Prognostic Factor In Colorectal Cancer Research Articles

S100 Staining Adds to the Prognostic Significance of the Combination of Perineural Invasion and Lymphovascular Invasion in Colorectal Cancer.

Studies have suggested that perineural invasion (PNI) and lymphovascular invasion (LVI) serve as independent prognostic factors in colorectal cancer (CRC). Currently, little is known regarding the combination of PNI and LVI as prognostic factors, independent of stage. We hypothesized that this combination was a better prognostic marker than either PNI or LVI alone, and that S100 staining would detect PNI not seen with hematoxylin and eosin (H&E). Surgical pathology slides were retrospectively reviewed for 151 stages I to IV CRC patients who had surgery between January 1, 2008 and December 8, 2008 at 3 Hackensack Meridian Health hospitals in New Jersey. PNI and LVI were detected by H&E staining and a subset of 127 patient samples were additionally examined for PNI by S100 staining. Correlation between staining characteristics and patient outcomes was assessed using the Pearson χ tests and the Fisher exact tests. Survival was analyzed using Kaplan-Meier methods. Of the 151 cases reviewed, 30.5% were positive for PNI and 35.1% were positive for LVI by H&E. The use of S100 staining for PNI enabled its detection in 27 additional cases. Median time from patient diagnosis to death was significantly shorter for patients who were positive for both PNI and LVI (P<0.001). PNI and LVI were individual markers for poor survival in CRC patients and their combined presence had an even worse outcome. Failure to detect PNI on H&E can be overcome by S100 staining.

ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer

The apoptosis-stimulating protein of p53 (ASPP) family of proteins can regulate apoptosis by interacting with the p53 family and have been identified to play an important role in cancer progression. Previously, we have demonstrated that ASPP2 downregulation can promote invasion and migration by controlling β-catenin-dependent regulation of ZEB1, however, the role of ASPP1 in colorectal cancer (CRC) remains unclear. We analyzed data from The Cancer Genome Atlas (TCGA) and coupled this to in vitro experiments in CRC cell lines as well as to experimental pulmonary metastasis in vivo. Tissue microarrays of CRC patients with information of clinical-pathological parameters were also used to investigate the expression and function of ASPP1 in CRC. Here, we report that loss of ASPP1 is capable of enhancing migration and invasion in CRC, both in vivo and in vitro. We demonstrate that depletion of ASPP1 could activate expression of Snail2 via the NF-κB pathway and in turn, induce EMT; and this process is further exacerbated in RAS-mutated CRC. ASPP1 could be a prognostic factor in CRC, and the use of NF-κB inhibitors may provide new strategies for therapy against metastasis in ASPP1-depleted CRC patients.

Low Claudin-1 Expression Has Association with Deep Invading and Higher-Grade Colorectal Adenocarcinoma

BackgroundClaudin-1 is a tight junction protein in the cell that organizes paracellular permeability and epithelial polarity and maintains apical cell-to-cell adhesion. Deregulation of claudin-1 homeostasis will play pivotal role in tumorigenesis, migration, and metastasis of colorectal cancer through a complex signaling pathway. This study investigated the association of claudin-1 expression and clinicopathological factors in colorectal adenocarcinoma. Methods This study was a cross-sectional study of 43 colorectal cancer patients. Each clinicopathological parameter data was divided into 2 categories; depth of tumor invasion (T3, T4), degree of tumor differentiation (low, high grade), tumor location (right, left), sex (man, woman) and age (&lt;60, ≥60 y.o). Claudin-1 expression was examined by the immunohistochemistry method and evaluated by H-Score method. The H-score cut off was determined by the mean value of 148. The difference of claudin-1 expression score with tumor depth invasion and age was analyzed by Independent t-test, and then the degree of differentiation, tumor location and sex were analyzed by Mann-Whitney. All variables were analyzed by the Chi-square analysis with a significance value of P&lt;.05.ResultsThere was a significant mean difference of claudin-1 expression between T3 and T4 tumors (P=.041; 95% CI 1.7-75.1). Tumor with low expression of claudin-1 was 2.5 times more likely to be found in tumor with invasion depth T4 rather than T3 (P=.023; 95% CI 1.5-48). In addition, tumor with low expression of claudin-1 was 0.2 times more likely to be found in the high-grade tumor (P=.001; 95% CI 0.07-0.4). Claudin-1 expression was not statistically significant in different tumor locations, sex and age group. ConclusionThere was mean difference in claudin-1 expression between T3 and T4 tumors, and between low- and high-grade tumors. The low claudin-1 expression is associated with tumor depth invasion and poorly differentiated tumors. Therefore, the use of claudin-1 as an additional prognostic factor in colorectal cancer is proposed.

