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.
Background
Inactivation of
TP53
, a tumor suppressor gene, is associated with the development of several malignancies, including gastric cancer (GC). The present study aimed to evaluate the ...correlation between the overexpression of p53 and survival in different Lauren-type GCs.
Methods
From May 2003 to December 2019, 3608 GC patients treated endoscopically or surgically at the Seoul National University Bundang Hospital were enrolled for the study. Immunohistochemical staining for p53 was performed on all endoscopic and surgical gastric specimens. Clinicopathologic characteristics with Lauren classification, survival rate, and cancer recurrence were analyzed according to p53 overexpression.
Results
Among 3608 GC patients, p53 overexpression was seen in 1334 patients (37%). p53 overexpression was associated with lower depth of invasion (
P
= 0.026) and Early gastric cancer (
P
= 0.044) in intestinal-type GC, and with advanced TNM stage (
P
< 0.001) and Advanced gastric cancer (
P
< 0.001) in diffuse-type GC. The overall survival (OS) and GC-specific survival (GCSS) were significantly lower in p53 overexpression positive patients. This significance was more pronounced and enhanced in the diffuse-type GC and was absent in the intestinal-type GC. In multivariate analyses, p53 overexpression was associated with poor OS in both subtypes of GC and cancer recurrence in diffuse-type GC. (OS in intestinal-type: adjusted hazard ratio aHR = 1.423,
P
= 0.022; OS in diffuse-type: aHR = 1.401
P
= 0.035; cancer recurrence in diffuse-type: aHR = 1.502,
P
= 0.039).
Conclusion
p53 overexpression was associated with poor prognosis in GC, especially in diffuse-type. In addition, p53 overexpression was associated with early stage disease in intestinal-type GC and with advanced stage disease in diffuse-type GC.
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.
Objective
Helicobacter pylori
(HP) is known to play an important role in the development of gastric cancer (GC). The aim of this study was to analyze the effect of HP eradication on the survival rate ...and cancer recurrence in patients who underwent subtotal gastrectomy for GC.
Design
Totally 1,031 patients diagnosed with gastric adenocarcinoma who received surgical treatment at the Seoul National University Bundang Hospital from 2003 to 2017 and positive for HP infection were analyzed. The overall and GC-related survival according to HP eradication were compared; risk factors for GC-specific death and cancer recurrence were analyzed, and propensity score matching (PSM) was performed.
Results
Statistically significant benefits of overall and GC-specific survival were observed in the eradicated group compared to the non-eradicated group (
P
< 0.001), and these benefits were maintained after PSM (
P
< 0.001) in both of early and advance stage. In Cox proportional hazards multivariate analyses, cancer stage (stage II, adjusted hazard ratio aHR = 9.33,
P
< 0.001; stage III or IV, aHR = 26.17,
P
< 0.001), and HP positivity (aHR = 3.41,
P
= 0.001) were independent risk factors for GC-specific death; cancer stage (cancer stage II, aHR = 7.08,
P
< 0.001; cancer stage III or IV, aHR = 19.64,
P
< 0.001) and HP positivity (aHR = 2.70;
P
= 0.005) were independent risk factors for cancer recurrence.
Conclusion
Our results suggest that HP needed to be conducted more intensively in patients who are surgically treated for GC, regardless of cancer stage.
The depside and depsidone series compounds of polyketide origin accumulate in the cortical or medullary layers of lichen thalli. Despite the taxonomic and ecological significance of lichen chemistry ...and its pharmaceutical potentials, there has been no single piece of genetic evidence linking biosynthetic genes to lichen substances. Thus, we systematically analyzed lichen polyketide synthases (PKSs) for categorization and identification of the biosynthetic gene cluster (BGC) involved in depside/depsidone production. Our in-depth analysis of the interspecies PKS diversity in the genus
and a related Antarctic lichen, Stereocaulon alpinum, identified 45 BGC families, linking lichen PKSs to 15 previously characterized PKSs in nonlichenized fungi. Among these, we identified highly syntenic BGCs found exclusively in lichens producing atranorin (a depside). Heterologous expression of the putative atranorin PKS gene (coined
) yielded 4-
-demethylbarbatic acid, found in many lichens as a precursor compound, indicating an intermolecular cross-linking activity of Atr1 for depside formation. Subsequent introductions of tailoring enzymes into the heterologous host yielded atranorin, one of the most common cortical substances of macrolichens. Phylogenetic analysis of fungal PKS revealed that the Atr1 is in a novel PKS clade that included two conserved lichen-specific PKS families likely involved in biosynthesis of depsides and depsidones. Here, we provide a comprehensive catalog of PKS families of the genus
and functionally characterize a biosynthetic gene cluster from lichens, establishing a cornerstone for studying the genetics and chemical evolution of diverse lichen substances.
Lichens play significant roles in ecosystem function and comprise about 20% of all known fungi. Polyketide-derived natural products accumulate in the cortical and medullary layers of lichen thalli, some of which play key roles in protection from biotic and abiotic stresses (e.g., herbivore attacks and UV irradiation). To date, however, no single lichen product has been linked to respective biosynthetic genes with genetic evidence. Here, we identified a gene cluster family responsible for biosynthesis of atranorin, a cortical substance found in diverse lichen species, by categorizing lichen polyketide synthase and reconstructing the atranorin biosynthetic pathway in a heterologous host. This study will help elucidate lichen secondary metabolism, harnessing the lichen's chemical diversity, hitherto obscured due to limited genetic information on lichens.
Current pharmacological treatments for Parkinson’s disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible ...dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.
