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We hereby describe a minimally invasive resection of a T1 pedicular osteoid osteoma next to the vertebral canal. The patient had an 18-month report of painful radiculopathy. We performed the surgery under 3D imaging guidance using navigation with an all-in-one device. Full procedure irradiation was 1.17 mSv for a 181-picture acquisition. Complete operative time incision to closure was 58 minutes. Despite sparing the vertebral stability without any fixation, the tumor resection was well-margined, thanks to the focused guidance. After surgery, the patient had complete relief of his symptoms at the 6-month follow-up. 3D imaging system coupled to navigation made the procedure safe without consuming time. The single Surgivisio® device allows comfortable 3D minimally invasive spine navigation surgery with the ergonomics of a C-arm.

Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.106, 8.106 and 12.106 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3+regulatory T cells and PD-1+ T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses.

Background: Early-life exposure to short half-life chemicals may influence adiposity growth, a precursor to obesity. Previous studies often relied on limited urine samples that inadequately represent exposure during pregnancy or infancy. Additionally, childhood adiposity is commonly estimated using body mass index, which does not accurately reflect body composition. We aimed to investigate associations between early-life exposures to phenols, parabens, phthalates and fat mass percent at 3 years of age among 341 mother-child couple from the SEPAGES cohort. We further assessed potential effect modification by sex., Methods: We measured 8 phenols, 4 parabens, 13 phthalates and 2 non-phthalate plasticizer metabolites from weekly pooled urine sample collected from mothers during pregnancy (three urine samples a day, median 18 and 34 gestational weeks), and from their infant (one urine sample a day, at 2 and 12 months). Clinical examinations at 3 years included standardized skinfold thickness measurements and bioelectrical impedance analysis to calculate fat mass percentage., Results: Positive associations were identified between prenatal exposures to bisphenol S, mono-benzyl phthalate (MBzP), monoethyl phthalate (MEP), and mono-n-butyl phthalate and fat mass percentage at 3 years, while triclosan showed a negative association. MBzP and MEP showed effect modification by sex, with stronger associations among females. No significant associations were detected for postnatal exposures., Conclusion: This study suggests associations between prenatal exposures to short half-life chemicals and percent fat mass in preschool children. Furthermore, this study is the first investigating the impact of prenatal bisphenol S exposure, highlighting the need for investigation of this overlooked compound., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Mantle cell lymphoma (MCL) is genetically characterized by the IG::CCND1 translocation mediated by an aberrant V(D)J rearrangement. CCND1 translocations and overexpression have been identified in occasional aggressive B-cell lymphomas with unusual features for MCL. The mechanism generating CCND1 rearrangements in these tumors and their genomic profile are not known. We have reconstructed the IG::CCND1 translocations and the genomic profile of 13 SOX11-negative aggressive B-cell lymphomas using whole genome/exome and target sequencing. The mechanism behind the translocation was an aberrant V(D)J rearrangement in three tumors and by an anomalous IGH class-switch recombination (CSR) or somatic hypermutation (SHM) mechanism in ten. The tumors with a V(D)J-mediated translocation were two blastoid MCL and one high-grade B-cell lymphoma. None of them had a mutational profile suggestive of DLBCL. The ten tumors with CSR/SHM-mediated IGH::CCND1 were mainly large B-cell lymphomas, with mutated genes commonly seen in DLBCL and BCL6 rearrangements in 6. Two cases, which transformed from marginal zone lymphomas, carried mutations in KLF2, TNFAIP3 and KMT2D. These findings expand the spectrum of tumors carrying CCND1 rearrangement that may occur as a secondary event in DLBCL mediated by aberrant CSR/SHM and associated with a mutational profile different from that of MCL., (© 2024. The Author(s).)

