Independent Marker Of Poor Prognosis Research Articles

Enzymatic activity of HIV-1 protease defines migration of tumor cells in vitro and enhances their metastatic activity in vivo

Overexpression of aspartic proteases, as cathepsin D, is an independent marker of poor prognosis in breast cancer, correlated with the incidence of clinical metastasis. We aimed to find if HIV-1 aspartic protease (PR) can play a similar role. Murine adenocarcinoma 4T1luc2 cells were transduced with lentivirus encoding inactivated drug-resistant PR, generating subclones PR20.1 and PR20.2. Subclones were assessed for production of reactive oxygen species (ROS), expression of epithelial-mesenchymal transition (EMT) factors, and in vitro migratory activity in the presence or absence of antioxidant N-acetyl cysteine and protease inhibitors. Tumorigenic activity was evaluated by implanting cells into BALB/c mice and following tumor growth by calipering and bioluminescence imaging in vivo, and metastases, by organ imaging ex vivo. Both subclones expressed PR mRNA, and PR20.2, also the protein detected by Western blotting. PR did not induce production of ROS, and had no direct effect on cell migration rate, however, treatment with inhibitors of drug-resistant PR suppressed the migratory activity of both subclones. Furthermore, expression of N-cadherin and Vimentin in PR20.2 cells and their migration were enhanced by antioxidant treatment. Sensitivity of in vitro migration to protease inhibitors and to antioxidant, known to restore PR activity, related the effects to the enzymatic activity of PR. In vivo, PR20.2 cells demonstrated higher tumorigenic and metastatic activity than PR20.1 or parental cells. Thus, HIV-1 protease expressed in breast cancer cells determines their migration in vitro and metastatic activity in vivo. This effect may aggravate clinical course of cancers in people living with HIV-1.

α5-nAChR/ADAM10 signaling mediates nicotine-related cutaneous melanoma progression via STAT3 activation.

Skin cutaneous melanoma (SKCM) is the skin malignancy with the highest mortality rate, and its morbidity rate is on the rise worldwide. Smoking is an independent marker of poor prognosis in melanoma. The α5-nicotinic acetylcholine receptor (α5-nAChR), one of the receptors for nicotine, is involved in the proliferation, migration and invasion of SKCM cells. Nicotine has been reported to promote the expression of a disintegrin and metalloproteinase 10 (ADAM10), which is the key gene involved in melanoma progression. Here, we explored the link between α5-nAChR and ADAM10 in nicotine-associated cutaneous melanoma. α5-nAChR expression was correlated with ADAM10 expression and lower survival in SKCM. α5-nAChR mediated nicotine-induced ADAM10 expression via STAT3. The α5-nAChR/ADAM10 signaling axis was involved in the stemness and migration of SKCM cells. Furthermore, α5-nAChR expression was associated with ADAM10 expression, EMT marker expression and stemness marker expression in nicotine-related mice homograft tissues. These results suggest the role of the α5-nAChR/ADAM10 signaling pathway in nicotine-induced melanoma progression.

Abstract 6935: Non-genetic routes of lung cancer evolution

Abstract Cancer cell plasticity underlies the progression of several solid tumors. In lung adenocarcinoma, morphological changes characterizing the transition from indolent to aggressive disease exhibit profound epigenetic and transcriptional reprogramming1. However, the extent, features, and drivers of cancer cell plasticity in the progression of human lung adenocarcinoma is still largely unexplored. Here, we assembled and analyzed a meta-cohort of 119 human lung tumors analyzed by single-cell RNA-sequencing, for a total of ~730,000 cells. Cancer cell heterogeneity was the result of differential activation of 17 transcriptional programs associated with common cancer phenotypes, such as proliferation, cell migration, and response to hypoxia, as well as alveolar lineage identity (AT2). In particular, AT2-specific expression of MHC-II was down-regulated with the progression of the disease and markedly reduced in KEAP1 and/or STK11 mutated samples, providing a rationale for the association between these mutations and immunotherapy resistance. Co-activation of transcriptional programs clustered tumor cells in 4 major cell states, which emerged with the progression of the disease. To explore spatial distribution of different cancer cell states, we generated and analyzed multiple spatial transcriptomics and proteomics lung adenocarcinoma cohorts. To this purpose we developed a new algorithm called CellCharter2. CellCharter identified distinct cancer-enriched niches within individual samples, corresponding to the cancer cell states that we discovered in the scRNA-seq cohort and exhibited specific interactions with the tumor microenvironment (TME). In particular, we identified a cancer cell state characterized by response-to-hypoxia and migratory phenotypes, which spatially segregated from highly proliferative cancer cell niches and formed specific interactions with tumor associated neutrophils. This cell state was enriched in advanced primary samples, it uniquely characterized metastatic samples, and was an independent marker of poor prognosis across multiple independent datasets. Overall, our work uncovered cell plasticity trajectories associated with the progression of lung adenocarcinoma and shed new light into the tumor-TME interactions at their origin. 1 Tavernari et al., Cancer Discovery, 20212 Varrone et al, Nat. Genetics, (in press) Citation Format: Giovanni Ciriello, Daniele Tavernari, Marco Varrone. Non-genetic routes of lung cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6935.

