Worse Survival Rate Research Articles

Survivin in Breast Cancer: A Review.

Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer-related death in women. Gene technology has led to the recognition that breast cancer is a heterogeneous disease composed of different biological subtypes, and genetic profiling enables the response to chemotherapy to be predicted. This fact emphasizes the importance of selecting sensitive diagnostic and prognostic markers in the early disease stage and more efficient targeted treatments for this disease. One such prognostic marker appears to be survivin. Many studies have shown that survivin is strongly expressed in different types of cancers. Its overexpression has been demonstrated in breast cancer, and high activity of the survivin gene has been associated with a poor prognosis and worse survival rates.

HALP score and GNRI: Simple and easily accessible indexes for predicting prognosis in advanced stage NSCLC patients. The İzmir oncology group (IZOG) study.

ObjectiveThe Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) Score and the Geriatric Nutrition Risk Index (GNRI) are used as prognostic factors in different types of cancers. In this study we analyzed the prognostic value of the HALP Score and the GNRI calculated prior to first-line treatment in patients diagnosed with de novo metastatic non-small cell lung cancer (mNSCLC).Materials and methodsDe novo mNSCLC patients were retrospectively evaluated from January 2016 to December 2019. Patients with Driver’s mutation, severe comorbidities, active infection, or insufficient organ function, and those receiving anti-inflammatory treatment were excluded from the study. Optimal cut-off points for the HALP score and the GNRI were calculated with the receiver operating characteristic (ROC) curve analysis. Predictive factors for overall survival (OS) were assessed with univariate and multivariate Cox proportional hazard analyses, and OS was studied with the Kaplan–Meier analysis.ResultsThe study included 401 patients in total. In the ROC curve analysis, the cut-off points were found 23.24 (AUC = 0.928; 95% CI: 0.901–0.955, p < 0.001) for HALP, and 53.60 (AUC = 0.932; 95% CI: 0.908–0.955, p < 0.001) for GNRI. Groups with lower HALP scores and lower GNRI had significantly shorter OS compared to those with higher HALP scores and GNRIs. Univariate analysis showed that male gender, smoking, high ECOG score, low HALP score and low GNRI were associated with worse survival rates. Multivariate analysis showed that low HALP score (HR = 2.988, 95% CI: 2.065–4.324, p < 0.001); low GNRI score (HR = 2.901, 95% CI: 2.045–4.114, p < 0.001) and smoking history (HR = 1.447, 95% CI: 1.046–2.001, p = 0.025) were independent factors associated with worse OS rates.ConclusionOur study showed the HALP score and the GNRI to be of prognostic value as simple, cost-effective, and useful markers that predict OS in de novo mNSCLC patients.

Higher plasma IL-6 and PTX3 are associated with worse survival in left heart failure with pulmonary hypertension

IntroductionLeft heart failure (LHF) is commonly complicated by pulmonary hypertension (PH), increasing morbidity and mortality. The present study aimed to evaluate the prognostic value of inflammatory proteins in LHF with PH (LHF-PH). Materials and methodsThe levels of 65 plasma proteins, analysed with proximity extension assay, were compared between healthy controls (n = 20), patients with LHF-PH (n = 67) comprising both HFpEF-PH (n = 31) and HFrEF-PH (n = 36), and in a LHF subpopulation before and after heart transplantation (HT, n = 19). Haemodynamic parameters were measured using right heart catheterization. ResultsPlasma levels of Interleukin 6 (IL-6) and Pentraxin related protein PTX3 (PTX3) were elevated in LHF-PH vs. controls (p < 0.001), and these decreased after HT compared to before HT (p < 0.001). Plasma IL-6 and PTX3 correlated to elevated NT-proBNP (r = 0.44, p = 0.0002 and r = 0.4, p = 0.0009, respectively). Additionally, IL-6 correlated with mean pulmonary arterial pressure (r = 0.4, p = 0.0009) and mean right atrial pressure (r = 0.51, p < 0.0001). Higher levels of IL-6 and PTX3 were associated with worse survival rates in patients with LHF-PH (Log rank p < 0.01). DiscussionIn patients with LHF-PH, higher plasma levels of IL-6 and PTX3 were associated with worse survival rates. Future larger studies to validate and investigate the direct clinical applicability of IL-6 and PTX3 as potential prognostic biomarkers are encouraged.