We report the case of a 14 year-old teenager who has SC hemoglobinosis and presented with a tumor syndrome with a retro-peritoneal mass, a supraclavicular lymph node and a mid-renal lesion. The microscopic examination revealed an undifferentiated tumor proliferation infiltrating the lymph node parenchyma. This tumor proliferation was INI1/SMARCB1-deficient, and expressed cytokeratins. Given the fact that the histopathological data showed an undifferentiated INI1-deficient carcinoma and that the patient has a kidney lesion and a sickle cell trait, the final diagnosis was lymph node metastasis of SMARCB1-deficient renal medullary carcinoma (OMS 2022)., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Fibro-osseous pseudotumor of the digits is a benign tumour closely related to myositis ossificans. It is a rare lesion seldom reported in the literature. We report the case of a 33-year-old woman with lancinating pain in the first phalanx of the second finger of the right hand, associated with inflammation. The histopathological examination of the surgical excision biopsy of the lesion revealed a spindle-shaped proliferation within a sclerosing, hyaline, and osteoid stroma. In our observation, immunohistochemistry and molecular biology are the main elements that helped to establish the diagnosis and eliminate the various differential diagnoses, despite a non-specific histopathological aspect., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically., Methods: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case., Results: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions., Conclusions: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Since its creation in 2010, the progressive structuration of the RENAPE network (Réseau national de prise en charge des tumeurs rares du péritoine) supported by the "Institut national du cancer" and the "Direction générale de l'offre de soins", allowed the optimization of the healthcare system involved in the management of the rare cancers of the peritoneum. In this setting, the RENA-PATH group has also been reinforced, notably by its recognized diagnostic expertise in pathology and its interface with the MESOPATH group. Moreover RENAPE and RENA-PATH led to guidelines diffusion through the integration, in 2019, to the ``Thesaurus National de Cancérologie Digestive'' (TNCD) and to post-university medical education programs. The aim of this article is to highlight the missions of the RENAPE and RENA-PATH, notably the equity in terms of expertise, access to the networks and their improvement in the management of peritoneal diseases., (Copyright © 2024. Published by Elsevier Masson SAS.)

Background and Aims: In colorectal cancer (CRC), HER2 targeting is a promising treatment and immune infiltrate is an important area of research and strategy. Data regarding HER2 status and immune infiltrate are lacking. The aim of this study was to compare the immune infiltrate between HER2 amplified and non-amplified categories in proficient MisMatchRepair (pMMR)/microsatellite stable (MSS) CRC., Methods: HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization were performed in a retrospective series of 654 CRC. Lymphocyte infiltrate was analysed by anti-CD3, CD8 and CD4 IHC and evaluated digitally using QuPath software., Results: Among the 654 CRC, we first observed a decreased CD3+ and CD8+ infiltrate between HER2 amplified (all IHC 3+ except one 2+) and non-amplified HER2 2+ IHC CRC (p = 0.059 and 0.072 respectively). A supplementary analysis of 258 pMMR/MSS CRC from the previous cohort, displaying all the IHC scores (0, 1+, 2+, 3+), showed a lower CD3+ infiltrate between HER2 amplified versus HER2 0 (p = 0.002), 1+ (p = 0.088) and non-amplified 2+ (p = 0.081) IHC cases., Conclusions: Our original findings suggest that in pMMR/MSS CRC, the immune infiltrate is reduced in HER2 amplified versus other HER2 categories. These data might be useful for future strategies combining anti-HER2 treatments and immune checkpoint inhibitors and need to be confirmed in larger CRC cohorts., Competing Interests: Conflict of Interest Chloé Molimard, Fanny Dor, Alexis Overs, Franck Monnien, Grégoire Gessain, Loïs Kedochim, Flavia D'Angelo, Marine Abad, Morgane Heberle, Valentin Derangère, François Ghiringhelli, Lucine Vuitton, Séverine Valmary-Degano, Christophe Borg, Zaher Lakkis, Frédéric Bibeau have no competing financial interests of personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Synovialosarcoma is a malignant mesenchymal tumor of young adults that occurs in the deep soft tissues, particularly around large joints. When it occurs in more unusual sites, it could present a significant diagnostic challenge. In this case, a 19-year-old girl was treated for a pyloric mass. A pyelic urine cytology performed simultaneously with a pyloric biopsy proved to be a significant element of orientation and perfectly concordant with the histopathological aspect of the pyelic mass after nephrectomy. We report here the first case of renal synovialosarcoma documented in pyelic urine., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Reinstating inflammation resolution represents an innovative concept to regain inflammation control in diseases marked by chronic inflammation. While most therapeutics target inflammatory molecules and inflammatory effector cells and mediators, targeting macrophages to initiate inflammation resolution to control neuroinflammation has not yet been attempted. Resolution-phase macrophages are critical in the resolution process to regain tissue homeostasis, and are programmed through the presence and elimination of apoptotic leukocytes. Hence, inducing resolution-phase macrophages might represent an innovative therapeutic approach to control and terminate dysregulated neuroinflammation., Methods: Here, we investigated if the factors released by in vitro induced resolution-phase macrophages (their secretome) are able to therapeutically reprogram macrophages to control neuroinflammation in the model of experimental autoimmune encephalomyelitis (EAE)., Results: We found that injection of the pro-resolutive secretome reduced demyelination and decreased inflammatory cell infiltration in the CNS, notably through the in vivo reprogramming of macrophages at the epigenetic level. Adoptive transfer experiments with in vivo or in vitro reprogrammed macrophages using such pro-resolutive secretome confirmed the stability and transferability of this acquired therapeutic activity., Conclusions: Overall, our data confirm the therapeutic activity of a pro-resolution secretome in the treatment of ongoing CNS inflammation, via the epigenetic reprogramming of macrophages and open with that a new therapeutic avenue for diseases marked by neuroinflammation., (© 2023. The Author(s).)

