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Hematological involvement (HI) is one of the life-threatening risk organs (ROs) in Langerhans cell histiocytosis (LCH). Lahey criteria have defined HI since 1975 as hemoglobin <10 g/dL and/or platelets <100 G/L and/or leukopenia (white blood cell count <4 G/L) and/or neutrophils <1.5 G/. Among the 2313 patients <18 years old enrolled in the French National Histiocytosis Registry (1983-2023), 331 developed HI (median age at diagnosis: 1 year); median follow-up lasted 8.1 years. Bone-marrow aspirate smears and biopsies may show reactive histiocytes, hemophagocytosis or myelofibrosis but never confirm the diagnosis. Fifty-eight (17%) patients developed macrophage-activation syndrome, sometimes related to acute Epstein-Barr virus or cytomegalovirus infection, sometimes months before typical LCH manifestations appeared. Hemoglobin and platelet thresholds for initiating transfusion(s) appear to accurately distinguish 2 groups: mild HI (MHI; >7 g/dL and >20 G/L, respectively) and severe HI (SHI; ≤7 g/dL and ≤20 G/L). Each entity has different organ involvements, laboratory parameters, mutational status, blood BRAFV600E loads, drug sensitivities and outcomes (respective MHI and SHI 10-year survival rates: 98% and 73%). Since 1998, mortality first declined with combination Cladribine-cytarabine therapy, and then with mitogen-activated protein-kinase inhibitors since 2014. Forty-one (12%) patients developed neurodegenerative complications that have emerged as a risk for long-term survivors. These results suggest limiting the HI-RO definition to SHI, as it encompasses almost all medical complications of LCH. Future clinical trials might demonstrate that targeted-therapy approaches would be better adapted for these patients, while MHI can be managed with classic therapies., (Copyright © 2024 American Society of Hematology.)

Any product injected to fill wrinkles can behave like a foreign body and cause unsightly granulomatous reactions. The subject is constantly evolving, subject to the vagaries of the market. Hyaluronic acid is the most injected product because it is resorbable and probably the least "toxic". In the event of sarcoidosis or an immune disorder, and in the event of vaccination against Covid, granulomas can develop even after very old injections., (Copyright © 2024. Published by Elsevier Masson SAS.)

Purpose: Understanding resistance to selective FGFR inhibitors is crucial to improve the clinical outcomes of patients with FGFR2-driven malignancies., Experimental Design: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from patients with tumors harboring activating FGFR2 alterations progressing on pan-FGFR-selective inhibitors, collected in the prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies., Results: Thirty-six patients were included. In cholangiocarcinoma, at resistance to both reversible inhibitors (e.g., pemigatinib and erdafitinib) and the irreversible inhibitor futibatinib, polyclonal FGFR2 kinase domain mutations were frequent (14/27 patients). Tumors other than cholangiocarcinoma shared the same mutated FGFR2 residues, but polyclonality was rare (1/9 patients). At resistance to reversible inhibitors, 14 residues in the FGFR2 kinase domain were mutated-after futibatinib, only the molecular brake N550 and the gatekeeper V565. Off-target alterations in PI3K/mTOR and MAPK pathways were found in 11 patients, often together with on-target mutations. At progression to a first FGFR inhibitor, 12 patients received futibatinib or lirafugratinib (irreversible inhibitors), with variable clinical outcomes depending on previous resistance mechanisms. Two patients with TSC1 or PIK3CA mutations benefited from everolimus. In cell viability assays on Ba/F3 and in pharmacologic studies on patient-derived xenografts, irreversible inhibitors retained better activity against FGFR2 kinase domain mutations, with lirafugratinib active against the recalcitrant V565L/F/Y., Conclusions: At progression to FGFR inhibitors, FGFR2-driven malignancies are characterized by high intra- and interpatient molecular heterogeneity, particularly in cholangiocarcinoma. Resistance to FGFR inhibitors can be overcome by sequential, molecularly oriented treatment strategies across FGFR2-driven tumors., (©2024 The Authors; Published by the American Association for Cancer Research.)

