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Over the last decade, Hippo signaling has emerged as a major tumor-suppressing pathway. Its dysregulation is associated with abnormal expression of YAP1 and TEAD -family genes. Recent works have highlighted the role of YAP1/TEAD activity in several cancers and its potential therapeutic implications. Therefore, identifying patients with a dysregulated Hippo pathway is key to enhancing treatment impact. Although recent studies have derived RNA-seq-based signatures, there remains a need for a reproducible and cost-effective method to measure the pathway activation. In recent years, deep learning applied to histology slides have emerged as an effective way to predict molecular information from a data modality available in clinical routine. Here, we trained models to predict YAP1/TEAD activity from H&E-stained histology slides in multiple cancers. The robustness of our approach was assessed in seven independent validation cohorts. Finally, we showed that histological markers of disease aggressiveness were associated with dysfunctional Hippo signaling., Competing Interests: The authors declare the following competing interests. B.S., V.C., O.D.D, J.E.L.D., A.H., R.B., C.M., A.R., E.D., K.V.L. and E.P. are employed by Owkin, Inc.; E.R., I.V., L.D., E.D.R., F.N., E.S., V.F., M.Cl. and M.Ce. are employed by Sanofi. H.P. received research funds from Owkin for RNA extraction and demographic data. M.E.: Personal fees, travel costs and speaker's honoraria from MSD, AstraZeneca, Janssen-Cilag, Cepheid, Roche, Astellas, Diaceutics, Owkin, BMS; research funding from AstraZeneca, Janssen-Cilag, STRATIFYER, Cepheid, Roche, Gilead, Owkin; advisory role for Diaceutics, MSD, AstraZeneca, Janssen-Cilag, GenomicHealth, Owkin, BMS. A.S.: Honoraria for advisory boards from Amgen, AstraZeneca, Boehringer Ingelheim, Ipsen, Janssen, Lilly, MSD, Pfizer, Roche, Takeda; consulting: AstraZeneca, BMS, Daiichi Sankyo, Janssen, Roche; symposiums: Amgen, AstraZeneca, BMS, Janssen, Pfizer, Sanofi, Takeda; congress: Janssen, Pfizer, Takeda. S.L.: Honoraria for advisory boards from Janssen, MSD, Sanofi, Abbvie; symposiums: MSD, Janssen. N.G.: Honoraria and/or consulting fees from Abbvie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Janssen, Lilly, Mirati, MSD, Novartis, Pfizer, Roche, Sanofi, Takeda, and received grants from MSD and AstraZeneca paid to institution outside of the present work. E.S. holds a patent for the TEAD500 signature (WO2023180385A1)., (© 2024 The Author(s).)

Significance: Novel individual biomarkers are needed to guide therapeutic decisions for patients with head and neck cancer. We report for the first time, granulomas of TREM2-expressing multinucleated giant macrophages in keratin-rich tumor niches, as a biomarker of favorable prognosis and developed a deep-learning model to automate its quantification on routinely stained pathological slides., (©2024 The Authors; Published by the American Association for Cancer Research.)

Motivation: Spatial transcriptomics allow to quantify mRNA expression within the spatial context. Nonetheless, in-depth analysis of spatial transcriptomics data remains challenging and difficult to scale due to the number of methods and libraries required for that purpose., Results: Here we present SpatialOne, an end-to-end pipeline designed to simplify the analysis of 10x Visium data by combining multiple state-of-the-art computational methods to segment, deconvolve, and quantify spatial information; this approach streamlines the analysis of reproducible spatial-data at scale., Availability and Implementation: SpatialOne source code and execution examples are available at https://github.com/Sanofi-Public/spatialone-pipeline, experimental data is available at https://zenodo.org/records/12605154. SpatialOne is distributed as a docker container image., (© The Author(s) 2024. Published by Oxford University Press.)

