Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

Ethyl Formate Fumigation for Controlling Two Major Aphid Pests, Aphis spiraecola and Aphis gossypii, on Passion Fruit, from Cultivation to Post-Harvest Storage.

Tropical and subtropical crops are being increasingly cultivated in South Korea, leading to an increase in damage by exotic insect pests. Consequently, ethyl formate (EF) is currently being considered for quarantine and pre-shipment fumigation. In this study, we evaluated the effectiveness of EF fumigation for controlling Aphis spiraecola Patch and Aphis gossypii Glover, two representative quarantine pests on passion fruit ("Pink Bourbon") during greenhouse cultivation and post-harvest storage. The efficacy of EF against both aphids in terms of the lethal concentration causing 50% mortality (LCt50%) and LCt99% was 1.36-2.61 g h/m3 and 3.73-7.55 g h/m3 under greenhouse conditions (23 °C), and 1.37-2.02 g h/m3 and 3.80-14.59 g h/m3 post-harvest (5 °C), respectively. EF at 4 g/m3 for 4 h resulted in 100% mortality of A. spiraecola, which was more resistant to EF, without causing phytotoxic damage to the trees in a 340 m3 greenhouse. Post-harvest fruit fumigation at 10 g/m3 for 4 h in a mid-size (0.8 m3) fumigation chamber resulted in complete disinfection. Moreover, the EF level decreased below the EF threshold within 10 min after natural ventilation in the greenhouse. Therefore, our results suggest EF fumigation as an effective method for controlling A. spiraecola and A. gossypii.

Totally laparoscopic versus laparoscopy-assisted distal gastrectomy: the KLASS-07, a randomized controlled trial.

BACKGROUNDS: Strong evidence is lacking as no confirmatory randomized controlled trials (RCTs) have compared the efficacy of totally laparoscopic distal gastrectomy (TLDG) with laparoscopy-assisted distal gastrectomy (LADG). We performed an RCT to confirm if TLDG is different from LADG. METHODS: The KLASS-07 trial is a multicentre, open-label, parallel-group, phase III, RCT of 442 patients with clinical stage I gastric cancer. Patients were enrolled from 21 cancer care centers in South Korea between January 2018 and September 2020 and randomized to undergo TLDG or LADG using blocked randomization with a 1:1 allocation ratio, stratified by the participating investigators. Patients were treated through R0 resections by TLDG or LADG as the full analysis set of the KLASS-07 trial. The primary endpoint was morbidity within postoperative day 30, and the secondary endpoint was QoL for 1 year. This trial is registered at ClinicalTrials.gov (NCT NCT03393182). RESULTS: 442 patients were randomized (222 to TLDG, 220 to LADG), and 422 patients were included in the pure analysis (213 and 209, respectively). The overall complication rate did not differ between the two groups (TLDG vs. LADG: 12.2% vs. 17.2%). However, TLDG provided less postoperative ileus and pulmonary complications than LADG (0.9% vs. 5.7%, P= 0.006; and 0.5% vs. 4.3%, P= 0.035, respectively). The QoL was better after TLDG than after LADG regarding emotional functioning at 6 months, pain at 3 months, anxiety at 3 and 6 months, and body image at 3 and 6 months (all P< 0.05). However, these QoL differences were resolved at 1 year. CONCLUSIONS: The KLASS-07 trial confirmed that TLDG is not different from LADG in terms of postoperative complication but has advantages to reduce ileus and pulmonary complications. TLDG can be a good option to offer better QoL in terms of pain, body image, emotion, and anxiety at 3-6 months.

The Impact of Different Types of Complications on Long-Term Survival After Total Gastrectomy for Gastric Cancer.