LncRNA UCA1 promotes pancreatic cancer cell migration by regulating mitochondrial dynamics via the MAPK pathway

PurposeLong non-coding RNA urothelial cancer associated 1 (UCA1) serves as an oncogene in various cancers. However, the mechanism underlying the role of UCA1 in pancreatic cancer remains unclear. This study aimed to explore the role of UCA1 in pancreatic cancer. MethodsThe expression and prognosis of UCA1 were analyzed using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The results were validated by immunohistochemistry (IHC) and qRT-PCR. The biofunctions of UCA1 were analyzed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The migration abilities and mitochondrial dynamics of PC cells were examined using the Transwell assay, mitochondrial membrane potential (MMP), and fluorescence. The mitochondrial-related protein and MAPK/ERK pathway markers were evaluated using western blotting. ResultsUCA1 expression was significantly higher in pancreatic cancer tissues than in normal tissues. High UCA1 expression indicated poor clinical outcomes and was associated with clinical features in patients with pancreatic cancer. Additionally, high UCA1 expression is a potential independent marker for poor prognosis. Subsequently, we demonstrated that UCA1 enhanced the migration capability, increased MMP, enhanced mitochondrial fusion, and inhibited mitochondrial autophagy in pancreatic cancer cells via the MAPK/ERK pathway. ConclusionUCA1 promotes the migration by regulating the mitochondrial dynamics of pancreatic cancer cells via the MAPK/ERK pathway. Our findings suggest that UCA1 may serve as a potential biomarker in pancreatic cancer prognosis.

Relationship between Exercise Test Parameters, Device-Delivered Electric Shock and Adverse Clinical Events in Patients with an Implantable Cardioverter Defibrillator for Primary Prevention.

(1) Background: Receiving the first internal electric shock is a turning point for patients with an implantable cardioverter defibrillator (ICD) for primary prevention. However, no study has investigated whether patients who receive a first device-delivered electric shock have a poor prognosis even at the time of ICD implantation. (2) Methods: We retrospectively identified 55 patients with ischemic (n = 31) or dilated (n = 24) cardiomyopathy who underwent ICD implantation for primary prevention with exercise test at the time of implantation. We recorded baseline characteristics, exercise test parameters, and clinical events. (3) Results: After a median follow-up of 5 years, we observed an association between an appropriate device-delivered electric shock, the occurrence of death or heart transplant, and the occurrence of the composite endpoint. There was also a significant relation between a VE/VCO2 slope >35 and the occurrence of the composite endpoint. Conversely, there was no significant association between negative outcomes on the exercise test and the occurrence of a device-delivered electric shock. (4) Conclusions: The exercise test performed at the time of ICD implantation do not predict the occurrence of device-delivered electric shock. The exercise test and the first electric shock are two independent markers of poor prognosis.

Smoking is an Independent Marker of Poor Prognosis in Cutaneous Melanoma.

Previous studies have suggested that persistent tobacco smoking impairs survival in cutaneous melanoma, but the effects of smoking and other prognostic factors have not been described in detail. This study examined the association of smoking (persistent, former, or never) with melanoma-specific (MSS) and overall survival (OS) in patients with cutaneous melanoma treated in Southwest Finland during 2005 to 2019. Clinical characteristics were obtained from electronic health records for 1,980 patients. Smoking status was available for 1,359 patients. Patients were restaged according to the 8th edition of the tumour-node-metastasis (TNM) classification. Smoking remained an independent prognostic factor for inferior melanoma-specific survival regardless of age, sex, stage, and comorbidities. The hazard ratio of death from melanoma was 1.81 (1.27-2.58, p = 0.001) in persistent and 1.75 (1.28-2.40, p = 0.001) in former smokers compared with never smokers. In 351 stage IV patients, smoking was associated with increased melanoma-specific and overall mortality: median MSS 10.4 (6.5-14.3), 14.6 (9.1-20.1), and 14.9 (11.4-18.4) months, p = 0.01 and median OS 10.4 (6.5-14.3), 13.9 (8.6-19.2), and 14.9 (11.7-18.1) months, p = 0.01 in persistent, former, and never smokers, respectively. In conclusion, since smoking represents an independent modifiable poor prognostic factor in patients with cutaneous melanoma, smoking habits should be proactively asked about by healthcare professionals, in order to support smoking cessation.