Background: France has the sixth highest incidence of oropharyngeal cancer (OPC) in Europe, but the epidemiological impact of high-risk HPV (HR-HPV) remains poorly documented. The objective of our study was to assess the proportion of OPCs caused by HR-HPV in Paris, and its suburbs, over the four past decades. This area accounts for almost one-fifth of the total population of France., Methods: OPCs diagnosed in 1981, 1986, 1991, 1996, 2001, 2006, 2011, 2016 and 2020/2021 in two of the main referral cancer centers for HNCs in Paris and its suburbs were retrieved from the tumor biobanks. HPV status was determined by p16-staining and HPV-DNA detection. Samples were considered HPV-driven if both assays were positive. Results were compared to the French cancer registry data., Results: Samples from 697 OPC patients were assessed (including 82 % of all samples diagnosed in 2001, 2006, 2011, 2016, 2021). The proportion of HPV-driven cases rose from 2.7 % to 53 % between 1981 and 2021. HPV16 was the dominant genotype during the study period. Of patients with HPV-driven OPC, 81 % were male and 42 % were smokers versus 80 % and 92 % in their HPV-negative counterparts. The age of OPC patients increased significantly, during the study period, independent of their HPV status CONCLUSION: The proportion of HPV-driven OPCs has significantly increased in Paris and its suburbs, during the last four decades. OPCs has become the 2nd predominant type of head and neck cancer, in France. This may be linked to the rise in HPV-driven cases and the decrease of tobacco and alcohol consumption in men., Competing Interests: Declaration of Competing Interest The authors have nothing to disclose, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Rare cancers constitute less than 10% of head and neck cancers and lack sufficient evidence for standardized care. The French Rare Head and Neck Cancer Expert Network (REFCOR) as established a national database to collect data on these rare cancers. This study aims to describe patient and tumour characteristics in this database., Methods: Prospective data collection was conducted across multiple centers. Survival analyses were performed using Kaplan Meier method and Log Rank test. Odds ratios were used for comparing proportions., Results: A total of 7208 patients were included over a period of 10 years. The most frequent histologies were: Not Otherwise Specified (NOS) adenocarcinoma 13 %, adenoid cystic carcinoma 12 %, squamous cell carcinoma of rare locations 10 %, mucoepidermoid carcinoma 9 %, intestinal-type adenocarcinoma (8 %). Tumours were located in sinonasal area (38 %); salivary glands (32 %); oral cavity / oropharynx / nasopharynx (16 %); larynx / hypopharynx (3 %); ears (1 %); others (3 %). Tumours were predominantly classified as T4 (23 %), N0 (54 %), and M0 (62 %). Primary treatment approach involved tumour resection (78 %) and / or radiotherapy (63 %). Patients with salivary gland cancers exhibited better 5-year overall survival (OS) rates (p < 0.05), and lower recurrence rates compared to patients with sinonasal, laryngeal/ hypopharyngeal cancers. No significant differences were observed in the other comparisons. Acinar cell carcinoma demonstrated the best OS while mucous melanoma had the poorest prognosis., Conclusion: Melanoma, carcinoma NOS, and sinonasal undifferenciated carcinoma still have poor prognoses. Efforts are being made, including training and guidelines, to expand network coverage (REFCOR, EURACAN), improve data collection and contribute to personalized therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The immunodetection of NUT protein is a reliable tool to identify NUT carcinoma, a rare and still underdiagnosed tumor entity. The technique was implemented in 2017 in our department, a tertiary reference center with a large recruitment in all tumor types, including head and neck and thoracic tumors. We evaluated its use over a 6-year period (2017-2022) to (a) describe the indications for the technique, (b) determine the number of NUT carcinomas detected and confirmed by Fluorescence in situ hybridization, and (c) describe briefly the characteristics of these tumors. Over the study period, 382 NUT immunodetections were performed; the annual number of requests varied from 45 to 83. All 21 pathologists of the department made at least one request (range: 1 to 94; annual mean: 18.2). 54.7% of immunodetections were performed for internal cases, 37% for cases submitted for consultation, and 8.3% for cases submitted for confirmation of a suspected diagnosis. The main indications were poorly differentiated tumors of the head and neck region (39%) and the thorax (19.6%), and difficult-to-classify soft tissue tumors (11.8%). Twelve cases of NUT carcinoma were detected by immunohistochemistry and confirmed by Fluorescence in situ hybridization. Seven were from the head and neck region (4.7% of the tumors tested), 4 from lung or mediastinum (5.3%), 1 from an unknown primary at the time of diagnosis. In conclusion, the implementation of NUT immunodetection in the daily workflow of a pathology department improves the detection of NUT carcinoma. This becomes essential with the emergence of potential targeted therapies., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials., Methods: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets., Results: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8 +  T-cells (~ 40%), CD4 +  FoxP3 - T-cells (~ 40%) and CD4 +  FoxP3 +  T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4 + FoxP3 + T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3 + cells among CD4 + T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8 +  T-cells and of CD4 +  FoxP3 - T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4 +  FoxP3 +  T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels., Conclusions: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type., (© 2023. The Author(s).)

Objectives: Chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) are frequent coexisting conditions and share type 2 inflammatory pathophysiology, with interleukin (IL)-4 and IL-13 as key cytokines. Dupilumab is a monoclonal antibody that blocks the shared receptor for IL-4 and IL-13. The objective of this analysis was to evaluate dupilumab's effect on type 2 inflammation biomarkers in patients with CRSwNP with/without coexisting asthma or NSAID-ERD from the SINUS-52 (NCT02898454) study., Methods: Patients received treatment with dupilumab or placebo for 52 weeks. Blood and urinary biomarkers were evaluated through 52 weeks, and nasal secretions and mucosa brushings through 24 weeks., Results: Of 447 patients, 60% had coexisting asthma and 27% had coexisting NSAID-ERD. At baseline, blood eotaxin-3, eosinophils, and periostin, nasal secretion eotaxin-3, and urinary leukotriene E 4 were significantly higher in patients with coexisting NSAID-ERD than without. Dupilumab reduced eotaxin-3, thymus and activation-regulated chemokine, periostin, and total immunoglobulin E in blood, eotaxin-3, periostin, IL-5, and eosinophil cationic protein in nasal secretions, and leukotriene E 4 in urine. Reductions were generally similar or greater in the subgroups with asthma and NSAID-ERD than without. Dupilumab also reduced MUC5AC and mast cell counts in nasal mucosa brushings., Conclusion: Dupilumab reduced local and systemic type 2 inflammatory biomarkers in patients with CRSwNP, including mast cells in nasal mucosa and cysteinyl leukotrienes in urine. These findings provide insight into the processes driving CRSwNP and the mechanisms of dupilumab's therapeutic effects., Clinical Trial Registry Name: SINUS-52 https://www.clinicaltrials.gov/ct2/show/NCT02898454., Clinicaltrials.gov Identifier: NCT02898454., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C Bachert reports advisory board fees from ALK, ASIT Biotech, AstraZeneca, GlaxoSmithKline, Intrexon Actobiotics, Novartis, Sanofi, and Stallergenes Greer. TM Laidlaw reports advisory board fees from GlaxoSmithKline, Novartis, Regeneron Pharmaceuticals Inc., and Sanofi. SH Cho reports research grants from National Institutes of Health, Regeneron Pharmaceuticals Inc., and Sanofi. J Mullol has received speaker fees from GlaxoSmithKline, Menarini, Merck Sharp & Dohme, Mylan-Meda Pharmaceuticals (Viatris), Novartis, Regeneron Pharmaceuticals Inc., Sanofi, UCB Pharma, and Uriach; clinical trial funding from Genentech-Roche, Regeneron Pharmaceuticals Inc., and Sanofi; research grants from Mylan-Meda Pharmaceuticals (Viatris) and Uriach; and advisory board fees from Genentech-Roche, Mylan-Meda Pharmaceuticals (Viatris), Novartis, Regeneron Pharmaceuticals Inc., Sanofi, and Uriach. S Naimi, A Jagerschmidt, E Laws, A Praestgaard, and LP Mannent are employees and may hold stock and/or stock options in Sanofi. BN Swanson and M Classe are former employees and may hold stock and/or stock options in Sanofi. S Harel, M Ruddy, and N Amin are former employees and may hold stock and/or stock options in Regeneron Pharmaceuticals Inc.

