Immunohistochemical Assessment of the P53 Protein as a Predictor of Non-Small Cell Lung Cancer Response to Immunotherapy.

BACKGROUND: Determining predictive biomarkers for immune checkpoint inhibitors (ICIs) is a current challenge in oncology. Previous studies on non-small cell lung cancer (NSCLC) have shown how TP53 gene mutations are correlated with different responses to ICIs. Strong and diffuse immuno-expression of p53 by immunohistochemistry (IHC) is interpreted as a likely indicator of a TP53 gene mutation. We aimed to assess the p53 protein expression via IHC in NSCLC as a predictive biomarker of the response to ICIs. METHODS: This was a retrospective hospital-based study of patients with NSCLC treated with Nivolumab in the University Hospital of Salamanca. All diagnostic biopsies were studied via IHC (measuring p53 protein expression, peroxidase anti-peroxidase immunohistochemistry technique using Leica BOND Polymer development kits). Survival analysis was performed by subgroups of expression of p53 and other factors using the Kaplan-Meier estimator and Cox proportional-hazards model. RESULTS: Seventy-three patients were included (59 men and 14 women). The median age was 68 (44-84) years. Thirty-six biopsies were adenocarcinoma, 34 were squamous, and three were undifferentiated. In 41 biopsies (56.2%), the cellular expression of p53 was <5% (Group A), and in 32 biopsies (43.8%), the expression was ≥5% (Group B). In the general analysis, no differences were observed in overall survival (OS) (A: 12 months vs B: 20 months; p = 0.070) or progression-free survival (PFS) (A: 4 m vs B: 7 m; p = 0.064). Significant differences were observed in adenocarcinomas for both OS (A: 8 m vs B: median not reached; p = 0.002) and PFS (A: 3 m vs 8 m; p = 0.013). No differences in PFS and OS were observed in squamous cell carcinoma. Significant differences were observed in OS in the PD-L1 negative group (0% expression) (A: 13 m vs B: 39 m; p = 0.024), but not in PFS (A: 3 m vs B: 7 m; p = 0.70). No differences were observed in the PD-L1 positive group. CONCLUSIONS: A trend toward a greater response to ICIs was observed in the PFS and OS of patients with high expression of p53 by IHC (TP53 mutation), especially in the PD-L1 negative adenocarcinoma subgroup. These results will make it possible to make future modifications to the clinical guidelines of NSCLC according to the expression of p53.

Resistance to Immune Checkpoint Inhibitors Secondary to Myeloid-Derived Suppressor Cells: A New Therapeutic Targeting of Haematological Malignancies.

Myeloid-derived suppressor cells (MDSCs) are a set of immature myeloid lineage cells that include macrophages, granulocytes, and dendritic cell precursors. This subpopulation has been described in relation to the tumour processes at different levels, including resistance to immunotherapy, such as immune checkpoint inhibitors (ICIs). Currently, multiple studies at the preclinical and clinical levels seek to use this cell population for the treatment of different haematological neoplasms, together with ICIs. This review addresses the different points in ongoing studies of MDSCs and ICIs in haematological malignancies and their future significance in routine clinical practice.

Redefining synchronous colorectal cancers based on tumor clonality.

To analyze the possible clonal origin of a part of Synchronous colorectal cancer (SCRC), we studied 104 paired-SCRCs from 52 consecutive patients without hereditary forms of CRC. We used a Single-Nucleotide Polymorphism array to characterize the genomic profiles, and subsequently used a statistical application to define them according to clonality within the same individual. We categorized the ensuing groups according to colonic location to identify differential phenotypes. The SCRC Monoclonal group (M) (19 cases) was divided into Monosegmental (MM) and Pancolonic (MP) groups. The SCRC Polyclonal group (P) (33 cases) was also divided into Monosegmental (PM) and Pancolonic (PP), the first exhibiting preference for left colon. The MM group showed a high rate of mucinous tumors, the lowest mean-number of tumors and associated-polyps, and the worst prognosis. The MP group included the largest mean-number of associated-polyps, best prognosis and familial cancer component. The PM group seemed to be a "frontier" group. Finally, the PP group also exhibited a mucin component, the highest mean-number of tumors (4.6) compared with the mean-number of polyps (7.7), poor prognosis and sporadic cases. Most relevant differential genomic regions within M groups were gains on 1q24 and 8q24, and deletions on 1p21 and 1p23 for MM, while within P were the gains on 7q36 and deletions on 1p36 for PM. The statistical application employed seems to define clonality more accurately in SCRC -more likely to be polyclonal in origin-, and together with the tumor locations, helped us to configure a classification with prognostic and clinical value.

