Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti-PD-1 antibodies. However, 50% of ...microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1
CD8
T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. SIGNIFICANCE: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.
.
.
Background and Aim
Knowledge of lymph node metastasis (LNM) status is crucial to determine whether patients with superficial esophageal squamous cell carcinoma (ESCC) can be cured with endoscopic ...resection alone, without the need for additional esophagectomy. The present study aimed to identify predictive factors and develop a prediction model for LNM in patients with superficial ESCC.
Methods
Clinicopathologic data from 501 patients with superficial ESCC treated with radical esophagectomy were reviewed. Stepwise logistic regression analysis determined the predictors of LNM. Using these predictors, a nomogram for predicting the risk of LNM was constructed and internally validated using a bootstrap resampling method.
Results
LNM rates of tumors invading the lamina propria, muscularis mucosa, and SM1 layers were 3.7%, 15.5%, and 40.7%, respectively. Deep tumor invasion depth, moderately or poorly differentiated histology, and lymphovascular invasion were independent predictors of LNM. ESCC with muscularis mucosa and SM1 invasion had odds ratios of 3.635 and 11.834, respectively, compared with that for ESCC confined to the lamina propria. Large tumor size (>2.0 cm) and presence of tumor budding showed borderline significance for LNM prediction. These five variables were incorporated into a nomogram. A constructed nomogram showed good calibration and good discrimination with an area under the receiver‐operating characteristic curve (area under the curve AUC) of 0.812. After bootstrapping, AUC was 0.811.
Conclusions
We developed a nomogram that can facilitate individualized prediction of risk of LNM in patients with superficial ESCC. This model can aid in decision‐making for the need for additional esophagectomy after endoscopic resection for superficial ESCC.
Few studies have compared the long-term outcomes of endoscopic resection and surgery. The aim of this study was to compare the long-term outcomes of endoscopic resection with those of surgery for ...early gastric cancer (EGC).
We reviewed prospectively collected data of patients who had undergone endoscopic resection (1,290 patients) or surgery (1,273 patients) for EGC. To reduce the effect of selection bias, we performed a propensity score-matching analysis between the two groups. The primary outcome was overall survival (OS). The secondary outcomes were disease-specific survival, disease-free survival (DFS), recurrence-free survival (RFS), occurrence of metachronous gastric cancer, treatment-related complications, length of hospital stay, and 30-day outcomes. The study was designed as a non-inferiority study and tested in an intention-to-treat analysis.
In a propensity-matched analysis of 611 pairs, the 10-year OS proportion was 96.7% in the endoscopic resection group and 94.9% in the surgery group (P=0.120) (risk difference -1.8%, 95% confidence interval (CI) -4.04-0.44, Pnon-inferiority=0.014), which met the non-inferiority criterion. In contrast, the 10-year RFS proportion was 93.5% in the endoscopic resection group and 98.2% in the surgery group (P<0.001) (risk difference 4.7%, 95% CI 2.50-6.97, Pnon-inferiority=0.820), which did not meet the non-inferiority criterion, mainly because of metachronous recurrence in the endoscopic resection group. The rate of early complications was higher in the endoscopic resection group than in the surgery group (9.0 vs. 6.6%, P=0.024), whereas the rate of late complications was higher in the surgery group than in the endoscopic resection group (0.5 vs. 2.9%, P<0.001). In the multiple Cox regression analysis, patient's age, the comorbidity index, the performance index, sex, tumor morphology, and depth of invasion were predictors of OS in patients with EGC.
Endoscopic resection might not be inferior to surgery with respect to OS in patients with EGC lesions that meet the absolute or expanded criteria. However, DFS, RFS, and metachronous RFS might be lower after endoscopic resection than after surgery.
Proteasomes, the primary mediators of ubiquitin-protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that USP14, a proteasome-associated ...deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.
Background: The aim of this study was to develop a prediction model for the presence and location of lymph node metastasis (LNM) in early gastric cancer.
Method: We reviewed medical records of 4 929 ...patients who underwent radical gastrectomy for early gastric cancer. Variables of age, sex, lymphatic invasion, depth of invasion, location, gross type, differentiation, and tumor size were analyzed. Logistic regression analysis was used to determine independent predictors of LNM at each LN station.
Result: Overall incidence of LNM was 9.1% (448/4 929 patients). For the presence of LNM, risk factors of age, sex, lymphatic invasion, depth of invasion, anatomical part, gross ulceration, size, and tumor differentiation were significantly associated with LNM. The area under the curve (AUC) for predicting LNM after validation was 0.834 for the test set. For the location of LNM, age, sex, lymphatic invasion, depth of invasion, anatomical part, circumferential portion, gross type, differentiation, and tumor size were significantly associated with LNM. The AUC of each LN station was favorable with the test set.
Conclusion: Predicting the location of metastatic LNs appeared to be possible in patients with early gastric cancer.
Background and Aim
Proton pump inhibitor (PPI)‐induced hypochondria can change the composition of the gut microbiota, inducing overgrowth of small bowel bacteria, which has been suggested to promote ...the development of fatty liver disease through the gut‐liver axis. In this study, we aimed to investigate the association between PPI use and the risk of fatty liver disease.
Methods
A retrospective cohort study was conducted using the Korean National Health Insurance Service‐National Sample Cohort, a nationwide population‐based representative sample, from January 1, 2002, to December 31, 2015. PPI use was identified from treatment claims and considered as a time‐varying variable.