Locally advanced cervical cancer (LACC) and anal and oropharyngeal squamous cell carcinoma (ASCC and OPSCC) are mostly caused by oncogenic human papillomaviruses (HPV). In this paper, we developed machine learning (ML) models based on clinical, biological, and radiomic features extracted from pre-treatment fluorine-18-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET) images to predict the survival of patients with HPV-induced cancers. For this purpose, cohorts from five institutions were used: two cohorts of patients treated for LACC including 104 patients from Gustave Roussy Campus Cancer (Center 1) and 90 patients from Leeds Teaching Hospitals NHS Trust (Center 2), two datasets of patients treated for ASCC composed of 66 patients from Institut du Cancer de Montpellier (Center 3) and 67 patients from Oslo University Hospital (Center 4), and one dataset of 45 OPSCC patients from the University Hospital of Zurich (Center 5). Radiomic features were extracted from baseline [18F]-FDG PET images. The ComBat technique was applied to mitigate intra-scanner variability. A modified consensus nested cross-validation for feature selection and hyperparameter tuning was applied on four ML models to predict progression-free survival (PFS) and overall survival (OS) using harmonized imaging features and/or clinical and biological variables as inputs. Each model was trained and optimized on Center 1 and Center 3 cohorts and tested on Center 2, Center 4, and Center 5 cohorts. The radiomic-based CoxNet model achieved C-index values of 0.75 and 0.78 for PFS and 0.76, 0.74, and 0.75 for OS on the test sets. Radiomic feature-based models had superior performance compared to the bioclinical ones, and combining radiomic and bioclinical variables did not improve the performances. Metabolic tumor volume (MTV)-based models obtained lower C-index values for a majority of the tested configurations but quite equivalent performance in terms of time-dependent AUCs (td-AUC). The results demonstrate the possibility of identifying common PET-based image signatures for predicting the response of patients with induced HPV pathology, validated on multi-center multiconstructor data., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Acinic cell carcinomas (AciCCs) are malignant tumours of the salivary glands. The aim of this work was to analyse data from the national REFCOR multicenter cohort (i) to investigate the prognostic factors influencing survival outcomes in AciCC, (ii) to assess the impact on survival of postoperative radiotherapy (RT) in patients treated for AciCC without high-grade transformation and (iii) to explore the prognostic impact of prophylactic neck dissection (ND) in patients treated for AciCC of the major salivary glands., Patients and Methods: Data from all the patients treated for salivary AciCC between 2009 and 2020 were extracted from the REFCOR database. Survival outcomes and prognostic factors influencing Disease-Free Survival (DFS) and Overall Survival (OS) were investigated using univariate and multivariate analyses. Propensity score matching was used to assess the impact of postoperative RT and prophylactic ND on DFS., Results: A total of 187 patients were included. After a median follow-up of 53 months, their 5-year OS and DFS rates were 92.8% and 76.2%, respectively. In multivariate analysis, male sex, older age, higher T and N status, and high grade were independently associated with a worse DFS. In the subpopulation analysed after propensity score matching, patients with cN0 AciCC without high-grade transformation who were treated by surgery and RT did not have an improved DFS compared to patients who were treated by surgery alone (hazard ratio (HR) = 0.87, p = 0.8). Factors associated with nodal invasion were T3-T4 status and intermediate/high histological grade. After propensity score matching, prophylactic ND was associated with a trend toward a better DFS (HR = 0.46, p = 0.16)., Conclusions: These results suggest that (i) long-term follow-up (>5 years) should be considered in patients with AciCC, (ii) treatment by surgery alone could be an option in selected cN0 patients with AciCC without high-grade transformation and (iii) prophylactic ND may be considered preferentially in patients with T3-T4 status and/or intermediate/high histological grade., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The objective of our study was to investigate changes over the past decade in patient age and the prevalence of HPV in the population of patients with oropharyngeal carcinoma (OPC) treated at our center., Methods: We performed a retrospective cohort study of patients treated at our cancer center for OPC between 2011 and 2021. Tissue biopsies were assessed for HPV status based on p16 staining for all patients., Results: There were 1,365 treated patients. The proportion of p16-positive patients increased from 43% in 2011 to 57.3% in 2021 (p = 0.01). The sex ratio was 3.6 M/1F for p16-positive and 3.7 M/1F for p16-negative patients (p = 0.94). The mean age increased from 60.2 y in 2011 to 63.6 y in 2021. The mean ages were 61.9 y for p16-positive and 61.7 y for p16-negative patients (p = 0.71), but there was a broader age distribution for the p16-positive patients (p = 0.03). The proportion of patients older than 70 y increased from 11% in 2011 to 28.2% in 2021, and this aging was similar between p16-positive (30.7% in 2021) and p16-negative (26.3% in 2021) patients. The 2-year and 5-year OS rates were 73.7% and 56.5% for the entire cohort. p16-positive patients had 2-year and 5-year OS rates of 86.8% and 77.4%, respectively, whereas p16-negative patients had 2-year and 5-year OS rates of 63.9% and 40.5%., Conclusions: Assessment of the change over the past decade in the population of patients with OPC at our center showed that HPV-positive OPC now appear to have overtaken HPV-negative cases in France, with 57.3% in 2021, and showed significant aging, with almost thirty percent of patients now older than 70 years. Those combined changes emphasize some of the challenges to be addressed in future OPC management., (© 2022. The Author(s).)

