Cytokines of the interleukin-1 (IL-1) family, such as IL-1α/β and IL-18, have pleiotropic activities in innate and adaptive immune responses in host defense and diseases. Insight into their ...biological functions helped develop novel therapeutic approaches to treat human inflammatory diseases. IL-33 is an important member of the IL-1 family of cytokines and is a ligand of the ST2 receptor, a member of the IL-1 receptor family. However, the role of the IL-33/ST2 axis in tumor growth and metastasis of breast cancer remains unclear. Here, we demonstrate that IL-33 is a critical tumor promoter during epithelial cell proliferation and tumorigenesis in the breast. IL-33 dose- and time-dependently increased Cancer Osaka Thyroid (COT) phosphorylation via ST2-COT interaction in normal epithelial and breast cancer cells. The IL-33/ST2/COT cascade induced the activation of the MEK-ERK (MEK-extracellular signal-regulated kinase), JNK-cJun (cJun N-terminal kinase-cJun) and STAT3 (signal transducer and activator of transcription 3) signaling pathways, followed by increased AP-1 and stat3 transcriptional activity. When small interfering RNAs of ST2 and COT were introduced into cells, IL-33-induced AP-1 and stat3 activity were significantly decreased, unlike that in the control cells. The inhibition of COT activity resulted in decreased IL-33-induced epithelial cell transformation, and knockdown of IL-33, ST2 and COT in breast cancer cells attenuated tumorigenicity of breast cancer cells. Consistent with these observations, ST2 levels were positively correlated with COT expression in human breast cancer. These findings provide a novel perspective on the role of the IL-33/ST2/COT signaling pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may, therefore, effectively inhibit carcinogenesis in the breast.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The ...efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.
In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred.
A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% 95% confidence interval {CI}, 56 to 75 vs. 43% 95% CI, 32 to 53; hazard ratio for disease progression or death, 0.49 95% CI, 0.33 to 0.74; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted.
Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).
To identify potential microRNA (miRNA) links between Smad3, a mediator of TGF-β (transforming growth factor-β) signaling, and E-cadherin, we characterized the miRNA profiles of two gastric cancer ...cell lines: SNU484-LPCX, which does not express Smad3, and SNU484-Smad3, in which Smad3 is overexpressed. We found that among differentially expressed miRNAs, miR-200 family members are overexpressed in SNU484-Smad3 cells. Subsequent studies, including analysis of the effects of silencing Smad3 in SNU484-Smad3 cells and a luciferase reporter assay, revealed that Smad3 directly binds to a Smad-binding element located in the promoter region of miR-200b/a, where it functions as a transcriptional activator. TGF-β did not affect the regulatory role of Smad3 in transcription of miR-200 and expression of epithelial-mesenchymal transition markers. We conclude that Smad3 regulates, at the transcriptional level, miR-200 family members, which themselves regulate ZEB1 and ZEB2, known transcriptional repressors of E-cadherin, at the posttranscriptional level in a TGF-β-independent manner. This represents a novel link between Smad3 and posttranscriptional regulation by miRNAs in epithelial-mesenchymal transition in gastric cancer cells.
Endovascular treatment with stent placement or stent-assisted coiling was recently introduced as an alternative to parent artery occlusion in intracranial vertebral artery dissections. We describe ...the efficacy and limitations of this method.
Fourteen patients with intracranial vertebral artery dissection were treated with stent placement (10 patients) or stent-assisted coiling (4 patients). Double overlapping stents were deployed in 4 of 10 patients with stent placement alone. Angiographic follow-up at 6 to 12 months was available in 13 patients.
In 13 patients with dissecting aneurysm, immediate angiographic outcomes were complete occlusion (1 patient), nearly complete (2 patients), and incomplete (10 patients). Follow-up angiograms of 12 of these patients showed complete occlusion (6 patients) and incomplete (6 patients; 1 unstable and 5 stable). Complete occlusion rates in follow-up angiograms were superior in double stent placement (75%) or stent-assisted Guglielmi detachable coil (GDC) embolization to stent placement alone (0%). There were no instances of postprocedural ischemic attacks, new neurologic deficits, and no new minor or major strokes before patient discharge. On the modified Rankin scale applied in follow-up, all patients were assessed as functionally improved or of stable clinical status.