Background: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs)., Materials and Methods: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021., Results: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme., Conclusions: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Despite optimal arterial anastomosis, some finger replantations fail. Our objective was to evaluate how the mechanism of injury (MOI) affects the artery's microscopic appearance and the success of anastomosis. We hypothesized that the MOI influences arterial histology and microsurgical success., Methods: This single-center prospective study enrolled patients who had an acute traumatic arterial injury of the hand and/or wrist. The proximal and distal ends of the artery were trimmed before anastomosis in every case. The arterial margins were analyzed in anatomical pathology. Clinical follow-up along with an ultrasound arterial patency check was carried out at 1 month postoperative., Results: Between 2018 and 2022, 104 patients were enrolled with a follow-up of 12 months. Macroscopically, 42% of the arterial margins were dilapidated. Histological analysis found damage in 74% of surgical specimens: blast (100%)>laceration by mechanical or power tool (92%; 82%)>amputation by mechanical or power tool (80%; 67%)>laceration by glass (50%)>crush injury (33%). The arterial margins were more likely to be normal based on the histological analysis when the MOI was laceration by glass (p<.05; OR=3.72) and the patient was 65 years or older (p<.01). Risk factors for anastomosis failure were an amputation by power tool (p<.01, OR 8.19) and shorter length of arterial resection (p<.02). The clinical failure rate was 7.8% and the patency failure rate was 10.4%., Discussion: Histological arterial lesions correlate with the MOI. Trimming >2mm from the proximal and distal arterial ends is recommended for all MOI before arterial end-to-end anastomosis. For blast injuries or amputation, we recommend trimming>4mm and using a vein bypass graft. This study's findings could lead to a change in surgical practices., Level of Evidence: II; well-conducted non-randomized comparative study; recommendation grade B: scientific presumption., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Follicular lymphoid hyperplasia induced by dasatinib is an entity recently described. It is sometimes difficult to rule out the diagnostic of small B-cell lymphoma. Usually, the node is swollen, with follicular architecture conserved, composed by germinal centers with variable size and shape, with a hight number of mitoses and tingible bodies macrophages inside. Follicular lymphoid hyperplasia is isolated or associated with multiple reactive patterns. The immunohistochemical profil of germinal centers is CD20+, CD10+, BCL6+, BCL2-. Swollen node disappears in a short time after dasatinib discontinuation. Clinicians and pathologists need to be aware of this entity, so as not to avoid mistakenly suspect lymphoma when lymphadenopathy occurs in a patient with chronic myeloid leukemia treated with dasatinib., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The French Society of Pathology (SFP) organized its first data challenge in 2020 with the help of the Health Data Hub (HDH). The organization of this event first consisted of recruiting nearly 5000 cervical biopsy slides obtained from 20 pathology centers. After ensuring that patients did not refuse to include their slides in the project, the slides were anonymized, digitized, and annotated by expert pathologists, and finally uploaded to a data challenge platform for competitors from around the world. Competing teams had to develop algorithms that could distinguish 4 diagnostic classes in cervical epithelial lesions. Among the many submissions from competitors, the best algorithms achieved an overall score close to 95%. The final part of the competition lasted only 6 weeks, and the goal of SFP and HDH is now to allow for the collection to be published in open access for the scientific community. In this report, we have performed a "post-competition analysis" of the results. We first described the algorithmic pipelines of 3 top competitors. We then analyzed several difficult cases that even the top competitors could not predict correctly. A medical committee of several expert pathologists looked for possible explanations for these erroneous results by reviewing the images, and we present their findings here targeted for a large audience of pathologists and data scientists in the field of digital pathology., (© 2022 The Author(s).)