Objectives: Our objective was to develop a predictive model using a machine learning signature to identify patients at high risk of relapse or death after treatment for HPV-positive oropharyngeal carcinoma., Materials and Methods: Pre-treatment variables of 450 patients with HPV-positive oropharyngeal carcinoma treated with a curative intent comprised clinical items, imaging parameters and histological findings. The events considered were progression or residual disease after treatment, the recurrent disease after a disease-free interval and death. The endpoints were the prediction of events and progression-free survival. After feature Z-score normalisation and selection, random forest classifier models were trained. The best models were evaluated on recall, the F-score, and the ROC AUC metric. The clinical relevance of the best prediction model was evaluated using Kaplan-Meier analysis with a log-rank test., Results: The best random forest model predicted the 5-year risk of relapse-free survival with a recall of 79.1%, an F1-score of 81.08%, and an AUC of the ROC curve of 0.89. The models performed poorly for the prediction of specific events of progression only, recurrence only or death only. The clinical relevance of the model was validated with a 5-year relapse-free survival of high-risk patients versus low-risk patients of 23.5% and 80%, respectively (p < 0.0001)., Conclusion: Patients with HPV-driven oropharyngeal carcinoma at high risk of relapse-free survival could be identified with a predictive machine learning model using patient data before treatment., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Sinonasal squamous cell carcinoma (SNSCC) is a rare and aggressive malignancy with poor prognosis. Human papilloma virus (HPV) can induce SNSCC although its incidence and impact on patients’ outcomes remains unclear. We performed a retrospective cohort study of patients with SNSCC treated consecutively in a comprehensive cancer center. HPV status was determined with p16 immunohistochemistry followed by RNA in situ hybridization (RNAscope). The incidence, clinical characteristics, and oncologic outcomes of HPV+SNSCC were assessed. P16 prognostic value was evaluated. Fifty-nine patients were included. Eleven (18.6%) SNSCC were p16+ with five (8.4%) doubtful cases. RNAscope was positive in nine cases (15.2%). Patients with HPV+SNSCC were younger (p = 0.0298) with a primary tumor originating mainly in nasal fossa (p < 10−4). Pathologic findings were not different according to HPV status. Among patients who were curatively treated, overall survival was better for HPV+SNSCC (p = 0.022). No prognostic value of p16 expression was reported. Patients with HPV+SNSCC have better oncologic outcomes, probably due to earlier tumor stage with primary location predominantly in the nasal fossa, a more suitable epicenter to perform a surgical resection with clear margins. P16 expression seems not to be a good surrogate of HPV status in SNSCC.

