Background
The chemokine CXCL13 is known to influence local anti‐tumor immunity by recruiting immune cells and forming tertiary lymphoid structures (TLS). It has been hypothesized that TLS, led by ...the expression of CXCL13, could be a predictive or prognostic biomarker for immunotherapy. We investigated the predictive value of CXCL13 to immune checkpoint inhibitors (ICI) in lung adenocarcinoma.
Methods
We constructed an exploratory dataset (n = 63) and a validation dataset (n = 57) in metastatic lung adenocarcinoma patients treated with ICI. Based on the clinical response, the difference in gene expression profile, including CXCL13, was evaluated.
Results
From the exploratory dataset, CXCL13 expression was significantly upregulated in the ICI responders (p = 0.002). Survival analysis using a cut‐off value of the median expression value of CXCL13 showed prolonged progression‐free survival (PFS) (p = 0.004) and overall survival (OS) (p = 0.007). CXCL13 expression was correlated with other immune response genes, such as GZMA, CD8A, IFNG, PRF1, TLS‐related gene sets and its receptor, CXCR5. Notably, subgroup analyses based on CXCL13 expression and CD8A showed that CXCL13‐upregulated patients demonstrated comparably prolonged survival regardless of CD8A expression. In the validation dataset, CXCL13 upregulation also demonstrated a significant prolongation of both PFS (p = 0.050) and OS (p = 0.026).
Conclusion
We observed that CXCL13 upregulation is correlated to better ICI response in lung adenocarcinoma. Our results support that CXCL13 could be an important chemokine in shaping the immunoactive tumor microenvironment which affects the anti‐tumor effect of ICI.
CXCL13 expression in lung adenocarcinoma showed predictive value to immune checkpoint inhibitor (ICI) treatment. CXCL13 expression was correlated with expression of other immune response genes. Higher median progression‐free survival and overall survival to ICI treatment are observed in CXCL13 upregulated group.
For patients with early stage EGFR-mutant–positive (EGFR-M+) NSCLC, curative surgery followed by adjuvant chemotherapy is considered the standard of care. This study evaluated the feasibility and ...efficacy of longitudinal monitoring of circulating tumor DNA (ctDNA) as a valuable biomarker for early detection of minimal residual disease (MRD) and provides identification of the group at high risk for recurrence in resected stages I to IIIA EGFR-M+ NSCLC.
Between August 2015 and October 2017, a total of 278 patients with curative resected, stages I to IIIA (American Joint Committee on Cancer seventh version) common EGFR-M+ NSCLC were analyzed. Radiological follow-up was accompanied with longitudinal monitoring of ctDNA using a droplet-digital polymerase chain reaction from baseline (preoperative), 4 weeks after curative surgery, and follow-up per protocol until 5 years. The primary outcomes were disease-free survival (DFS) according to the status of ctDNA positivity at landmark points and the sensitivity of longitudinal monitoring of ctDNA.
Among 278 patients, preoperative baseline ctDNA was detected in 67 (24%) patients: 23% (stage IA), 18% (IB), 18% (IIA), 50% (IIB), and 42% (IIIA) (p = 0.06). Of patients with baseline ctDNA, 76% (51 of 67) had clearance at 4 weeks after surgery (postoperative). Patients were classified into the following three groups; group A, baseline ctDNA negative (n = 211) versus group B, baseline ctDNA positive but postoperative MRD negative (n = 51) versus group C, baseline ctDNA positive and postoperative MRD positive (n = 16). The 3-year DFS rate was significantly different among the three groups (84% for group A, 78% for group B, and 50% for group C, p = 0.02). After adjusting for clinicopathologic variables, ctDNA still remains an independent risk factor for DFS along with stage (p < 0.001) and micropapillary subtype (p = 0.02). With longitudinal monitoring of ctDNA, MRD was detected before radiological recurrence in 69% of patients with exon 19 deletion and in 20% with L858R mutation.