Abnormal expression of ABCD3 is an independent prognostic factor for colorectal cancer.

ATP binding cassette subfamily D member 3 (ABCD3) is a member of the superfamily of ATP-binding cassette (ABC) transporters, which serve crucial roles in the process of tumor cell resistance to chemotherapy. The present study investigated the diagnostic and prognostic capabilities of ABCD3 in colorectal cancer (CRC) by bioinformatics analysis. Gene expression data and corresponding clinical information of patients with CRC were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The results demonstrated that ABCD3 mRNA level was decreased in CRC tissues compared with normal tissues following Wilcoxon test analysis. Furthermore, ABCD3 protein expression was significantly higher in normal colon tissues compared with colon adenocarcinoma tissues according to the Human Protein Atlas. In addition, the area under the Receiver Operating Characteristic curve based on comparison between the tumor and normal groups derived from TCGA and GEO databases demonstrated that the use of ABCD3 mRNA level may be used for the diagnosis of CRC. ABCD3 expression was significantly associated with clinical stage, T stage, and lymph node status following Kruskal-Wallis test or Wilcoxon rank sum test, logistic regression and χ2 test. Furthermore, the results from Kaplan-Meier survival analysis indicated that low ABCD3 mRNA expression had a poorer prognosis value compared with ABCD3 high expression in patients with CRC. In addition, results from univariate Cox regression analysis indicated that ABCD3 mRNA expression was associated with overall survival (OS), and results from multivariate Cox analysis indicated that ABCD3 mRNA expression may be considered an independent prognostic factor from other clinical factors, such as clinical stage, sex and age. The results from Gene Set Enrichment Analysis demonstrated that the ABCD3 high-expression phenotype was differentially enriched in five biological processes, including apoptosis, cell cycle, renal cell carcinoma, thyroid cancer and colorectal cancer. The findings from this study demonstrated that ABCD3 mRNA expression may be considered as a potential diagnostic and prognostic biomarker in patients with CRC. ABCD3 expression levels may participate in the regulation of cell apoptosis and cell cycle. In addition, GSEA analysis identified Kyoto Encyclopaedia of Genes and Genomes pathways for renal cell carcinoma, thyroid cancer and CRC involving ABCD3.

Prognostic factors for survival in colorectal cancer patients with brain metastases undergoing whole brain radiotherapy: multicenter retrospective study

Whole brain radiotherapy (WBRT) is a mainstay of the treatment for brain metastases (BM). We evaluated prognostic factors in colorectal cancer (CRC) patients undergoing WBRT for BM. The medical records of 106 CRC patients undergoing WBRT for BM between 2000 and 2014 at three institutions were reviewed. Patient and tumor factors were analyzed to identify the prognostic factors for overall survival (OS) calculated from the date of BM diagnosis to the date of death or last follow-up. Surgical resection of BM was performed in six patients. The dose of WBRT was 30 Gy, and boost radiotherapy or stereotactic radiosurgery (8–23 Gy) was given to 15 patients. Systemic therapy for BM was administered in one patient before WBRT and 26 patients after WBRT. The median follow-up time was 3.9 months (range, 0.4–114.1 months). The median OS time was 3.9 months, and the 1-year OS rate was 18.2%. Older age (>65 years), multiple BM (≥3), elevated level of carcinoembryonic antigen (CEA, >5 ng/ml) at BM diagnosis, and extracranial metastases were adverse prognostic factors for OS. Patient with 0–1 factor showed better OS (at 1 year, 76.9%) than patients with 2 factors (16.7%) or 3–4 factors (4.2%; p < 0.001). In conclusion, we evaluated age, the number of BM, CEA level, and extracranial metastases as the prognostic factors for OS in CRC patients undergoing WBRT. Our result might be useful to develop prognostic models predicting survival for patients whom WBRT is intended for.

Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan.

BACKGROUNDIt is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC).AIMTo estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis.METHODSWe enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival.RESULTSWe observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues.CONCLUSIONOur data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.

ISG-15 as an independent prognostic factor in Egyptian patients with colorectal carcinoma

Background and aim Colorectal cancer (CRC) is a heterogeneous disease, with a diverse immune cell infiltrate. Interferon-stimulating gene 15 (ISG-15) is a type I interferon-regulated gene that is secreted by diverse inflammatory cells. The aim of this work was to evaluate the role of ISG-15 in CRC and to correlate its expression with clinicopathological data and patient survival. Materials and methods This retrospective case–control study included 87 chemo-naive CRC cases, 12 adenomas, and 59 non-neoplastic colonic tissue cases from Egyptian patients; all cases were stained for ISG-15 antibody. Results The present study showed that high expression of ISG-15 was correlated with malignant transformation in colorectal tissues, as higher epithelial H-score of ISG-15 was significantly associated with malignant group in comparison with non-neoplastic group (P=0.004). Epithelial overexpression of ISG-15 in CRC was significantly associated with smaller tumor size (P=0.023 and 0.011). Stromal overexpression of ISG-15 in CRC was significantly associated well-differentiated tumors (P=0.026). Moreover, ISG-15 overexpression in epithelium and stroma was associated with long survival period in CRC (P=0.02 and 0.001, respectively). More importantly, ISG-15 expression, either epithelial or stromal, was an independent prognostic factor in CRC. Conclusion High expression of ISG-15 correlates with malignant transformation in colorectal tissues, as ISG-15 is overexpressed in CRC in comparison with non-neoplastic and is associated with factors of good prognosis. In CRC, ISG-15 overexpression is associated with longer overall survival. Epithelial ISG-15 expression is the most independent prognostic factor in CRC.

Prediction of Prognostic Biomarkers and Construction of an Autophagy Prognostic Model for Colorectal Cancer Using Bioinformatics.

Objective:The incidence of colorectal cancer is increasing every year, and autophagy may be related closely to the pathogenesis of colorectal cancer. Autophagy is a natural catabolic mechanism that allows the degradation of cellular components in eukaryotic cells. However, autophagy plays a dual role in tumorigenesis. It not only promotes normal cell survival and tumor growth but also induces cell death and suppresses tumors survival. In addition, the pathogenesis of various conditions, including inflammation, neurodegenerative diseases, or tumors, is associated with abnormal autophagy. The present work aimed to examine the significance of autophagy-related genes (ARGs) in prognosis prediction, to construct an autophagy prognostic model, and to identify independent prognostic factors for colorectal cancer (CRC).Methods:This study discovered a total of 36 ARGs in CRC cases using The Cancer Genome Atlas (TCGA) and Human Autophagy-dedicated (HADd) databases along with functional enrichment analysis. Then, an autophagy prognostic model was constructed using univariate Cox regression analysis, and the key prognostic genes were screened. Finally, independent prognostic markers were determined through independent prognostic analysis and clinical correlation analysis of key genes.Results:Of the 36 differentially expressed ARGs, 13 were related to prognosis, as determined by univariate Cox regression analysis. A total of 6 key genes were obtained by a multivariate Cox regression analysis. Independent prognostic values were shown by 3 genes, namely, microtubule-associated protein 1 light chain 3 (MAP1LC3C), small GTPase superfamily and Rab family (RAB7A), and WD-repeat domain phosphoinositide-interacting protein 2 (WIPI2) by independent prognostic analysis and clinical correlation.Conclusions:In this study, molecular bioinformatics technology was employed to determine and construct a prognostic model of autophagy for colon cancer patients, which revealed 3 autophagy-related features, namely, MAP1LC3C, WIPI2, and RAB7A.

