L1) of 16 patients (2.7%) and stromal immune cells (sPD-L1) of 165 patients (28.4%). Multivariable analysis of disease-free survival (DFS) showed that MSI-H and sPD-L1-positivity were independent prognostic factors hazard ratio 0.301 (0.123-0.736), 0.714 (0.514-0.991); P = 0.008, 0.044), as were receiving chemotherapy, age, tumor grade, and TNM stage. Although adjuvant chemotherapy improved DFS in the microsatellite-stable (MSS) group (5-year DFS: 66.8% vs 54.1%; P = 0.002); no benefit was observed in the MSI-H group (5-year DFS: 83.9% vs 85.7%; P = 0.931). In the MSS group, sPD-L1-negative patients, but not sPD-L1-positive patients, had significant survival benefit from adjuvant chemotherapy compared with surgery only (5-year DFS: 66.1% vs 50.7%; P = 0.001).
MSI status and PD-L1 expression are clinically actionable biomarkers for stratifying patients and predicting benefit from adjuvant chemotherapy after D2 gastrectomy for stage II/III gastric cancer.
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