DUSP10 upregulation is a poor prognosticator and promotes cell proliferation and migration in glioma.

Dual-specificity phosphatase 10 (DUSP10) correlates with inflammation, cytokine secretion, cell proliferation, survival, and apoptosis. However, its role in glioma is unclear. Herein, we sought to examine the expression and the underlying carcinogenic mechanisms of DUSP10 action in glioma. DUSP10 expression in glioma was significantly higher than that in normal brain tissues. High DUSP10 expression indicated adverse clinical outcomes in glioma patients. Increased DUSP10 expression correlated significantly with clinical features in glioma. Univariate Cox analysis showed that high DUSP10 expression was a potential independent marker of poor prognosis in glioma. Furthermore, DUSP10 expression in glioma correlated negatively with its DNA methylation levels. DNA methylation level of DUSP10 also correlated negatively with poor prognosis in glioma. More importantly, DUSP10 expression correlated positively with the infiltration of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells in glioma. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis confirmed that DUSP10 participated in signaling pathways involved in focal adhesion, TNF cascade, Th17 cell differentiation, and NF-kappa B cascade. Finally, we uncovered that DUSP10 was dramatically upregulated in glioblastoma (GBM) cells and that the knockdown of DUSP10 inhibited glioma cell proliferation and migration. Our findings suggested that DUSP10 may serve as a potential prognostic biomarker in glioma.

Stromal CD10 Expression in Breast Carcinoma and its Association with ER, PR, and HER2/neu Using Immunohistochemistry: A Cross-sectional Study

Introduction: Breast cancer is a common and deadly malignancy affecting women worldwide. Various immune markers, such as Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2/neu), are commonly used to assess prognosis. Currently, ongoing research aims to evaluate molecular pathways that contribute to invasion and metastasis. One important immunomarker under investigation is CD10, a zinc-dependent Matrix Metalloproteinase (MMP) that degrades bioactive peptides. CD10 expression in the tumour stroma has been associated with the biological aggressiveness of several epithelial malignancies, including breast carcinoma. Aim: To analyse the association between stromal CD10 expression and different prognostic factors, such as age, histological grade, and status of ER, PR, and HER2/neu markers, in patients with breast cancer. Materials and Methods: This institutional-based, crosssectional study was conducted at the Department of Pathology, Nil Ratan Sircar Medical College and Hospital (NRSMC) in Kolkata, West Bengal, India over a period of one and a half years (February 2021 to July 2022). It included 120 cases of breast carcinoma diagnosed through histopathological examination of formalin fixed paraffin embedded sections, which were prepared from trucut biopsies and resection specimens referred from the Department of General Surgery, NRSMC. CD10 expression was assessed by Immunohistochemistry (IHC) in all cases and scored as negative, weak, or strong. The study examined the association between CD10 expression and the following parameters: age, histopathological grade, and the status of ER, PR, and HER2/neu markers. Data were entered into Microsoft Excel (MS) for statistical analysis. The significance of the study was determined using the Chi-square test, and data were analysed using Statistical Package for the Social Sciences (SPSS) version 23.0 (IBM, Illinois, US). A p-value of <0.05 was considered statistically significant. Results: The study included a total of 120 cases, with 119 cases of female breast cancer (99.16%) and one case of male breast cancer (0.84%). The mean±SD age of the patients was 54±5.038 years (range 44 to 67 years). The majority of cases 102 (85.00%) were diagnosed as Invasive Ductal Carcinoma (IDC), Not Otherwise Specified (NOS), followed by IDC-special types 18 (15.00%). CD10 expression was evaluated in all cases, and stromal CD10 positivity was observed in 79 out of 120 cases (65.80%), with 39 individuals (49.40%) showing weak positivity and 40 cases (50.60%) showing strong positivity. The remaining 41 cases (34.16%) were CD10 negative. Grade 3 cancers were predominant in this study 62 (51.66%). It was noted that CD10 stromal positivity increased with higher grade. Most of the cancers in this study were negative for ER, PR, and HER2/ Neu (78, 65.00%; 84, 70.00%; and 67, 55.83%, respectively). Stromal CD10 expression showed a significant association with ER (p-value=0.00001), HER2/neu (p-value=0.000089), tumour grade (p-value=0.0012), and an insignificant association with age (p-value0.264) and PR (p-value=0.256). Conclusion: Therefore, CD10 expression is strongly associated with well-established prognostic markers, namely higher tumour grade, HER2/neu negativity, and ER negativity. This indicates that CD10 can not only be used as an independent marker of poor prognosis but also as a target for the development of novel therapies.

