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Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management.
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BACKGROUND: Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. METHODS: We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). RESULTS: CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. CONCLUSIONS: These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.
Subject(s)
Cancer-Associated Fibroblasts , Nephritis, Interstitial , Stomach Neoplasms , Animals , Humans , Cancer-Associated Fibroblasts/metabolism , Cell Line, Tumor , Cell Movement/genetics , Fibroblasts/metabolism , Integrin beta1/genetics , Integrin beta1/metabolism , Nephritis, Interstitial/metabolism , Nephritis, Interstitial/pathology , RNA, Small Interfering/metabolism , Stomach Neoplasms/pathology , Tumor MicroenvironmentABSTRACT
Phages MidnightRain and Gusanita, with siphovirus morphology, were isolated on Arthrobacter globiformis B-2979. MidnightRain's genome consists of 53,674 bp, encoding 101 putative genes and 1 tRNA, whereas Gusanita's genome is 42,742 bp, encoding 68 putative genes and 2 tRNAs.
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OBJECTIVE: To build a novel classifier using an optimized 3D-convolutional neural network for predicting high-grade small bowel obstruction (HGSBO). SUMMARY BACKGROUND DATA: Acute SBO is one of the most common acute abdominal diseases requiring urgent surgery. While artificial intelligence and abdominal computed tomography (CT) have been used to determine surgical treatment, differentiating normal cases, HGSBO requiring emergency surgery, and low-grade SBO (LGSBO) or paralytic ileus is difficult. METHODS: A deep learning classifier was used to predict high-risk acute SBO patients using CT images at a tertiary hospital. Images from three groups of subjects (normal, nonsurgical, and surgical) were extracted; the dataset used in the study included 578 cases from 250 normal subjects, with 209 HGSBO and 119 LGSBO patients; over 38 000 CT images were used. Data were analyzed from 1 June 2022 to 5 February 2023. The classification performance was assessed based on accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS: After fivefold cross-validation, the WideResNet classifier using dual-branch architecture with depth retention pooling achieved an accuracy of 72.6%, an area under receiver operating characteristic of 0.90, a sensitivity of 72.6%, a specificity of 86.3%, a positive predictive value of 74.1%, and a negative predictive value of 86.6% on all the test sets. CONCLUSIONS: These results show the satisfactory performance of the deep learning classifier in predicting HGSBO compared to the previous machine learning model. The novel 3D classifier with dual-branch architecture and depth retention pooling based on artificial intelligence algorithms could be a reliable screening and decision-support tool for high-risk patients with SBO.
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Deep Learning , Intestinal Obstruction , Humans , Retrospective Studies , Artificial Intelligence , Tomography, X-Ray Computed/methods , Neural Networks, Computer , Intestinal Obstruction/diagnostic imaging , Intestinal Obstruction/etiology , Intestinal Obstruction/surgeryABSTRACT
Various prospective surgical trials have been conducted on treating patients with gastric cancer. In clinical practice, patients and surgeons may hesitate to participate in prospective surgical trials due to trial-related complications. In this study, we evaluated the effects of participation in prospective surgical trials on surgical outcomes after radical gastrectomy for gastric cancer. This study included 1689 patients who underwent curative gastrectomy for gastric cancer between 2016 and 2020. The propensity score weighting (PSW) method was used to adjust for differences in baseline clinicopathological characteristics between patients who participated and those who did not participate in prospective surgical clinical trials. Perioperative outcomes and overall survival were compared between groups. Of the 1689 patients, 309 (18.3%) participated in surgical clinical trials (SCT group). Before PSW, the SCT group had a similar operation time, intraoperative blood loss, complications, major complications, and hospital stay as the non-SCT group but had superior overall survival. After PSW, overall survival and perioperative outcomes were not significantly different between the groups. The present study suggests that participation in prospective surgical trials was not associated with surgical outcomes. Patients and surgeons may participate in prospective surgical trials without fearing adverse effects on surgical outcomes.