Assessment of Histo-Pathological Outcomes of Colorectal Cancer

Background: Careful and accurate pathology reporting of colorectal cancer resection is vital because pathology reports are used to inform the prognosis, evaluate the quality of other clinical services, surgery and oncology and plan the treatment of patients. Objectives: To evaluate histopathological outcomes of resected colorectal specimens in terms of adequacy of resection, quality of pathological reports and the demographic data of the patients in El Demerdash Hospital in the period between June 2016 to June 2018. Patients and methods: This is a retrospective study conducted at Ain Shams University Hospital by collecting the data from histopathological reports of 142 patients who underwent surgical resection and histopathological assessment of colorectal cancers. Results: In our 2-year study period, 142 patients were included, mean age 52.95 years (56% male) and (43% female). The most common site was ano-rectal tumors (30.3%). (92.3%) of pathology reports were fulfilling the criteria of qualified reports. Adequacy of resection in colon cancer was (70.7%) and it was higher than that of rectal cancer (44%). In the group of patients who received NAT there were 43.5% adequate LNS harvesting. Conclusion: One of the most important prognostic factors in colorectal cancers is adequacy of resection. It was higher in colon cancer than that of rectal cancer. The commonest factor that affects the resection adequacy is the lymph node harvesting, which was apparently less in cases of rectal cancer. This may be attributed to the effect of neoadjuvant therapy on lymph nodes depletion, giving a false picture of inadequate resection.

The role of tumor budding in colorectal adenocarcinoma: Possible involvement of the intestinal cancer stem cell marker Lgr5.

Tumor budding (TB) is a promising prognostic factor in colorectal cancer (CRC) that is independent of tumor-node-metastasis (TNM) staging. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a stem cell marker and a member of the canonical Wnt-signaling cascade. It is involved in colorectal carcinogenesis. However, its role in CRC progression and TB needs to be clarified. TB was assessed in both H and E and CK immunostained sections of 92 CRC cases. Associations between TB grade and different clinicopathological parameters were evaluated. Lgr5 expression in CRC cases and its association with TB grade and other clinicopathological features was also evaluated. H and E stained sections revealed low- and high-grade budding in 55 (59.8%) and 37 (40.2%) tumors, respectively, whereas Cytokeratin Immunohistochemistry (CK-IHC) showed low- and high-grade budding in 31 (33.7%) and 61 (66.3%) tumors, respectively. TB grade (in H and E and CK stained sections) was significantly associated with adverse pathological prognostic variables including vascular invasion (P = 0.03 and 0.001), lymph node metastasis (P = 0.001 and 0,001), advanced Dukes (P = 0.000 and 0.000), and TNM (P = 0.001 and 0.000) stages and inversely associated with Tumor infiltrating lymphocytes (TILS) (P = 0.02 and 0.0001) which is known to be a good prognostic indicator. Lgr5 protein was positively expressed in 52.2% (48/92) of the CRCs. Immunoreactivity of Lgr5 was significantly associated with histological grade (P = 0.01), lymph node metastasis (P = 0.002), vascular invasion (P = 0.02), TNM stage (P = 0.000), Dukes stage (P = 0.000), and TILS (P = 0.03). Furthermore, Lgr5 was found to be significantly associated with TB estimated in both H and E and CK stained tumors (P = 0.003 and 0.001 respectively). This study supported the relevance of TB in the assessment of CRC aggressiveness. It also revealed that Lgr5 expression is related to morphologic features in the invasive front of CRC. Lgr5 could have an important role in forming a morphologic feature at the invasive front associated with the aggressiveness of the tumor.

Prevalence and characteristics of PIK3CA mutation in mismatch repair-deficient colorectal cancer.