These results suggest that patients with baseline ctDNA-positive or MRD-positive status were associated with poor DFS in curative resected stages I to IIIA EGFR-M+ NSCLC and that longitudinal monitoring of ctDNA, a noninvasive method, might be useful to detect early recurrence before radiological recurrence.
Aims
A waiting period of more than 3 months is recommended for patients before undergoing cardiac resynchronization therapy (CRT). However, due to an anticipated high mortality rate, early ...implementation of CRT might be beneficial for some patients. We aimed to evaluate the rate and the probability of left ventricular (LV) function improvement and their predictors in patients with heart failure (HF) with indications for CRT.
Methods and results
From March 2011 to February 2014, a total of 5625 hospitalized patients for acute HF were consecutively enrolled in 10 tertiary hospitals. Among them, we analysed 1792 patients (mean age 63.96 ± 15.42 years, female 63.1%) with left ventricular ejection fraction (LVEF) ≤ 35% at the baseline echocardiography and divided them into three groups: 144 with left bundle branch block (LBBB), 136 with wide QRS complexes without LBBB, and 1512 not having these findings (control). We compared and analysed these three groups for improvement of LV function at follow‐up echocardiography. In patients who met CRT indications (patients with LBBB or wide QRS complexes without LBBB), logistic regression was performed to identify risk factors for no improvement of LV. No improvement of LV was defined as LVEF ≤ 35% at follow‐up echocardiography or the composite adverse outcomes: death, heart transplantation, extracorporeal membrane oxygenation, or use of a ventricular assist device before follow‐up echocardiography. A classification tree was established using the binary recursive partitioning method to predict the outcome of patients who met CRT indications. In a median follow‐up of 11 months, LVEF improvement was observed in 24.3%, 15.4%, and 40.5% of patients with LBBB, wide QRS complexes without LBBB, and control, respectively. Patients meeting CRT indications had higher 3 month mortality rates than the control (24.6% vs. 17.7%, P = 0.002). Multivariable logistic regression analysis revealed that large LV end‐systolic dimension odds ratio (OR) 1.10, 95% confidence interval (CI) 1.05–1.15, P < 0.001, low LVEF (OR 0.92, 95% CI 0.87–0.98, P = 0.006), diabetes requiring insulin (OR 6.49, 95% CI 2.53–19.33, P < 0.001), and suboptimal medical therapy (OR 6.85, 95% CI 3.21–15.87, P < 0.001) were significant factors predictive of no improvement. A decision tree analysis was consistent with these results.
Conclusions
Patients with CRT indications had higher mortality during their follow‐up compared with control. LV function improvement was rare in this population, especially when they had some risk factors. These results suggest that the uniform waiting period before CRT implantation could be reconsidered and individualized.
Purpose: We examined the effect of GV1001 in castration castration-resistant prostate cancer (CRPC) cell growth and invasion and explored the potential molecular mechanisms of action. Materials and ...Methods: The in vitro anti-cancer effects of GV1001 in CRPC cells were examined using cell viability assay, TUNEL assay, and flow cytometry analysis. To evaluate the effects of GV1001 on different steps of angiogenesis, wound healing assay, transwell invasion assay, endothelial cell tube formation assay, and western blot analysis were performed. Finally, the anti-cancer effects of GV1001 on tumor growth in vivo were examined in a CRPC xenograft model. Results: GV1001 inhibited cell viability and induced apoptosis in CRPC cells in vitro, accompanied by down-regulation of Bcl-2 and caspase-3. GV1001 also inhibited different steps of angiogenesis, such as migration, invasion, and endothelial tube formation, along with decreased expression of MMP-2, MMP-9, and CD31 and increased expression of TIMP-1 and TIMP-2. Mechanistically, GV1001 significantly decreased the levels of phosphorylated AKT, phosphorylated p65, and VEGF in CRPC cells in a dose-dependent manner. GV1001 was effective in suppressing tumor growth and inducing apoptosis in a CRPC xenograft mouse model. Conclusions: Our data demonstrated that GV1001 inhibited cell viability, induced apoptosis, and inhibited angiogenesis in CRPC cells by inhibition of the AKT/NF-κB/VEGF signaling pathway.