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Stomach Neoplasms , Surgeons , Humans , Stomach Neoplasms/surgery , Prognosis , Prospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Thromboembolic events (TEEs) are significant adverse events that can cause serious morbidities and mortality in cancer patients receiving chemotherapy. Patients with gastric cancer (GC) treated with palliative chemotherapy have been reported to experience a TEE incidence of 5-27%. However, very few reports have addressed TEEs in adjuvant chemotherapy (AC) for GC. METHODS: This study retrospectively analyzed 611 GC patients (stage II: 309, III: 302) who started AC with capecitabine/oxaliplatin (167 patients) or S-1 (444 patients) after undergoing curative resection between January 2013 and June 2020 at a single center. The incidence of TEEs during AC or within 1 year after AC completion was investigated, while analyzing the factors that influenced the TEEs' occurrence. RESULTS: TEEs were confirmed in 20 patients (3.3%), and TEEs occurred in almost all patients in the S-1 group (19 patients). The most common TEE types were cerebral infarction and pulmonary thromboembolism (five patients each). Although old age (≥ 70 years, p < 0.0001), S-1 treatment (p = 0.021), and hypertension (p = 0.017) were identified as significant risk factors for TEEs in univariate analysis, only old age showed a statistically significant correlation with TEEs' occurrence in multivariate analysis (odds ratio: 3.07; 95% confidence interval 1.11-8.48; p = 0.031). CONCLUSIONS: TEEs occurred in fewer patients with GC who had been treated with AC than patients who had received palliative chemotherapy in previous reports. However, elderly GC patients who are undergoing AC require more careful surveillance for possible TEEs, considering relatively higher incidence of them.
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Stomach Neoplasms , Thromboembolism , Humans , Aged , Retrospective Studies , Stomach Neoplasms/drug therapy , Stomach Neoplasms/surgery , Stomach Neoplasms/complications , Thromboembolism/chemically induced , Thromboembolism/epidemiology , Chemotherapy, Adjuvant/adverse effects , Oxaliplatin/therapeutic useABSTRACT
Surgical oncologist plays a pivotal role in treating patients with cancer in the era of precision medicine. In this article, we summarized traditional roles of surgical oncologists and suggested further additional ones for the modern day in the multidisciplinary approach to gastric cancer treatment.
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OBJECTIVE: The aim of this study was to audit the 22 items and assessed each item's predictive value on surgical outcomes. BACKGROUND: The KLASS-02 trial revealed that the oncologic outcomes of laparoscopic distal gastrectomy are not inferior to open distal gastrectomy in patients with advanced gastric cancer. The surgeons participating in this trial were chosen based on the assessment scores from the KLASS-02-QC trial, which used 22 items for standardization of D2 lymphadenectomy and quality control. METHODS: We reviewed proficiency scores (PSs) for 22 items for 20 surgeons who participated in KLASS-02. The surgeons were divided into 2 groups according to PS, and the perioperative outcomes of 924 patients enrolled in KLASS-02 were compared between groups. Each item's predictive value for perioperative outcome was then assessed using multivariable regression models. RESULTS: Of the total 924 patients, 529 were operated on by high-score surgeons (high PS) and 395 were operated on by low-score surgeons (low-PS). High-PS group had less intraoperative blood loss, longer operation times, and fewer complications, major complications, reoperations, and shorter first flatus and hospital stay than low-PS group ( P =0.006, P <0.001, P <0.001, P <0.001, P =0.042, P =0.013, and P <0.001, respectively). Some items used in KLASS-02-QC predicted perioperative outcomes, such as intraoperative blood loss, major complications, reoperation, and hospital stay. CONCLUSIONS: Although this study only analyzed data associated with qualified surgeons, the 22 items effectively assessed the surgeons based on PS. A high score was associated with longer operation times, but better perioperative outcomes.