Background: Chromosomal instability (CIN) and microsatellite instability (MSI) account for the major causes of colorectal cancer (CRC). As an important component of the CIN pathway, PIK3CA mutation is a negative prognostic factor in CRC. However, the relationship between PIK3CA mutation and mismatch repair (MMR) status has not been well clarified.Methods: MMR status was determined by immunohistochemical assay. KRAS, NRAS, BRAF, PIK3CA and TP53 mutations were comparatively analyzed in 424 MMR-proficient (pMMR) and 104 MMR-deficient (dMMR) CRC tumors using next-generation sequencing (NGS).Results: PIK3CA mutation was more commonly mutated in dMMR tumors. PIK3CA mutation less commonly coexisted with KRAS/NRAS/BRAF and TP53 mutations, but more likely coexisted with HER2 and PTCH1 mutations in dMMR tumors compared with pMMR tumors. In tumors with concurrent RAS/BRAF and PIK3CA mutations, PIK3CA and RAS/BRAF mutant allele frequencies (MAFs) were highly concordant in dMMR tumors, whereas PIK3CA MAFs were significantly lower than the corresponding RAS/BRAF MAFs in pMMR tumors, implying that PIK3CA mutation may occur in the early stage of dMMR CRC.Conclusions: The molecular pathogenesis is different between dMMR and pMMR tumors with PIK3CA mutation in CRC. PIK3CA mutation may act as a clonally dominant truncal mutation in dMMR CRC. Thus, combination of PIK3CA mutation and MMR status might determine a specific group of CRC to select treatment or elevate prognosis.

Expression of Raptor and Rictor and their relationships with angiogenesis in colorectal cancer.

Mammalian target of rapamycin (mTOR) has two subtypes, i.e., mTORC1 and mTORC2, which contain the Raptor and Rictor core molecules, respectively. The effect of Raptor and Rictor on hypoxia inducible factor (HIF)-1α, HIF-2α, and vascular endothelial growth factor (VEGF) in colorectal cancer (CRC) is unclear. In this work, we investigated the correlations among Raptor, Rictor, HIF-1α, HIF-2α, and VEGF expression in CRC. We subsequently analyzed the clinicopathological features of patients. Immunohistochemistry, western blot, and RT-PCR analyses were performed to detect the expression of Raptor, Rictor, HIF-1α, HIF-2α, and VEGF in 120 cases of CRC and 60 cases of normal colorectal mucosa. CD34 was used to label microvascular density (MVD), which was found to be higher in patients with positive Raptor or Rictor than in those with negative Raptor or Rictor. The positive rates of Raptor, Rictor, HIF-1α, HIF-2α, and VEGF in CRC were significantly higher than in normal colorectal mucosa. Raptor expression was positively correlated with HIF-1α and VEGF but not with HIF-2α expression. By contrast, Rictor expression was positively correlated with HIF-2α and VEGF but not with HIF-1α expression. Survival analysis further indicated that Raptor, Rictor, HIF-1α, HIF-2α, VEGF and lymph node metastasis were independent prognostic factors in CRC. To conclude, Raptor and Rictor expression was related to the initiation and development of CRC and angiogenesis in different ways. The combined detection of Raptor and Rictor is important for patients with colorectal carcinoma in prognosis and optimal therapy.

Changes in the classification of malignant colon epithelial neoplasms. (WHO, 2019, 5th edition)

There are not many changes compared to 2010 in WHO classification (2019) of colon adenocarcinomas. Cribriform comedo-type adenocarcinoma (ICD-O code: 8201/3), spindle cell carcinoma (8032/3), squamous cell carcinoma (8070/3) are excluded; carcinoma with a sarcomatoid component (8033/3), poorly cohesive carcinoma (8490/3) and adenoma-like adenocarcinoma (8262/3) were added. The important histological characteristics in the conclusion should indicate the presence of lymphatic invasion, intra- and extramural vascular invasion, perineural invasion, grading, «tumor budding» and the immune microenvironment. In the 5th edition of the classification a large section has been added regarding molecular diagnostics and molecular prognostic factors of colorectal cancer. Correspondence was found between two different classifications based on two different approaches: genomic (according to DNA analysis) and transcriptomic (according to RNA analysis). According to the genomic classification two large groups of colorectal cancer are distinguished: hypermutated and non-hypermutated cancers that correspond to molecular pathways with the development of microsatellite and chromosomal instabilities, respectively. The section of neuroendocrine tumors did not undergo significant changes. It is not recommended to use the term «carcinoid» to refer to a neuroendocrine tumor G1, that is, the term «carcinoid» is excluded.