PURPOSE: This study aimed to investigate the impact of different types of complications on long-term survival following total gastrectomy for gastric cancer. MATERIALS AND METHODS: A total of 926 patients who underwent total gastrectomy between 2008 and 2016 were included. Patients were divided into the morbidity and no-morbidity groups, and long-term survival was compared between the 2 groups. The prognostic impact of postoperative morbidity was assessed using a multivariate Cox proportional hazard model, which accounted for other prognostic factors. In the multivariate model, the effects of each complication on survival were analyzed. RESULTS: A total of 229 patients (24.7%) developed postoperative complications. Patients with postoperative morbidity showed significantly worse overall survival (OS) (5-year, 65.0% vs. 76.7%, P<0.001) and cancer-specific survival (CSS) (5-year, 74.2% vs. 83.1%, P=0.002) compared to those without morbidity. Multivariate analysis adjusting for other prognostic factors showed that postoperative morbidity remained an independent prognostic factor for OS (hazard ratio [HR], 1.442; 95% confidence interval [CI], 1.136-1.831) and CSS (HR, 1.463; 95% CI, 1.063-2.013). There was no significant difference in survival according to the severity of complications. The following complications showed a significant association with unfavorable long-term survival: ascites (HR, 1.868 for OS, HR, 2.052 for CSS), wound complications (HR, 2.653 for OS, HR, 2.847 for CSS), and pulmonary complications (HR, 2.031 for OS, HR, 1.915 for CSS). CONCLUSIONS: Postoperative morbidity adversely impacted survival following total gastrectomy for gastric cancer. Among the different types of complications, ascites, wound complications, and pulmonary complications exhibited significant associations with long-term survival.

Splenic hilar lymph node dissection enhances survival in Bormann type 4 gastric cancer.

Splenic hilar (no.10) lymph node dissection during total gastrectomy is no longer recommended for advanced proximal gastric cancer. However, the treatment efficacy of no.10 lymph node dissection in Borrmann type 4 tumors remains unclear. We enrolled 539 patients who underwent total gastrectomy for Borrmann type 4 tumors between 2006 and 2016 in four major institutions in Korea. We compared the long-term survival of the no.10 lymph node dissection (n = 309) and no-dissection groups (n = 230) using the propensity score (inverse probability of treatment weighting). The treatment effects of no.10 lymph node dissection were estimated in the weighted sample using the Cox proportional hazards regression model with a robust sandwich-type variance estimator. After inverse probability of treatment weighting, there were 540.4 patients in the no.10 lymph node dissection group and 532.7 in the no-dissection group. The two groups showed well-balanced baseline characteristics, including tumor node metastasis stage. The 5-year survival rates in the no.10 lymph node dissection and no-dissection groups were 45.7% and 38.6%, respectively (log-rank p = 0.036, hazard ratio 0.786, 95% confidence interval 0.630-0.982). Multivariate analysis revealed that no.10 lymph node dissection was an independent favorable prognostic factor (adjusted hazard ratio 0.747, 95% confidence interval 0.593-0.940) after adjusting for other prognostic factors. Sensitivity analyses in other inverse probability of treatment weighting models and the propensity score matching model showed similar results. Patients undergoing no.10 lymph node dissection showed improved survival compared to those without. No.10 lymph node dissection is recommended during total gastrectomy for patients with Borrmann type 4 gastric cancer.

Development of a Concurrent Treatment Technique of Ethyl Formate and Mixtures (Nitrogen, Phosphine) to Control Citrus Mealybug (Planococcus citri).

Currently, the fumigant ethyl formate (EF) is stored as a liquified gas in metal cylinders mixed with carbon dioxide (CO2), but this product type is expensive to manufacture, transport, and maintain in cylinders. To address these problems, we developed a new EF fumigation technique with a nitrogen (N2) carrier. In this report, the susceptibility of citrus mealybugs, one of the most resistant mealybugs to fumigants, to EF was assessed; the phytotoxicity of an EF + N2 concurrent treatment applied to banana fruit was examined to evaluate the efficacy compared to the current EF + CO2 product; and the increased efficacy with a phosphine (PH3) addition to EF + N2 was also assessed. Concurrent treatment of EF and N2 was performed at an LC50 concentration of EF. N2 was applied in seven doses from concentrations of 79% to 95%. The phytotoxicity of EF to bananas was assessed by applying EF at 35 mg/L with N2 at 79%, and the color, sugar content, and weight loss of bananas were measured for 14 days after treatment. The EF with N2 treatment resulted in more than 50% mortality at all growth stages of the mealybug, and there was no significant difference between the untreated and treated banana fruits. EF mixed with PH3 showed a higher efficacy than treatment with EF alone, but only a slight increase in efficacy was observed when the PH3 concentration increased. These results indicate that concurrent treatment with EF and N2 can be used to control mealybugs on banana fruits, and combined treatment with EF and PH3 can also enhance the efficacy against mealybugs.