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Laparoscopy , Stomach Neoplasms , Surgeons , Humans , Blood Loss, Surgical , Gastrectomy/adverse effects , Treatment Outcome , Lymph Node Excision/adverse effects , Quality Control , Reference Standards , Stomach Neoplasms/surgery , Laparoscopy/adverse effects , Retrospective StudiesABSTRACT
Importance: Patients undergoing proximal gastrectomy (PG) with double-tract reconstruction (DTR) have been reported to have an incidence of reflux esophagitis that is as low as that observed after total gastrectomy (TG). It is unclear whether PG has an advantage over TG for the treatment of patients with upper early gastric cancer (GC). Objective: To evaluate the effect of laparoscopic PG with DTR (LPG-DTR) vs laparoscopic TG (LTG) on levels of hemoglobin and vitamin B12 supplementation required among patients with clinically early GC in the upper third of the stomach (upper-third early GC). Design, Setting, and Participants: This multicenter open-label superiority randomized clinical trial was conducted at 10 institutions in Korea. A total of 138 patients with upper-third cT1N0M0 GC were enrolled between October 27, 2016, and September 9, 2018. Follow-up ended on December 3, 2020. Interventions: Patients were randomized to undergo either LPG-DTR or LTG. Main Outcomes and Measures: The primary co-end points were change in hemoglobin level and cumulative amount of vitamin B12 supplementation at 2 years after LPG-DTR or LTG. The secondary end points included morbidity, postoperative reflux esophagitis, quality of life, overall survival, and disease-free survival. Quality of life outcomes were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) 30-item core questionnaire (C30) and the EORTC QLQ stomach cancer-specific questionnaire at 3 months, 12 months, and 24 months. Results: Among 138 patients (mean [SD] age, 60.0 [10.9] years; 87 men [63.0%]; all of Asian race and Korean ethnicity), 68 (mean [SD] age, 56.7 [10.4] years; 39 men [57.4%]) were randomized to receive LPG-DTR and 69 (mean [SD] age, 61.3 [11.3] years; 48 men [69.6%]) were randomized to receive LTG. The mean (SD) changes in hemoglobin levels from baseline to month 24 were -5.6% (7.4%) in the LPG-DTR group and -6.9% (8.3%) in the LTG group, for an estimated difference of -1.3% (95% CI, -4.0% to 1.4%; P = .35). The mean (SD) cumulative amount of vitamin B12 supplementation was 0.4 (1.3) mg in the LPG-DTR group and 2.5 (3.0) mg in the LTG group, for an estimated difference of 2.1 mg (95% CI, 1.3-2.9 mg; P < .001). The late complication rates in the LPG-DTR and LTG groups were 17.6% and 10.1%, respectively (P = .31). The incidence of reflux esophagitis was not different between the LPG-DTR and LTG groups (2.9% vs 2.9%; P = .99). Compared with the LTG group, the LPG-DTR group had better physical functioning scores (85.2 [15.6] vs 79.9 [19.3]; P = .03) and social functioning scores (89.5 [17.9] vs 82.4 [19.4]; P = .03) on the EORTC QLQ-C30. Two-year overall survival (98.5% vs 100%; P = .33) and disease-free survival (98.5% vs 97.1%; P = .54) did not significantly differ between the LPG-DTR vs LTG groups. Conclusions and Relevance: In this study, patients with upper-third early GC who received LPG-DTR required less vitamin B12 supplementation than those who received LTG, with no increase in complication rates and no difference in overall and disease-free survival rates. There was no difference in change in hemoglobin level between groups. In addition, the LPG-DTR group had better physical and social functioning than the LTG group. These findings suggest that LPG-DTR may be as safe as LTG and may be a function-preserving procedure for the treatment of patients with upper-third early GC. Trial Registration: ClinicalTrials.gov Identifier: NCT02892643.
Subject(s)
Laparoscopy , Stomach Neoplasms , Humans , Male , Middle Aged , Dietary Supplements , Gastrectomy/methods , Hemoglobins , Laparoscopy/adverse effects , Quality of Life , Stomach Neoplasms/surgery , Treatment Outcome , Vitamin B 12/therapeutic use , FemaleABSTRACT
BACKGROUND: The benefit of regular follow-up after curative resection for gastric cancer is controversial as there is no evidence that it will improve survival. This study assessed whether regular follow-up leads to improved survival in patients after surgery for gastric cancer. METHODS: A secondary analysis was undertaken of patients who participated in an RCT of laparoscopic versus open distal gastrectomy for advanced gastric cancer between November 2011 and April 2015. Depending on whether patients were compliant with the initial trial follow-up protocol or not, they were analysed as having had either regular or irregular follow-up. Clinicopathological characteristics, recurrence patterns, detection, treatments, and survival were compared between the groups. RESULTS: The regular and irregular follow-up groups comprised 712 and 263 patients respectively. Disease recurrence within 36 months was more common in the regular group than in the irregular group (17.0 versus 11.4 per cent; P = 0.041). Recurrence patterns did not differ between the groups. The 3-year recurrence-free survival rate was worse in the regular than in the irregular group (81.2 versus 86.5 per cent; P = 0.031). However, the 5-year overall survival rate was comparable (84.5 versus 87.5 per cent respectively; P = 0.160). Multivariable analysis revealed that type of follow-up was not an independent factor affecting 5-year overall survival. CONCLUSION: Regular follow-up after radical gastrectomy was not associated with improved overall survival.