HPV16 E6-Activated OCT4 Promotes Cervical Cancer Progression by Suppressing p53 Expression via Co-Repressor NCOR1.

Human papillomaviruses (HPV), mainly HPV16 and HPV18, of high-risk classification are involved in cervical cancer carcinogenesis and progression. Octamer-binding transcription factor 4 (OCT4) is a key transcription factor that is increased in various cancer types. Cervical cancer patients with higher levels of OCT4 had worse survival rates. However, the definite mechanisms underlying its function in the development of cervical cancer still remain to be explicated. Here, our study demonstrated that OCT4 expression was slightly increased in cervical cancer tissues than in precancerous ones. However, OCT4 was significantly upregulated in HPV16-positive tissues, in contrast to the expression profiling for p53. Moreover, knockdown of HPV16 E6 in SiHa cells suppressed the expression of OCT4 with impaired activities of cell proliferation, migration, and invasion, while it recovered the expression of p53. Overexpression of OCT4 and p53 exerted opposite roles on cell proliferation, migration, invasion, and colony formation of cervical cancer cells. More importantly, the enforced expression of OCT4 augmented p53-inhibited cell migration, invasion, and colony formation in human cervical cancer by promoting EMT. Finally, we identified that OCT4 could bind to the p53 promoter region to repress p53 expression by recruiting co-repressor NCOR1 using luciferase, ChIP, and co-IP experiments. We further illustrated that OCT4 not only increased the lung metastasis of cervical cancer but also effectively reversed p53-inhibited lung metastasis. In conclusion, our results suggested that HPV16 E6 activated the expression of OCT4 and subsequently crippled the transcription of p53 via co-repressor NCOR1, which contributed to cervical cancer progression.

Abstract 1127: Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines

Abstract KRAS is the most frequently mutated oncogene in lung adenocarcinoma, in which is related to poor treatments response and worse survival rates than other driver mutations. KRAS activates MAPK and mTOR pathways, and even after sotorasib treatment, a novel KRAS inhibitor, the duration of responses to this monotherapy are excessively short. In this context, metformin is able to inhibit PI3K and mTOR pathways; therefore, combined use of metformin with sotorasib aids to diminish the activity of both signaling pathways. We performed a dose-effect curve to determine IC50 of sotorasib, and IC10 of metformin to treat lung cancer cell lines harboring different mutational profiles: A549 (KRAS G12S), and H522 (TP53) in order to study the effects of the combination compared to the monotherapy of each drug at MTT assay and western blot analysis. In detail, we evaluated drug-induced cytotoxicity, apoptosis, and activity of MAPK and mTOR pathways. Our results show a synergic effect in cytotoxicity by MTT assay, as well as increased inhibition of MAPK pathway inhibition at combinational treatment, compared to monotherapies in A549 cell lines; conversely, we did not find significant effects on cytotoxicity and signaling inhibition in H522 cell line. In conclusion, the combined treatment of metformin and sotorasib show synergistic effects in drug-induced cytotoxicity and inhibition of MAPK pathways in lung cancer cell lines. Citation Format: Norma Yanet Hernandez-Pedro, Jose Lucio-Lozada, Pedro Barrios-Bernal, Maritza Ramos-Ramírez, Oscar Arrieta. Effect of the combined therapy of sotorasib and metformin in non-small cell lung cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1127.

Abstract 6049: Identifying shared features of low-H3K27me3 pediatric brain tumors

