Adhesion of B16 malignant melanoma cells to the endothelium and to subendothelia matrix components

During the haematogenous spread of tumours, the metastasizing cells must arrest within the blood vessels of the organs they colonize. There is still much debate upon the mechanism of such arrest, whether it is due to mechanical trapping or, more specifically, to adhesion of the tumour cells to the blood vessel wall. This work demonstrates that tumour cells are capable of adhering to blood vessel wall components. According to the hypothesis of specific adhesion, it is thought that metastasizing tumour cells would only come into contact with the vessel wall for a very short time and therefore their adhesion to the vessel wall must be extremely rapid. It has been shown in the past that tumour cells can adhere rapidly to components of the blood vessel wall such as exposed sub-endothelial matrix. Adhesion to endothelial cells was believed to occur at a much slower rate and therefore the involvement of the endothelium during the arrest phase of the metastatic process was thought to be marginal. The experiments carried out during this study show that, in vitro, tumour cells do adhere to the endothelium at a rate comparable to that for isolated components of the sub-endothelial matrix. Furthermore, this work provides some evidence that the molecular basis for such rapid adhesion to the endothelium may be different from the ones involved in the adhesion to known components of the sub-endothelial matrix

Mechanisms of ST-segment elevation myocardial infarction in patients with atrial fibrillation, prior stenting and long-standing chronic coronary syndrome

Background: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) and chronic coronary syndromes beyond 1 year after percutaneous coronary intervention (PCI) is a matter of debate. For these patients, guidelines recommend oral anticoagulation (OAC) alone, but the risk of thrombotic complications remains a concern. The aim of this study was to characterize the incidence, presentation and use of antithrombotic therapy in patients with AF, prior stenting > 12 months and new ST-segment elevation myocardial infarction (STEMI). Methods: Consecutive patients were selected from an institutional registry over a 3-year period if they matched the following criteria: 1) STEMI undergoing primary PCI; 2) AF; 3) chronic coronary syndrome with prior stenting > 12 months. Results: Among 852 consecutive STEMI patients undergoing primary PCI, the prevalence of AF was 4.1%, and 6 (0.9%) patients met all the inclusion criteria. Substantial heterogeneity in antithrombotic treatment for these patients was noted (e.g., OAC alone, OAC plus a single antiplatelet agent, no antithrombotic therapy). In 50% of patients, the STEMI episode was linked to a previously stented lesion or documented plaque. Conclusions: This case review illustrates the wide heterogeneity in antithrombotic pharmacotherapy among AF patients presenting with STEMI > 12 months after PCI. The underlying reason for STEMI is only partly related to disease progression or stent-related events. This finding suggests that multiple mechanisms of recurrence may be advocated, and are not only limited to antithrombotic therapy but may be explained by the natural history of coronary artery disease in remote vessels

Inter- and Intra-Observer Agreement of PD-L1 SP142 Scoring in Breast Carcinoma:A Large Multi-Institutional International Study

The assessment of PD-L1 expression in TNBC is a prerequisite for selecting patients for immunotherapy. The accurate assessment of PD-L1 is pivotal, but the data suggest poor reproducibility. A total of 100 core biopsies were stained using the VENTANA Roche SP142 assay, scanned and scored by 12 pathologists. Absolute agreement, consensus scoring, Cohen's Kappa and intraclass correlation coefficient (ICC) were assessed. A second scoring round after a washout period to assess intra-observer agreement was carried out. Absolute agreement occurred in 52% and 60% of cases in the first and second round, respectively. Overall agreement was substantial (Kappa 0.654-0.655) and higher for expert pathologists, particularly on scoring TNBC (6.00 vs. 0.568 in the second round). The intra-observer agreement was substantial to almost perfect (Kappa: 0.667-0.956), regardless of PD-L1 scoring experience. The expert scorers were more concordant in evaluating staining percentage compared with the non-experienced scorers (R2 = 0.920 vs. 0.890). Discordance predominantly occurred in low-expressing cases around the 1% value. Some technical reasons contributed to the discordance. The study shows reassuringly strong inter- and intra-observer concordance among pathologists in PD-L1 scoring. A proportion of low-expressors remain challenging to assess, and these would benefit from addressing the technical issues, testing a different sample and/or referring for expert opinions

Mechanisms of ST-segment elevation myocardial infarction in patients with atrial fibrillation, prior stenting and long-standing chronic coronary syndrome

Background: The optimal antithrombotic regimen for patients with atrial fibrillation (AF) and chronic coronary syndromes beyond 1 year after percutaneous coronary intervention (PCI) is a matter of debate. For these patients, guidelines recommend oral anticoagulation (OAC) alone, but the risk of thrombotic complications remains a concern. The aim of this study was to characterize the incidence, presentation and use of antithrombotic therapy in patients with AF, prior stenting > 12 months and new ST-segment elevation myocardial infarction (STEMI). Methods: Consecutive patients were selected from an institutional registry over a 3-year period if they matched the following criteria: 1) STEMI undergoing primary PCI; 2) AF; 3) chronic coronary syndrome with prior stenting > 12 months. Results: Among 852 consecutive STEMI patients undergoing primary PCI, the prevalence of AF was 4.1%, and 6 (0.9%) patients met all the inclusion criteria. Substantial heterogeneity in antithrombotic treatment for these patients was noted (e.g., OAC alone, OAC plus a single antiplatelet agent, no antithrombotic therapy). In 50% of patients, the STEMI episode was linked to a previously stented lesion or documented plaque. Conclusions: This case review illustrates the wide heterogeneity in antithrombotic pharmacotherapy among AF patients presenting with STEMI > 12 months after PCI. The underlying reason for STEMI is only partly related to disease progression or stent-related events. This finding suggests that multiple mechanisms of recurrence may be advocated, and are not only limited to antithrombotic therapy but may be explained by the natural history of coronary artery disease in remote vessels

Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours

The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS