Characterisation of clinico-pathological features and immune microenvironment of colorectal liver metastases

Surgical resection of colorectal liver metastases (CRLM) is the first choice of treatment when possible, aims to maximize patient survival and represents the only hope for a cure. In the last few years, the introduction of new molecules for neoadjuvant chemotherapy has made it possible to reduce tumour size to allow for a surgical resection, which may not otherwise have been feasible. Nonetheless, metastatic colorectal cancer continues to have a poor prognosis. In this thesis we undertook an in-depth analysis of the pathological characterization of CRLM to understand which parameters influence prognosis in a retrospective and in a prospective cohort of patients resected for CRLM. Then we explored the possible role of morphological heterogeneity of the pathological features regarding outcome. Our investigations demonstrated the clinical relevance of a complete pathological evaluation of all CRLM to stratify patient prognosis after surgery and attempted to provide another piece in the puzzle to understand tumoural heterogeneity and its possible influence on disease outcome.(MED - Sciences médicales) -- UCL, 202

Nodular regenerative hyperplasia of the liver : An insight into the epidemiology and the clinical characteristics of a rare and poorly understood entity.

INTRODUCTION: Recently, the Vascular Liver Disease Interest Group (VALDIG) proposed the new term porto-sinusoidal vascular disorder to include different conditions sharing three specific histological lesions: obliterative portal venopathy, incomplete septal cirrhosis and nodular regenerative hyperplasia (NRH). However, little is known about the clinical significance of these lesions as well as the outcome of these patients. [...

Evaluation of the correlation between KRAS mutated allele frequency and pathologist tumorous nuclei percentage assessment in colorectal cancer suggests a role for zygosity status

Evaluation of molecular tumour heterogeneity relies on the tumorous nuclei percentage (TNP) assessment by a pathologist, which has been criticised for being inaccurate and suffering from interobserver variability. Based on the 'Big Bang theory' which states that KRAS mutation in colorectal cancer is mostly homogeneous, we investigated this issue by performing a critical analysis of the correlation of the KRAS mutant allele fraction with the TNP in 99 colorectal tumour samples with a positive KRAS mutation status as determined by next-generation sequencing. Our results yield indirect evidence that the KRAS zygosity status influences the correlation between these parameters and we show that a well-trained pathologist is indeed capable of accurately assessing TNP. Our findings indicate that tumour zygosity, a feature which has largely been neglected until now, should be taken into account in future studies on (colorectal) molecular tumour heterogeneit

Immunity to live: an immunopathoscore using the consensus Immunoscore to best define the risk of recurrence and death in stage IV metastatic patients.

The consensus Immunoscore is a routine assay quantifying the adaptive immune response within the tumor microenvironment. Its evaluation in the primary tumor of patients with stages I/II/III colorectal cancer (CRC) has prognostic value that has been confirmed in multiple studies. For metastatic patients, the evaluation of the consensus Immunoscore within resected metastases also significantly predicts the recurrence and survival of Stage IV patients. Since recurrence rates post-surgery are still very high, it is important to best evaluate risk parameters using the main patho-molecular and immune parameters. After preoperative treatment and curative resection of 582 metastases from 221 patients, clinico-pathological parameters, mutation, and Immunoscore within metastases were assessed. Immunoscore and clinico-pathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariable analysis. A Pathological Score (PS) that combines relevant clinico-pathological factors for relapse and Immunoscore was significantly ( < .0001) associated with Time to recurrence. In multivariable analysis, only Immunoscore ( < .001) and mutations (= .03) were prognostic and significantly associated with overall survival. Thus, among all parameters clinically relevant in the metastatic settings, PS and Immunoscore allow the stratification of stage IV CRC patients and identify patients with higher risk of recurrence. Immunoscore remained the major prognostic factor for overall survival (OS). In its latest edition, the WHO classification of Digestive System Tumors introduced for the first time the immune response as an essential and desirable diagnostic criterion for CRC. These novel results highlight the clinical utility of Immunoscore in Stage IV patients

Calcific Degeneration of CorMatrix 4 Years After Bicuspidization of Unicuspid Aortic Valve.

We report the long-term outcomes of a 12-year-old boy who underwent bicuspidization of a severely stenotic unicuspid aortic valve with CorMatrix small intestinal submucosal extracellular matrix (CorMatrix Cardiovascular, Roswell, GA). CorMatrix supported favorable immediate surgical and echocardiographic outcomes and maintained stable growing functional dynamics for 2 years. At 52.5 months in situ, however, the valve failed with severe calcification, fibrosis, and retraction necessitating a redo operation. Reconstructive operations with CorMatrix are feasible, but this result questions its capacity for constructive remodeling in left-sided valve repair

The role of the pathologist and clinical implications in colorectal liver metastasis.

Colorectal liver metastases (CRLM) affect about 50% of colorectal cancer patients. With the improvement of neoadjuvant chemotherapy and the introduction of targeted therapy, resectability of CRLM and survival rates have improved over time. However, 60-70% of patients still recur. Several pathological and molecular parameters have been described as prognostic factors after CRLM resection. These parameters encompass not only tumoral features, but also non-tumoral ones, such as chemotherapy related liver injury, or factors related to tumour environment, namely Immunoscore. This review summarizes these prognostic indicators to clarify which patho-molecular parameters should be addressed in the pathological report

Hypoxia-inducible factor 2 alpha impairs human cytotrophoblast syncytialization: new insights in placental dysfunction and fetal growth restriction

Insufficient remodeling of uterine arteries causes pregnancy-related diseases, including fetal growth restriction and preeclampsia. In these situations, reduced maternal blood flow in the placenta is thought to be responsible for the persistence of a low oxygen environment throughout pregnancy. We hypothesized that a chronic activation of transcription factors hypoxia-inducible factors (HIFs) actively participate in placental underdevelopment, which impairs fetal growth. The computer-assisted analysis in pathological placentas revealed an increased number of HIF-2α-positive nuclei in the syncytium compared to normal human placentas, while HIF-1α stabilization was unchanged. Specific involvement of HIF-2α was confirmed in primary human cytotrophoblasts rendered deficient for HIF1A or HIF2A. Silencing HIF2A increased the expression of main syncytialization markers as well as differentiation and syncytium formation. It also improved placental growth factor bioavailability. None of these changes was seen when silencing HIF1A. Conversely, the experimental induction of HIF-2α expression repressed forskolin-induced differentiation in BeWo choriocarcinoma cells. Our mechanistic insights evidence that transcription factor HIF-2α impairs placental function, thus suggesting its participation in fetal growth restriction when placentas become chronically hypoxic. Furthermore, it suggests the possibility to develop novel molecular targeting therapies for placental dysfunction