Intracranial vertebral artery dissections were acceptably treated with stent placement or stent-assisted coiling, and the patency could be preserved at follow-up. However, the efficiency of stent placement alone for intracranial vertebral artery dissecting aneurysm was limited. Stent-assisted coil embolization or double stent placements are a viable alternative for complete occlusion of dissecting aneurysms.
Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. ...Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting.
IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279.
Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61) with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05) with atezolizumab, and 8·51 months (6·41–10·71) with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99) for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34) for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%) of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%) of 90 in the atezolizumab group, and 46 (58%) of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 11% of 179), anaemia (ten 6%), increased blood creatine phosphokinase (12 7%), and fatigue (eight 4%). Serious adverse events were reported in 71 (40%) of 179 patients in the combination group, 15 (17%) of 90 in the atezolizumab group, and 18 (23%) of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis) and one in the regorafenib group (intestinal perforation).
IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer.
F Hoffmann-La Roche Ltd/Genentech Inc.
Obesity is associated with poor clinical outcomes in critically ill patients. However, under some clinical conditions, obesity has protective effects. Bloodstream infections (BSI) are among the most ...common nosocomial infections associated with extracorporeal membrane oxygenation (ECMO). BSI during ECMO is associated with higher mortality rates and poorer clinical outcomes.
To analyse whether body mass index (BMI) is associated with BSI during ECMO or with in-hospital mortality.
All adult patients who had received ECMO support for >48 h were included in the analysis. The analysis of total duration of ECMO support, in-hospital mortality and BSI was stratified by BMI category. The Cox proportional hazards model was used to compare the risk of BSI among BMI categories.
In total, 473 patients were enrolled in the study. The average age was 56.5 years and 65.3% were men. The total duration of ECMO was approximately 11.8 days, with a mortality rate of 47.1%. The incidence rates of BSI and candidaemia were 20.5% and 5.5%, respectively. The underweight group required ECMO for respiratory support, whereas the overweight and obese groups required ECMO for cardiogenic support (P<0.0001). No significant difference in BSI rate was found (P=0.784). However, after adjusting for clinical factors, patients in Group 4 (BMI 25.0–<30.0 kg/m2) exhibited lower mortality compared with patients in Group 2 (normal BMI) (P=0.004).
BMI was not associated with risk of BSI, but patients with higher BMI showed lower in-hospital mortality associated with ECMO support.
Summary
Background
It remains unclear whether initial compact lipiodol uptake after transarterial chemoembolisation (TACE) is associated with improved survival in patients with hepatocellular ...carcinoma (HCC).
Aim
To reveal the clinical relevance of compact lipiodolisation after TACE.
Methods
We studied 490 patients with unresectable HCC who had first been treated with TACE. Compact lipiodolisation was defined as the absence of an arterial enhancing lesion, reflecting complete lipiodol uptake, as assessed by dynamic computed tomography (CT) 1 month after treatment. The rate of initial compact lipiodolisation was analysed according to multiplicity and size of tumour, and survival of patients who achieved compact lipiodolisation was compared to that of patients who did not.
Results
Of the 490 patients, 409 (83.5%) were in Child–Pugh class A and 81 (16.5%) in class B. The rate of initial compact lipiodolisation in single HCCs was higher than that in multinodular HCCs (33.7% vs. 14.6%, P < 0.001). Among single HCCs, the rate of compact lipiodolisation in tumours ≤5, 5–10 and >10 cm was 46.6%, 13.6%, and 0% respectively. The 1‐, 3‐ and 5‐year survival rates of patients with compact uptake were 92.7%, 70.7% and 52.4% compared to 60.8%, 28.0% and 16.9% in patients with noncompact lipiodolisation. Multivariate analysis revealed that Child–Pugh class, alpha‐fetoprotein level, tumour node metastasis stage, portal vein thrombosis and initial compact lipiodolisation were independent predictors of survival.
Conclusions
Initial compact lipiodol uptake after transarterial chemoembolisation is associated with improved survival in patients with unresectable hepatocellular carcinoma. Accordingly, initial complete lipiodolisation should be considered a relevant therapeutic target.
Mitochondrial function in retinal pigmented epithelial (RPE) cells and extracellular vesicle (EV) formation/release are related through the lysosomal and exocytotic pathways that process and ...eliminate intracellular material, including mitochondrial fragments. We propose that RPE cells with impaired mitochondria will release EVs containing mitochondrial miRNAs that reflect the diminished capacity of mitochondria within these cells.