Background and Purpose: There have been no studies to date of patterns of events after oropharyngeal squamous cell carcinoma (OPC) treatment comprising disease progression immediately after treatment or after a disease-free interval (DFI), and causes of death, according to HPV status., Materials and Methods: Patients with a T1-4, N0-3, M0 OPC who completed treatment in a curative intent at our center between 2011 and 2020 were analyzed. A DFI was defined as the absence of the disease confirmed by both physical and radiological evaluation., Results: We analyzed 888 patients, of who 451 were p16-positive and 437 were p16-negative. The 5-year survival rates were 82.4% vs. 44%, respectively (p < 0.0001, HR 0.24). The rates of disease progression at the end of the treatment without a DFI were 7.8% vs. 21.1% in the p16-positive vs. the p16-negative patients (p < 0.0001, OR 0.38). The 5-year competing risks of disease recurrence after a DFI were 5.6% vs. 20.5%, respectively (p < 0.0001, HR 0.26). Patients who were p16-positive had a lower risk of death from OPC disease (p < 0.0001, HR 0.23). The 5-year competing risks of a second primary cancer during follow-up were 16.1% vs. 49.9% (p = 0.0002) in the p16-positive vs. the p16- negative patients. Patients who were p16-positive had a lower risk of death from intercurrent causes (p < 0.0001, HR 0.17)., Conclusion: Clinical trials and medical interventions dedicated to each category of events and causes of death are needed to improve survival in HPV-positive and HPV-negative OPC patients., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Transforming growth factor-beta (TGFβ) can limit the efficacy of cancer treatments, including radiotherapy (RT), by inducing an immunosuppressive tumor environment. The association of TGFβ with impaired T cell infiltration and antitumor immunity is known, but the mechanisms by which TGFβ participates in immune cell exclusion and limits the efficacy of antitumor therapies warrant further investigations., Methods: We used the clinically relevant TGFβ receptor 2 (TGFβR2)-neutralizing antibody MT1 and the small molecule TGFβR1 inhibitor LY3200882 and evaluated their efficacy in combination with RT against murine orthotopic models of head and neck and lung cancer., Results: We demonstrated that TGFβ pathway inhibition strongly increased the efficacy of RT. TGFβR2 antibody upregulated interferon beta expression in tumor-associated macrophages within the irradiated tumors and favored T cell infiltration at the periphery and within the core of the tumor lesions. We highlighted that both the antitumor efficacy and the increased lymphocyte infiltration observed with the combination of MT1 and RT were dependent on type I interferon signaling., Conclusions: These data shed new light on the role of TGFβ in limiting the efficacy of RT, identifying a novel mechanism involving the inhibition of macrophage-derived type I interferon production, and fostering the use of TGFβR inhibition in combination with RT in therapeutic strategies for the management of head and neck and lung cancer., Competing Interests: Competing interests: PH, ED and MM declare funding from Eli Lilly for this work. LM, CC, ED, LM and MM declare grants from Roche Genentech, Servier, AstraZeneca, Merck Serono, Bristol-Myers Squibb, Boehringer Ingelheim, AC Biosciences and MSD outside the submitted work. ED declares personal fees from Roche Genentech, AstraZeneca, MSD, AMGEN, Accuray and Boehringer Ingelheim outside the submitted work. ED declares shared patents with NH-Theraguix and Clevexel., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe coronavirus disease 2019 (COVID-19). Recently, early clinical data reported the feasibility of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown., Methods and Materials: Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and toll-like receptor (TLR)-3 stimulation in human lung macrophages., Results: Low doses of RT (0.5-1 Gray) decreased LPS-induced pneumonia, and increased the percentage of nerve- and airway-associated macrophages producing interleukin (IL) 10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses of RT increased IL-10 production by infiltrating immune cells into the lung. Irradiation of TLR-3 ligand-stimulated human lung macrophages ex vivo increased IL-10 secretion and decreased interferon γ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased., Conclusions: Our data highlight a mechanism by which low doses of RT regulate lung inflammation and skew lung macrophages toward an anti-inflammatory profile. These data provide a preclinical mechanistic support to clinical trials evaluating low doses of RT, such as COVID-19-induced ARDS., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Pathology is the cornerstone of cancer care. Pathomics, which represents the use of artificial intelligence in digital pathology, is an emerging and promising field that will revolutionize medical and surgical pathology in the coming years. This review provides an overview of pathomics, its current and future applications and its most relevant applications in Head and Neck cancer care., Recent Findings: The number of studies investigating the use of artificial intelligence in pathology is rapidly growing, especially as the utilization of deep learning has shown great potential with Whole Slide Images. Even though numerous steps still remain before its clinical use, Pathomics has been used for varied applications comprising of computer-assisted diagnosis, molecular anomalies prediction, tumor microenvironment and biomarker identification as well as prognosis evaluation. The majority of studies were performed on the most frequent cancers, notably breast, prostate, and lung. Interesting results were also found in Head and Neck cancers., Summary: Even if its use in Head and Neck cancer care is still low, Pathomics is a powerful tool to improve diagnosis, identify prognostic factors and new biomarkers. Important challenges lie ahead before its use in a clinical practice, notably the lack of information on how AI makes its decisions, the slow deployment of digital pathology, and the need for extensively validated data in order to obtain authorities approval. Regardless, pathomics will most likely improve pathology in general, including Head and Neck cancer care in the coming years., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Olfactory neuroblastomas (ONBs) are rare malignant tumours that arise in the nasal vault. To date, the Hyams grade remains the only widely used histological grading system. However, it is based only on morphological criteria, and has not been updated since 1988. The objective of this study was to explore the prognostic potential of the Ki67 proliferation index (PI) and tumour-infiltrating lymphocytes (TILs) in ONB., Methods and Results: A retrospective study was conducted on a bicentric series of 45 cases. The Ki67 PI was determined by counting at least 1000 nuclei on whole slides. TILs were evaluated with CD20, CD4 and CD8 immunohistochemical markers on whole slides. In this series, Hyams grades I, II, III and IV accounted for 13.4%, 44.4%, 20% and 22.2% of all cases, respectively. The Ki67 PI ranged from 1 to 93; the Ki67 PI was significantly higher in Hyams grade III-IV ONBs than in Hyams grade I-II ONBs (P < 0.0001). A Ki67 PI of ≥25 was associated with poorer survival (P = 0.02). TILs were present in both stromal and intratumoral compartments, but were located predominantly in the stromal component of the tumour. The numbers of intratumoral CD8+ cells/mm 2 and CD4+ cells/mm 2 were greater in high-grade ONBs than in low-grade ONBs (P = 0.0015 and P = 0.043, respectively). The numbers of T cells/mm 2 and B cells/mm 2 were not associated with survival, but a CD4/CD8 ratio of >2 was significantly associated with shorter survival (P = 0.04)., Conclusion: Our findings suggest that the Ki67 PI and TILs could be used as prognostic markers, as a potential alternative to the Hyams grade., (© 2019 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Purpose of Review: Salivary gland carcinomas (SGCs) are rare tumors of the head and neck with a wide diversity of histologic subtypes characterized by specific morphological, immunohistochemical, and genetic features as well as particular clinical behavior. Chemotherapy is employed almost exclusively with a palliative aim in patients with metastatic and/or recurrent disease and has demonstrated poor activity., Recent Findings: Important advances have been made in the understanding of the molecular pathogenesis of SGCs. Recent studies using next-generation sequencing and genomic and expression profiling methods have identified several genomic alterations of potential clinical significance. We discuss here the recent and most important advances in SGCs biomarkers and their clinical implication. Last years, immune checkpoint inhibitors (ICIs) have changed the landscape of oncology. We report here the few available data in SGCs., Summary: A strategy based on molecular screening and targeted therapy seems to be the best approach for treating patients with SGCs, in the future. More data on ICI's efficacy and biomarkers of response are required to define the place of immunotherapy in the management of SGCs.

Background: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked, and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear., Methods: In order to elucidate potential mechanisms leading to CRS in humans, we have established a type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. The sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs)., Results: After 22 weeks, a typical type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased, and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired., Conclusion: Our mouse model of CRS displayed an allergic response to HDM + SEB administration, including the type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although the sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia., (© 2018 The Authors. Allergy Published by John Wiley & Sons Ltd.)