Acute graft-versus-host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram-negative bacteria are well-known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein-mediated transport to the liver (i.e., the so-called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL-deficient (Apoa1 tm1Unc ) recipient mice developed exacerbated aGVHD. Repeated administration of HDL isolated from human plasma significantly decreased the mortality and the severity of aGVHD. While the potential role of HDL in scavenging circulating LPS was examined in this study, it appears that HDL plays a more direct immunomodulatory role by limiting or controlling aGVHD. Notably, HDL infusion mitigated liver aGVHD by diminishing immune infiltration (e.g., interferon-γ-secreting CD8 + T cells and non-resident macrophages), systemic and local inflammation (notably cholangitis). Hence, our results revealed the interest of HDL-based therapies in the prevention of aGVHD., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

The french society of pathology (SFP) organized in 2020 its first data challenge with the help of Health Data Hub (HDH). The organisation of this event first consisted in recruiting almost 5000 slides of uterus cervical biopsies obtained in 20 pathology centers. After having made sure that patients did not refuse to include their slides in the project, the slides were anonymised, digitized and annotated by expert pathologists, and were finally uploaded on a data challenge platform for competitors all around the world. Competitors teams had to develop algorithms that could distinguish among four diagnostic classes in epithelial lesions of uterine cervix. Among many submissions by competitors, the best algorithms obtained an overall score close to 95%. The best 3 teams shared 25k€ prizes during a special session organised during the national congress of the SFP. The final part of the competition lasted only 6 weeks and the goal of SFP and HDH is now to allow for the collection to be published in open access. This final step will allow data scientists and pathologists to further develop artificial intelligence algorithms in this medical area., (Copyright © 2021. Published by Elsevier Masson SAS.)

Confirmed diagnosis of alveolar echinococcosis (AE) is based on pathological criteria and molecular evidence. This parasite-borne disease, caused by the cestode Echinococcus multilocularis, sparingly involves humans as a dead-end host. In humans, the parasite mainly colonizes the liver but can colonize any organ and cause atypical forms, often difficult to characterize clinically. Moreover, molecular methods may be suitable to make the diagnosis of AE in cases of atypical forms, extra-hepatic localizations, or immunosuppressed patients. The aim of this study was to determine the most relevant published PCR techniques, for diagnosis of AE in patients and adopt the best strategy for molecular diagnosis depending on the nature of the tested sample. In this study, we evaluated nine end-point PCR assays and one real-time PCR assay (qPCR), targeting mitochondrial genes, using a total of 89 frozen or formalin-fixed paraffin-embedded (FFPE) samples from either 48 AE or 9 cystic echinococcosis patients. Targeted fragment-genes ranged from 84 to 529 bp. Six PCR assays were able to amplify the DNA of 100% of the frozen AE-samples and for one PCR, 69.8% of the FFPE AE-samples. The 16S rrnL PCR (84 bp) was positive in PCR for 77% of the AE samples and in qPCR for 86.5%. The sensitivity of the PCR assays was higher for fresh samples and FFPE samples stored for less than 5 years. The qPCR assay further increased sensitivity for the tested samples, confirming the need for the development of an Echinococcus spp. qPCR to improve the molecular diagnosis of echinococcoses., (© J. Knapp et al., published by EDP Sciences, 2022.)

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin ( Fn1 ). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD., Competing Interests: FB, MC, PS, and SP are shareholders of MED’INN’Pharma SAS. FB, MC, and SP are employed by MED’INN’Pharma SAS which develops the SuperMApo biologic drug candidate. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Martin-Rodriguez, Gauthier, Bonnefoy, Couturier, Daoui, Chagué, Valmary-Degano, Gay, Saas and Perruche.)