Results
During 1 463 556 person‐years of follow‐up, 75 727 patients had at least one PPI prescription, and 3735 patients developed fatty liver disease. The hazard ratio for fatty liver disease comparing PPI users with non‐PPI users was 1.68 (95% confidence interval, 1.61–1.75). When adjusted for multiple confounders, including age, sex, body mass index, smoking, alcohol intake, exercise, income level, and comorbidities, the association was still significant (hazard ratio, 1.50; 95% confidence interval, 1.44–1.57). After considering the amounts of PPIs stratified by cumulative defined daily dose, the dose–response effect was observed until 180 days. Subgroup analysis also revealed that PPI use was correlated to an increased risk of fatty liver disease.
Conclusions
This current national wide cohort study suggests that PPI use was associated with an increased risk of fatty liver disease compared with non‐use of PPIs. Clinicians should consider fatty liver as a potential risk when prescribing PPI.
This study presents an optimisation method for slotless permanent magnet synchronous machines to maximise torque density. The slotless structure with outer rotor and Halbach array has been selected ...to limit iron losses, torque ripple, cogging torque, and high-order harmonics. High-speed operation compounds both ac copper loss and mechanical stress. The former causes a temperature rise in the machine, while the latter is induced by strong centrifugal forces. A finite-element analysis-based optimisation method that utilises a parallel multistart, mesh adaptive direct search strategy is proposed to consider ac copper loss and mechanical stress as constraint variables. Finally, the torque densities of titanium and aermet shell designs were compared to show how material selection provides a trade-off in terms of torque production, mechanical stress, and weight.
Intestinal-type gastric carcinoma exhibits a multistep carcinogenic sequence from adenoma to carcinoma with a gradual increase in genomic alterations. But the roles of microRNAs (miRNA) in this ...multistage cascade are not fully explored. To identify differentially expressed miRNA (DEM) during early gastric carcinogenesis, we performed miRNA microarray profiling with 24 gastric cancers and precursor lesions (7 early gastric cancer EGC, 3 adenomas with high-grade dysplasia, 4 adenomas with low-grade dysplasia, and 10 adjacent normal tissues). Alterations in the expression of 132 miRNA were detected; these were categorized into three groups based on their expression patterns. Of these, 42 miRNAs were aberrantly expressed in EGC. Five miRNA (miR-26a, miR-375, miR-574-3p, miR-145, and miR-15b) showed decreased expression since adenoma. Expression of two miRNA, miR-200C and miR-29a, was down-regulated in EGCs compared to normal mucosa or adenomas. Six miRNA (miR-601, miR-107, miR-18a, miR-370, miR-300, and miR-96) showed increased expression in gastric cancer compared to normal or adenoma samples. Five representative miRNAs were further validated with RT-qPCR in independent 77 samples. Taken together, these results suggest that the dysregulated miRNA show alterations at the early stages of gastric tumorigenesis and may be used as a candidate biomarker.
Cold atmospheric plasma (CAP) has been extensively investigated in the local treatment of cancer due to its potential of reactive oxygen species (ROS) generation in biological systems. In this study, ...we examined the synergistic effect of combination of CAP and cisplatin-mediated chemotherapy of oral squamous cell carcinoma (OSCC) in vitro. SCC-15 OSCC cells and human gingival fibroblasts (HGF-1) cells were treated with cisplatin, and then, the cells were irradiated with CAP. Following this, viability and apoptosis behavior of the cells were investigated. The viability of SCC-15 cells was inhibited by cisplatin with a dose-dependent manner and CAP treatment time. HGF-1 cells also showed decreased viability by treatment with cisplatin and CAP. Combination of 1 μM cisplatin plus 3 min of CAP treatment or 3 μM cisplatin plus 1 min of CAP treatment showed a synergistic anticancer effect with appropriate cytotoxicity against normal cells. ROS generation and dead cell staining were also increased by the increase in CAP treatment time. Furthermore, tumor-suppressor proteins and apoptosis-related enzymes also increased according to the treatment time of CAP. We showed the synergistic effect of cisplatin and CAP treatment against SCC-15 cells with low cytotoxicity against normal cells.
Background and Aim
Previous studies suggested an association between Helicobacter pylori infection and osteoporosis; however, large‐scale longitudinal studies are lacking to elucidate this ...association.
Methods
A cohort study of 10 482 women without osteoporosis at baseline who participated in a repeated health‐screening examination including an H. pylori‐specific immunoglobulin G antibody test was conducted to evaluate the association between H. pylori and osteoporosis development. Osteoporosis was diagnosed using dual‐energy X‐ray absorptiometry.
Results
During the 77 515.3 person‐years of follow‐up, women with H. pylori infection had a higher rate of incident osteoporosis than those who were uninfected. In a multivariable model adjusted for age, body mass index (BMI), menopausal status, smoking status, regular exercise, comorbidities (including hypertension, diabetes mellitus, dyslipidemia, stroke, or ischemic heart disease), and concomitant medications, the hazard ratio (HR) for incident osteoporosis in women with H. pylori infection compared with that in women without infection was 1.23 (95% confidence interval CI, 1.03–1.45). The association between H. pylori and osteopenia development was also evident. In the multivariable analysis, menopause (HR, 1.68; 95% CI, 1.31–2.16) and increasing age (HR, 1.07; 95% CI, 1.06–1.08) were identified as significant risk factors for osteoporosis, whereas higher BMI (HR, 0.84; 95% CI, 0.81–0.87) was a protective factor for the risk of osteoporosis.
Conclusions
In this cohort study, H. pylori infection was associated with an increased risk of osteoporosis, independent of risk factors and confounding factors.
PDF