Abstract Brain tumors have the worse survival rates of all childhood malignancies, and a better understanding of their biology is needed for therapeutic development. Two especially devastating subtypes of pediatric brain tumors—diffuse midline gliomas, H3K27M-mutant (DMGs) and posterior fossa ependymomas, group A (PFAs) are both characterized by a hallmark of global reduction of histone 3 lysine 27 trimethylation, a mark associated with transcriptional repression. DMGs primarily harbor mutations of histone 3 (H3K27M) that inhibit the function of the H3 methyltransferase enhancer of zeste homolog 2 (EZH2)-containing polycomb repressive complex (PRC2). Most PFAs overexpress EZH inhibitory protein (EZHIP), resulting in a similar effect on PRC2 activity. Intriguingly, a small subset of DMGs found to be lacking H3K27M mutations express EZHIP, and a fraction of histological PFAs lacking EZHIP expression harbor H3K27M mutations. Given the highly similar putative driving alterations and epigenetic features in these two tumor types, we undertook a systematic evaluation of the clinical and molecular features of each tumor class to elucidate additional shared features and potential targetable vulnerabilities. We performed detailed analyses of genomic aberrations, gene expression, and epigenomic landscapes to identify key similarities and differences in tumor biology. From preliminary studies, our findings demonstrate similar H3K27me3 landscapes with convergence of residual tri-methylated loci between PFA and DMG tumors. We additionally found shared recurrent copy number gain of the long arm of chromosome 1 (1q) and identified several 1q genes whose expression correlated with survival differences in cohorts of both tumors. Together, these findings better define the commonalities and differences of these highly aggressive, low-H3K27me3 pediatric brain tumors and will provide a framework for understanding which therapeutic strategies may translate from one tumor to the other. Citation Format: Matthew Pun, Drew Pratt, Sriram Venneti. Identifying shared features of low-H3K27me3 pediatric brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6049.

Young-Onset Gastrointestinal Adenocarcinoma Incidence and Survival Trends in the Northern Territory, Australia, with Emphasis on Indigenous Peoples.

Simple SummaryThis study from the Australian Northern Territory’s Cancer Registry data provides evidence for a significant decrease in incidence of gastrointestinal (oesophageal, stomach, small intestine, colon, rectum, and pancreas) adenocarcinomas over the last 3 decades in individuals aged >50 years, whilst the younger (18–50 years) cohort has remained unchanged with a (non-significant) trend towards an increase. There has been a significantly improved overall survival in both age cohorts. An insight into these trends amongst Australia’s Indigenous (who constitute 31% of the territory’s population) confirms that while the incidence was significantly lower in Indigenous patients compared to non-Indigenous patients, in both age cohorts, Indigenous patients had worse survival rates. This study calls for a concerted effort aimed at investigating the existence of modifiable sociodemographic factors underlying these disturbing trends. There is a need to enhance preventative strategies, as well as to improve the delivery of cancer care and its uptake amongst Indigenous peoples.Background and Aims: A concerning rise in incidence of young-onset cancers globally led to the examination of trends in incidence and survival of gastrointestinal (GI) adenocarcinomas in the Northern Territory (NT), Australia, over a 28-year period, with a special emphasis on Indigenous peoples. Methods: This cross-sectional analysis of a prospective longitudinal database, NT Cancer Registry (1990–2017), includes all reported cases of GI (oesophagus, gastric, small intestinal, pancreas, colon, and rectum) adenocarcinomas. Poisson regression was used to estimate incidence ratio ratios, and survival was modelled using Cox proportional hazard models separately for people aged 18–50 years and >50 years. Results: A total of 1608 cases of GI adenocarcinoma were recorded during the time of the study. While the overall incidence in people 18–50 years remained unchanged over this time (p = 0.51), the rate in individuals aged >50 years decreased (IRR = 0.65 (95% CI 0.56–0.75; p < 0.0001)). Incidence rates were significantly less in females >50 years (IRR = 0.67 95% CI 0.59–0.75; p < 0.0001), and their survival was significantly better (HR = 0.84 (95%CI 0.72–0.98; p < 0.03)) compared to males. Overall survival across all GI subsites improved in both age cohorts, especially between 2010 and 2017 (HR = 0.45 (95%CI 0.29–0.72; p < 0.0007) and HR = 0.64 (95%CI 0.52–0.78; p < 0.0001), respectively) compared to 1990–1999, driven by an improvement in survival in colonic adenocarcinoma alone, as the survival remained unchanged in other GI subsites. The incidence was significantly lower in Indigenous patients compared to non-Indigenous patients, in both age cohorts (18–50 years IRR = 0.68 95% CI 0.51–0.91; p < 0.009 and >50 years IRR = 0.48 95% CI 0.40–0.57; p < 0.0001). However, Indigenous patients had worse survival rates (18–50 years HR = 2.06 95% CI 1.36–3.11; p < 0.0007 and >50 years HR = 1.66 95% CI 1.32–2.08; p < 0.0001). Conclusions: There is a trend towards an increased incidence of young-onset GI adenocarcinomas in the NT. Young Indigenous patients have lower incidence but worse survival across all GI subsites, highlighting significant health inequities in life expectancy. Targeted, culturally safe Indigenous community-focussed programs are needed for early detection and patient-centred management of GI adenocarcinomas.

