Prognostic and Predictive Value of Immunoscore in Stage III Colorectal Cancer: Pooled Analysis of Cases From the SCOT and IDEA-HORG Studies.

Purpose: Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials.

Methods: Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing.

Immunoscore immune checkpoint using spatial quantitative analysis of CD8 and PD-L1 markers is predictive of the efficacy of anti- PD1/PD-L1 immunotherapy in non-small cell lung cancer.

Background: Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking.

Methods: Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic test, was used on 471 routine single FFPE-slides, and the duplex-immunohistochemistry CD8 and PD-L1 staining was quantified using digital-pathology.

Dissecting tumor lymphocyte infiltration to predict benefit from immune-checkpoint inhibitors in metastatic colorectal cancer: lessons from the AtezoT RIBE study.

Background: Tumor immune cells influence the efficacy of immune-checkpoint inhibitors (ICIs) and many efforts aim at identifying features of tumor immune microenvironment able to predict benefit from ICIs in proficient mismatch repair (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

Methods: We characterized tumor immune cell infiltrate, by assessing tumor-infiltrating lymphocytes (TILs), Immunoscore, Immunoscore-IC, and programmed death ligand-1 (PD-L1) expression in tumor samples of patients with mCRC enrolled in the AtezoTRIBE study, a phase II randomized trial comparing FOLFOXIRI/bevacizumab/atezolizumab to FOLFOXIRI/bevacizumab, with the aim of evaluating the prognostic and predictive value of these features.

Results: Out of 218 patients enrolled, 181 (83%), 77 (35%), 157 (72%) and 162 (74%) specimens were successfully tested for TILs, Immunoscore, Immunoscore-IC and PD-L1 expression, respectively, and 69 (38%), 45 (58%), 50 (32%) and 21 (13%) tumors were classified as TILs-high, Immunoscore-high, Immunoscore-IC-high and PD-L1-high, respectively.

An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer.

Purpose: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC.

Prognostic and predictive value of Immunoscore and its correlation with ctDNA in stage II colorectal cancer.

This study aimed to validate the prognostic value of Immunoscore (IS) in stage II colorectal cancer (CRC), and explore the roles of IS and circulating tumor DNA (ctDNA) in the adjuvant treatment for early-stage CRC. Resected tumor samples from stage II CRC patients were collected from the Sun Yat-sen University Cancer Center. The densities of CD3+ and CD8+ lymphocytes were quantified and converted to IS and classified into Low, Intermediate (Int), and High groups according to predefined cutoffs.

Immunoscore Is Prognostic in Low-Risk and High-Risk Stage III Colon Carcinomas Treated With Adjuvant Infusional Fluorouracil, Leucovorin, and Oxaliplatin in a Phase III Trial.

Purpose: The recommended duration of adjuvant fluoropyrimidine and oxaliplatin chemotherapy for patients with stage III colon cancer is based on tumor classification into clinically low-risk (T N) and high-risk (T or N) groups. We determined whether Immunoscore can enhance prognostication within these risk groups.

Materials And Methods: Patients with stage III colon carcinomas (N = 600) were randomly selected from the infusional fluorouracil, leucovorin, and oxaliplatin arm of adjuvant trial NCCTG N0147 (Alliance for Clinical Trials in Oncology).

Upfront FOLFOXIRI plus bevacizumab with or without atezolizumab in the treatment of patients with metastatic colorectal cancer (AtezoTRIBE): a multicentre, open-label, randomised, controlled, phase 2 trial.

Background: Immune checkpoint inhibitors have not shown clinical benefit to patients with metastatic colorectal cancer who had proficient mismatch repair (pMMR) or microsatellite stable (MSS) tumours in previous studies. Both an active combination chemotherapy (FOLFOXIRI; fluorouracil, leucovorin, oxaliplatin, and irinotecan) and bevacizumab seem able to increase the immunogenicity of pMMR or MSS tumours. We aimed to provide preliminary evidence of benefit from the addition of the anti-PD-L1 agent atezolizumab to first-line FOLFOXIRI plus bevacizumab in patients with metastatic colorectal cancer.

Comparison of Immune Response Assessment in Colon Cancer by Immunoscore (Automated Digital Pathology) and Pathologist Visual Scoring.

Adjunction of immune response into the TNM classification system improves the prediction of colon cancer (CC) prognosis. However, immune response measurements have not been used as robust biomarkers of pathology in clinical practice until the introduction of Immunoscore (IS), a standardized assay based on automated artificial intelligence assisted digital pathology. The strong prognostic impact of the immune response, as assessed by IS, has been widely validated and IS can help to refine treatment decision making in early CC.