Gene Regulatory Networks and Signaling Pathways in Palatogenesis and Cleft Palate: A Comprehensive Review.

Palatogenesis is a complex and intricate process involving the formation of the palate through various morphogenetic events highly dependent on the surrounding context. These events comprise outgrowth of palatal shelves from embryonic maxillary prominences, their elevation from a vertical to a horizontal position above the tongue, and their subsequent adhesion and fusion at the midline to separate oral and nasal cavities. Disruptions in any of these processes can result in cleft palate, a common congenital abnormality that significantly affects patient's quality of life, despite surgical intervention. Although many genes involved in palatogenesis have been identified through studies on genetically modified mice and human genetics, the precise roles of these genes and their products in signaling networks that regulate palatogenesis remain elusive. Recent investigations have revealed that palatal shelf growth, patterning, adhesion, and fusion are intricately regulated by numerous transcription factors and signaling pathways, including Sonic hedgehog (Shh), bone morphogenetic protein (Bmp), fibroblast growth factor (Fgf), transforming growth factor beta (Tgf-ß), Wnt signaling, and others. These studies have also identified a significant number of genes that are essential for palate development. Integrated information from these studies offers novel insights into gene regulatory networks and dynamic cellular processes underlying palatal shelf elevation, contact, and fusion, deepening our understanding of palatogenesis, and facilitating the development of more efficacious treatments for cleft palate.

Increased miR-200c levels disrupt palatal fusion by affecting apoptosis, cell proliferation, and cell migration.

The mammalian palate separates the oral and nasal cavities, facilitating proper feeding, respiration, and speech. Palatal shelves, composed of neural crest-derived mesenchyme and surrounding epithelium, are a pair of maxillary prominences contributing to this structure. Palatogenesis reaches completion upon the fusion of the midline epithelial seam (MES) following contact between medial edge epithelium (MEE) cells in the palatal shelves. This process entails numerous cellular and molecular occurrences, including apoptosis, cell proliferation, cell migration, and epithelial-mesenchymal transition (EMT). MicroRNAs (miRs) are small, endogenous, non-coding RNAs derived from double-stranded hairpin precursors that regulate gene expression by binding to target mRNA sequences. Although miR-200c is a positive regulator of E-cadherin, its role in palatogenesis remains unclear. This study aims to explore the role of miR-200c in palate development. Before contact with palatal shelves, mir-200c was expressed in the MEE along with E-cadherin. After palatal shelf contact, miR-200c was present in the palatal epithelial lining and epithelial islands surrounding the fusion region but absent in the mesenchyme. The function of miR-200c was investigated by utilizing a lentiviral vector to facilitate overexpression. Ectopic expression of miR-200c resulted in E-cadherin upregulation, impaired dissolution of the MES, and reduced cell migration for palatal fusion. The findings imply that miR-200c is essential in palatal fusion as it governs E-cadherin expression, cell death, and cell migration, acting as a non-coding RNA. This study may contribute to clarifying the underlying molecular mechanisms in palate formation and provides insights into potential gene therapies for cleft palate.

FOXA2 and STAT5A regulate oncogenic activity of KIF5B-RET fusion.

KIF5B-RET gene rearrangement occurs in ~1% of lung adenocarcinomas. Recently, targeted agents that inhibit RET phosphorylation have been evaluated in several clinical studies; however, little is known about the role of this gene fusion in driving lung cancer. Immunohistochemistry was used to evaluate the expression of the FOXA2 protein in tumor tissues of patients with lung adenocarcinoma. KIF5B-RET fusion cells proliferated in a cohesive form and grew tightly packed with variable-sized colonies. The expression of RET and its downstream signaling molecules, including p-BRAF, p-ERK, and p-AKT, increased. In KIF5B-RET fusion cells, the intracellular expression of p-ERK was higher in the cytoplasm than in the nucleus. Two transcription factors, STAT5A and FOXA2, exhibiting significantly different expressions at the mRNA level, were finally selected. p-STAT5A was highly expressed in the nucleus and cytoplasm, whereas the expression of the FOXA2 protein was lower; however, it was much higher in the nucleus than in the cytoplasm. Compared with the expression of FOXA2 in the RET rearrangement-wild NSCLC (45.0%), high expression (3+) were observed in most RET rearrangement NSCLCs (94.4%). Meanwhile, KIF5B-RET fusion cells began to increase belatedly from day 7 and only doubled on day 9 in 2D cell culture. However, tumors in mice injected with KIF5B-RET fusion cells began to rapidly increase from day 26. In cell cycle analyses, the KIF5B-RET fusion cells in G0/G1 were increased on day 4 (50.3 ± 2.6%) compared with the empty cells (39.3 ± 5.2%; P = 0.096). Cyclin D1 and E2 expressions were reduced, whereas CDK2 expression slightly increased. pRb and p21 expression was diminished compared with the empty cells, TGF-ß1 mRNA was highly expressed, and the proteins were accumulated mostly in the nucleus. Twist mRNA and protein expression was increased, whereas Snail mRNA and protein expression was decreased. Particularly, in KIF5B-RET fusion cells treated with FOXA2 siRNA, the expression of TGF-ß 1 mRNA was remarkably reduced but Twist1 and Snail mRNA were increased. Our data suggest that cell proliferation and invasiveness in KIF5B-RET fusion cells are regulated by the upregulation of STAT5A and FOXA2 through the continuous activation of multiple RET downstream signal cascades, including the ERK and AKT signaling pathways. We found that TGF-ß1 mRNA, where significant increments were observed in KIF5B-RET fusion cells, is regulated at the transcriptional level by FOXA2.

Supraclavicular cephalic vein draining into the internal jugular vein via the external jugular vein.

PURPOSE: The aim of this study is to report rare anatomical variations of the cephalic vein (CV) in a 77-year-old Korean male cadaver. CASE REPORT: On the right upper arm, the CV located lateral to the deltopectoral groove passed anterior to the clavicle at the lateral one-fourth of the clavicle without anastomosis to the axillary vein. It was connected to the transverse cervical and suprascapular veins by two communicating branches in the middle of its course at the neck, and opened into the external jugular vein at its junction with the internal jugular veins. The suprascapular and anterior jugular veins were flowed into the subclavian vein at the jugulo-subclavian venous confluence, and were connected by a short communicating branch. CONCLUSION: Detailed knowledge of the variations in the CV is expected to be helpful in decreasing unpredicted injuries and possible postoperative complications when invasive venous access is performed through the CV.

The impact of the 30-day postoperative complications on the quality of life following gastrectomy for gastric carcinoma: A prospective study.

BACKGROUND: The effect of postoperative complications on long-term quality of life (QoL) is controversial in abdominal surgery. This study aimed to investigate the impact of 30-day postoperative complications on long-term QoL after gastrectomy. METHOD: This is a longitudinal cohort study that enrolled 908 patients undergoing gastrectomy for gastric cancer between 2016 and 2017. QoL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) generic cancer (QLQ C-30) and gastric module (STO-22) preoperatively and at 1, 6, 12, and 24 months postoperatively. Patients were divided into the morbidity (30-day postoperative complications) and no-morbidity groups, and the postoperative QoL change was compared using a linear mixed model. RESULTS: The mean age was 62.5 ± 12.0 years. Subtotal and total gastrectomy was performed in 763 (84.0%) and 145 (16.0%) patients, respectively. There were 189 (20.8%) patients developing postoperative complications. The morbidity group showed worse scores in several functions and symptoms of QoL at the baseline. However, the two groups showed no significant difference in postoperative changes in most functions and symptoms of the QLQ C-30 and STO-22 (Pgroup × time > 0.05). The recovery of global health (Pgroup × time < 0.001) and anxiety (Pgroup × time = 0.008) was slightly better in the morbidity group. The subgroup analysis of patients developing major abdominal complications showed similar results. CONCLUSION: The morbidity group showed worse QoL in several functions and symptoms at the baseline. However, postoperative complications had little influence on QoL change following gastrectomy for gastric cancer.