Esthesioneuroblastoma (ENB) is a rare cancer of the olfactory mucosa, with no established molecular stratification to date. We report similarities of ENB with tumors arising in the neural crest and perform integrative analysis of these tumors. We propose a molecular-based subtype classification of ENB as basal or neural, both of which have distinct pathological, transcriptomic, proteomic, and immune features. Among the basal subtype, we uncovered an IDH2 R172 mutant-enriched subgroup (∼35%) harboring a CpG island methylator phenotype reminiscent of IDH2 mutant gliomas. Compared with the basal ENB methylome, the neural ENB methylome shows genome-wide reprogramming with loss of DNA methylation at the enhancers of axonal guidance genes. Our study reveals insights into the molecular pathogenesis of ENB and provides classification information of potential therapeutic relevance., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sinonasal epithelial hamartomas occurring in adults are classified as seromucinous hamartoma (SMH) or respiratory epithelial adenomatoid hamartoma (REAH). We describe herein a novel subtype of adult sinonasal hamartoma that contains olfactory epithelium, a histologic feature not previously reported in the literature. Our pathology department database was retrospectively searched for sinonasal hamartomas containing areas of olfactory epithelium. Six relevant cases (3 male and 3 female patients; age, 30 to 77 y) were retrieved, and available pathology slides and clinical and imaging data from patient charts were reviewed. Five of the lesions were unilateral solitary, polypoid, pedunculated masses, 38 to 80 mm in length, lodged in the nasal olfactory cleft. The sixth lesion was associated with bilateral nasal polyposis, and its precise localization was not known. All patients were treated by transnasal endoscopic surgery. None of the 3 patients who had received adequate follow-up evaluation exhibited recurrence. Histologically, all lesions resembled SMH or REAH, with areas of olfactory epithelium comprising olfactory receptors and sustentacular and basal cells. Olfactory epithelium was observed at the lesion surface or in invaginated gland-like structures, and it contained focal aggregates of filamentous cell processes. Some olfactory receptor cells or cell processes were also present in the seromucinous gland component of lesions. Olfactory receptor cells expressed CD56 (neural cell adhesion molecule), and the filamentous aggregates contained CD56, neurofilaments, and synaptophysin. Aside from SMH and REAH, we have described a third subtype of adult sinonasal hamartoma-olfactory epithelial hamartoma-which shares the benign character of the other 2.

Aims: Translocation renal cell carcinoma (tRCC) is a rare subtype of kidney tumour characterized by translocations involving the transcription factor TFE3 or TFEB. tRCC was introduced into the World Health Organization classification in 2004, but much is still unknown about the natural history, clinicopathological features and outcomes of the disease. The aim of this study was to describe the landscape of fusion transcript in a large single-institution series of fluorescence in-situ hybridization (FISH)-confirmed tRCCs and then to compare it to morphological and clinical data., Methods and Results: Paired-end RNA sequencing was performed within a prospective database of the Department of Pathology, Centre Hospitalier Régional Universitaire (Lille, France). The diagnosis of tRCC was confirmed by FISH. Among a total of 1130 identified renal cell carcinomas, 21 cases (1.9%) showed rearrangement of the TFE3 (n = 20) or (TFEB) (n = 1) gene. Median patient age was 31 years (range = 15-47), and the female-to-male ratio was 6:1. Five different TFE3 fusion transcripts were identified; the most frequent TFE3 partners were PRCC (n = 4) and SFPQ (n = 4). The other partners involved were ASPCR1 (n = 1) and MED15 (n = 1) genes as well as a novel TFE3 partner, GRIPAP1., Conclusions: We identified a new fusion partner, GRIPAP1. The prognostic role of transcript type could not be determined because our number of cases was too small. Four patients (19%) died of the disease, all of which presented with a lymph node involvement at diagnosis. We confirm that tRCC can be an aggressive tumour, especially those of advanced clinical stage., (© 2017 John Wiley & Sons Ltd.)

Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal tumors initially described in the lung. About half of them exhibit expression of the ALK1 protein, generally resulting from a gene rearrangement. Paranasal sinus IMTs are extremely uncommon, and gene rearrangement of ALK1 is very rare in this localization. A 47-year-old woman presented with rapidly progressive vision loss in her left eye. Clinical and imaging work-up revealed a tumor invading the left ethmoidal and sphenoidal sinuses and extending into the nasal cavity, the orbit and the skull base. Complete tumor resection was performed using an endonasal approach. Pathological examination revealed a paranasal localization of IMT, positive for ALK1 immunostaining. FISH analysis showed an ALK1 gene rearrangement. This case illustrates the local aggressive potential for IMTs. Treatment is primarily surgical, but targeted therapies (crizotinib) might be a solution for ALK1 rearranged cases with a poor prognosis.

A 72-year-old woman with history of breast cancer only treated surgically was referred to our department for pulmonary hypertension (PH) suspicion. Echocardiogram revealed elevated right ventricular systolic pressure. Computed tomography (CT) angiogram showed no pulmonary embolism (PE), but lung scan revealed two ventilation-perfusion mismatch areas. Right cardiac catheterization established precapillary PH. Despite treatment with PH specific therapy (sildenafil, ambrisentan, and epoprostenol), her condition worsened rapidly with acute right heart failure (RHF). She died 22 days after admission. Post-mortem microscopic examination showed a rare combination of PH etiologies consistent with metastasis of breast cancer in pulmonary vasculature including the rare pulmonary tumour thrombotic microangiopathy (PTTM).

In this study, a possible link between the innate immune recognition receptor TLR3 and metabolic reprogramming in Head and Neck carcinoma (HNC) cells was investigated. The effects of TLR3 stimulation/knock-down were assessed under several culture conditions in 4 HNC cell-lines by cell growth assays, targeted metabolomics, and glycolysis assays based on time-resolved analysis of proton release (Seahorse analyzer). The stimulation of TLR3 by its synthetic agonist Poly(A:U) resulted in a faster growth of HNC cells under low foetal calf serum conditions. Targeted analysis of glucose metabolism pathways demonstrated a tendency towards a shift from tricarboxylic acid cycle (Krebs cycle) to glycolysis and anabolic reactions in cells treated with Poly(A:U). Glycolysis assays confirmed that TLR3 stimulation enhanced the capacity of malignant cells to switch from oxidative phosphorylation to extra-mitochondrial glycolysis. We found evidence that HIF-1α is involved in this process: addition of the TLR3 agonist resulted in a higher cell concentration of the HIF-1α protein, even in normoxia, whereas knocking-down TLR3 resulted in a lower concentration, even in hypoxia. Finally, we assessed TLR3 expression by immunohistochemistry in a series of 7 HNSCC specimens and found that TLR3 was detected at higher levels in tumors displaying a hypoxic staining pattern. Overall, our results demonstrate that TLR3 stimulation induces the Warburg effect in HNC cells in vitro, and suggest that TLR3 may play a role in tumor adaptation to hypoxia.