Impact of Immunoscore on the Management of Stage II Colon Cancer Patients: A Physician Survey.

Background: Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it.

The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival.

(1) Background-The five-year overall survival (OS) of muscle-invasive bladder cancer (MIBC) with neoadjuvant chemotherapy and cystectomy is around 50%. There is no validated biomarker to guide the treatment decision. We investigated whether the Immunoscore (IS) could predict the pathologic response to neoadjuvant chemotherapy and survival outcomes.

A new sensitive PCR assay for one-step detection of 12 IDH1/2 mutations in glioma.

Introduction: Mutations in isocitrate dehydrogenase genes IDH1 or IDH2 are frequent in glioma, and IDH mutation status is a strong diagnostic and prognostic marker. Current IDH mutation screening is performed with an immunohistochemistry (IHC) assay specific for IDH1 R132H, the most common mutation. Sequencing is recommended as a second-step test for IHC-negative or -equivocal cases.

Genomic Grade Index (GGI): feasibility in routine practice and impact on treatment decisions in early breast cancer.

Purpose: Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations.

Methods: Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium.

[Amyotrophic lateral sclerosis, a disease with a complex diagnosis].

Amyotrophic lateral sclerosis is a degenerative disease with no known cause, no specific presenting symptoms and which results in incapacity and disability. Diagnosis is often delayed. Multi-disciplinary care is essential.

BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance.

Hereditary breast cancers are frequently caused by germline BRCA1 mutations. The BRCA1(C61G) mutation in the BRCA1 RING domain is a common pathogenic missense variant, which reduces BRCA1/BARD1 heterodimerization and abrogates its ubiquitin ligase activity. To investigate the role of BRCA1 RING function in tumor suppression and therapy response, we introduced the Brca1(C61G) mutation in a conditional mouse model for BRCA1-associated breast cancer.

Transient ischaemic attack mimics revealing focal subarachnoid haemorrhage.

We describe here 7 elderly patients with a transient neurological deficit due to a focal subarachnoid haemorrhage, identified from the Dijon Stroke Registry over 4 years. These 7 patients presented a clinical pattern marked by focal paraesthesia, with several stereotyped focal episodes (5 of the 7 cases), lasting less than 30 min (6 of the 7 cases), and associated with a cognitive decline (4 of the 7 cases). Headache was present in only 1 case.

Trends in incidence, risk factors, and survival in symptomatic lacunar stroke in Dijon, France, from 1989 to 2006: a population-based study.

Background And Purpose: Lacunar infarcts are usually regarded as benign stroke, but population-based studies are required to assess the exact place of this stroke subtype in cerebrovascular pathology.

Methods: We evaluated trends in incidence rates, risk factor profiles, and survival rates in symptomatic lacunar stroke from a prospective population-based registry from 1989 to 2006.

Results: We recorded 2536 ischemic strokes.

A short region of the promoter of the breast cancer associated PLU-1 gene can regulate transcription in vitro and in vivo.

The recently cloned gene PLU-1 shows restricted expression in adult tissues, with high expression being found in testis, and transiently in the pregnant mammary gland. However, both the gene and the protein product are specifically up-regulated in breast cancer. To investigate the control of expression of the PLU-1 gene, we have cloned and functionally characterised the 5' flanking region of the gene, which was found to contain another putative gene.

Brca1 expression is regulated by a bidirectional promoter that is shared by the Nbr1 gene in mouse.

The lack of functionally disrupting mutations of BRCA1 in sporadic breast tumours has suggested that other mechanisms, including dysregulation of gene expression, might be important in tumour development. We have analysed the control of expression of murine Brca1 and the adjacent gene, Nbr1, which lie head-to-head and are separated by less than 300 bp. Our results show that the expression of these two genes is under complex regulation, through a bidirectional promoter.

BRCA1 methylation: a significant role in tumour development?

Cancer is a multistep process resulting from an accumulation of genetic mutations leading to dysfunction of critical genes, including tumour suppressor genes. Epigenetic changes are now also recognised as an important alternative mechanism of gene inactivation. In particular, aberrant methylation of the promoter region of a gene can lead to silencing ultimately contributing to the initiation or malignant progression of tumours.

Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: Identification of a novel deletion consistent with BRCA1:psiBRCA1 recombination.

Inherited susceptibility to breast cancer results from germline mutations in one of a number of genes including BRCA1. A significant number of BRCA1-linked familial breast cancer patients, however, have no detectable BRCA1 mutation. This could be due in part to the inability of commonly used mutation-detection techniques to identify mutations outside the BRCA1 coding region.