Comprehensive Study of Microsatellite Instability Testing and Its Comparison With Immunohistochemistry in Gastric Cancers

Purpose@#In this study, polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing was comprehensively analyzed and compared with immunohistochemistry (IHC) for mismatch repair (MMR) protein expression in patients with gastric cancer (GC). @*Materials and Methods@#In 5,676 GC cases, PCR-based MSI testing using five microsatellites (BAT-26, BAT-25, D5S346, D2S123, and D17S250) and IHC for MLH1 were performed. Reevaluation of MSI testing/MLH1 IHC and additional IHC for MSH2, MSH6, and PMS2 were performed in discordant/indeterminate cases. @*Results@#Of the 5,676 cases, microsatellite stable (MSS)/MSI-low and intact MLH1 were observed in 5,082 cases (89.5%), whereas MSI-high (MSI-H) and loss of MLH1 expression were observed in 502 cases (8.8%). We re-evaluated the remaining 92 cases (1.6%) with a discordant/ indeterminate status. Re-evaluation showed 1) 37 concordant cases (0.7%) (18 and 19 cases of MSI-H/MMR-deficient (dMMR) and MSS/MMR-proficient (pMMR), respectively), 2) 6 discordant cases (0.1%) (3 cases each of MSI-H/pMMR and MSS/dMMR), 3) 14 MSI indeterminate cases (0.2%) (1 case of dMMR and 13 cases of pMMR), and 4) 35 IHC indeterminate cases (0.6%) (22 and 13 cases of MSI-H and MSS, respectively). Finally, MSI-H or dMMR was observed in 549 cases (9.7%), of which 47 (0.8%) were additionally confirmed as MSI-H or dMMR by reevaluation. Sensitivity was 99.3% for MSI testing and 95.4% for MMR IHC. @*Conclusions@#Considering the low incidence of MSI-H or dMMR, discordant/indeterminate results were occasionally identified in GCs, in which case complementary testing is required.These findings could help improve the accuracy of MSI/MMR testing in daily practice.

Role of non‑pulmonary vein triggers in persistent atrial fibrillation

Pulmonary vein isolation is an well-established treatment strategy for atrial fibrillation (AF), and it is especially effective for patients with paroxysmal AF. However, the success rate is limited for patients with persistent AF, because non-pul‑ monary vein triggers which increase AF recurrence are frequently found in these patients. The major non-pulmonary vein triggers are from the left atrial posterior wall, left atrial appendage, ligament of Marshall, coronary sinus, superior vena cava, and crista terminalis, but other atrial sites can also generate AF triggers. All these sites have been known to contain atrial myocytes with potential arrhythmogenic electrical activity. The prevalence and clinical characteristics of these non-pulmonary vein triggers are well studied; however, the clinical outcome of catheter ablation for persistent AF is still unclear. Here, we reviewed the current ablation strategies for persistent AF and the clinical implications of major non-pulmonary vein triggers.

The Clinicopathological Features of Mixed Carcinoma in 7,215Patients with Gastric Cancer in a Tertiary Hospital in South Korea

Background/Aims@#There are few reports regarding mixed carcinoma, defined as a mixture of glandular and poorly cohesive components, in patients with gastric cancer (GC). The aim of this study was to evaluate the proportion and characteristics of mixed carcinoma in GC patients. @*Methods@#A total of 7,215 patients diagnosed with GC at Seoul National University Bundang Hospital were enrolled from March 2011 to February 2020. GC was divided into four groups (wellmoderately differentiated GC, poorly differentiated GC, poorly cohesive carcinoma, and mixed carcinoma). The proportion of each GC type and the clinicopathological features were analyzed and divided into early GC and advanced GC. @*Results@#The proportion of mixed carcinoma was 10.9% (n=787). In early GC, submucosal invasion was the most common in poorly differentiated (53.7%), and mixed carcinoma ranked second (41.1%). Mixed carcinoma showed the highest proportion of lymph node metastasis in early GC (23.0%) and advanced GC (78.3%). In advanced GC, the rate of distant metastasis was 3.6% and 3.9% in well-moderately differentiated GC and mixed carcinoma, respectively, lower than that in poorly differentiated GC (6.4%) and poorly cohesive carcinoma (5.7%), without statistical significance. @*Conclusions@#Mixed carcinoma was associated with lymph node metastasis compared to other histological GC subtypes. And it showed relatively common submucosal invasion in early GC, but the rates of venous invasion and distant metastasis were lower in advanced GC. Further research is needed to uncover the mechanism underlying these characteristics of mixed carcinoma (Trial registration number: NCT04973631).