The use of special stains in the detection of vascular invasion in cases of colon cancer in resource-limited settings in Africa

Background: Vascular invasion (VI) is a well-established independent prognostic factor in colorectal cancer (CRC) associated with the hematogenous spread and high risk of mortality. Its accurate detection is essential in identifying a high-risk group of patients who may benefit from adjuvant therapy and also to detect the risk of disease recurrence. The aim of the study was to determine the value of an elastic tissue stain in assessing vascular invasion in CRC. Materials and Methods: Formalin-fixed paraffin-embedded histologically confirmed CRC blocks were retrieved from the archives of the Histopathology Department of the Komfo Anokye Teaching Hospital. Duplicate sections were made from each block and divided into two, with one part of the sections stained with hematoxylin and eosin (H and E) and the other with Verhoeff–Van Gieson (VVG) stain. Both H and E and VVG-stained sections were assessed for vascular invasion. Findings were put in tables and charts. Results: Forty-one cases were used for our study, comprising 40 adenocarcinomas (six well differentiated, 26 moderately differentiated, and eight poorly differentiated) and one high-grade non-Hodgkin large cell lymphoma. The mean age of our patient was 55 years, with a male-to-female ratio of 1:1.4. Of the 41 sections stained with H and E, venous invasion (VI) was detected in 14 cases (34%), whereas VVG was detected vascular invasion in 18 cases of the 27 undetected by H and E in addition to all the 14 cases detected by H and E (78%). Conclusion: The application of the VVG elastic tissue stain enhanced the sensitivity of detecting VI as compared to the use of H and E alone, and thus, recommendations should be made to include elastic tissue stains in CRC pathology reporting to bring therapeutic benefits to patients in our environment.

Downregulation of human leukocyte antigen Class I expression: An independent prognostic factor in colorectal cancer.

In the present study, we evaluated the clinical prognostic value of human leukocyte antigen (HLA (Class I tumor cell expression in a series of colorectal cancer (CRC) patients and also explored the association of this expression profile with molecular features such as mutation status of KRAS and BRAF, microsatellite stability status, and clinicopathological characteristics of the patients. Formalin-fixed paraffin-embedded tumor tissue of 258 CRC patient's sections were immunohistochemically stained and subsequently quantified for HLA Class I expression by the tumor cells. Determination of microsatellite instability (MSI) tumor status was ascertained using mononucleotide repeat microsatellite targets. KRAS and BRAF mutations were screened by polymerase chain reaction (PCR)-sequencing and cast-PCR, respectively. HLA Class I expression was normal in 91 cases (35.3%), downregulated in 119 (46.1%), and loss of expression in 48 (18.6%) cases. Forty (15.5%) tumors were MSI-H (MSH), 49 were MSI-L (19%), and 169 were microsatellite stable (MSS) (65.5%). Thirty-six (14%) and 15 (5.8%) of the patients exhibited mutation in the KRAS and BRAF, respectively. It was found that patients with downregulated expression of HLA Class I were associated with Stage II tumors (P < 0.001) and a MSS tumor status (P < 0.001), while patients with loss of expression were associated with MSH status (P < 0.001). Univariate and multivariate analyses revealed that HLA Class I downregulated expression was an independent prognostic parameter for shorter overall patient survival time (hazard ratio: 1.8, P = 0.003). HLA Class I expression is an independent and sensitive clinical prognostic marker that might be used in CRC patients.

Validation of the International Tumor Budding Consensus Conference (ITBCC) 2016 recommendation in squamous cell carcinoma of the lung-a single-center analysis of 354 cases.