Subject(s)
Laparoscopy , Stomach Neoplasms , Humans , Neoplasm Recurrence, Local/surgery , Laparoscopy/methods , Survival Rate , Gastrectomy/methods , Treatment OutcomeABSTRACT
BACKGROUND: Personalized survival prediction is important in gastric cancer patients after gastrectomy based on large datasets with many variables including time-varying factors in nutrition and body morphometry. One year after gastrectomy might be the optimal timing to predict long-term survival because most patients experience significant nutritional change, muscle loss, and postoperative changes in the first year after gastrectomy. We aimed to develop a personalized prognostic artificial intelligence (AI) model to predict 5 year survival at 1 year after gastrectomy. METHODS: From a prospectively built gastric surgery registry from a tertiary hospital, 4025 gastric cancer patients (mean age 56.1 ± 10.9, 36.2% females) treated gastrectomy and survived more than a year were selected. Eighty-nine variables including clinical and derived time-varying variables were used as input variables. We proposed a multi-tree extreme gradient boosting (XGBoost) algorithm, an ensemble AI algorithm based on 100 datasets derived from repeated five-fold cross-validation. Internal validation was performed in split datasets (n = 1121) by comparing our proposed model and six other AI algorithms. External validation was performed in 590 patients from other hospitals (mean age 55.9 ± 11.2, 37.3% females). We performed a sensitivity analysis to analyse the effect of the nutritional and fat/muscle indices using a leave-one-out method. RESULTS: In the internal validation, our proposed model showed AUROC of 0.8237, which outperformed the other AI algorithms (0.7988-0.8165), 80.00% sensitivity, 72.34% specificity, and 76.17% balanced accuracy. In the external validation, our model showed AUROC of 0.8903, 86.96% sensitivity, 74.60% specificity, and 80.78% balanced accuracy. Sensitivity analysis demonstrated that the nutritional and fat/muscle indices influenced the balanced accuracy by 0.31% and 6.29% in the internal and external validation set, respectively. Our developed AI model was published on a website for personalized survival prediction. CONCLUSIONS: Our proposed AI model provides substantially good performance in predicting 5 year survival at 1 year after gastric cancer surgery. The nutritional and fat/muscle indices contributed to increase the prediction performance of our AI model.
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Stomach Neoplasms , Female , Humans , Male , Prognosis , Stomach Neoplasms/surgery , Artificial Intelligence , Gastrectomy/adverse effects , Gastrectomy/methods , AlgorithmsABSTRACT
PURPOSE: Appropriate preclinical mouse models are needed to evaluate the response to immunotherapeutic agents. Immunocompetent mouse models have rarely been reported for gastric cancer. Thus, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) in immunocompetent mouse models using various murine gastric cancer cell lines. MATERIALS AND METHODS: We constructed subcutaneous syngeneic tumors with murine gastric cancer cell lines, YTN3 and YTN16, in C57BL/6J mice. Mice were intraperitoneally treated with IgG isotype control or an anti-programmed death-ligand 1 (PD-L1) neutralizing antibody. We used immunohistochemistry to evaluate the tumor-infiltrating immune cells of formalin-fixed paraffin-embedded mouse tumor tissues. We compared the protein and RNA expression between YTN3 and YTN16 cell lines using a mouse cytokine array and RNA sequencing. RESULTS: The mouse tumors revealed distinct histological and molecular characteristics. YTN16 cells showed upregulation of genes and proteins related to immunosuppression, such as Ccl2 (CCL2) and Csf1 (M-CSF). Macrophages and exhausted T cells were more enriched in YTN16 tumors than in YTN3 tumors. Several YTN3 tumors were completely regressed by the PD-L1 inhibitor, whereas YTN16 tumors were unaffected. Although treatment with a PD-L1 inhibitor increased infiltration of T cells in both the tumors, the proportion of exhausted immune cells did not decrease in the non-responder group. CONCLUSION: We confirmed the histological and molecular features of cancer cells with various responses to ICI. Our models can be used in preclinical research on ICI resistance mechanisms to enhance clinical efficacy.