This study aimed to evaluate the value of programmed death-ligand 1 (PD-L1) copy number (CN) alteration as an additional biomarker to standard immunohistochemistry (IHC) in predicting response to ...immune checkpoint inhibitor (ICI) therapy in advanced NSCLC.
Before ICI monotherapy, tumor PD-L1 CN alteration (gain, neutral, or loss) was called using whole-exome sequencing data and compared with IHC results (tumor proportion score ≥50, 1–49, or 0). Progression-free survival (PFS) and overall survival were correlated with both biomarkers. In addition, the impact of CN alteration was further evaluated in two independent cohorts using next-generation sequencing panel.
A total of 291 patients with advanced-stage NSCLC met the study inclusion criteria. Although the IHC classification distinguished the best responsive group (tumor proportion score ≥ 50), the CN-based classification distinguished the worst responsive group (CN loss) from the others (PFS, p = 0.020; overall survival, p = 0.004). After adjusting for IHC results, CN loss was an independent risk factor for progression (adjusted hazard ratio = 1.32, 95% confidence interval: 1.00–1.73, p = 0.049) and death (adjusted hazard ratio = 1.39, 95% confidence interval: 1.05–1.85, p = 0.022). A risk classification system was developed on the basis of IHC and CN profiles, which outperformed the conventional IHC system. In the validation cohorts, CN loss determined by next-generation sequencing panel was independently associated with worse PFS after ICI treatment, revealing its practical value.
This is the first study to directly compare CN alterations with IHC results and survival outcomes after anti–PD-(L)1 therapy. Tumor PD-L1 CN loss can serve as an adjunct biomarker to predict the lack of response. Prospective studies are required to further validate this biomarker.
Idiopathic spontaneous intraperitoneal hemorrhage is both rare and potentially fatal. The incidence of gastroepiploic artery rupture, especially a non-aneurysmal rupture, is extremely low. We report ...the case of an elderly woman who was mistakenly diagnosed with procedure-related bleeding after gastroscopy. A 0.3 cm polyp was identified and removed during the procedure. The patient later developed shock due to which gastroscopy was repeated; however, no unusual findings were observed. Therefore, abdominopelvic computerized tomography was performed and gastroepiploic artery rupture was detected. Transcatheter arterial embolization was immediately performed without laparotomy, without any complications. The bleeding was controlled, and the patient was discharged after embolization. It is important to acknowledge the possibility of spontaneous rupture of the visceral arteries in elderly individuals with hypertension or atherosclerosis, especially in the event of sudden abdominal pain or shock immediately after an endoscopic procedure. This is the first case report of idiopathic spontaneous rupture of the right gastroepiploic artery successfully managed by transcatheter arterial embolization in South Korea.
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a mutation in the aldolase B gene. HFI patients exhibit nausea, vomiting, abdominal pain, hypoglycemia, and elevated ...liver enzymes after dietary fructose exposure. Chronic exposure might lead to failure to thrive, liver failure, renal failure, and, eventually, death. HFI usually manifests in infants when they are being weaned off of breastmilk. Because HFI has an excellent prognosis when patients maintain a strict restrictive diet, some patients remain undiagnosed due to the voluntary avoidance of sweet foods. In the past, HFI was diagnosed using a fructose tolerance test, liver enzyme assays or intestinal biopsy specimens. Currently, HFI is diagnosed through the analysis of aldolase B mutations. Here, HFI was diagnosed in a 41-year-old woman who complained of sweating, nausea, and vomiting after consuming sweets. She had a compound heterozygous mutation in the aldolase B gene; gene analysis revealed pathogenic nonsense (c.178C>T, p.Arg60Ter) and frameshift (c.360_363delCAAA, p.Asn120LysfsTer32) variants. This is the first report of a Korean HFI patient diagnosed in adulthood.