194-OR: The Effect of Level of Spinal Cord Injury on the Prevalence of Diabetes

Persons with spinal cord injury (SCI) develop diabetes at much higher rates than those with able bodies. Glycemic effect of SCI is exaggerated in those with higher level of injury (LOI) (e.g.: tetraplegia [TP]) compared to those with lower LOI (e.g.; paraplegia [PP]) . We hypothesized that prevalence and incidence of diabetes is higher in those with higher LOI among SCI patients. In a retrospective cohort study of veterans with spinal cord injury, from 20to 2021, electronic record data on weight, height, gender, ethnicity, level of injury (TP vs. PP) , glucose and A1C levels, and antidiabetic medications were obtained. Diabetes was defined by random glucose &amp;gt;200 mg/dl and HbA1C&amp;gt;6.5%. A total of 9persons with SCI were identified (440 TP/ 471 PP,48 F/863 M, age (22-90) , BMI (13.1-51.4)) . The prevalence of diabetes at the first visit among those with TP and PP was similar (21vs. 20%) . Among 728 nondiabetic subjects with SCI, 1 (34%) with TP vs. 127 (34%) with PP developed type 2 diabetes over a median period of 40m (18-93) vs. 39m (15-75) (p=0.3) . Groups were similar for age and gender distribution, but PP had greater BMI compared to TP (p&amp;lt;0.01) . Despite similar A1C and plasma glycemia between the 2 groups at their first encounters, PP subjects had higher glycemic control estimated by A1C at the time of DM conversion or their last encounter (6.4± 1.7% vs. 6.0± 1.1%, p&amp;lt;0.05) . Of note, a larger number of diabetic patients in this cohort did not receive any antidiabetes medications (76% in TP/ 65% in PP, p=0.09) . At the end of 20-year study period, there were a total of 72 deaths in TP patients with diabetes compared to 60 deaths in PP patients with diabetes (61% vs. 47%, p&amp;lt;0.05) . Our findings indicate that despite greater amount of innervated lean muscle mass and lesser impaired autonomic nervous signaling in persons with PP compared to TP, rate of diabetes development and glycemic control are relatively similar among those with the high and low LOI. However, among SCI patients with diabetes those with TP had worse survival rate than PP. Disclosure M.Trbovich: None. R.Dimas: None. M.J.Mader: None. M.Salehi: None.

Clinical powers of Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1) for head-neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSC) is one of the most common cancer types in the world. The study in molecular markers for HNSC prognosis is of great significance. We hypothesized that Aminoacyl tRNA Synthetase Complex Interacting Multifunctional Protein 1 (AIMP1), a gene that encodes a cytokine, is a critical biomarker for HNSC. We acquired clinical data, mRNA expression data, protein staining data, and single-cell expression data of HNSC from open databases and evaluated the clinical prognostic value of AIMP1, and explored the potential roles of AIMP1 in HNSC biology and tumor immune microenvironment. AIMP1 was overexpressed in HNSC compared to normal tissues. Higher AIMP1 expression was associated with a worse survival rate. A survival nomogram was constructed for HNSC patients. One thousand two hundred and eighty-one genes were identified as positively associated with AIMP1 and enriched in proliferation-related terminologies, while 303 genes were identified as negatively associated with AIMP1 and enriched in terminologies related to skin development and immune cell regulation. AIMP1 was positively correlated with stemness, cell cycle, and DNA repair, and negatively correlated with angiogenesis, quiescence, metastasis, hypoxia, inflammation, EMT, DNA damage, and invasion in single cells. AIMP1 was expressed higher in malignant cells than immune cells and there was no difference in AIMP1 expression among immune cell types. AIMP1 high group had a lower immune score, stroma score, and microenvironment score. AIMP1 is a potential diagnostic and prognostic biomarker for HNSC patients and can potentially affect the proliferation and tumor immune microenvironment of HNSC cells. This study provided a novel molecular marker for the improvement of clinical HNSC treatment.