There are no universally accepted grading systems in pulmonary squamous cell carcinoma (pSQCC). Recently, tumor budding, cell nest size, and spread through airspaces (STAS) have been proposed as grading scheme candidates. Tumor budding is a well-established independent prognostic factor in colorectal cancer. The International Tumor Budding Consensus Conference (ITBCC) provided consensus on scoring in 2016, albeit for colorectal cancers. Here, we aimed to validate the ITBCC method in pSQCC and evaluate additional proposed grading parameters. We analyzed a fully clinico-pathologically annotated Western single-center cohort of 354 consecutive primary resected pSQCC (resected 2000-2013). Patients with SQCC of other organs were excluded to reliably exclude lung metastases. We assessed conventional grading, keratinization, STAS, and tumor budding according to ITBCC recommendations, and correlated them with clinico-pathological parameters and survival. Tumor budding was low (0-4 buds/0.785 mm2) in 41%, intermediate (5-9 buds/0.785 mm2) in 30%, and high (≥10 buds/0.785 mm2) in 29% of cases (mean bud count = 7.45 (H&E), min = 0, max = 84). Cell nests of 1, 2-4, 5-15, >15 cells were present in 68%, 20%, 5%, 7%, respectively. We detected STAS in 33% of cases, desmoplasia in 68%. Tumor budding assessed as continuous and categorized variables was highly concordant between hematoxylin and eosin (H&E) and pancytokeratin (AE1/AE3) stained slides (P < 0.001) and significantly associated with tumor size, UICC/AJCC pT, pN, stage (all P < 0.001) and presence of mediastinal lymph node metastases (H&E: P = 0.028). Tumor budding was a significant prognostic parameter for overall, disease-specific, and progression-free survival (PFS) (all P < 0.001). ITBCC tumor budding categories were independent prognostic factors for overall survival (HR = 1.581; 95% CI 1.186-2.108; P = 0.002), disease-specific survival (HR = 1.710; 95% CI 1.111-2.632; P = 0.015), and PFS (HR = 1.457; 95% CI 1.123-1.890; P = 0.005). STAS or conventional tumor grade had no prognostic value. In conclusion, we confirm tumor budding as an independent prognostic marker in pSQCC and validate the ITBCC 2016 scoring recommendations in pSQCC.

Expression of Serpin B9 as a Prognostic Factor of Colorectal Cancer.

Treatment of colorectal cancer (CRC) does not reflect immune interactions between tumours and macro-organisms. Serpin B9 is known as an inhibitor of Granzyme B. The aim of this study was to evaluate the impact of the expression of Serpin B9 in CRC and healthy colon tissue on prognosis. This retrospective study included 74 CRC patients in all stages. Analysis of gene expression was performed with quantitative polymerase chain reaction with reverse transcription using specific primers and master mix Xceed qPCR SG. Expression was normalized to the reference genes GAPDH, ACTB, and PSMC. Increased expression of Serpin B9 in healthy tissue was significantly associated with longer overall survival (OS). This association was found both in all patients and in the group of patients with distant metastases. The presented results support previous evidence of positive influence of the interaction between immune system and tumour on the prognosis of CRC.

Tumor budding outperforms ypT and ypN classification in predicting outcome of rectal cancer after neoadjuvant chemoradiotherapy

BackgroundBudding is a complementary prognostic factor for colorectal cancer. In this study, we aimed to clarify the role of tumor budding in rectal cancer patients after preoperative chemoradiotherapy.MethodsA total of 124 patients with rectal cancer treated with neoadjuvant chemoradiotherapy and consecutive surgery were included. Surgical specimens were evaluated for budding and routine clinicopathological features. Budding was evaluated on hematoxylin and eosin (H&E)-stained slides and by cytokeratin immunohistochemical (IHC) staining.ResultsA budding rate of 36.9% (n = 38) by H&E and 55.6% (n = 55) by IHC was observed. Budding was significantly associated with a high ypT and ypN status, poor differentiation, and low degrees of tumor regression. Moreover, budding was strongly predictive of a worse patient outcome, as measured by tumor recurrence or death. In multivariate analyses, budding remained the only significant parameter for overall survival and was even superior to the ypT and ypN status (budding in H&E: hazard ratio (HR) 2.72, 95% confidence interval (95% CI) 1.15–6.44, p = 0.023; budding in IHC: HR 5.19, 95% CI 1.62–16.61, p = 0.006).ConclusionBudding is a strong prognostic predictor of survival in rectal cancer patients after neoadjuvant therapy. A standardized evaluation of tumor budding after neoadjuvant therapy may thus aid in risk stratification and guide the clinical management of patients with rectal cancer. Immunostaining can help to enhance the diagnostic accuracy and prognostic significance.