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•Reactive astrocytes in SNpc produce excessive GABA via MAO-B in animal models of PD•Aberrant tonic inhibition causes reduced DA production in neurons and motor deficits•Dormant neurons are rescued by MAO-B inhibition or optogenetic neuronal activation
Heo et al. report that astrocytic GABA-mediated aberrant tonic inhibition of DA neurons leads to a reduction in TH expression and dopamine production, causing dormant DA neurons and motor deficits. Blocking astrocytic GABA synthesis by MAO-B inhibition or optogenetic activation of dormant DA neurons reverses PD pathology.
Advanced Electromaterials: New Challenges Yoon, Seok‐Jin; Park, Hyung‐Ho
Physica status solidi. A, Applications and materials science,
October 24, 2018, Volume:
215, Issue:
20
Journal Article
The lysosomal membrane protein Niemann‐Pick type C1 (NPC1) and Niemann‐Pick type C2 (NPC2) are main players of cholesterol control in the lysosome and it is known that the mutation on these proteins ...leads to the cholesterol trafficking‐related neurodegenerative disease, which is called the NPC disease. The mutation R518W or R518Q on the NPC1 is one of the type of disease‐related mutation that causes cholesterol transports to be cut in half, which results in the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment of the cell. Even though there has been significant progress with understanding the cholesterol transport by NPC1 in combination with NPC2, especially after the structural determination of the full‐length NPC1 in 2016, many details such as the interaction of the full‐length NPC1 with the NPC2, the molecular motions responsible for the cholesterol transport during and after this interaction, and the structure and the function relations of many mutations are still not well understood. In this study, we report the extensive molecular dynamics simulations in order to gain insight into the structure and the dynamics of NPC1 lumenal domain for the cholesterol transport and the disease behind the mutation (R518W). It was found that the mutation induces a structural shift of the N‐terminal domain, toward the loop region in the middle lumenal domain, which is believed to play a central role in the interaction with NPC2 protein, so the interaction with the NPC2 protein might be less favorable compared to the wild NPC1. Also, the simulation indicates the possible re‐orientation of the N‐terminal domain with both the wild and the R518W‐mutated NPC1 after receiving the cholesterol from the NPC2 that align to form an internal tunnel, which is a possible pose for further action in cholesterol trafficking. We believe the current study can provide a better understanding of the cholesterol transport by NPC1 especially the role of NTD of NPC1 in combination with NPC2 interactions.
We have performed a series of molecular dynamics simulation with lumenal domain Niemann‐Pick type C1 (NPC1) protein, which is one of the key protein that controls the cholesterol transport in lysosome, to investigate the dynamic role of N‐terminal domain (NTD). The simulation shows that the NTD makes proper orientation change for cholesterol trafficking depending on the environment. The same simulation with R518W‐mutated NPC1 shows possible reduced interaction between NPC1 and NPC2, which works in tandem with NPC1. The current modeling study provides insight into the structure and function relation of NPC1, including the disease causing R518W mutation in NPC1.
Background
Frail older adults are at increased risk of post‐operative morbidity compared with robust counterparts. Simple methods testing frailty such as grip strength or gait speed have shown ...promising results for predicting post‐operative outcome, but there is a debate regarding the most appropriate and precise frailty assessment method. We compared the predictive value of multidimensional frailty score (MFS) with grip strength, gait speed, or conventional risk stratification tool for predicting post‐operative complications in older surgical patients.
Methods
From January 2016 to June 2017, 648 older surgical patients (age ≥ 65 years) were included for analysis. MFS was calculated based on the preoperative comprehensive geriatric assessment. Grip strength and gait speed were measured before surgery. The primary outcome was a composite of post‐operative complications (e.g. pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned intensive care unit admission). The secondary outcome was the 6 month all‐cause mortality.
Results
Among 648 patients (mean age 76.6 ± 5.4 years, 52.8% female), 66 (10.2%) patients experienced post‐operative complications, and the 6 month mortality was 3.9% (n = 25). Grip strength, gait speed, MFS, and American Society of Anesthesiologists (ASA) classification could predict post‐operative complication but only MFS (hazard ratio = 1.581, 95% confidence interval 1.276–1.959, P < 0.001) could predict 6 month mortality after adjustment. MFS (C‐index = 0.750) had a superior prognostic utility compared with age (0.638, P = 0.008), grip strength (0.566, P < 0.001), and ASA classification (0.649, P = 0.004). MFS improved the predictive value on age C‐index of 0.638 (age) vs. 0.758 (age + MFS), P < 0.001 and ASA classification C‐index of 0.649 (ASA) vs. 0.765 (ASA + MFS), P < 0.001 for post‐operative complication; however, gait speed or grip strength did not provide additional prognostic value in both age and ASA.
Conclusions
Multidimensional frailty score based on preoperative comprehensive geriatric assessment showed better utility than age, grip strength, gait speed, or ASA classification for predicting post‐operative complication and 6 month mortality. MFS also showed incremental predictive ability for post‐operative complications with the addition of age and ASA classification. Accordingly, MFS is superior to grip strength or gait speed for predicting complications among older surgical patients.
Background
Epstein–Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5–16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated ...the clinicopathological characteristics of EBVaGC including survival rate in South Korea.
Methods
A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV–ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed.
Results
A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (
P
< 0.001), a predominant presence in the proximal stomach (
P
< 0.001), a higher proportion of undifferentiated cancer (
P
< 0.001), and a lower cancer stage (
P
= 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio HR = 1.025,
P
< 0.001), tumor size (HR = 1.109,
P
< 0.001), and cancer stage (stage2 HR = 4.761,
P
< 0.001; stage3 HR = 13.286,
P
< 0.001; stage4 HR = 42.528,
P
< 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620,
P
= 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (
P
= 0.021) and GC-specific survival (
P
= 0.007) on the Kaplan–Meier survival curve. However, this effect was evident only in males.
Conclusions
EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females.
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