Prognostic Values of Tissue and Serum Angiogenic Growth Factors Depend on the Phenotypic Subtypes of Colorectal Cancer.

We classified colorectal cancer (CRC) patients into four phenotypic subgroups and investigated the prognostic value of angiogenic growth factors across subgroups. Preoperative serum concentrations and tissue expressions of VEGF, bFGF, and PDGF-bb were determined among 322 CRC patients. We classified patients into phenotypic subgroups (immune, canonical, metabolic, and mesenchymal) according to a method described in our earlier work. Among the metabolic subgroup, patients with high serum concentrations of VEGF, bFGF, or PDGF-bb exhibited a significantly improved prognosis. Moreover, those with high VEGF tissue expressions exhibited a significantly improved prognosis among patients in the metabolic subgroup. Among immune patients, a high VEGF serum expression is associated with a worse prognosis. A high serum bFGF concentration is associated with a favorable prognostic factor among patients with a canonical tumor phenotype. A high PDGF-bb tissue expression is associated with non-metastasized disease and with the immune, canonical, and metabolic subtypes. To our knowledge, this is the first study to show that the prognostic value of angiogenic growth factors differs between phenotypic subtypes.

Phenotypic subtypes predict outcomes in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally. The Colorectal Cancer Subtyping Consortium used the transcriptome-based method to classify CRC according to four molecular subtypes, each showing different genomic alterations and prognoses: CMS1 (microsatellite instable [MSI] immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal). To expedite the clinical implementation of such methods, easier and preferably tumor phenotype-based methods are needed. In this study, we describe a method to divide patients into four phenotypic subgroups using immunohistochemistry. Moreover, we analyze disease-specific survival (DSS) among different phenotypic subtypes and the associations between the phenotypic subtypes and clinicopathological variables. METHODS: We categorized 480 surgically treated CRC patients into four phenotypic subtypes (immune, canonical, metabolic, and mesenchymal) using the immunohistochemically determined CD3-CD8 tumor-stroma index, proliferation index, and tumor-stroma percentage. We analyzed survival rates for the phenotypic subtypes in different clinical patient subgroups using the Kaplan-Meier method and Cox regression analysis. Associations between phenotypic subtypes and clinicopathological variables were examined using the chi-square test. RESULTS: Patients with immune subtype tumors exhibited the best 5-year DSS, while mesenchymal subtype tumors accompanied the worst prognosis. The prognostic value of the canonical subtype showed wide variation among different clinical subgroups. Immune subtype tumors were associated with being female, stage I disease, and a right-side colon location. Metabolic tumors, however, were associated with pT3 and pT4 tumors, and being male. Finally, a mesenchymal subtype associated with stage IV disease, a mucinous histology, and a rectal tumor location. CONCLUSIONS: Phenotypic subtype predicts patient outcome in CRC. Associations and prognostic values for subtypes resemble the transcriptome-based consensus molecular subtypes (CMS) classification. In our study, the immune subtype stood out with its exceptionally good prognosis. Moreover, the canonical subtype showed wide variability among clinical subgroups. Further studies are needed to investigate the concordance between transcriptome-based classification systems and the phenotypic subtypes.

High tissue expression of TLRs combined with high density of tumor infiltrating lymphocytes predicts a better prognosis in colorectal cancer patients.

BACKGROUND: Colorectal cancer causes 935,000 cancer deaths yearly. High local immune cell infiltration serves as a positive prognostic factor in CRC. Toll-like receptors (TLRs) induce innate immune responses and lead to adaptive immune system activation. TLRs play protumorigenic and antitumorigenic roles. We aimed to explore the relationship between TLR immunoexpressions and the infiltration densities of T-lymphocytes in CRC. METHODS: Immunohistochemical TLR2, TLR4, TLR5, and TLR7 positivity and the density of CD3- and CD8-positive cells in tumoral and stromal tissue were evaluated from the tissue microarray slides of 549 consecutive CRC surgical patients treated at Helsinki University Hospital, Finland, between 1998 and 2005. We calculated the associations and correlations using Pearson's chi-square and Spearman's correlation tests, generating survival curves using the Kaplan-Meier method. RESULTS: Positive intratumoral CD3 and CD8 densities associated with a high TLR2 expression (p < 0.001 and p = 0.001, respectively) and a high TLR4 expression (p = 0.013 and p = 0.025). A low TLR5 immunoexpression associated with negative intratumoral CD3 (p = 0.001) and CD8 (p = 0.011) and a low stromal CD3 (p = 0.001). No association or correlation emerged between TLR7 immunoexpression and CD3 or CD8 cell density. A low CD3-CD8 tumor-stroma index indicated a worse prognosis among all TLR subgroups, except the TLR7-negative subgroup. CONCLUSIONS: We detected significant associations and correlations between high tissue TLR2, TLR4, and TLR5 immunoexpressions and high densities of CD3- and CD8-positive cells. Combining these markers may improve the prognostic evaluation of CRC patients.

Tumor-associated CD3- and CD8-positive immune cells in colorectal cancer: The additional prognostic value of CD8+-to-CD3+ ratio remains debatable.

BACKGROUND: A large number of infiltrating CD3- and CD8-positive inflammatory cells indicates an improved survival in colorectal cancer (CRC), similar to many other cancers. OBJECTIVE: We investigated the prognostic value of different combinations of CD3- and CD8-positive immune cells in CRC patients. METHODS: The densities of CD3- and CD8-positive cells in intratumoral and stromal tissues were evaluated from 539 patients, for which we calculated a CD3 tumor-stroma index, a CD8 tumor-stroma index, and a CD3-CD8 tumor-stroma index. RESULTS: High CD3 and CD8 tumor-stroma indices associated with stage I to II disease (p <  0.001 for both). The CD3 tumor-stroma index associated with a colonic tumor location (p = 0.006), while the CD8 tumor-stroma index associated with right-sided tumors (p <  0.001) and histological grade 3 tumors (p = 0.032). High intratumoral and stromal densities for CD3- and CD8-positive immune cells, the CD3 tumor-stroma index, the CD8 tumor-stroma index, and the CD3-CD8 tumor-stroma index all indicated a better DSS. CONCLUSIONS: The CD3 tumor-stroma index carries a strong prognostic value in CRC, and none of the CD3 and CD8 combinations we analyzed proved superior.

Prenatal exposures and infant brain: Review of magnetic resonance imaging studies and a population description analysis.

Brain development is most rapid during the fetal period and the first years of life. This process can be affected by many in utero factors, such as chemical exposures and maternal health characteristics. The goal of this review is twofold: to review the most recent findings on the effects of these prenatal factors on the developing brain and to qualitatively assess how those factors were generally reported in studies on infants up to 2 years of age. To capture the latest findings in the field, we searched articles from PubMed 2012 onward with search terms referring to magnetic resonance imaging (MRI), brain development, and infancy. We identified 19 MRI studies focusing on the effects of prenatal environment and summarized them to highlight the recent advances in the field. We assessed population descriptions in a representative sample of 67 studies and conclude that prenatal factors that have been shown to affect brain metrics are not generally reported comprehensively. Based on our findings, we propose some improvements for population descriptions to account for plausible confounders and in time enable reliable meta-analyses to be performed. This could help the pediatric neuroimaging field move toward more reliable identification of biomarkers for developmental outcomes and to better decipher the nuances of normal and abnormal brain development.