Study of the PD-L1 expression, T-cells density and immunoscore in paired baseline tumor biopsies and surgical specimens in squamous cell carcinoma of the oral cavity.

OBJECTIVES: Primary objective was to evaluate the correlation between immune marker expression in baseline tumor biopsies and their respective surgical specimens in squamous cell carcinoma of the oral cavity (OCSCC). Secondary objective was to assess the impact of these markers on overall (OS) and disease-free survival (DFS). MATERIALS AND METHODS: Patients with a histological diagnosis of oral squamous cell carcinoma treated surgically between 2012 and 2020 were included in this retrospective, translational monocentric study. The expression of PD-L1, T-cells markers and an OCSCC-adapted immunoscore were evaluated by multiplex immunohistochemistry. RESULTS: One hundred and four patients (mean: 58 years) were included. Seventy patients had paired samples available. Poor correlation was highlighted for PD-L1-positive surface expression (r = 0.29) and combined positive score (CPS). For CPS ≥ 20 and CPS ≥ 1, correlation coefficient r was 0.24 and 0.46 respectively. T-cells density showed also poor correlation with a r of 0.57 and 0.31 for CD3 and CD8 T-cells, respectively. Univariate survival analyses showed significant better OS and DFS (P < 0.05) for patients with stage III-IV OCSCC with a high compared to a low immunoscore, based on surgical samples only. CONCLUSION: Our study showed poor correlation in PD-L1 expression, CPS, T-cells density and immunoscore between baseline tumor biopsies and surgical resection specimens. In addition, the immunoscore may emerge as a potential prognostic factor in advanced squamous cell carcinoma of the oral cavity. If surgical specimens are available, they may be of interest for clinical practice decision.

Digital Pathology for Better Clinical Practice.

(1) Background: Digital pathology (DP) is transforming the landscape of clinical practice, offering a revolutionary approach to traditional pathology analysis and diagnosis. (2) Methods: This innovative technology involves the digitization of traditional glass slides which enables pathologists to access, analyze, and share high-resolution whole-slide images (WSI) of tissue specimens in a digital format. By integrating cutting-edge imaging technology with advanced software, DP promises to enhance clinical practice in numerous ways. DP not only improves quality assurance and standardization but also allows remote collaboration among experts for a more accurate diagnosis. Artificial intelligence (AI) in pathology significantly improves cancer diagnosis, classification, and prognosis by automating various tasks. It also enhances the spatial analysis of tumor microenvironment (TME) and enables the discovery of new biomarkers, advancing their translation for therapeutic applications. (3) Results: The AI-driven immune assays, Immunoscore (IS) and Immunoscore-Immune Checkpoint (IS-IC), have emerged as powerful tools for improving cancer diagnosis, prognosis, and treatment selection by assessing the tumor immune contexture in cancer patients. Digital IS quantitative assessment performed on hematoxylin-eosin (H&E) and CD3+/CD8+ stained slides from colon cancer patients has proven to be more reproducible, concordant, and reliable than expert pathologists' evaluation of immune response. Outperforming traditional staging systems, IS demonstrated robust potential to enhance treatment efficiency in clinical practice, ultimately advancing cancer patient care. Certainly, addressing the challenges DP has encountered is essential to ensure its successful integration into clinical guidelines and its implementation into clinical use. (4) Conclusion: The ongoing progress in DP holds the potential to revolutionize pathology practices, emphasizing the need to incorporate powerful AI technologies, including IS, into clinical settings to enhance personalized cancer therapy.

Association of Serum Levels and Immunohistochemical Labelling of Des-Gamma-Carboxy-Prothrombin in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

Hepatocellular cancer (HCC) is one of the main reasons for liver transplantation (LT). Biomarkers, such as alpha-foetoprotein (AFP) and Des-gamma-carboxy-prothrombin (DCP), can be helpful in defining the recurrence risk post LT. This study aims to evaluate the association between the intensity of DCP immunohistochemical labelling and serum DCP levels in patients undergoing LT for HCC. We carried out a prospective monocentric study including patients who all underwent LT for cirrhosis between 2016 and 2018 and all fell under the Milan criteria. The accepted diagnostic criteria for HCC were contrast-enhanced imaging and histology. Thirty-nine patients were followed for a median of 21 months, with HCC lesions categorized into negative, focally positive, and diffusely positive groups based on DCP immunohistochemistry. The serum DCP levels were significantly higher in the positive groups (258 mAU/mL for the focally and 257 mAU/mL for the diffusely positive) than in the negative group (48 mAU/mL) (p = 0.005) at diagnosis and at the time of liver transplantation (220 mAU/mL for the diffuse positive group). Microvascular invasion (58.8% vs. 19.0% for the diffusely positive and negative groups, respectively, p < 0.001) and lesion size (20 mm in the diffusely labelled group versus 12 mm in the other groups, p = 0.002) were significantly correlated with DCP labelling. Late recurrence occurred only in the positive groups; in the negative group, it occurred within the first 3 months after transplantation. DCP labelling in liver lesions correlates with serum levels and a more aggressive tumour profile. Further investigation is needed to determine if highly DCP-labelled tumours allow for the better selection of high-risk patients before LT.