Inflammation-related parameter serve as prognostic biomarker in esophageal squamous cell carcinoma.

The aim of this study was to explore the predictive role of inflammation-related parameters in prognosis of esophageal squamous cell carcinoma (ESCC). A total of 370 ESCC patients subjected to curative surgery were enrolled. All patients had complete medical records and did not receive preoperative adjuvant therapy. Preoperative systemic immune-inflammation index (SII) was calculated as platelet count × neutrophil count/lymphocyte count, prognostic nutrition index (PNI) as albumin concentration (g/L) + 5 × total lymphocyte count (109/L), and systemic inflammation response index (SIRI) as neutrophil count × monocyte count/lymphocyte count. The optimal cut-off values of preoperative SII, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), PNI, and SIRI were determined via receiver operating characteristic (ROC) analysis, and their correlations with clinical parameters and survival analyzed. NLR was associated with gender (P = 0.022), and PLR (P = 0.037), PNI (P = 0.017) was associated with survival status, LMR was related with gender (P = 0.034) and survival status (P = 0.01), SIRI was correlated with gender (P = 0.000), smoking history (P = 0.000) and drinking history (P = 0.004). Survival analysis indicated that high PLR (P = 0.042), low LMR (P = 0.001), and low PNI (P = 0.007) were predictive of poor prognosis of ESCC. Stratified analysis revealed the prognostic predictor roles of distinct markers in different ESCC subgroups. SII and SIRI were predominantly correlated with the clinical outcome in the lymphatic metastasis subgroup. Further univariate analysis disclosed that T stage, smoking history, lymphatic metastasis, TNM staging, PLR, LMR, and PNI potentially serve as influencing factors(P < 0.05). Multivariate analysis identified T stage (HR = 1.781, P = 0.002), TNM staging (HR = 8.617, P = 0.001) and LMR (HR = 0.504, P = 0.001) as independent predictors for outcomes of ESCC. Low LMR could serve as an independent marker of poor prognosis in patients with ESCC. Inflammation-related markers have distinct predictive roles in ESCC subgroups with different features.

What are the problems with the current staging of discontinuous tumour nodules (DTNs) in colorectal carcinoma? Is there a better way?

Discontinuous extramural tumour nodules (DTNs) are deposits of metastatic carcinoma in soft tissue not associated with lymph nodes. Although they are established as an adverse prognostic factor in colorectal carcinoma (CRC), under the AJCC eighth edition staging system their presence does not upstage patients who also have lymph node metastases. Counterintuitively, in some situations the presence of lymph node metastases may in effect downstage a patient with DTNs from pN1c to pN1a/b. Therefore, we sought to critically assess the significance of DTNs in a large unselected single institution cohort of patients undergoing surgical resection for CRC. Of 3822 CRC patients undergoing surgical resection from 2005 to 2021, DTNs were present in 686 (18.0%). In univariate (HR=2.687, 95CI 2.355-3.065; p<0.001) and multivariate analysis (HR=1.805, 95CI 1.529-2.132; p<0.001) in a model including age, gender, stage, grade, location, lymph node ratio and apical lymph node status, DTNs were associated with worse overall survival (OS). N1c patients (DTN present but no nodal metastasis) demonstrated worse OS compared to the current pN1a group (p<0.001) and were least different to the current pN2a group (p=0.571). Within the current N1a (p=0.013), N1b (p=0.004) and N2a (p=0.002) groups, patients who also had DTNs had worse OS. DTNs were associated with worse OS for all stage III CRCs combined (p<0.001), and for stage IIIB (p<0.001) and stage IIIC (p=0.007) individually. We conclude that DTNs are an independent adverse prognostic factor that should be considered in the staging system in a way that is additional to (rather than integrated with) the number of involved lymph nodes. We then assess a simple suggestion for how this could be achieved by increasing the overall stage by one group in the presence of DTNs (requiring the creation of a new stage IIID).