We screened ARPE-19 cells for miRNAs that localize to the mitochondria, exhibit biological activity, and are present in EVs released by both untreated cells and cells treated with rotenone to induce mitochondrial injury. EVs were characterized by vesicle size, size distribution, presence of EV biomarkers: CD81, CD63, and syntenin-1, miRNA cargo, and number concentration of EVs released per cell.
We found that miR-494-3p was enriched in ARPE-19 mitochondria. Knockdown of miR-494-3p in ARPE-19 cells decreased ATP production and mitochondrial membrane potential in a dose-dependent manner, and decreased basal oxygen consumption rate and maximal respiratory capacity. Increased number of EVs released per cell and elevated levels of miR-494-3p in EVs released from ARPE-19 cells treated with rotenone were also measured.
ARPE-19 mitochondrial function is regulated by miR-494-3p. Elevated levels of miR-494-3p in EVs released by ARPE-19 cells indicate diminished capacity of the mitochondria within these cells.
EV miR-494-3p is a potential biomarker for RPE mitochondrial dysfunction, which plays a central role in non-neovascular age-related macular degeneration, and may be a diagnostic biomarker for monitoring the spread of degeneration to neighboring RPE cells in the retina.
•miR-494-3p is enriched in the mitochondria of ARPE-19 cells.•miR-494-3p regulates mitochondrial function in ARPE-19 cells.•EV miR-494-3p released by ARPE-19 cells indicates mitochondrial dysfunction.
Summary
Background The pathogenesis of melasma has not yet been clearly demonstrated. We tried to determine whether the stem cell factor (SCF) and its receptor c‐kit are involved in the mechanism of ...hyperpigmentation of melasma because this factor is highly implicated in the stimulation of melanocyte function in vitro and in vivo.
Objectives The present study was conducted to investigate the expression of SCF and c‐kit on the lesions of melasma compared with nonlesional skin.
Patients/methods Skin samples were obtained from lesional and nonlesional facial skin of 60 Korean women with melasma. Immunohistochemistry and reverse transcriptase‐polymerase chain reaction (RT‐PCR) analysis was performed to determine the expression of SCF and c‐kit in melasma.
Results The expression of SCF was significantly increased at the lesional dermis compared with nonlesional dermis. However, there was no significant difference in the expression of SCF in lesional and nonlesional epidermis. The expression of c‐kit was significantly increased at lesional epidermis compared with nonlesional skin. RT‐PCR of SCF and c‐kit mRNAs demonstrated increased expression of both types of transcripts in the lesional skin compared with nonlesional skin.
Conclusions These results suggest that the increased expression of SCF in the dermis and of c‐kit in the epidermis play an important role in the mechanism of hyperpigmentation in melasma.
Despite the high prevalence of tuberculosis (TB) and the disease burden of osteoporosis and osteoporotic fractures, there is still a lack of well-designed, large-scale studies demonstrating ...associations among them. We aimed to investigate the effect of TB on the incidence of osteoporosis and osteoporotic fractures.
This was a nationwide population–based cohort study.
This study was conducted using the National Health Insurance Service Database of South Korea. We included patients with newly diagnosed TB aged >40 years from January 2006 to December 2017. An uninfected control for each TB patient was randomly extracted by frequency matching for sex, age, income level, residence, and registration date at a 2:1 ratio. The primary outcome was the incidence of osteoporosis and osteoporotic fractures between the two groups, adjusted for sex, age, income level, residence, comorbidities, body mass index, blood pressure, laboratory tests, alcohol drinking, and smoking. The risk factors associated with osteoporosis or osteoporotic fractures were also investigated.
A total of 164,389 patients with TB and 328,778 matched controls were included (71.9% males). The mean duration of follow-up was 7.00 ± 3.49 years. The incidence of osteoporosis in patients with TB was 6.1 cases per 1000 person-years, which was significantly higher than that in matched controls (adjusted hazard ratio aHR 1.349, 95% confidence interval CI 1.302–1.398, P < 0.001). The incidence of osteoporotic fractures was also higher in patients with TB than in controls (aHR 1.392, 95% CI 1.357–1.428, P < 0.001). Among fractures, the risk of hip fracture was the highest (aHR 1.703, 95% CI 1.612–1.798, P < 0.001).
TB independently contributes to the incidence of osteoporosis and osteoporotic fractures, particularly hip fractures.
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