Correction: Study of Association between Pre-Senile Cataracts and the Polymorphisms rs2228000 in XPC and rs1042522 in p53 in Spanish Population.

[This corrects the article DOI: 10.1371/journal.pone.0156317.].

Toward a Molecular Classification of Synchronous Colorectal Cancer: Clinical and Molecular Characterization.

BACKGROUND: Two or more primary colorectal tumors coexisting at the time of diagnosis are considered to be synchronous tumors. It is estimated that synchronous colorectal cancer (SCRC) only accounts for 1.1% to 8.1% of all colorectal cancers (CRCs), and its molecular basis is still poorly understood. PATIENTS AND METHODS: We evaluated the microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP) statuses in a series of 49 patients (98 tumors) diagnosed with sporadic SCRC at the 12 de Octubre University Hospital with the aim of improving the molecular characterization of this type of tumor. We considered Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis (MAP) as exclusion criteria. RESULTS: Molecular subgrouping on the basis of MSI and CIMP enabled us to define 4 groups that corresponded to the molecular classification proposed for single-tumor CRC. We observed a significant predominance of MSI tumors at the right side regardless of the methylation pattern, and a significant prevalence of microsatellite-stable tumors either at the left side or throughout the entire colon (P = .026). Furthermore, we defined some molecular features frequently observed in sporadic SCRC such as a low-frequency of MSI (8.2%). We observed a high concordance in terms of MSI between simultaneous tumors (93.9%) and a lower concordance in terms of CIMP (51%) between such tumors. CONCLUSION: Our findings support the hypothesis that SCRC involves an environmental rather than a genetic component in which various etiologic factors might modify tumor progression. Further studies are required to refine the molecular characterization of SCRC.

Characterization of a new duplicate delta-opioid receptor from zebrafish.

A new full-length cDNA (ZFOR4) that encodes an opioid receptor has been isolated from the teleost zebrafish. The encoded polypeptide is 375 amino acids long and shows high sequence similarity to other delta-opioid receptors, including ZFOR1, the other delta-opioid receptor from zebrafish previously characterized by us. In situ hybridization studies have revealed that ZFOR4 mRNA is highly expressed in particular brain areas that coincide with the expression of the delta-opioid receptor in other species. Pharmacological analysis of ZFOR4 shows specific and saturable binding with [(3)H] diprenorphine, displaying one binding site with K(D) = 3.42 +/- 0.38 nM and a receptor density of 6231 +/- 335 fmol/mg protein. Competition-binding experiments were performed using [(3)H]diprenorphine and several unlabelled ligands (peptidic and non-peptidic). The order of affinity obtained is Met-enkephalin>Naloxone>Leu-enkephalin>Dynorphin A>>BW373U86>Morphine>>>> [D-Pen(2),D-Pen(5)]-Enkephalin, U69,593. [(35)S]GTPgammaS stimulation studies show that the endogenous ligands Met- and Leu-enkephalin and the non-peptidic delta agonist BW373U86 were able to fully activate ZFOR4. Our results prove the existence of two functional duplicate genes of the delta-opioid receptor in the teleost zebrafish.

Single-nucleotide polymorphisms in the promoter region of the PARKIN gene and Parkinson's disease.

Mutations in the PARKIN gene have been identified in families with recessively inherited Parkinson disease (PD). Common DNA-polymorphisms at the PARKIN gene could contribute to the risk for PD in the general population. Here we searched for DNA-polymorphisms in the PARKIN promoter. We found two single nucleotide polymorphisms (-324 A/G and -797 A/G). In order to analyse the association of PD with these and two previously described polymorphisms (1281 G/A, Asp394Asn, and 601 G/A, Ser167Asn) we genotyped 105 patients and 150 healthy controls. Allele and genotype frequencies for the four polymorphisms did not differ between patients and controls, or between patients with an early-onset (< or =40 years; n = 20) and a late-onset (>40 years; n = 85). According to our data, the genetic variation at the PARKIN gene (including promoter polymorphisms) did not contribute to the risk of developing PD in the general population.