Definitions of Histological Abnormalities in Inflammatory Bowel Disease: an ECCO Position Paper.

Histological assessment of endoscopic biopsies in inflammatory bowel disease [IBD] plays an important role in clinical management, investigative studies, and clinical trials. Scoring schemes consisting of multiple histological items and offering considerable precision are widely available. However, definitions of histological abnormalities are often inconsistent. Furthermore, interobserver variability for their recognition and assessment may be high. The European Crohn's and Colitis Organisation [ECCO] formed an expert panel to explore definitions of histological abnormalities in IBD, with the aim of improving the quality of diagnosis and facilitating development of scoring schemes. The process confirmed that the current definitions often have no evidence base and vary between sources. Using available evidence and expert knowledge, the panel produced a series of ECCO consensus position statements on histological features in IBD.

Multi-Institutional Evaluation of Pathologists' Assessment Compared to Immunoscore.

BACKGROUND: The Immunoscore (IS) is a quantitative digital pathology assay that evaluates the immune response in cancer patients. This study reports on the reproducibility of pathologists' visual assessment of CD3+- and CD8+-stained colon tumors, compared to IS quantification. METHODS: An international group of expert pathologists evaluated 540 images from 270 randomly selected colon cancer (CC) cases. Concordance between pathologists' T-score, corresponding hematoxylin-eosin (H&E) slides, and the digital IS was evaluated for two- and three-category IS. RESULTS: Non-concordant T-scores were reported in more than 92% of cases. Disagreement between semi-quantitative visual assessment of T-score and the reference IS was observed in 91% and 96% of cases before and after training, respectively. Statistical analyses showed that the concordance index between pathologists and the digital IS was weak in two- and three-category IS, respectively. After training, 42% of cases had a change in T-score, but no improvement was observed with a Kappa of 0.465 and 0.374. For the 20% of patients around the cut points, no concordance was observed between pathologists and digital pathology analysis in both two- and three-category IS, before or after training (all Kappa < 0.12). CONCLUSIONS: The standardized IS assay outperformed expert pathologists' T-score evaluation in the clinical setting. This study demonstrates that digital pathology, in particular digital IS, represents a novel generation of immune pathology tools for reproducible and quantitative assessment of tumor-infiltrated immune cell subtypes.

Tumor Microenvironment Modifications Induced by Afatinib in Squamous Cell Carcinoma of the Head and Neck: A Window-of-Opportunity Study (EORTC-90111-24111).

PURPOSE: The EORTC-90111-24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies. PATIENTS AND METHODS: Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study. RESULTS: IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls. CONCLUSIONS: Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.

Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia.

BACKGROUND: The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis. METHODS: AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells. RESULTS: AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020). CONCLUSIONS: With this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context.

Specific HIF-2α (Hypoxia-Inducible Factor-2) Inhibitor PT2385 Mitigates Placental Dysfunction In Vitro and in a Rat Model of Preeclampsia (RUPP).

BACKGROUND: Preeclampsia is one of the leading causes of maternal mortality worldwide and is strongly associated with long-term morbidity in mothers and newborns. Referred to as one of the deep placentation disorders, insufficient remodeling of the spiral arteries during the first trimester remains a major cause of placental dysfunction. Persisting pulsatile uterine blood flow causes abnormal ischemia/reoxygenation phenomenon in the placenta and stabilizes the HIF-2α (hypoxia-inducible factor-2α) in the cytotrophoblasts. HIF-2α signaling impairs trophoblast differentiation and increases sFLT-1 (soluble fms-like tyrosine kinase-1) secretion, which reduces fetal growth and causes maternal symptoms. This study aims to evaluate the benefits of using PT2385-an oral specific HIF-2α inhibitor-to treat severe placental dysfunction. METHODS: To evaluate its therapeutic potential, PT2385 was first studied in primary human cytotrophoblasts isolated from term placenta and exposed to 2.5% O2 to stabilize HIF-2α. Viability and luciferase assays, RNA sequencing, and immunostaining were used to analyze differentiation and angiogenic factor balance. The ability of PT2385 to mitigate maternal manifestations of preeclampsia was studied in the selective reduced uterine perfusion pressure model performed in Sprague-Dawley rats. RESULTS: In vitro, RNA sequencing analysis and conventional techniques showed that treated cytotrophoblast displayed an enhanced differentiation into syncytiotrophoblasts and normalized angiogenic factor secretion compared with vehicle-treated cells. In the selective reduced uterine perfusion pressure model, PT2385 efficiently decreased sFLT-1 production, thus preventing the onset of hypertension and proteinuria in pregnant dams. CONCLUSIONS: These results highlight HIF-2α as a new player in our understanding of placental dysfunction and support the use of PT2385 to treat severe preeclampsia in humans.