Red Blood Cell Distribution Width: A Prognostic Marker in Patients With Type B Aortic Dissection Undergoing Endovascular Aortic Repair.

BackgroundRed blood cell distribution width (RDW) is associated with cardiovascular mortality. However, the relationship between preoperative RDW and outcomes after thoracic endovascular aortic repair (TEVAR) in type B aortic dissection (TBAD) remains to be determined.MethodsWe review the records of 678 patients with TBAD and treated with TEVAR in three centers. Patients were divided into two groups according to the admission RDW cut-off by receiver operating characteristic curve analysis [≤13.5% (n = 278) and >13.5% (n = 400)]. The association between RDW and long-term mortality was evaluated using Cox survival analysis. Additionally, we used general additive models (GAM) with restricted cubic splines (RCS) to explore non-linear relationships between RDW and outcomes.ResultsSubjects with a high RDW had significantly higher in-hospital mortality rates (1.4 vs. 4.3%, P = 0.038). A total of 70 subjects died after a median follow-up period of 3.3 years. Kaplan–Meier analysis showed that subjects with an RDW >13.5% had worse survival rates than those with lower RDW values (P < 0.001). Multivariate Cox proportional hazard modeling revealed that an RDW >13.5% was an independent predictor of long-term mortality (adjusted HR = 2.27, P = 0.006). Also, we found that there was a non-linear relationship between RDW and mortality from RCS, and RDW of 13.5% might be an inflection point to distinguish the long-term mortality risk of TBAD patients.ConclusionAs an inexpensive and routinely measured parameter, RDW holds promise as a novel prognostic marker in patients with TBAD receiving TEVAR. We found that an RDW >13.5% on admission was independently associated with increased long-term mortality.

Regorafenib inhibits epithelial-mesenchymal transition and suppresses cholangiocarcinoma metastasis via YAP1-AREG axis

Cholangiocarcinoma (CCA) is a subtype of bile duct cancer usually diagnosed late with a low survival rate and no satisfactorily systemic treatment. Recently, regorafenib has been accepted as a second-line treatment for CCA patients. In this study, we investigated the potential signal transduction pathways mediated by regorafenib. We established a transcriptomic database for regorafenib-treated CCA cells using expression microarray chips. Our data indicate that regorafenib inhibits yes-associated protein 1 (YAP1) activity in various CCA cells. In addition, we demonstrated that YAP1 regulates epithelial-mesenchymal transition (EMT)-related genes, including E-cadherin and SNAI2. We further examined YAP1 activity, phosphorylation status, and expression levels of YAP1 downstream target genes in the regorafenib model. We found that regorafenib dramatically suppressed these events in CCA cells. Moreover, in vivo results revealed that regorafenib could significantly inhibit lung foci formation and tumorigenicity. Most importantly, regorafenib and amphiregulin (AREG) neutralize antibody exhibited synergistic effects against CCA cells. In a clinical setting, patients with high YAP1 and EMT expression had a worse survival rate than patients with low YAP1, and EMT expression did. In addition, we found that YAP1 upregulated the downstream target amphiregulin in CCA. Our findings suggest that AREG neutralizing antibody antibodies combined with regorafenib can reverse the CCA metastatic phenotype and EMT in vitro and in vivo. These findings provide novel therapeutic strategies to combat the metastasis of CCA.

A review of the anticancer properties of bee products and their molecular mechanisms: An overview on lung cancer

Lung cancer is one of the most common types of cancer in the world, and it represents a significant percentage of all diagnosed cancers. Despite better clinical outcomes associated with current drugs, lung cancer has a worse survival rate than any of the other commonly occurring malignancies. Evidence suggests that natural products offer promising potential for improving the current treatment approaches and/or developing novel treatment strategies. Bee products such as honey, propolis, and venom have been reported to exert anti-cancer effects on a variety of human cancer cell lines, thereby paving the way for a wide range of treatment possibilities. The current review focuses on the cytotoxic effects of bee bioactive compounds on all types of cancer, and the molecular pathways by which they might reduce tumor cell growth or trigger apoptosis of cancer cells, with particular reference to lung cancer. This strategy could potentially improve the efficacy of current remedies, reduce the doses of chemotherapy drugs, and decrease adverse effects of chemotherapy drugs. Furthermore, in vitro studies on anti-cancer properties of bee products are carefully reviewed. The results reveal that bee products have the potential to become effective treatment agents against many forms of cancer in the future.