Comprehensive analysis of LAMC1 expression and prognostic value in kidney renal papillary cell carcinoma and clear cell carcinoma.

Background: Laminin subunit gamma 1 (LAMC1) protein is associated with tumor cell invasion and metastasis. However, its role in kidney cancer remains unclear. In this work, we sought to probe the expression as well as its carcinogenic mechanisms of LAMC1 in kidney renal papillary cell carcinoma (KIRP) and kidney renal clear cell carcinoma (KIRC). Methods: Public databases including TIMER, Oncomine, UALCAN, TISIDB, TCGA, Kaplan–Meier plotter, UCSC Xena, cBioPortal, SurvivalMeth, KEGG, GeneMANIA, Metascape, GSCALite and GDSC were adopted, and the expression, clinical pathological correlation, prognostic signatures, dominant factors influencing LAMC1 expression, DNA methylation levels, gene mutations, copy number variations, functional networks, and drug sensitivity were analyzed. Expression of LAMC1 protein in clinical KIRP and KIRC was validated using tissue array. Results: LAMC1 expression in KIRP and KIRC were significantly higher than those in normal tissues. High LAMC1 expression indicated poor overall survival in KIRP patients and better overall survival in KIRC patients. Through the univariate and multivariate Cox analysis, we found that high LAMC1 expression was a potential independent marker for poor prognosis in KIRP, however it implied a better prognosis in KIRC by univariate Cox analysis. In addition, the LAMC1 expression in KIRP and KIRC was negatively correlated with methylation levels of LAMC1 DNA. Interestingly, LAMC1 expression was positively correlated with the infiltration of CD8+ T cells, dendritic cells and neutrophils in KIRP; however, it was positively correlated with the infiltration of CD4+ T cells, macrophages and neutrophils but negatively correlated with B cells in KIRC. Moreover, high level of CD8+ T cells is beneficial for KIRC prognosis but opposite for KIRP. LAMC1 may participate in signaling pathways involved in formation of adherens junction and basement membrane in KIRP and KIRC, and the high expression of LAMC1 is resistant to most drugs or small molecules of the Genomics of Drug Sensitivity in Cancer database. Conclusion: Enhanced LAMC1 expression suggests a poor prognosis in KIRP while a better prognosis in KIRC, and these opposite prognostic signatures of LAMC1 may be related to different immune microenvironments.

Nerve invasion as an independent predictor of poor prognosis in gastric cancer after curative resection.

The study aims to reveal the clinical significance of perineural invasion (PNI) for gastric cancer prognosis and determine the risk factors of PNI in gastric cancer. This study retrospectively analyzed 350 patients who were diagnosed with GC and underwent curative surgical resection. Variables used to analyze survival included gender, age, degree of differentiation, T classification, lymph node metastasis, lymphovascular invasion, nerve invasion, mucinous adenocarcinoma component, and signet ring cell carcinoma component. The tumors of all patients were surgically resected. All resected specimens were stained with hematoxylin-eosin and immunohistochemical. The data for the patient’s lymphovascular invasion and PNI came from the collected pathological reports. The results of the survival analysis showed that T staging (P < .001), lymph node metastasis (P < .001), lymphovascular invasion (P = .013), PNI (P = .001), and signet ring cell carcinoma components (P = .046) affect the survival time and have a statistically significant difference. Multivariate analysis indicated that the positivity of PNI was an independent prognostic factor (P = .014). T staging (P = .006) and lymph node metastasis (P = .013) were independent prognostic parameters too. Using the Spearman correlation analysis, the following clinicopathological indicators were associated with PNI positivity, such as tumor differentiation, T staging, lymph node metastasis, vascular invasion, and signet ring cell carcinoma components (P < .05). PNI is an independent marker of poor prognosis in patients with gastric cancer.

CD9 mediates the uptake of extracellular vesicles from cancer-associated fibroblasts that promote pancreatic cancer cell aggressiveness.