Impact of Body Mass Index on Survival Depending on Sex in 14,688 Patients with Gastric Cancer in a Tertiary Hospital in South Korea

Background/Aims@#The incidence and prognosis of gastric cancer (GC) shows sex difference.This study aimed to evaluate the effect of body mass index (BMI) on GC survival depending on sex. @*Methods@#The sex, age, location, histology, TNM stages, BMI, and survival were analyzed in GC patients from May 2003 to February 2020 at the Seoul National University Bundang Hospital. @*Results@#Among 14,688 patients, there were twice as many males (66.6%) as females (33.4%).However, under age 40 years, females (8.6%) were more prevalent than males (3.1%). Cardia GC in males showed a U-shaped distribution for underweight (9.6%), normal (6.4%), overweight (6.1%), obesity (5.6%), and severe obesity (9.3%) but not in females (p=0.003). Females showed decreased proportion of diffuse-type GC regarding BMI (underweight [59.9%], normal [56.8%], overweight [49.5%], obesity [44.8%], and severe obesity [41.7%]), but males did not (p<0.001). Both sexes had the worst prognosis in the underweight group (p<0.001), and the higher BMI, the better prognosis in males, but not females. Sex differences in prognosis according to BMI tended to be more prominent in males than in females in subgroup analysis of TNM stages I, II, and III and the operative treatment group. @*Conclusions@#GC-specific survival was affected by BMI in a sex-dependent manner. These differences may be related to genetic, and environmental, hormonal factors; body composition; and muscle mass (Trial registration number: NCT04973631).

Molecular and Immune Profiling of Syngeneic Mouse Models Predict Response to Immune Checkpoint Inhibitors in Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

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.

Circulating Extracellular-Vesicle-Incorporated MicroRNAs as Potential Biomarkers for Ischemic Stroke in Patients With Cancer / 대한뇌졸중학회지

Background@#and Purpose This study aimed to evaluate whether extracellular-vesicle-incorporated microRNAs (miRNAs) are potential biomarkers for cancer-related stroke. @*Methods@#This cohort study compared patients with active cancer who had embolic stroke of unknown sources (cancer-stroke group) with patients with only cancer, patients with only stroke, and healthy individuals (control groups). The expression profiles of miRNAs encapsulated in plasma exosomes and microvesicles were evaluated using microarray and validated using quantitative real-time polymerase chain reaction. The XENO-QTM miRNA assay technology was used to determine the absolute copy numbers of individual miRNAs in an external validation cohort. @*Results@#This study recruited 220 patients, of which 45 had cancer-stroke, 76 were healthy controls, 39 were cancer controls, and 60 were stroke controls. Three miRNAs (miR-205-5p, miR-645, and miR-646) were specifically incorporated into microvesicles in patients with cancer-related stroke, cancer controls, and stroke controls. The area under the receiver operating characteristic curves of these three miRNAs were 0.7692–0.8510 for the differentiation of patients with cancer-stroke from cancer-controls and 0.8077–0.8846 for the differentiation of patients with cancer-stroke from stroke controls. The levels of several miRNAs were elevated in the plasma exosomes of patients with cancer, but were lower than those in plasma microvesicles. An in vivo study showed that systemic injection of miR-205-5p promoted the development of arterial thrombosis and elevation of D-dimer levels. @*Conclusion@#Stroke due to cancer-related coagulopathy was associated with deregulated expression of miRNAs, particularly microvesicle-incorporated miR-205-5p, miR-645, and miR-646. Further prospective studies of extracellular-vesicle-incorporated miRNAs are required to confirm the diagnostic role of miRNAs in patients with stroke and to screen the roles of miRNAs in patients with cancer.

