1,721,111 research outputs found
Alterations in Natural Killer Cells in Colorectal Cancer Patients with Stroma AReactive Invasion Front Areas (SARIFA)
Full text linkBackground: Recently, our group introduced Stroma AReactive Invasion Front Areas (SARIFA) as an independent prognostic predictor for a poorer outcome in colon cancer patients, which is probably based on immunologic alterations combined with a direct tumor-adipocyte interaction: the two together reflecting a distinct tumor biology. Considering it is already known that peripheral immune cells are altered in colorectal cancer (CRC) patients, this study aims to investigate the changes in lymphocyte subsets in SARIFA-positive cases and correlate these changes with the local immune response. Methods: Flow cytometry was performed to analyze B, T, and natural killer (NK) cells in the peripheral blood (PB) of 45 CRC patients. Consecutively, lymphocytes in PB, tumor-infiltrating lymphocytes (TILs), and CD56+ and CD57+ lymphocytes at the invasion front and the tumor center were compared between patients with SARIFA-positive and SARIFA-negative CRCs. Results: Whereas no differences could be observed regarding most PB lymphocyte populations as well as TILs, NK cells were dramatically reduced in the PB of SARIFA-positive cases. Moreover, CD56 and CD57 immunohistochemistry suggested SARIFA-status-dependent changes regarding NK cells and NK-like lymphocytes in the tumor microenvironment. Conclusion: This study proves that our newly introduced biomarker, SARIFA, comes along with distinct immunologic alterations, especially regarding NK cells
Stroma AReactive Invasion Front Areas (SARIFA), tumour immune microenvironment, and survival in colorectal cancer
No full textAbstract
Background:
SARIFA (Stroma AReactive Invasion Front Areas), defined as the direct contact between a tumour cell cluster and adipose cells at the invasion margin, has been proposed as a prognostic marker in gastrointestinal cancers. We hypothesized that SARIFA is associated with an immunosuppressive tumour microenvironment.
Methods:
SARIFA status was evaluated in two large colorectal cancer cohorts (N = 1876). Survival analyses were performed using multivariable Cox regression. Immune cell densities were analysed utilizing multiplex and conventional immunohistochemistry combined with digital image analysis.
Results:
SARIFA-positivity was independently associated with a shorter cancer-specific survival in both cohorts [Cohort 1: hazard ratio (HR) for SARIFA-positive (vs. negative) 1.75 (95% CI 1.35–2.25), P < 0.0001; Cohort 2: HR for SARIFA-positive (vs. negative) 2.09 (95% CI 1.43–3.05), P = 0.0001]. SARIFA-positivity was associated with lower densities of CD3+ T cells, CD66b+ granulocytes, M1-like macrophages, and CD14+HLA-DR+ mature monocytic cells, but higher densities of M2-like macrophages and CD14+HLA-DR- immature monocytic cells. Mean Cohen’s kappa for SARIFA evaluation between eight investigators was 0.80.
Conclusions:
SARIFA status is a highly reproducible, independent prognostic factor in colorectal cancer. SARIFA-positivity is associated with lower densities of antitumourigenic immune cells and the polarisation of macrophages towards a protumourigenic M2-like phenotype.Abstract
Background:
SARIFA (Stroma AReactive Invasion Front Areas), defined as the direct contact between a tumour cell cluster and adipose cells at the invasion margin, has been proposed as a prognostic marker in gastrointestinal cancers. We hypothesized that SARIFA is associated with an immunosuppressive tumour microenvironment.
Methods:
SARIFA status was evaluated in two large colorectal cancer cohorts (N = 1876). Survival analyses were performed using multivariable Cox regression. Immune cell densities were analysed utilizing multiplex and conventional immunohistochemistry combined with digital image analysis.