Fibroblast Activation Protein Specific Optical Imaging in Non-Small Cell Lung Cancer.

Fibroblast activation protein (FAP) is a cell surface propyl-specific serine protease involved in the regulation of extracellular matrix. Whilst expressed at low levels in healthy tissue, upregulation of FAP on fibroblasts can be found in several solid organ malignancies, including non-small cell lung cancer, and chronic inflammatory conditions such as pulmonary fibrosis and rheumatoid arthritis. Their full role remains unclear, but FAP expressing cancer associated fibroblasts (CAFs) have been found to relate to a poor prognosis with worse survival rates in breast, colorectal, pancreatic, and non-small cell lung cancer (NSCLC). Optical imaging using a FAP specific chemical probe, when combined with clinically compatible imaging systems, can provide a readout of FAP activity which could allow disease monitoring, prognostication and potentially stratify therapy. However, to derive a specific signal for FAP any sequence must retain specificity over closely related endopeptidases, such as prolyl endopeptidase (PREP), and be resistant to degradation in areas of active inflammation. We describe the iterative development of a FAP optical reporter sequence which retains FAP specificity, confers resistance to degradation in the presence of activated neutrophil proteases and demonstrates clinical tractability ex vivo in NSCLC samples with an imaging platform.

Real-world effectiveness of immunotherapies in pre-treated, advanced non-small cell lung cancer Patients: A systematic literature review

BackgroundClinical trials have shown immunotherapy (IO) to be more effective than chemotherapy in pre-treated, advanced non-small cell lung cancer (NSCLC). However, there is a lack of understanding of its effectiveness in clinical practice, and among patient groups that are often underrepresented in trials. We aimed to summarize the existing real-world evidence (RWE) on the survival outcomes of IO in second- or higher line in advanced NSCLC. MethodsWe conducted a systematic review of real-world observational studies that reported overall survival (OS) estimates with IO, primarily nivolumab, pembrolizumab or atezolizumab, in adult, previously treated advanced or recurrent NSCLC patients. Meta-analysis was conducted using random-effect models to pool 1- and 2-year OS rates across studies. Additional subgroups were examined among patients treated with IO, including the elderly, those with poor performance status (PS) and those exhibiting metastasis. ResultsIn total, 66 studies were included, of which 46 (70%) included a nivolumab-specific study arm. Pooled 1-year and 2-year OS rates with nivolumab monotherapy were 45.6% (95% CI; 43.4–47.8) and 28.0% (95% CI; 24.8–31.4), respectively, compared to 43.9% (95% CI; 39.1–48.8) and 20.4% (95% CI; 14.7–27.6) in the mixed immune checkpoint inhibitors (ICI) group. OS rates with nivolumab were slightly lower in elderly compared to non-elderly populations. Poor PS was associated with worse survival rates, with a pooled one-year OS estimate of 27.1% in PS ≥ 2 vs 51.6% in PS < 2. The pooled 2-year OS rate with nivolumab in patients with and without brain metastases was 22.1% and 26.1% respectively, and this difference was significant in 36% of individual studies. ConclusionsWhile the OS benefits of IO seen in real-world studies among pre-treated, advanced NSCLC patients are consistent with pivotal clinical trials, these tend to vary for the more vulnerable patient groups, such as patients with poor PS, which are often excluded from trials. Further research is needed to investigate findings in patients with brain and liver metastases.

Extracorporeal Membrane Oxygenation After Norwood Surgery in Patients With Hypoplastic Left Heart Syndrome: A Retrospective Single-Center Cohort Study From Brazil.

