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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.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.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).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.

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.

BackgroundTransforming 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.MethodsWe 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.ResultsWe demonstrated that TGFβ pathway inhibition strongly increased the efficacy of RT. TGFβR2 antibody upregulated interferon beta (IFNβ) expression in tumor-associated macrophages (TAMs) 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 inhibition of immune exclusion observed with the combination of MT1 and RT were dependent on type I interferon signaling.ConclusionsThese 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.

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.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/mmOur findings suggest that the Ki67 PI and TILs could be used as prognostic markers, as a potential alternative to the Hyams grade.

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.

Histopathological image segmentation is a challenging and important topic in medical imaging with tremendous potential impact in clinical practice. State of the art methods rely on hand-crafted annotations which hinder clinical translation since histology suffers from significant variations between cancer phenotypes. In this paper, we propose a weakly supervised framework for whole slide imaging segmentation that relies on standard clinical annotations, available in most medical systems. In particular, we exploit a multiple instance learning scheme for training models. The proposed framework has been evaluated on multi-locations and multi-centric public data from The Cancer Genome Atlas and the PatchCamelyon dataset. Promising results when compared with experts' annotations demonstrate the potentials of the presented approach. The complete framework, including $6481$ generated tumor maps and data processing, is available at https://github.com/marvinler/tcga_segmentation., Accepted MICCAI 2020; added code + results url; 10 pages, 3 figures

Severe pneumonia and acute respiratory distress syndrome (ARDS) have been described in patients with severe COVID-19. Recently, early clinical data reported the efficacy of low doses of radiation therapy (RT) in the treatment of ARDS in patients with severe COVID-19. However, the involved mechanisms remained unknown. Here, we used airways-instilled lipopolysaccharide (LPS) and influenza virus (H1N1) as murine models of pneumonia, and Tolllike receptor (TLR)-3 stimulation in human lung macrophages. Low doses RT (0.5-1 Gy) decreased LPS induced pneumonia, and increased the percentage of Nerve- and Airway-associated Macrophages (NAMs) producing IL-10. During H1N1 viral infection, we observed decreased lung tissue damage and immune cell infiltration in irradiated animals. Low doses 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 IFNγ production in the culture supernatant. The percentage of human lung macrophages producing IL-6 was also decreased. Our data highlight one of the mechanisms by which low doses RT regulate lung inflammation and skew lung macrophages towards an anti-inflammatory profile. These data provide the preclinical rationale for the use and for the optimization of low doses RT in situations such as COVID-19-induced ARDS.

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.

// Mathieu Veyrat 1 , Sylvere Durand 2 , Marion Classe 3 , Tanja Matijevic Glavan 4 , Natalie Oker 1, 5 , Nikiforos-Ioannis Kapetanakis 1 , Xiaojun Jiang 1 , Aurore Gelin 1 , Philippe Herman 5 , Odile Casiraghi 6 , David Zagzag 7 , David Enot 2 , Pierre Busson 1 , Benjamin Verillaud 1, 5 1 University Paris-Sud (Paris 11), CNRS-UMR 8126, Gustave Roussy, Villejuif, France 2 Equipe 11 Labelisee par la Ligue Nationale Contre le Cancer, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France, Metabolomics and Molecular Cell Biology Platforms, Gustave Roussy, Villejuif, France 3 Department of Pathology, Lariboisiere Hospital, AP-HP, University Paris-Diderot Paris 7, Paris, France 4 Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia 5 Department of Head and Neck surgery, Lariboisiere Hospital, AP-HP, University Paris-Diderot Paris 7, Paris, France 6 Department of Biopathology, Gustave Roussy, Villejuif, France 7 Department of Neuropathology, New York University School of Medicine, New York, NY, USA Correspondence to: Benjamin Verillaud, email: benjamin.verillaud@gmail.com Keywords: toll-like receptor 3, innate immunity, warburg effect, HIF, metabolomics Received: February 12, 2015 Accepted: October 19, 2016 Published: October 25, 2016 ABSTRACT 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.

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.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.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 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.

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.

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).

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, clinicopathologic 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 FISH confirmed tRCCs and then to confront 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 Regional Universitaire (Lille, France). The diagnosis of tRCC was confirmed by fluorescence in situ hybridization. Among a total of 1,130 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 to 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. This article is protected by copyright. All rights reserved.

Summary: 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. : Classe et al. report an integrative multi-omics analysis of esthesioneuroblastomas (ENBs) and identify two subgroups of ENBs: neural-like and basal-like. These subgroups are linked to cell ontogeny and are associated with distinct clinicopathological features and patient outcomes. Notably, one-third of basal ENBs harbor an IDH2 R172 mutation with a CpG island methylator phenotype. Keywords: esthesioneuroblastomas, IDH2, neural, basal, DNA methylation, sequencing, genetics, epigenetics, survival, ki67

International audience; 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.

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.

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.

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).

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. Pediatr Blood Cancer 2014;61:1698–1700. © 2014 Wiley Periodicals, Inc.

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.

4572Background: 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 suggest an overlap of ...