Little is known about the efficacy of salvage chemotherapy for patients with metastatic, noncutaneous melanoma after the failure of dacarbazine-based chemotherapy. Because of the high incidence of ...noncutaneous melanoma in Korea, we assessed the outcomes of paclitaxel/carboplatin (PC) salvage chemotherapy in patients with noncutaneous metastatic melanoma. We retrospectively analyzed patients with metastatic melanoma who received intravenous paclitaxel (175 mg/m) plus intravenous carboplatin (area under the curve 5) on day 1 of a 21-day cycle as salvage chemotherapy at Samsung Medical Center (SMC) between February 2009 and February 2012. The overall response rate, overall survival, and progression-free survival were evaluated. Thirty-two patients with a median age of 54 years (range 24-72 years) received PC as salvage chemotherapy. All patients had been pretreated with a median of three systemic chemotherapies. Of the 32 patients, 10 (31.3%) had cutaneous melanoma, eight (25%) had acral melanoma, 10 (31.3%) had mucosal melanoma, and two (6.3%) had ocular melanoma. In response to treatment, seven of the 32 patients (21.9%) achieved partial response and 11 (34.4%) had stable disease. The median progression-free survival was 2.53 months for all patients, 4.3 months for patients with controlled disease (partial response and stable disease), and 1.37 months for patients with progressive disease (P=0.0001). The median overall survival was 5.2 months. No significant difference was noted between patients with noncutaneous and cutaneous metastatic melanoma (P=0.75). PC salvage chemotherapy may be a reasonable therapeutic option for heavily pretreated metastatic melanoma patients. Salvage therapy with this combination had definite clinically meaningful benefits in patients with metastatic melanoma, including those with noncutaneous melanoma.
Objectives: The purpose of this study was to investigate the overall research trends and factors influencing dental fears in the last 10 years (2007-2017) and provide recommendations for future ...research. Methods: The literature review focused on dental fear research in Korea. Inclusion criteria of selected studies were as follows: studies that examined fear in middle school students or older, studies undertaken between 2007-2017, and studies that examined trends and factors relating to dental fears. Results: Findings from this literature review showed that the most commonly used tool for measuring dental fear was the Dental Fear Survey (DFS). A lack of trust towards the dentist increased dental fear among patients. Women managed fear better than men. Past pain experiences increased dental fear. The most frequent intervention for reducing fear was sound (41.7%). Most of the intervention studies demonstrated a reduction of fear, with the exception of interventions using ear plugs. Fear was increased in studies involving ear plugs. Conclusions: Based on the results of the study, specific measures should be taken to alleviate past pain experiences, such as the fear of anesthetic injections and sensations of the dental drill. Continuous research is needed to reduce dental fear.
We investigated the efficacy and toxicity of a weekly schedule of docetaxel and cisplatin as a first-line treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M ...HNSCC).
In this study, 18 patients with previously diagnosed R/M HNSCC were treated with combination chemotherapy of weekly docetaxel 35 mg/m2 (day 1 and 8) and cisplatin 70 mg/m2 (day 1) as first-line chemotherapy, repeated every 3 weeks.
Partial response and stable disease were observed in six patients (33.3%; 95% confidence interval CI, 11.1% to 55.6%) and six patients (33.3%; 95% CI, 11.1% to 55.6%), respectively. The median overall survival and progression-free survival were 11.26 months (95% CI, 8.87 to 15.83) and 5.68 months (95% CI, 4.80 to 6.51), respectively. The major toxicity was grade 1/2 anemia (50%). Grade 3/4 neutropenia was observed in one patient (5.6%). Among the non-hematologic toxicities, grade 1/2 hepatotoxicity was most common (22.2%), and grade 3/4 infection was observed in one patient (5.6%). There was no treatment-related mortality.
For patients with R/M HNSCC, a cisplatin and weekly docetaxel regimen showed high efficacy with tolerable toxicity as a first-line treatment.
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