BackgroundExtracorporeal membrane oxygenation (ECMO) is increasingly being used to support patients after the repair of congenital heart disease.ObjectiveWe report our experience with patients with a single functional ventricle who were supported by ECMO after the Norwood procedure, reviewing the outcomes and identifying risk factors for mortality in these patients.MethodsIn this single-center retrospective cohort study, we enrolled 33 patients with hypoplastic left heart syndrome (HLHS) who received ECMO support after the Norwood procedure between January 2015 and December 2019. The independent variables evaluated in this study were demographic, anatomical, and those directly related to ECMO support (ECMO indication, local of initiation, time under support, and urinary output while on ECMO). The dependent variable was survival. A p < 0.05 was considered statistically significant.ResultsThe ECMO support was applied in 33 patients in a group of 120 patients submitted to Norwood procedure (28%). Aortic atresia was present in 72.7% of patients and mitral atresia in 51.5%. For 15% of patients, ECMO was initiated in the operating room; for all other patients, ECMO was initiated in the intensive care unit. The indications for ECMO in the cardiac intensive care unit were cardiac arrest in 22 (79%) of patients, low cardiac output state in 10 (18%), and arrhythmia in 1 patient (3%). The median time under support was 5 (2–25) days. The median follow-up time was 59 (4–150) days. Global survival to Norwood procedure was 90.9% during the 30-day follow-up, being 33.3% for those submitted to ECMO. Longer ECMO support (p = 0.004) was associated with a higher risk of death in the group submitted to ECMO.ConclusionsThe mortality of patients with HLHS who received ECMO support after stage 1 palliation was high. Patients with low urine output were related to worse survival rates, and longer periods under ECMO support (more than 9 days of ECMO) were associated with 100% mortality. Earlier ECMO initiation before multiorgan damage may improve results.

Inhibition of lncRNA NEAT1 sensitizes medulloblastoma cells to cisplatin through modulating the miR-23a-3p-glutaminase (GLS) axis

ABSTRACT Medulloblastoma (MB) is a commonly occurring brain malignancy in adolescence. Currently, the combination of chemotherapy with subsequent irradiation is a regular therapeutic strategy. However, high dosage of chemotherapy is associated with drug resistance and side effects. The long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), which is frequently overexpressed in diverse human tumors, is correlated with worse survival rate in cancer patients. Currently, the precise roles of NEAT1 in MB and chemoresistance remain unclear. Our study aimed to investigate the biological functions of NEAT1 in cisplatin-resistant medulloblastoma. We report that NEAT1 was significantly upregulated in medulloblastoma patient specimens. Silencing NEAT1 significantly suppressed MB cell proliferation and sensitized MB cells to cisplatin. In cisplatin-resistant MB cell line, DAOY Cis R, NEAT1 expression, and glutamine metabolism were remarkably upregulated in cisplatin-resistant cells. Under low glutamine supply, cisplatin-resistant cells displayed increased cisplatin sensitivity. Bioinformatical analysis and luciferase assay uncovered that NEAT1 functions as a ceRNA of miR-23a-3p to downregulate its expressions in MB cells. Moreover, miR-23a-3p was apparently downregulated in MB patient tissues and cisplatin resistant MB cells. We identified GLS (glutaminase), a glutamine metabolism enzyme, was directly targeted by miR-23a-3p in MB cells. Rescue experiments demonstrated restoration of miR-23a-3p in NEAT1-overexpressing DAOY cisplatin resistant cells successfully overcame the NEAT1-promoted cisplatin resistance by targeting GLS. In general, our results revealed new molecular mechanisms for the lncRNA-NEAT1-mediated cisplatin sensitivity of MB.

Semaphorin 6C Suppresses Proliferation of Pancreatic Cancer Cells via Inhibition of the AKT/GSK3/β-Catenin/Cyclin D1 Pathway.

Semaphorins (SEMAs) are axon guidance factors that participate in axonal connections and nerve system development. However, the functional roles of SEMAs in tumorigenesis are still largely uncovered. By using in silico data analysis, we found that SEMA6C was downregulated in pancreatic cancer, and its reduction was correlated with worse survival rates. RNA sequencing revealed that cell cycle-related genes, especially cyclin D1, were significantly altered after blockage of SEMA6C by neutralizing antibodies or ectopic expressions of SEMA6C. Mechanistic investigation demonstrated that SEMA6C acts as a tumor suppressor in pancreatic cancer by inhibiting the AKT/GSK3 signaling axis, resulting in a decrease in cyclin D1 expression and cellular proliferation. The enhancement of cyclin D1 expression and cyclin-dependent kinase activation in SEMA6C-low cancer created a druggable target of CDK4/6 inhibitors. We also elucidated the mechanism underlying SEMA6C downregulation in pancreatic cancer and demonstrated a novel regulatory role of miR-124-3p in suppressing SEMA6C. This study provides new insights of SEMA6C-mediated anti-cancer action and suggests the treatment of SEMA6C-downregulated cancer by CDK4/6 inhibitors.