Results:
SARIFA-positivity was independently associated with a shorter cancer-specific survival in both cohorts [Cohort 1: hazard ratio (HR) for SARIFA-positive (vs. negative) 1.75 (95% CI 1.35–2.25), P < 0.0001; Cohort 2: HR for SARIFA-positive (vs. negative) 2.09 (95% CI 1.43–3.05), P = 0.0001]. SARIFA-positivity was associated with lower densities of CD3+ T cells, CD66b+ granulocytes, M1-like macrophages, and CD14+HLA-DR+ mature monocytic cells, but higher densities of M2-like macrophages and CD14+HLA-DR- immature monocytic cells. Mean Cohen’s kappa for SARIFA evaluation between eight investigators was 0.80.
Conclusions:
SARIFA status is a highly reproducible, independent prognostic factor in colorectal cancer. SARIFA-positivity is associated with lower densities of antitumourigenic immune cells and the polarisation of macrophages towards a protumourigenic M2-like phenotype
Prognostic and Predictive Value of SARIFA-status Within Molecular Subgroups of Colorectal Cancer:Insights From the Netherlands Cohort Study
Full text linkWe recently proposed Stroma AReactive Invasion Front Areas (SARIFA), defined as direct tumor-adipocyte interaction at the invasion front, as a novel hematoxylin-and-eosin (H&E)-based histopathological prognostic biomarker in various cancers. Given that microsatellite instability, BRAF, and RAS mutation status are routinely tested for colorectal cancers (CRC), studying SARIFA's additional prognostic value within these molecular subgroups is crucial. In addition, exploring whether the survival benefit from adjuvant therapy differs according to SARIFA-status may enhance patient treatment and outcome. SARIFA-status, BRAF, RAS, and DNA mismatch repair (MMR) status were available for 1726 CRC patients from the prospective Netherlands Cohort Study (NLCS, 1986-2006). In this study, we investigated (1) the relationship between SARIFA-status and CRC molecular characteristics, (2) the prognostic value of SARIFA-status within these molecular subgroups, and (3) whether SARIFA-status was associated with survival benefit from adjuvant therapy. SARIFA-positive CRCs more frequently showed a BRAF mutation compared to SARIFA-negative CRCs (P<0.001). BRAF-mutant/MMR-proficient CRCs were enriched in SARIFA-positive cases. SARIFA-positivity was associated with poor CRC-specific (HR range: 1.47 to 1.78) and overall survival (HR range: 1.35 to 1.70) within all molecular subgroups except MMR-deficient CRCs. Patients with SARIFA-positive CRC showed a CRC-specific survival benefit from adjuvant therapy compared to surgery alone (HR CRC-specific: 0.59; 95% CI: 0.44-0.79), while no CRC-specific survival benefit was observed for patients with SARIFA-negative CRC. To conclude, our results indicate that SARIFA-positivity is more common in the aggressive subset of BRAF-mutant and BRAF-mutant/MMR-proficient CRCs. Moreover, SARIFA-positivity provides additional prognostic value within molecular subgroups based on BRAF, RAS, and MMR status, suggesting that it may enhance prognostic stratification of CRC patients.</p
Novel biomarker SARIFA in colorectal cancer: highly prognostic, not genetically driven and histologic indicator of a distinct tumor biology
No full textAbstract
SARIFA (Stroma AReactive Invasion Front Areas) has recently emerged as a promising histopathological biomarker for colon and gastric cancer. To elucidate the underlying tumor biology, we assessed SARIFA-status in tissue specimens from The-Cancer-Genome-Atlas (TCGA) cohorts COAD (colonic adenocarcinoma) and READ (rectal adenocarcinoma). For the final analysis, 207 CRC patients could be included, consisting of 69 SARIFA-positive and 138 SARIFA-negative cases. In this external validation cohort, H&E-based SARIFA-positivity was strongly correlated with unfavorable overall, disease-specific, and progression-free survival, partly outperforming conventional prognostic factors. SARIFA-positivity was not associated with known high-risk genetic profiles, such as BRAF V600E mutations or microsatellite-stable status. Transcriptionally, SARIFA-positive CRCs exhibited an overlap with CRC consensus molecular subtypes CMS1 and CMS4, along with distinct differential gene expression