Prepregnancy Glucose Levels Within Normal Range and Its Impact on Obstetric Complications in Subsequent Pregnancy: A Population Cohort Study

Background@#We sought to identify the influence of prepregnancy glucose levels on obstetric complications in subsequent pregnancy. @*Methods@#Women in Republic of Korea who had given birth between January 1st, 2007 and December 31st, 2010 were enrolled. The database of the Health Insurance Review and Assessment Service and data from a national health screening program for infants and children were used. Subjects were divided into seven groups according to their fasting glucose levels. @*Results@#59,619 women were included for analysis, and 10.4%, 13.7%, 19.1%, 21.5%, 16.0%, 11.6%, and 7.5% women had glucose levels of 100 mg/dL. Each 5 mg/dL increase in prepregnancy fasting glucose levels was associated with increased risk of gestational diabetes and macrosomia in subsequent pregnancy. Adjusted risk ratio for gestational diabetes per standard deviation prepregnancy glucose > 100 mg/dL was 2.015 (95% confidence interval, 1.649–2.462) and for macrosomia an adjusted risk ratio 1.389 (95% confidence interval, 1.147–1.682). @*Conclusion@#Higher prepregnancy glucose level within normal range was related to gestational diabetes and macrosomia in following pregnancy. Our results may aid in the identification of women at future risk of obstetric complications and may guide to stratify women into normal and intensified care.Tweetable abstractHigher prepregnancy glucose in normal range is associated with gestational diabetes and macrosomia.

Exploring ideal operative time for best outcomes in gastric cancer surgery: A multi-institutional study based on KLASS-07 database.

Objective: While a rushed operation can omit essential procedures, prolonged operative time results in higher morbidity. Nevertheless, the optimal operative time range remains uncertain. This study aimed to estimate the ideal operative time range and evaluate its applicability in laparoscopic cancer surgery. Methods: A prospectively collected multicenter database of 397 patients who underwent laparoscopic distal gastrectomy were retrospectively reviewed. The ideal operative time range was statistically calculated by separately analyzing the operative time of uneventful surgeries. Finally, intraoperative and postoperative outcomes were compared among the shorter, ideal, and longer operative time groups. Results: The statistically calculated ideal operative time was 135.4-165.4 min. The longer operative time (LOT) group had a lower rate of uneventful, perfect surgery than the ideal or shorter operative time (IOT/SOT) group (2.8% vs. 8.8% and 2.2% vs. 13.4%, all P<0.05). Longer operative time increased bleeding, postoperative morbidities, and delayed diet and discharge (all P<0.05). Particularly, an uneventful, perfect surgery could not be achieved when the operative time exceeded 240 min. Regardless of ideal time range, SOT group achieved the highest percentage of uneventful surgery (13.4%), which was possible by surgeon's ability to retrieve a higher number of lymph nodes and perform ≥150 gastrectomies annually. Conclusions: Operative time longer than the ideal time range (especially ≥240 min) should be avoided. If the essential operative procedure were faithfully conducted without compromising oncological safety, an operative time shorter than the ideal range leaded to a better prognosis. Efforts to minimize operative time should be attempted with sufficient surgical experience.

Differential RNA expression of immune-related genes and tumor cell proximity from intratumoral M1 macrophages in acral lentiginous melanomas treated with PD-1 blockade.

Immune checkpoint inhibitors (ICIs) offer improved survival for patients with advanced malignant melanomas. However, only a subset of these patients exhibit an objective response rate of 10-40 % with ICIs. We aimed to ascertain the effects of RNA signatures and the spatial distribution of immune cells on the treatment outcomes of patients with malignant melanomas undergoing ICI therapy. Clinical data were retrospectively collected from ICI-treated patients with malignant melanoma; RNA expression profiles were examined via next-generation sequencing, whereas the composition, density, and spatial distribution of immune cells were determined via multiplex immunohistochemistry. Patients with poor and good responses to ICIs showed significant differences in mRNA expression profiles. Different spatial distributions of T-cells, macrophages, and NK cells as well as RNA signatures of immune-related genes were found to be closely related to therapeutic outcomes in ICI-treated patients with malignant melanomas. The spatial distributions of PD-1+ T-cells and activated M1 macrophages showed a significant correlation with favorable responses to ICIs. Our findings highlight the clinical relevance of the spatial proximity of immune cell subsets in the treatment outcomes of metastatic malignant melanoma.