In pancreatic ductal adenocarcinoma (PDAC), signaling from stromal cells is implicated in metastatic progression. Tumor-stroma cross-talk is often mediated through extracellular vesicles (EVs). We previously reported that EVs derived from cancer-associated stromal fibroblasts (CAFs) that are abundant in annexin A6 (ANXA6+ EVs) support tumor cell aggressiveness in PDAC. Here, we found that the cell surface glycoprotein and tetraspanin CD9 is a key component of CAF-derived ANXA6+ EVs for mediating this cross-talk. CD9 was abundant on the surface of ANXA6+ CAFs isolated from patient PDAC samples and from various mouse models of PDAC. CD9 colocalized with CAF markers in the tumor stroma, and CD9 abundance correlated with tumor stage. Blocking CD9 impaired the uptake of ANXA6+ EVs into cultured PDAC cells. Signaling pathway arrays and further analyses revealed that the uptake of CD9+ANXA6+ EVs induced mitogen-activated protein kinase (MAPK) pathway activity, cell migration, and epithelial-to-mesenchymal transition (EMT). Blocking either CD9 or p38 MAPK signaling impaired CD9+ANXA6+ EV-induced cell migration and EMT in PDAC cells. Analysis of bioinformatic datasets indicated that CD9 abundance was an independent marker of poor prognosis in patients with PDAC. Our findings suggest that CD9-mediated stromal cell signaling promotes PDAC progression.

Pneumothorax in Critically Ill COVID-19 Patients in the Indian Subcontinent.

To explore the incidence and risk factors, as well as mortality, in critically ill COVID-19 patients who developed pneumothorax (PTX) and/or pneumomediastinum (PNM). A retrospective cohort study was undertaken to analyse data of all patients with moderate to severe COVID-19 disease who were either RTPCR positive or had a clinico-radiological diagnosis. The exposure group consisted of COVID-19 patients who presented with PTX/PNM, whereas the non-exposure group consisted of patients who did not develop PTX and/or PNM during the stay. Incidence of PTX/PNM was observed to be 1.9% among critically ill COVID-19 patients. 94.4% (17/18) of patients in the PTX group received positive pressure ventilation (PPV); the majority of these patients were on non-invasive ventilation when they developed PTX/PNM; only one patient was receiving conventional oxygen therapy. COVID-19 patients who developed PTX/PNM had 2.7 times higher mortality. A mortality rate of 72.2% was observed in COVID-19 patients who developed PTX/PNM. Development of PTX/PNM in critically ill COVID-19 patients is associated with more severe disease involvement, and institution of PPV is an additional risk factor. Significantly high mortality was observed following PTX/PNM in critically ill COVID-19 patients and is an independent marker of poor prognosis in COVID-19 disease.

Calculated Tumor-Associated Neutrophils Are Associated with the Tumor-Stroma Ratio and Predict a Poor Prognosis in Advanced Gastric Cancer.

The tumor-associated neutrophils (TANs) value and tumor—stroma ratio (TSR) are promising prognostic parameters in the tumor microenvironment. We aimed to evaluate the prognostic role and relationship of TANs and TSR in gastric cancer. Our study comprised 157 patients who underwent gastrectomy for advanced gastric cancer. TANs were assessed by immunohistochemical staining (CD15 and CD66b) and were analyzed with an image analyzer. TANs have been known to have different functional subpopulations of N1 (anti-tumor) and N2 (pro-tumor). We developed “calculated TANs with pro-tumor function (cN2; CD15 minus CD66b)”. The TSR was evaluated using hematoxylin and eosin staining. High-grade CD15-positive, cN2 in the tumor center, and TSR were significantly related to poor disease-free survival (DFS). TSR and cN2 were independent prognostic factors for DFS (hazard ratio (HR) = 2.614; p = 0.001, HR = 3.976; p = 0.002) and cN2 in the tumor center showed a positive correlation with TSR (R = 0.179, p = 0.025). While CD66b stained both N1 and N2, CD15 detected most of N2. Combining both markers revealed a novel cN2, which was an independent marker of poor prognosis. The transformation from N1 to N2 predominantly occurred in the tumor center, and was associated with TSR.