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. A recently described nuclear-grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The present study was undertaken to validate this grading system in epithelioid malignant peritoneal mesothelioma (EMPM) and to compare to combined grade, including nuclear atypia, mitotic count, and tumor necrosis. Cases of EMPM, from 1995 to 2018, were analyzed from 7 French institutions from RENAPE network. Solid growth, tumor necrosis, nuclear atypia, and mitotic count were evaluated by at least 3 pathologists from the RENAPATH group. The predictions in terms of OS and PFS of nuclear grade and combined grade were analyzed. Nuclear grade was computed combining nuclear atypia score and mitotic count into a grade of I-III. Another system combining nuclear atypia score, mitotic score, and tumor necrosis was evaluated and defined as a combined grade I-III. A total of 138 cases were identified. The median follow-up was 38.9 months (range: 1.1-196.6). Nuclear and combined grades III were independently associated with a shorter OS (p < 0.05), and a shorter PFS (p < 0.05). Patients with combined grade I tumors had the best overall and progression-free survivals, in comparison to nuclear grade I. In this large multicentric study, combined grade and nuclear grade were the best independent predictors of OS and PFS in EMPM. These systems should be easily described by pathologists involved into the management of malignant peritoneal mesothelioma, because of their potential therapeutic implications., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant peritoneal mesothelioma. The relationship between a strong adaptive immune response and a better prognosis in malignant solid tumors is widely known. Due to the low incidence of epithelioid malignant peritoneal mesothelioma (EMPM), very little is known about their immune micro-environment. We encountered several cases of tertiary lymphoid structures in EMPM in a previous study and aimed to investigate in the same series the prevalence, clinicopathological features, and the prognostic impact associated with tertiary lymphoid structures in EMPM (TLS-EMPM). Cases of EMPM, from 1995 to 2018, were retrieved from 7 French institutions from the RENAPE Network. The predictions in terms of overall survival (OS) and progression-free survival (PFS) of TLS-EMPM were analyzed. We report 52 cases of TLS-EMPM among a series of 138 cases of EMPM. TLS-EMPM was significantly associated with neoadjuvant chemotherapy, and was not a prognostic indicator for OS (p = 0.652) and PFS (p = 0.804) in our series. TLS is a component of the host immune response to EMPM significantly associated with neoadjuvant chemotherapy, but was not a predictor of prognosis for overall and progression-free survivals in this series. These findings provide another possible etiology for tertiary lymphoid structures., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

High-risk HPV (hrHPV) testing has been implemented as a primary screening tool for cervical cancer in numerous countries. However, there is still a need for relevant triage strategies to manage hrHPV positive women to avoid excessive referral to colposcopy. The objective of this study was to assess, in women infected by hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 2102 women positive for hrHPV, 885 had no lesion or mild cytological abnormalities at baseline and had at least one follow-up (FU) visit. HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 15% developed a high-grade lesion during the FU. An HPV16 viral load cut-off set at 3.2 log 10 GE/10 3 cells permitted to identify a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80-3.97; p ≤ 0.0001). No specific HPV18 viral load threshold could have been defined in regard to the present study. In multivariate analysis, HPV16 load (absence/log 10 GE/10 3 cells < 3.2 vs. ≥3.2), RLU/PC 239 (1-100 pg/mL vs. >100 pg/mL) and cytology (normal vs abnormal) were independently associated with a significant increased risk of high-grade lesion development and were used to construct the prognostic score. In conclusion, HPV16 load is a relevant biomarker to identify women at high risk for developing cervical precancerous lesions.