Background: Inverted papillomas (IP) inserted in the frontal sinus and/or recess may be treated by using an endoscopic endonasal or an external approach. There are still few data available on this uncommon localization of IPs., Objective: To report our experience in the management of IP of the frontal drainage pathway, to describe a previously unreported specific complication of this surgery, and to discuss the optimal surgical strategy., Methods: A retrospective study of the patients at a tertiary care center between 2004 and 2014 who were operated on for an IP with an insertion in the frontal recess and/or the frontal sinus. Clinical charts were reviewed for demographics, clinical presentation, imaging findings, surgical treatment, and outcome., Results: Twenty-seven patients were included. Patients were operated on by using a purely endoscopic approach (Draf procedure; n = 14 [51.9%]) when the IP was inserted in the frontal recess and/or the frontal sinus infundibulum (with a nasoseptal-septoturbinal flap placed on the exposed bone in four patients), or by using a combined endoscopic and open approach (osteoplastic flap procedure; n = 13 [48.1%]) when the IP invaded the frontal sinus beyond the infundibulum. There were two recurrences (7.4%), with a mean follow-up of 40 months (range, 9-123 months). During follow-up, single or multiple iatrogenic frontal mucoceles were observed in 10 patients (37%), with a mean delay of 60 months (range, 27-89 months). These mucoceles occurred both after using endoscopic (n = 3) or combined (n = 7) approaches, and required a surgical treatment in eight patients. No postoperative mucocele was observed in the four patients who had had a septal flap., Conclusion: In our experience, an approach based on the localization of the IP insertion provided acceptable results in terms of the local control rate (92.6%). However, the significant rate of postoperative mucoceles indicated that specific strategies (such as local flaps) still need to be developed to avoid this iatrogenic complication.

Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients.

Rhino-sinusal infections are serious diseases and possibly lethal. When they are invasive, we easily discuss apergilloses and mucormycoses. The confirmation of the diagnosis of mucormycosis need an extensive surgery for precise histopathological and mycological evaluation. The pathologist may be faced to other rare mycoses such as phaeohyphomycoses, which present different morphological features than mucormycoses and Aspergillus. Once the diagnosis is established, an appropriate antifungal treatment is quickly started. The aim of our work is to report two observations of phaeohyphomycoses, to describe their histopathological features, to discuss complementary diagnostic methods and to present the main differential diagnoses., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

We reported a rare case of cutaneous metastases of renal cell carcinoma (RCC) with an Xp11.2 translocation in a 15-year-old female. Clinicians should be aware of the possibility of this uncommon site of metastasis, which can indicate multivisceral dissemination of the disease. We discuss the feasibility and opportunity of treating such a patient with multiple line of tyrosine kinase inhibitor (TKI) targeting vascular endothelial and platelet-derived growth factor receptors., (© 2014 Wiley Periodicals, Inc.)

Background: Progressive renal-function decline caused by chronic allograft nephropathy is the main cause of long-term failure after kidney transplantation. Moreover, chronic cyclosporine (CsA)-induced nephrotoxicity is an important nonimmunologic factor contributing to graft dysfunction and loss, and adverse events may require CsA withdrawal., Methods: Tacrolimus (Tac) replaced CsA-based immunosuppression in 133 transplant patients (114 kidney, 15 kidney-pancreas, 4 pancreas after kidney) with progressive loss of renal function (71% of patients) or CsA intolerance (29% of patients) not responding to CsA dose-lowering. The primary end-points of this prospective study focusing on renal function were the safety and efficacy of Tac immunosuppression., Results: Tac was generally well tolerated but definitively withdrawn for 23 (17%) patients (21 graft failures, 1 case of diabetes, and 1 case of clinical intolerance). Differential creatinemia (creatinemia-nadir creatinemia after transplantation) decreased significantly from 85.4+/-9.8 to 39.0+/-7.5 mumol/L (P<0.001; mean+/-SEM) after 1 year and 3.6+/-18.1 mumol/L (P<0.01) after 4 years. For patients with CsA intolerance, switch to Tac improved intolerance symptoms in all cases. Blood urea, creatinine clearance, blood total cholesterol, and triglycerides improved significantly, and the percentage of hypertensive patients remained stable with no de novo hypertension. During follow-up, one patient experienced an acute rejection episode (not histologically proven), and four died. Twenty-one (16%) transplants failed, significantly more frequently in patients with advanced renal impairment before Tac (P<0.0001)., Conclusion: Switching from CsA to Tac can be an alternative strategy in kidney-transplant patients suffering from chronic allograft dysfunction or CsA toxicity. The persistently improved renal function over several months of evaluation suggests that in these patients, Tac might be less nephrotoxic than CsA and could prolong transplant function despite CsA failure.