Long-term survival of a patient with liver metastases from clear cell gastric adenocarcinoma after multimodality treatment including interventional oncology techniques: case report

BackgroundGastric cancer (GC) is the fourth most common cancer and the third leading cancer-related cause of death worldwide since most patients are diagnosed at an advanced stage. The majority of GCs are adenocarcinomas (ACs), and the poorly characterized clear cell AC represents a unique subgroup of GCs and is an independent marker of poor prognosis. Even though the prognosis for patients with advanced GC is poor we present a report of a patient with long-term survival despite having liver metastases from clear cell gastric AC.Case presentationA 45-year-old male with clear cell gastric AC underwent subtotal gastrectomy and postoperative chemoradiation. Only a year and a half after his initial treatment the disease spread to his liver. He received two lines of chemotherapy treatment within the next two years before a right hepatectomy was suggested. Due to an initially insufficient future liver remnant (FLR), transarterial chemoembolization (TACE) and portal vein embolization (PVE) were performed, which made the surgical procedure possible. Shortly after a disease progression in the remaining liver was detected. In the following three years the patient was treated with a carefully planned combination of systemic therapy and different interventional oncology techniques including selective internal radiation therapy (SIRT) and TACE. And as illustrated, an attentive, patient-tailored, multimodality treatment approach can sometimes greatly benefit our patients as he had an overall survival of 88 months despite the poor prognosis of his disease.ConclusionTo the best of our knowledge, this report is the first to describe a patient with liver metastases from clear cell gastric AC treated with interventional oncology techniques (PVE, TACE, and SIRT) in combination with other locoregional and systemic therapies thereby presenting that these interventional oncology techniques can be successfully integrated into long-term management of non-conventional liver tumors.

Neutrophil-lymphocyte Ratio as Independent Prognostic Factor among Breast Cancer Patients in a Tertiary Care Hospital, Kolkata, India

Introduction: The most important prognostic factor for breast cancer is tumour stage and tumour grade. However, the assessment of the above parameters are time-consuming and require expertise. Thus evaluation of the prognosis of breast cancer is still limited to tertiary care hospitals, with appropriate facilities for histopathological techniques. Recently, inflammatory blood markers have shown a role as a prognostic factor. Out of all the inflammatory blood markers, neutrophil-lymphocyte ratio has emerged as the most useful. Abundant evidence suggests the role of NLR as an adverse prognostic factor in breast cancer. NLR is simple and inexpensive. It can be easily obtained, as the differential count of every patient is done routinely. Thus it can act as an indicator of high-risk patients who are likely to show poor prognosis. Though NLR has been found to play a role in prognosis prediction in breast cancer, much is unknown in this field. Aim: To assess the effectiveness of Neutrophil-Lymphocyte Ratio (NLR) as an independent prognostic parameter among breast cancer patients in a tertiary care hospital in Kolkata, India. Materials and Methods: This observational cross-sectional study was conducted in Department of Pathology, Nil Ratan Sircar Medical College and Hospital, Kolkata, West Bengal, India, where 140 female patients undergoing mastectomy for breast cancer were studied from 1st February 2019 to 31st January 2020. The clinicopathological parameters, histopathological parameters, and molecular subtypes were evaluated. NLR was calculated and related with the other prognostic parameters. Data entry was done in Microsoft Excel and analysis was done using Statistical Package for Social Sciences (SPSS) software version 20.0. One way Analysis of Variance (ANOVA) test and Chi-square test was conducted to assess the relationship of NLR with various other prognostic factors. Results: Out of 140 patients, 78 patients showed NLR values within 1.8 to 3.33. Higher NLR (&gt;3.33) was associated with poor prognostic factors like higher T stage (T4) {17 (53.1%)}, higher stage (stage III) 95 (67.8%), skin involvement 19 (47.5%), Lymphovascular involvement in 23 (39.7%), perineural involvement in 10 (71.4%) and in patients with HER2 positive molecular subtype in 8 (5.7%). Conclusion: This study suggests that a high NLR value was associated with poor prognosis in breast cancer patients. Thus, it can be used as an independent marker of poor prognosis and can help guide the treatment of breast cancer patients. The more we study the role of NLR, the more useful it will be in predicting the course of breast cancer as early as possible.