Fat clearance and conventional fixation identified ypN0 rectal cancers following intermediate neoadjuvant radiotherapy have similar long-term outcomes.

BACKGROUNDAs a prognostic factor for colorectal cancer, lymph node (LN) status, particularly the number of LN harvested, has been demonstrated to be essential in the evaluation of quality control in terms of surgical specimen. Neoadjuvant chemoradiation, however, decreases the LN harvest. Therefore, certain approaches (such as fat clearance or methylene blue) has drawn significant attention in order to raise LN yield.AIMTo compare the long-term oncologic outcome of ypN0 rectal cancer identified using fat clearance (FC) or conventional fixation (CF) following 30 Gy in 10 fractions (30 Gy/10f) of neoadjuvant radiotherapy (nRT).METHODSThree hundred and eighty-two patients with resectable and locally advanced rectal cancer were treated by 30 Gy/10f intermediate nRT (biologically equivalent dose of 36 Gy) plus total mesorectal excision. Two specimen fixation methods (FC or CF) were non-randomly used. The ypN0 status was identified in 124 and 101 patients in the FL and CF groups, respectively. Primary endpoints were local recurrence-free survival (LRFS) and cancer-specific survival (CSS).RESULTSThe median follow-up of patients was 5.1 years. The median numbers of retrieved LNs in the FC and CF groups were 19.5 (range, 4-47) and 12 (range, 0-44), respectively, with a significant difference (P = 0.000). The percentages of patients with 12 or more retrieved nodes were 82.3% and 50.5% (101/159) in the FC and CF groups, respectively, with a significant difference (P = 0.000). The LRFS at 5 years were 95.7% and 94.6% in the FC and CF groups, respectively, without statistical difference (P = 0.819). The CSS at 5 years were 92.0% and 87.2% in the FC and CF groups, respectively, without statistical difference (P = 0.482).CONCLUSIONFor patients with ypN0 rectal cancer who underwent 30 Gy/10f preoperative radiotherapy, the increased retrieval of LNs using fat clearance is not associated with survival benefit. This time-consuming fixation method has a low efficacy as a routine practice.

MALAT1 rs664589 Polymorphism Inhibits Binding to miR-194-5p, Contributing to Colorectal Cancer Risk, Growth, and Metastasis

Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) is an evolutionarily highly conserved lncRNA that contributes to colorectal cancer development. However, the exact molecular mechanisms connecting MALAT1 to colorectal cancer have not been fully elucidated. Here, we performed a case-control study in 1,078 patients with colorectal cancer and 1,175 healthy controls to evaluate the association between potentially functional genetic variants of MALAT1 and survival outcomes in patients with colorectal cancer. MALAT1 rs664589 CG/GG genotypes significantly increased the associated risk and decreased overall survival of patients with colorectal cancer compared with the CC genotype. In vitro and in vivo experiments showed that the rs664589 C to G mutation facilitated carcinogenesis and metastasis of colorectal cancer. Mechanistically, the miRNA miR-194-5p targeted MALAT1 for degradation in the nucleus in an Ago2-dependent manner; the rs664589 G allele altered the binding of MALAT1 to miR-194-5p, resulting in increased expression of MALAT1. Colorectal cancer cells and human tissues with the rs664589 CG/GG genotype expressed significantly higher MALAT1 than those with the rs664589 CC genotype. Multivariate Cox regression analysis showed that MALAT1 was a poor prognostic factor of colorectal cancer. In summary, MALAT1 with the rs664589 G allele demonstrates altered binding to miR-194-5p in the nucleus, leading to increased MALAT1 expression and enhanced colorectal cancer development. SIGNIFICANCE: These findings highlight the functional role of MALAT1 polymorphism in colorectal cancer metastasis and survival as well as the underlying mechanism.