patterns, linked to lipid metabolism and increased stromal cell infiltration scores (SIIS). Gene-expression-based drug sensitivity prediction revealed a differential treatment response in SARIFA-positive CRCs. In conclusion, SARIFA represents the H&E-based counterpart of an aggressive tumor biology, demonstrating a partial overlap with CMS1/4 and also adding a further biological layer related to lipid metabolism. Our findings underscore SARIFA-status as an ideal biomarker for refined patient stratification and novel drug developments, particularly given its cost-effective assessment based on routinely available H&E slides
Stroma AReactive Invasion Front Areas (SARIFA) - a new easily to determine biomarker in Colon cancer - results of a retrospective study
Full text linkSimple Summary
Many studies have used histomorphological features to more precisely predict the prognosis of patients with colon cancer, focusing on tumor budding, poorly differentiated clusters, and the tumor–stroma ratio. Here, we introduce SARIFA: Stroma AReactive Invasion Front Area(s). We defined SARIFA as the direct contact between a tumor gland/tumor cell cluster (≥5 cells) and inconspicuous surrounding adipose tissue in the invasion front. SARIFA shows an excellent interobserver reliability and high prognostic value and is thus a promising histomorphological prognostic indicator for adipose-infiltrative adenocarcinomas of the colon.
Abstract
Many studies have used histomorphological features to more precisely predict the prognosis of patients with colon cancer, focusing on tumor budding, poorly differentiated clusters, and the tumor–stroma ratio. Here, we introduce SARIFA: Stroma AReactive Invasion Front Area(s). We defined SARIFA as the direct contact between a tumor gland/tumor cell cluster (≥5 cells) and inconspicuous surrounding adipose tissue in the invasion front. In this retrospective, single-center study, we classified 449 adipose-infiltrative adenocarcinomas (not otherwise specified) from two groups based on SARIFA and found 25% of all tumors to be SARIFA-positive. Kappa values between the two pathologists were good/very good: 0.77 and 0.87. Patients with SARIFA-positive tumors had a significantly shorter colon-cancer-specific survival (p = 0.008, group A), absence of metastasis, and overall survival (p < 0.001, p = 0.003, group B). SARIFA was significantly associated with adverse features such as pT4 stage, lymph node metastasis, tumor budding, and higher tumor grade. Moreover, SARIFA was confirmed as an independent prognostic indicator for colon-cancer-specific survival (p = 0.011, group A). SARIFA assessment was very quick (<1 min). Because of low interobserver variability and good prognostic significance, SARIFA seems to be a promising histomorphological prognostic indicator in adipose-infiltrative adenocarcinomas of the colon. Further studies should validate our results and also determine whether SARIFA is a universal prognostic indicator in solid cancers
The relationship between stroma AReactive invasion front areas (SARIFA), warburg-subtype and survival: results from a large prospective series of colorectal cancer patients
Full text linkBACKGROUND: Stroma AReactive Invasion Front Areas (SARIFA) is a recently identified haematoxylin & eosin (H&E)based histopathologic biomarker in gastrointestinal cancers, including colorectal cancer (CRC), defined as direct contact between tumour cells and adipocytes at the tumour invasion front. The current study aimed at validating the prognostic relevance of SARIFA in a large population-based CRC series as well as at investigating the relationship between SARIFA-status and previously established Warburg-subtypes, both surrogates of the metabolic state of the tumour cells. METHODS: SARIFA-status (positive versus negative) was determined on H&E slides of 1,727 CRC specimens. Warburg-subtype (high versus moderate versus low) data was available from our previous study. The associations between SARIFA-status, Warburg-subtype, clinicopathological characteristics and CRC-specific as well as overall survival were investigated. RESULTS: 28.7% (n=496) CRC were SARIFA-positive. SARIFA-positivity was associated