ARHGAP6 EXPRESSION IS ASSOCIATED WITH MOLECULAR RISK AND IMPACTS CLINICAL OUTCOMES IN ACUTE MYELOID LEUKEMIA

Despite the advances in the large-scale generation of genomic data from acute myeloid leukemia (AML) patients, much effort is still needed to convert these data into biological functions, which may pave avenues for the discovery of new prognostic markers and therapeutic targets. In a previous study, four cytoskeleton-related genes (ARHGAP6, EZR, MAP3K11 and PAK1) were identified as a prognostic factor in AML. In the present study, we detail the prognostic impact, as well as its functional genomic associations, of the ARHGAP6 gene in AML patients. Clinical and genomic data were obtained from the TCGA AML cohort (n = 173). The clinical impact (overall survival [OS] and disease-free survival [DFS]) for ARHGAP6 expression was investigated by the proportional hazards Cox regression model. Functional genomic analyzes were performed by gene set enrichment analysis (GSEA) and Gene Ontology (GO) from differentially expressed (DEG) genes obtained from the Galaxy tool. All p values were two sided with a significance level of 5%. ARGHAP6 expression was higher in the intermediate and high molecular risk groups in AML patients (all p < 0.01). High ARGHAP6 expression was identified as an independent risk factor for OS (HR = 1.92; p = 0.001) and DFS (HR = 1.96; p = 0.01) when analyzed with confounders, age, gender, white blood cell count, and molecular risk. In the GSEA, a total of 30 cellular and molecular events were found to be positively enriched in high ARHGAP6-expressing AML patients, which we highlighted the signaling pathways: IL6/JAK2/STAT3 (NES: 1.62; p < 0.001), NOTCH (NES: 1.60; p < 0.001), KRAS (NES: 1.59; p < 0.001), IL2/STAT5 (NES: 1.51; p < 0.001), TGF BETA (NES: 1.39; p = 0.03) and BETA CATENIN SIGNALING (NES: 1.36; p = 0.04). In GO analyses, high ARHGAP6 expression was associated with important processes for cancer development and progression such as cell signaling mediated by surface receptors, signal transduction, linkage to growth factors, and regulation of cell population proliferation (all p < 0.001). ARHGAP6 is a RhoGAP that acts converting RhoGTPases in its inactive GDP-bound state, which may regulate the interactions of signaling molecules with the actin cytoskeleton. It promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology. The role of ARHGAP6 is still poorly established in cancer, but it is known to modulate pathways of RhoGTPases. In this sense, our study is a pioneer in the identification of this gene in processes related to neoplastic hematopoiesis, which will guide future investigations. ARHGAP6 gene expression was identified as an independent marker of poor prognosis in AML patients. The GSEA suggested that high ARHGAP6 expression is associated with activation of relevant processes to the malignant phenotype of AML. FAPESP, CNPq and CAPES.

Elevated tumor expression of Astroprincin (FAM171A1) is an independent marker of poor prognosis in colon cancer

BackgroundColon cancer (CC) is one of the most commonly diagnosed malignancies worldwide. Several biomarkers have been suggested for improved prognostic evaluation, but few have been implemented in clinical practice. There is a need for biomarkers that predict the tumor behavior in CC and allow stratification of patients that would benefit from adjuvant therapy. We recently identified and functionally characterized a previously unknown protein that we called ASTROPRINCIN (APCN) due to its abundance in astrocytes. APCN, also annotated as FAM171A1, is found in trophoblasts of early placenta. We demonstrated that high expression levels of APCN in cancer cells induced motility and ability of invasive growth in semisolid medium.MethodsWe screened by immunohistochemistry a tissue microarray material from the tumors of 429 CC patients with clinical follow-up in a test series and 255 CC patients in a validation series.ResultsWe showed that low or absent APCN expression correlates with a favorable prognosis while high APCN expression was a sign of an adverse outcome. Cox uni- and multivariable analysis revealed that elevated tumor expression of APCN constitutes a robust marker of poor prognosis independent of stage, grade, patient’s age, or gender.ConclusionOur findings demonstrate that APCN is a novel independent prognostic marker in CC and could potentially select patients for more intense postoperative adjuvant treatment and follow-up.

Cytoplasmic LXR expression is an independent marker of poor prognosis for patients with early stage primary breast cancer

PurposeThe aim of this study was to investigate the expression of liver X receptors α/β (LXR) in primary breast cancer (BC) tissues and to analyze its correlations with clinicopathological parameters including patient survival.MethodsIn a well-characterized cohort of 305 primary BC, subcellular distribution of LXR was evaluated by immunohistochemistry. Correlations with clinicopathological characteristics as well as with patient outcome were analyzed.ResultsLXR was frequently localized in both nuclei and cytoplasms of BC cells, with stronger staining in nuclei. Total and nuclear LXR expression was positively correlated with ER and PR status. Overall survival analysis demonstrated that cytoplasmic LXR was significantly correlated with poor survival and appeared as an independent marker of poor prognosis, in stage I but not in stage II–III tumorsConclusionAltogether, these data suggest that cytoplasmic LXR could be defined as a prognostic marker in early stage primary BC.