A pregnant patient with ALK-positive non-small cell lung cancer treated with alectinib: A case report and review of the literature.

Oncogenic rearrangements in the anaplastic lymphoma kinase (ALK) gene account for 5% of non-small cell lung cancer (NSCLC) cases. ALK inhibitors have markedly improved the outcome of metastatic ALK-positive NSCLC (ALK+ mNSCLC) by increasing long-term overall survival. Although a diagnosis of NSCLC during pregnancy or the peripartum period is rare, ALK+ NSCLC accounts for 38% of NSCLC cases in women of childbearing age (18-45 years old). The younger age and prolonged survival of patients with ALK+ mNSCLC bring new challenges for lung cancer and obstetrics research, and raises questions related to pregnancy and family planning. The present study described normal fetal development and no obstetric complications in a patient infected with HIV diagnosed with ALK+ mNSCLC, who became pregnant during treatment with alectinib, a third-generation ALK inhibitor.

Akkermansia muciniphila Reduces Peritonitis and Improves Intestinal Tissue Wound Healing after a Colonic Transmural Defect by a MyD88-Dependent Mechanism.

Anastomotic leakage is a major complication following colorectal surgery leading to peritonitis, complications, and mortality. Akkermansia muciniphila has shown beneficial effects on the gut barrier function. Whether A. muciniphila reduces peritonitis and mortality during colonic leakage is unknown. Whether A. muciniphila can directly modulate the expression of genes in the colonic mucosa in humans has never been studied. We investigated the effects of a pretreatment (14 days) with live A. muciniphila prior to surgical colonic perforation on peritonitis, mortality, and wound healing. We used mice with an inducible intestinal-epithelial-cell-specific deletion of MyD88 (IEC-MyD88 KO) to investigate the role of the innate immune system in this context. In a proof-of-concept pilot study, healthy humans were exposed to A. muciniphila for 2 h and colonic biopsies taken before and after colonic instillation for transcriptomic analysis. Seven days after colonic perforation, A.-muciniphila-treated mice had significantly lower mortality and severity of peritonitis. This effect was associated with significant improvements of wound histological healing scores, higher production of IL22, but no changes in the mucus layer thickness or genes involved in cell renewal, proliferation, or differentiation. All these effects were abolished in IEC-MyD88 KO mice. Finally, human subjects exposed to A. muciniphila exhibited an increased level of the bacterium at the mucus level 2 h after instillation and significant changes in the expression of different genes involved in the regulation of cell cycling, gene transcription, immunity, and inflammation in their colonic mucosa. A. muciniphila improves wound healing during transmural colonic wall defect through mechanisms possibly involving IL22 signaling and requiring MyD88 in the intestinal cells. In healthy humans, colonic administration of A. muciniphila is well tolerated and changes the expression of genes involved in the immune pathways.

Prevalence and characteristics of cystic fibrosis liver disease: a study highlighting the lack of histological diagnosis.

BACKGROUND AND AIMS: Cystic fibrosis liver disease (CFLD) is the third leading cause of death in patients with cystic fibrosis (CF). We aim to determine the prevalence of CFLD in a cohort of adult patients with CF and to characterise liver involvement in this population highlighting the importance of histological diagnosis. METHODS: We retrospectively studied a cohort of patients with CF. Inclusion criteria were age ≥ 18 and minimum 1 year of follow-up. We excluded lung transplant patients. CFLD was defined as having 2 out of 3 criteria: persistent elevation of transaminases and/or gamma-glutamyltransferase; abnormal ultrasound; and abnormal transient elastography. Non-invasive fibrosis biomarkers were calculated in CFLD patients. Adult-onset CFLD (Ad-CFLD) was defined as CFLD ≥18 years. Severe CFLD (s-CFLD) was defined as CFLD with cirrhosis and/or portal hypertension. RESULTS: We included 113 patients. Median age was 29 years, 58 were male. Forty patients had CFLD. Median age at CFLD diagnosis was 10 years. Twenty-one patients had s-CFLD. Two s-CFLD patients had nodular regenerative hyperplasia, 1 had hepatocellular carcinoma and 4 underwent liver transplantation. Six patients had ad-CFLD. Both CFLD and s-CFLD groups were compared to a non-CFLD group. The CFLD group had significantly more males (p = 0.034). S-CFLD group had worse pulmonary function (p = 0.015). CONCLUSION: Thirty five percent of adult patients with CF, mainly males, had CFLD. Nineteen percent had s-CFLD and had worse pulmonary function. With recent reports unravelling different pathophysiological mechanisms in CFLD, we believe it is important to better characterise liver involvement using liver biopsy.

Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).

Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.

Is ABO-Incompatible Living Donor Liver Transplantation Really a Good Alternative for Pediatric Recipients?

BACKGROUND: ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been proposed to compensate for donor shortage. To date, few studies have reported detailed ABOi LDLT results in large series of pediatric patients. C4d complement deposition in graft capillaries has been reported to be associated with antibody-mediated rejection in solid organ transplantation. METHODS: A retrospective case-control study was conducted, comparing clinical outcomes of each of 34 consecutive pediatric ABOi LDLT recipients with those of 2 non-ABOi pairs (n = 68), matched according to pre-transplant diagnostic criteria, age, and date of transplantation. In addition, we studied the C4d immunostaining pattern in 22 ABOi and in 36 non-ABOi recipients whose liver biopsy was performed within the first 4 post-transplant weeks for suspected acute rejection. RESULTS: The incidence of biliary complications was higher in ABOi recipients (p < 0.05), as were the incidence of acute humoral rejection (p < 0.01) and the incidence of retransplantation (p < 0.05). All children who required retransplantation were older than 1 year at the time of ABOi LDLT. Positive C4d immunostaining was observed in 13/22 (59%) ABOi recipients versus 3/36 (8.3%) non-ABOi recipients (p < 0.0001). CONCLUSIONS: ABOi LDLT is a feasible option for pediatric end-stage liver disease but carries increased risks for the recipient, especially for children older than 1 year, even with a specific preparation protocol. C4d immunostaining may be a hallmark of acute humoral rejection in ABOi liver transplantation.

Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore.

Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the main patho-molecular and immune parameters of all surgical specimens. Two hundred twenty-one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan-Meier method and compared by log-rank tests. Cox proportional hazard models were used for uni- and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2-year TTR rate PS 0-1: 49.8.% (95% CI: 42.2-58.8) versus PS 2-4: 20.9% (95% CI: 13.4-32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82-3.53), p < 0.0000; and 2-year TTR rate I 0: 25.7% (95% CI: 16.3-40.5) versus I 3-4: 60% (95% CI: 47.2-76.3), HR = 2.87 (95% CI: 1.73-4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR [I 3-4 versus I 0] = 4.25, 95% CI: 1.95-9.23; p = 0.0001). Immunoscore (HR [I 3-4 versus I 0] = 0.27, 95% CI: 0.12-0.58; p = 0.0009) and RAS mutation (HR [mutated versus WT] = 1.66, 95% CI: 1.06-2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.

The real incidence of biliary tract complications after adult liver transplantation: the role of the prospective routine use of cholangiography during post-transplant follow-up.

Biliary tract complications (BTCs) still burden liver transplantation (LT). The wide reporting variability highlights the absence of systematic screening. From 2000 to 2009, simultaneous liver biopsy and direct biliary visualization were prospectively performed in 242 recipients at 3 and 6 months (n = 212, 87.6%) or earlier when indicated (n = 30, 12.4%). Median follow-up was 148 (107-182) months. Seven patients (2.9%) experienced postprocedural morbidity. BTCs were initially diagnosed in 76 (31.4%) patients; 32 (42.1%) had neither clinical nor biological abnormalities. Acute cellular rejection (ACR) was present in 27 (11.2%) patients and in 6 (22.2%) BTC patients. Nine (3.7%) patients with normal initial cholangiography developed BTCs after 60 (30-135) months post-LT. BTCs directly lead to 7 (2.9%) re-transplantations and 14 (5.8%) deaths resulting in 18 (7.4%) allograft losses. Bile duct proliferation at 12-month biopsy proved an independent risk factor for graft loss (P = 0.005). Systematic biliary tract and allograft evaluation allows the incidence and extent of biliary lesions to be documented more precisely and to avoid erroneous treatment of ACR. The combination 'abnormal biliary tract-canalicular proliferation' is an indicator of worse graft outcome. BTCs are responsible for important delayed allograft and patient losses. These results underline the importance of life-long follow-up and appropriate timing for re-transplantation.

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, RAS 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 (P < .0001) associated with Time to recurrence. In multivariable analysis, only Immunoscore (P < .001) and RAS mutations (P= .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.

Hypoxia-inducible factor 2 alpha impairs human cytotrophoblast syncytialization: New insights into 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 chronic activation of transcription factors hypoxia-inducible factors (HIFs) actively participates 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 and preeclampsia when placentas become chronically hypoxic. Furthermore, it suggests the possibility to develop novel molecular targeting therapies for placental dysfunction.