with more advanced disease stage, higher pT category, and more frequent lymph node involvement (all p<0.001). SARIFA-positivity was more common in Warburg-high CRC. 44.2% (n=219) of SARIFA-positive CRCs were Warburg-high compared to 22.8% (n=113) being Warburg-low and 33.1% (n=164) being Warburg-moderate (p<0.001). In multivariable-adjusted analysis, patients with SARIFA-positive CRCs had significantly poorer CRC-specific (HR 1.65; 95% CI 1.41-1.93) and overall survival (HR 1.46; 95% CI 1.28-1.67) independent of clinically known risk factors and independent of Warburg-subtype. Combining the SARIFA-status and the Warburg-subtype to a combination score (SARIFA-negative/Warburg-high versus SARIFA-positive/Warburg-low versus SARIFA-positive/Warburg-high, and so on) did not improve the survival prediction compared to the use of SARIFA-status alone (SARIFA-negative + Warburg-high: HR 1.08; 95% CI 0.84-1.38; SARIFA-positive + Warburg-low: HR 1.79; 95% CI 1.32-2.41; SARIFA-positive + Warburg-high: HR 1.58; 95% CI 1.23-2.04). CONCLUSIONS: Our current study is the by far largest external validation of SARIFA-positivity as a novel independent negative prognostic H&E-based biomarker in CRC. In addition, our study shows that SARIFA-positivity is associated with the Warburg-high subtype. Further research is warranted to provide a more mechanistic understanding of the underlying tumour biology. Based on our data, we conclude SARIFA-status should be implemented in pathologic routine practice to stratify CRC patients
Novel biomarker SARIFA in colorectal cancer: highly prognostic, not genetically driven and histologic indicator of a distinct tumor biology
Full text linkSARIFA (Stroma AReactive Invasion Front Areas) has recently emerged as a promising histopathological biomarker for colon and gastric cancer. To elucidate the underlying tumor biology, we assessed SARIFA-status in tissue specimens from The-Cancer-Genome-Atlas (TCGA) cohorts COAD (colonic adenocarcinoma) and READ (rectal adenocarcinoma). For the final analysis, 207 CRC patients could be included, consisting of 69 SARIFA-positive and 138 SARIFA-negative cases. In this external validation cohort, H&E-based SARIFA-positivity was strongly correlated with unfavorable overall, disease-specific, and progression-free survival, partly outperforming conventional prognostic factors. SARIFA-positivity was not associated with known high-risk genetic profiles, such as BRAF V600E mutations or microsatellite-stable status. Transcriptionally, SARIFA-positive CRCs exhibited an overlap with CRC consensus molecular subtypes CMS1 and CMS4, along with distinct differential gene expression patterns, linked to lipid metabolism and increased stromal cell infiltration scores (SIIS). Gene-expression-based drug sensitivity prediction revealed a differential treatment response in SARIFA-positive CRCs. In conclusion, SARIFA represents the H&E-based counterpart of an aggressive tumor biology, demonstrating a partial overlap with CMS1/4 and also adding a further biological layer related to lipid metabolism. Our findings underscore SARIFA-status as an ideal biomarker for refined patient stratification and novel drug developments, particularly given its cost-effective assessment based on routinely available H&E slides
Stroma AReactive Invasion Front Areas (SARIFA) improves prognostic risk stratification of perioperative chemotherapy treated oesophagogastric cancer patients from the MAGIC and the ST03 trial
Full text linkBackground: Tumour-associated fat cells without desmoplastic stroma reaction at the invasion front (Stroma AReactive Invasion Front Areas (SARIFA)) is a prognostic biomarker in gastric and colon cancer. The clinical utility of the SARIFA status in oesophagogastric cancer patients treated with perioperative chemotherapy is currently unknown. Methods: The SARIFA status was determined in tissue sections from patients recruited into the MAGIC (n = 292) or ST03 (n = 693) trials treated with surgery alone (S, MAGIC) or perioperative chemotherapy (MAGIC, ST03). The relationship between SARIFA status, clinicopathological factors, overall survival (OS) and treatment was analysed. Results: The SARIFA status was positive in 42% MAGIC trial S patients, 28% MAGIC and 48% ST03 patients after pre-operative chemotherapy. SARIFA status was related to OS in MAGIC trial S patients and was an independent prognostic biomarker in ST03 trial patients (HR 1.974, 95% CI 1.555–2.507, p < 0.001). ST03 patients with lymph node metastasis (ypN + ) and SARIFA-positive tumours had poorer OS than patients with ypN+ and SARIFA-negative tumours (p logrank < 0.001). Conclusions: The SARIFA status has clinical utility as prognostic biomarker in oesophagogastric cancer patients irrespective of treatment modality. Whilst underlying biological mechanisms warrant further investigation, the SARIFA status might be used to identify new drug targets, potentially enabling repurposing of existing drugs targeting lipid metabolism.</p
Stroma AReactive Invasion Front Areas (SARIFA) improves prognostic risk stratification of perioperative chemotherapy treated oesophagogastric cancer patients from the MAGIC and the ST03 trial
Full text linkBACKGROUND: Tumour-associated fat cells without desmoplastic stroma reaction at the invasion front (Stroma AReactive Invasion Front Areas (SARIFA)) is a prognostic biomarker in gastric and colon cancer. The clinical utility of the SARIFA status in oesophagogastric cancer patients treated with perioperative chemotherapy is currently unknown. METHODS: The SARIFA status was determined in tissue sections from patients recruited into the MAGIC (n = 292) or ST03 (n = 693) trials treated with surgery alone (S, MAGIC) or perioperative chemotherapy (MAGIC, ST03). The relationship between SARIFA status, clinicopathological factors, overall survival (OS) and treatment was analysed. RESULTS: The SARIFA status was positive in 42% MAGIC trial S patients, 28% MAGIC and 48% ST03 patients after pre-operative chemotherapy. SARIFA status was related to OS in MAGIC trial S patients and was an independent prognostic biomarker in ST03 trial patients (HR 1.974, 95% CI 1.555–2.507, p < 0.001). ST03 patients with lymph node metastasis (ypN + ) and SARIFA-positive tumours had poorer OS than patients with ypN+ and SARIFA-negative tumours (plogrank < 0.001). CONCLUSIONS: The SARIFA status has clinical utility as prognostic biomarker in oesophagogastric cancer patients irrespective of treatment modality. Whilst underlying biological mechanisms warrant further investigation, the SARIFA status might be used to identify new drug targets, potentially enabling repurposing of existing drugs targeting lipid metabolism
Stroma AReactive Invasion Front Areas (SARIFA) predict poor survival in adenocarcinomas of the stomach and gastrooesophageal junction: a validation study
No full text<jats:title>Abstract</jats:title><jats:p>Recently, the presence of “Stroma AReactive Invasion Front Areas” (SARIFA) has been described as a promising adverse prognostic factor in gastric cancer. However, the validity of this approach still needs to be tested. The aim of this study was to independently assess the utility of the proposed method in a well-characterised cohort of primary resected adenocarcinomas of stomach and gastrooesophageal junction (<jats:italic>n</jats:italic> = 392). SARIFA status was analysed on routine slides of resection specimens. Cases were divided into SARIFA-positive and negative groups and analysed in relation to clinicopathological and survival data. SARIFA positivity was found in 15.1% (<jats:italic>n</jats:italic> = 59) cases and was significantly associated with Lauren phenotype (<jats:italic>p</jats:italic> &lt; 0.001), pT (<jats:italic>p</jats:italic> = 0.001), pN (<jats:italic>p</jats:italic> = 0.018), UICC stage (<jats:italic>p</jats:italic> = 0.031), tumour budding (<jats:italic>p</jats:italic> = 0.002), overall survival (<jats:italic>p</jats:italic> &lt; 0.001) and cancer-specific survival (<jats:italic>p</jats:italic> &lt; 0.001). SARIFA-positive tumours had a worse prognosis in the multivariate setting (HR = 1.847, 95% CI: 1.300–2.624, <jats:italic>p</jats:italic> = 0.001). SARIFA status is an independent prognostic factor in gastric cancer, in particular in locally advanced tumours.</jats:p>
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