Reduction of Cancer-Induced Thrombocytosis as a Biomarker of Improved Outcomes in Advanced Gastric Cancer.

Background: Interplay between non-specific inflammatory reaction and tumor microenvironment in gastric cancer (GC) can be measured indirectly by assessing fluctuations in concentration of platelets. Cytotoxic chemotherapy affects these morphotic elements directly by inducing myelosuppression. It was hypothesized that chemotherapy not only directly affects malignant cells, but also through immunomodulation related to myelosuppression. Methods: Metastatic GC patients (N: 155) treated with chemotherapy +/− trastuzumab were enrolled in this retrospective study. Platelet pretreatment concentration (PLT-count) and the deepest level of platelet reduction, as well as other inflammatory and general confounders were collected in the first 12 weeks of treatment (PLT-red). Martingale residuals were used to visualize the relationship between PLT-count, PLT-red, and overall survival (OS). Multiple multivariate Cox regression models were built to assess the impact of platelet reduction on OS and progression-free survival (PFS). Results: Reduction of PLT (PLT-red) to 60% of baseline concentration was associated with improved survival rates (HR = 0.60, p = 0.026 for OS and HR 0.56, p = 0.015 for PFS). Cross-classification into four groups based on PLT-count (high vs low) and PLT-red (high vs low) showed significantly worse survival rates in both high PLT-count (HR = 3.60, p = 0.007 for OS and HR = 2.97, p = 0.024 for PFS) and low PLT-count (HR = 1.75, p = 0.035 for OS and HR = 1.80, p = 0.028 for PFS) patients with insufficient platelets reduction. Conclusion: Thrombocytosis reduction represents a novel, clinically important, prognostic factor for OS and PFS in patients with stage IV GC.

An Integrated Pan-Cancer Analysis of ADAMTS12 and Its Potential Implications in Pancreatic Adenocarcinoma.

BackgroundA Disintegrin and Metallopeptidase with Thrombospondin Type 1 Motif 12 (ADAMTS12), a member of the ADAMTS family of multidomain extracellular protease enzymes, is involved in the progression of many tumors. However, a pan-cancer analysis of this gene has not yet been performed. Its role in pancreatic adenocarcinoma (PAAD) also remains unclear.MethodsThe Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression data (GTEx) databases were used to analyze ADAMTS12 expression in pan-cancer. We assessed the expression, clinical characteristics, prognostic significance, copy number alteration, methylation, and mutation of ADAMTS12 and its correlation with the tumor immune microenvironment. qRT-PCR and immunohistochemistry assays were also performed to validate the expression of ADAMTS12 in PAAD.ResultsThrough bioinformatics analysis and preliminary experimental verification, ADAMTS12 was found to be substantially overexpressed in PAAD. High expression level of ADAMTS12 was correlated with worse survival rates in patients with PAAD and high infiltration levels of tumor-associated macrophages, cancer-associated fibroblasts, immune checkpoint proteins, and immunosuppressive genes.ConclusionOur findings suggest ADAMTS12 as a potential prognostic biomarker in PAAD. Elevated ADAMTS12 expression may also indicate an immunosuppressive microenvironment.

The Genomics of Colorectal Cancer in Populations with African and European Ancestry.

KRAS (particularly KRASG12D/G13), APC, and PIK3CA were more frequently altered in AFR who had a lower frequency of MSI-H tumors. There were no differences in actionable kinase driver alterations. In young-onset colorectal cancer, both ancestries had a similar frequency of MSI-H/TMB-H tumors, but strikingly different trends in APC. See related commentary by Eng and Holowatyj, p. 1187. This article is highlighted in the In This Issue feature, p. 1171.