Background: Ischemia, the main cause of ureteral necrosis in renal transplantation, cannot alone explain the late occurrence of some fistulas beyond the first postoperative month. The aim of this study, performed on a cohort of 1,629 consecutive kidney transplantations, was to analyze the risk factors implicated in the occurrence of ureteral necrosis and its impact on graft and patient survival., Methods: Between January 1990 and December 2001, 1,629 renal transplantations were performed in the authors' center. All biologic and clinical data were computerized in a cross-audited and validated data bank (Données Informatisées et Validées en Transplantation). The parameters studied were donor age, gender, cause of death and serum creatinine before procurement; and recipient age, gender, initial disease, panel reactive antibody, retransplantation, cold ischemia time, delayed graft function, human leukocyte antigen incompatibilities, induction and maintenance immunosuppression, right or left kidney, number of arteries, site of transplantation and the presence or not of a double-J stent. The follow-up parameters were the number and timing of acute rejection episodes, cytomegalovirus (CMV) infection (viremia, polymerase chain reaction), and acute pyelonephritis. Ureteral histologic analysis was performed in 25 cases (necrosis, leukocyte infiltration, and CMV or BK virus inclusions). Uni- and multivariate statistical tests were used (alpha risk at 5%). All of the patients with ureteral necrosis had undergone neoureterocystostomy or ureteral anastomosis with the native ureter but with a systematic double-J stent., Results: Ureteral necrosis occurred in 52 of the 1,629 patients (3.2%) and was significantly and independently correlated with donor age (P=0.041) and delayed graft function (P=0.016). CMV infections were also higher in the necrosis group (P=0.001), but donor CMV status was not statistically different between the two groups (36.2% vs. 36.7%). Ureteral histologic studies showed CMV and BK virus inclusions in 4 and 2 cases, respectively, and arterial and venous thrombosis in 4 and 16 cases, respectively. No pattern of ureteral rejection was observed. Ureteral necrosis did not affect the 10-year patient and graft survival, which were 87% and 66%, respectively, for the necrosis group and 86% and 58%, respectively, for the control group (P=not significant)., Conclusions: The authors' data provide new information concerning a classic surgical complication after kidney transplantation. The link they have identified between the occurrence of ureteral necrosis, donor age, and delayed graft function reemphasizes the interdependence between surgical and medical complications in kidney transplantation.

Background: The aim of the present study was to assess long-term survival of cadaveric second kidney allografts performed in our center and to determine risk factors predictive of long-term graft outcome., Methods: Of 1704 kidney transplantations performed between January 1985 and March 1998, 233 were second grafts. The majority of the recipients were sensitized. All patients were treated with the same quadruple immunosuppressive regimen., Results: Kaplan-Meier analysis documented graft survival of 89% at 1 year, 76% at 5 years, and 53% at 10 years. Graft survival was similar for second and primary kidney transplants performed during the same period of time. When long-term second graft survival was examined, only two risk factors were found to be significant: (1) the degree of human leukocyte antigen (HLA) DR mismatch (MM) and (2) the number of acute rejection episodes. Multivariate analysis of several pre- and posttransplant variables also confirmed the importance of HLA MM (DR> A), but also, identified serum creatinine at 12 months as the most significant predictor of graft survival. In addition, the Cox proportional hazards model revealed that only the year of transplantation had an independent significant effect on acute rejection occurrence (RR = 0.591, 95%CI 0.437 to 0.801, P < 0.0007). Indeed, the incidence of acute rejection was found to decrease over time (44% of patients experienced at least one episode of acute rejection before 1990 vs. 17% after 1990)., Conclusion: Finally, second graft long-term outcome shows an improved evolution according to the time period resulting from a strong decrease in acute rejection incidence and the impact of creatinine at 12 months.

Background: The significance of a positive B-cell crossmatch (BCM) in kidney transplantation has always been controversial in the evaluation of its implications on graft survival and specificity of the antibodies involved., Methods: We have investigated the sera of 62 recipients of a kidney allograft transplanted across a positive BCM (T negative) for the presence of autoantibodies and anti-human leukocyte antigen (HLA) class I and II antibodies, using a combination of lymphocytotoxicity, enzyme-linked immunosorbent assay (ELISA), and flow cytometry tests. The controls were the 930 patients transplanted over the same period of time with a negative T and BCM., Results: Autoantibodies were detected in 16%, and donor specific anti-HLA class II antibodies, mainly DQ, in 23% of the patients. None had antibodies against donor HLA class I. The target of the antibodies was not identified in 61%. Graft survival was comparable in the controls and in the +BCM patients, with nondonor-specific HLA reactivity. Patients with donor-specific anti-HLA class II antibodies had lower early graft survival and a higher incidence of vascular rejection. However, long-term allograft survival was similar to that of the other groups., Conclusion: These data suggest that in 77% of the patients, BCM positivity was not related with anti-HLA antibodies, and, in this case, graft survival was similar to that of the -BCM controls. In a minority of patients, anti-HLA class II antibodies were responsible for the +BCM, and their presence was associated with lower early, but not long-term, graft survival. Consequently, a +BCM should not systematically contraindicate kidney transplantation.

Background: Recipients of simultaneous kidney-pancreas transplantation receive a combination of polyclonal antithymocyte globulin (ATG), cyclosporin or tacrolimus, mycophenolate mofetil (MMF) and corticosteroids (Cs). To avoid the side effects and adverse events associated with Cs, we investigated a new immunosuppressive regimen without Cs after simultaneous kidney-pancreas transplantation., Methods: A total of 28 consecutive patients who underwent simultaneous kidney-pancreas transplantation were included in this study. All patients received ATG, cyclosporin, and MMF., Results: All patients but one tolerated the ATG course well. MMF was definitively discontinued in three patients because of leukopenia. Cytomegalovirus infection was diagnosed in eight patients (28.5%). Only two patients (7%) required an antirejection treatment. Patient, kidney, and pancreas survival is currently 96.4, 96.4, and 75%, respectively., Conclusions: The combination of ATG, cyclosporin, and MMF, without Cs, was well tolerated. The unexpectedly low (7%) incidence of acute kidney rejection observed suggests that Cs may partially interfere with the immunosuppressive effect of ATG.