NUT carcinoma (NC), formerly known as NUT midline carcinoma, is a rare and very aggressive cancer. It is genetically defined by the presence of acquired chromosomal rearrangement of the NUTM1 (NUclear protein in Testis Midline carcinoma family member 1) gene at chromosome 15q14 with a member of the bromodomain-containing protein (BRD) family gene, usually BRD4. Although primarily reported in the head and neck, and mediastinum locations of younger individuals, it is now established that NC arises in multiple sites in patients of all ages, with no gender predilection. NC is very likely to be underdiagnosed because of a lack of awareness of both clinicians and pathologists on the one hand, and of a nonspecific histological presentation on the other hand. As it is indistinguishable from other poorly differentiated carcinomas, pathologists should consider NC as a differential diagnosis of any poorly differentiated tumour. Diagnosis is now easily made by immunohistochemistry, using a highly sensitive and specific NUT monoclonal antibody. Despite chemo- or chemo-radiotherapy, the prognosis of this tumour remains very poor. We report here a series of 3 cases of NC with different clinical and pathological presentations in order to draw attention on some common morphological features that can help clinicians and pathologists to think about this rare entity., (Copyright © 2021. Published by Elsevier B.V.)

Follicular lymphomas (FLs) with MYC rearrangements (MYC-R) and extra copies of MYC (MYC-EC) are rare and the prognosis impact is uncertain. We conducted a retrospective study including 321 FL patients, among whom 259 (81%) had no 8q24 alterations and 62 (19%) were assigned to 8qAlt. Forty-five cases were classified as MYC-EC and six as MYC-R. MYC-R patients were significantly older (P = 0·008), had higher follicular lymphoma international prognostic index (FLIPI) stage (P = 0·05) and β2-microglobulin (β2m; P = 0·05). Among patients treated with immuno-chemotherapy, four presented a MYC-R and 25 a MYC-EC. Univariate analysis showed the absence of significant difference between MYC-EC and normal MYC (MYC-NL) regarding progression-free survival (PFS; HR1·3; 95% CI [0·4-1·6]) and specific overall survival (SOS; HR 1·6; 95% CI [0·4-5·7]). Those results were compared to data from the PRIMA trial. This confirmed that MYC-EC had no impact on PFS (P = 0·86) or SOS (P = 0·9). Conversely, MYC-R was associated with a trend to inferior outcome regarding PFS (HR : 6·1; 95% CI [2·2-17·1]; P = 0·00026), lymphoma-related death (SOS; HR 13·6; 95% CI [2·9-65]; P = 0·00014) and risk of transformation (transformation-free survival (TFS); HR 82·7; 95% CI [14·8-463·4]; P < 0·0001). In conclusion, MYC-EC has no prognostic impact in FL but MYC-R FL tended to be associated with an increased risk of transformation and poorer outcome., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Sarcomas are rare tumours that represent less than 1% of all malignant tumours in adults. Liposarcomas are among the most common malignant mesenchymal tumours. They are preferentially located in the limbs and the retroperitoneum. Liposarcomas primarily arising in the digestive tract are exceptional with a few cases reported in the literature. Their clinical presentation is variable and the symptoms are not specific. Anatomopathological examination remains the gold standard for the diagnosis and the classification of these tumours, which are divided into 5 histological types according to the 5th edition of the WHO classification of soft tissue tumours. We report two observations of unusual digestive liposarcomas, located in the oesophagus and the colon, emphasizing the variability of the diagnostic challenges, depending on the clinical presentation, the histological type and the analysed material., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Objective: Peritoneal or mesenteric tumours may correspond to several tumour types or tumour-like conditions, some of them being represented by histiocytosis. This rare condition often poses diagnostic difficulties that can lead to important time delay in targeted therapies. Our aim was to describe main features of histiocytoses with mesenteric localisation that can improve the diagnostic process., Design: We performed a retrospective study on 22 patients, whose peritoneal/mesenteric biopsies were infiltrated by histiocytes., Results: Abdominal pain was the revealing symptom in 10 cases, and 19 patients underwent surgical biopsies. The diagnosis of histiocytosis was proposed by initial pathologists in 41% of patients. The other initial diagnoses were inflammation (n=7), sclerosing mesenteritis (n=4) and liposarcoma (n=1). The CD163/CD68+CD1a- histiocytes infiltrated subserosa and/or deeper adipose tissues in 16 and 14 cases, respectively. A BRAF V600E mutation was detected within the biopsies in 11 cases, and two others were MAP2K1 mutated. The final diagnosis was histiocytosis in 18 patients, 15 of whom had Erdheim-Chester disease. The median diagnostic delay of histiocytosis was 9 months. Patients treated with BRAF or MEK inhibitors showed a partial response or a stable disease. One patient died soon after surgery, and five died by the progression of the disease., Conclusion: Diagnosis of masses arising in the mesentery should be carefully explored as one of the possibilities in histiocytosis. This diagnosis is frequently missed on mesenteric biopsies. Molecular biology for detecting the mutations in BRAF or in genes of the MAP kinase pathway is a critical diagnostic tool., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Despite a growing incidence in developed countries and a recent improved understanding of its pathogenesis, anal cancer management has not evolved over the past decades and drug combination used as first-line regimen still largely depends on clinician preferences. Aiming at paving the way for precision medicine, a large cohort of 372 HIV-negative patients diagnosed over a 20-year time period with locally advanced anal carcinoma was collected and carefully characterized at the clinical, demographic, histopathologic, immunologic, and virologic levels. Both the prognostic relevance of each clinicopathological parameter and the efficacy of different concurrent chemoradiation strategies were determined. Overall, the incidence of anal cancer peaked during the sixth decade (mean: 63.4) and females outnumbered males (ratio: 2.51). After completion of treatment, 95 (25.5%) patients experienced progression of persistent disease or local/distant recurrence and 102 (27.4%) died during the follow-up period (median: 53.8 months). Importantly, uni-multivariate analyses indicated that both negative HPV/p16 ink4a status and aberrant p53 expression were far better predictors for reduced progression-free survival than traditional risk factors such as tumor size and nodal status. As for overall survival, the significant influences of age at diagnosis, p16 ink4a status, cTNM classification as well as both CD3 + and CD4 + T-cell infiltrations within tumor microenvironment were highlighted. Cisplatin-based chemoradiotherapy was superior to both radiotherapy alone and other concurrent chemoradiation therapies in the treatment of HPV-positive tumors. Regarding their HPV-uninfected counterparts, frequent relapses were observed, whatever the treatment regimen administered. Taken together, our findings reveal that current anal cancer management and treatment have reached their limits. A dualistic classification according to HPV/p53 status should be considered with implications for therapy personalization and optimization.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN. We demonstrated that both retroviral and lentiviral engineering CD28/4-1BB CD123 CAR T cells exhibit effector functions against BPDCN cells through CD123 antigen recognition and that they efficiently kill BPDCN cell lines and BPDCN-derived PDX cells. In vivo, CD28/4-1BB CD123 CAR T-cell therapy displayed strong efficacy by promoting a decrease of BPDCN blast burden. Furthermore we showed that T cells from BPDCN patient transduced with CD28/4-1BB CD123 CAR successfully eliminate autologous BPDCN blasts in vitro. Finally, we demonstrated in humanized mouse models that these effector CAR T cells exert low or no cytotoxicity against various subsets of normal cells with low CD123 expression, indicating a potentially low on-target/off-tumor toxicity effect. Collectively, our data support the further evaluation for clinical assessment of CD28/4-1BB CD123 CAR T cells in BPDCN neoplasm.