Subject(s)
Immune Checkpoint Inhibitors , Stomach Neoplasms , Animals , Mice , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics , Mice, Inbred C57BL , T-Lymphocytes , Cytokines , Cell Line, TumorABSTRACT
Advances in cancer screening and early detection, as well as improvements in surgical techniques and therapeutics, have contributed to decreasing gastric cancer mortality. The number of gastric cancer survivors continues to rise; however, long-term follow-up has revealed an increase in the risk of post-gastrectomy symptoms or other health problems, such as extra-gastric secondary primary cancer (SPC), in these survivors. Therefore, evidence-based screening for new primary cancer is needed in these populations; however, the incidence of SPC varies by country or continent and its characteristics have not been clearly reported. The characteristics of SPC are of increasing interest to both treatment providers and gastric cancer survivors; thus, this literature review explores not only the epidemiology and biology of SPC but also clinical and biological factors that influence its prognosis.
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Gluconobacter sphaericus has not yet been used in biotransformation studies. In this study, G. sphaericus SJF2-1, which produces a diffusible pigment, was isolated from grape. The spent culture medium became dark black when the cells were grown in medium containing glucose and then autoclaved. This bacterium produced 2,5-diketo-D-gluconate (2,5-DKG) from D-glucose and D-gluconate. When 5% D-glucose was used, the conversion efficiency was approximately 52.4% in a flask culture. 2,5-DKG is a precursor of 2-keto-L-gulonic acid, which is a key intermediate in the industrial production of L-ascorbic acid. The complete genome sequence of G. sphaericus SJF2-1 was determined for the first time in the G. sphaericus species. The total size was 3,198,086 bp, with 2867 protein-coding sequences; one chromosome and six plasmids were identified. From the genome of SJF2-1, multiple genes homologous to those involved in the conversion of D-glucose to 2,5-DKG were identified. In particular, six different genes encoding membrane-associated flavoprotein-cytochrome c complexed dehydrogenase were identified and divided into two different lineages. This study suggests the potential of G. sphaericus SJF2-1 to mass-produce 2,5-DKG and other D-glucose oxidation products.
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Gastrectomy is the main treatment option for gastric cancer patients. Laparoscopic approach has become popular as an alternative to open method during the last decades, and clinical trials have revealed safety and feasibility in the short- and long-term outcomes of laparoscopic gastrectomy. The aim of this review is to summarize the results of prospective clinical trials and propose future perspectives for laparoscopic gastrectomy.
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Purpose: The discrepancy between preoperative and final pathological staging has been a long-standing challenge for the application of clinical trials or appropriate treatment options. This study aimed to demonstrate the accuracy of preoperative staging of locally advanced gastric cancer using data from a large-scale randomized clinical trial. Materials and methods: Of the 1050 patients enrolled in the clinical trial, 26 were excluded due to withdrawal of consent (n = 20) or non-surgery (n = 6). The clinical and pathological staging was compared. Risk factor analysis for underestimation was performed using univariate and multivariate analyses. Results: Regarding T staging by computed tomography, accuracy rates were 74.48, 61.62, 58.56, and 85.16% for T1, T2, T3 and T4a, respectively. Multivariate analysis for underestimation of T staging revealed that younger age, ulcerative gross type, circular location, larger tumor size, and undifferentiated histology were independent risk factors. Regarding nodal status estimation, 54.9% of patients with clinical N0 disease were pathologic N0, and 36.4% of patients were revealed to have pathologic N0 among clinical node-positive patients. The percentage of metastasis involvement at the D1, D1+, and D2 lymph node stations significantly increased with the advanced clinical N stage. Among all patients, 29 (2.8%), including 26 with peritoneal seeding, exhibited distant metastases. Conclusions: Estimating the exact pathologic staging remains challenging. A thorough evaluation is mandatory before treatment selection or trial enrollment. Moreover, we need to set a sufficient case number when we design the clinical trial considering the stage migration.