Oncotype DX (ODX) is a multi-gene expression signature designed for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients to predict the recurrence score (RS) and chemotherapy (CT) benefit. The aim of our study is to develop a prediction tool for the three RS's categories based on deep multi-layer perceptrons (DMLP) and using only the morphoimmunohistological variables. We performed a retrospective cohort of 320 patients who underwent ODX testing from three French hospitals. Clinico-pathological characteristics were recorded. We built a supervised machine learning classification model using Matlab software with 152 cases for the training and 168 cases for the testing. Three classifiers were used to learn the three risk categories of the ODX, namely the low, intermediate, and high risk. Experimental results provide the area under the curve (AUC), respectively, for the three risk categories: 0.63 [95% confidence interval: (0.5446, 0.7154), p < 0.001], 0.59 [95% confidence interval: (0.5031, 0.6769), p < 0.001], 0.75 [95% confidence interval: (0.6184, 0.8816), p < 0.001]. Concordance rate between actual RS and predicted RS ranged from 53 to 56% for each class between DMLP and ODX. The concordance rate of low and intermediate combined risk group was 85%.We developed a predictive machine learning model that could help to define patient's RS. Moreover, we integrated histopathological data and DMLP results to select tumor for ODX testing. Thus, this process allows more relevant use of histopathological data, and optimizes and enhances this information.