Objective: Breast cancer is the leading cancer in women in terms of incidence and mortality. The literature currently identifies several risk factors, some modifiable and others not. Because of its multifactorial nature, the combination of factors either increases or reduces the risk of cancer. Since 2004, the first commission's rapport of the French National Environmental Health Plan has recognized the significant impact of occupational exposure on the development of breast cancer. However, neither primary nor secondary preventive measures have yet been implemented in work environment., Method: Based on available literature, we reviewed current knowledge of breast cancer risk factors associated with occupational exposure., Results: The risk factors identified were ionizing radiation, magnetic fields, certain endocrine disruptors, ethylene oxide and night shift work., Conclusion: Recognition of breast cancer as an occupational disease is complicated. In some cases, however, it may be possible, particularly in cases of multifactorial exposure. This work should help to raise awareness among employers and reinforce preventive measures in the workplace., (Copyright © 2024. Published by Elsevier Masson SAS.)

Mooren's ulcer is a painless and idiopathic ulcer of the peripheral cornea related to autoimmunity against a corneal stromal antigen, calgranulin C. Corneal involvement is isolated. There are no specific histopathological features to differentiate Mooren's ulcer from pseudo-Mooren's, the latter being part of a systemic disease. Mooren ulcer is a diagnosis of elimination based on a complete etiological check-up. However, histopathological examination, when performed, could provide additional data to support the diagnosis. We report the case of a 78-year-old female patient who presented with Mooren's ulcer. The patient had complained of red eye and photophobia for two weeks. Initial visual acuity was "counting fingers". Clinical examination revealed a perforated perilimbic ulcer with an iris prolapse. Based on the peripheral ulcerative keratitis, with a negative etiological work-up and anatomopathological analysis of the cornea, the diagnosis of Mooren's ulcer was proposed. This rare case illustrates the need for a multidisciplinary approach involving ophthalmologists, pathologists, and internists, to reach a diagnosis and optimize the functional prognosis., (Copyright © 2024. Published by Elsevier Masson SAS.)

Ovarian cancers are gynecological cancers with a poor prognosis. Most ovarian cancers are high-grade serous carcinomas. It is now accepted that they are very often tubal in origin. Their management has undergone major advances in recent years. Their clinical manifestations are not very specific, and no screening test has yet -proved its worth, which explains why they are often diagnosed late. The diagnostic phase is essentially based on ultrasound and abdomino-pelvic CT scans, for reasons of ease of access. Other -examination modalities, such as MRI and above all PET-Ct, are playing an increasingly important role in the initial management of extension or thera-peutic follow-up. Even with notable advances in diagnosis and treatment, the overall prognosis remains poor., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Low-risk gestational trophoblastic neoplasia (GTN) are currently receiving monochemotherapy as first-line therapy. In the case of a resistance, a second-line mono- or polychemotherapy is proposed. As an alternative to these toxic and historic chemotherapy agents, the efficacy of the anti-PD-L1 monoclonal antibody (avelumab) was assessed in the TROPHIMMUN phase II trial Cohort A. Avelumab yielded a 53% cure rate with an acceptable tolerance profile, including normal further pregnancy and delivery. Beyond the blockade of PD-1/PD-L1 interactions, avelumab effect could rely on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by FcγR3A-expressing natural killer (NK) cells., Objective: This translational study aimed at testing whether ADCC is involved in avelumab efficacy on GTN and if FcγR3A affinity polymorphism could help predicting the response to avelumab in GTN., Study Design: The expression of PD-L1 by the tumor and the phenotype of NK cells infiltrating GTN were verified by performing transcriptomic and proteomic analyses. Then, JEG-3 choriocarcinoma cells were cocultured with human NK cells in presence and absence of avelumab. The impact of FcγR3A functional polymorphism was assessed on the activation status of NK cells and the viability of JEG-3 choriocarcinoma cells. Finally, the data from TROPHIMMUN trial were reanalyzed to determine the impact of the FcγR3A polymorphism of patients on their response to avelumab., Results: We confirmed that FcγR3A+ NK cells infiltrated PD-L1-expressing GTN. In vitro, avelumab-coated JEG-3 choriocarcinoma cells induced NK cell activation, which promoted the destruction of JEG-3 cells. NK cell activation was abolished when the Fc portion of avelumab was removed, demonstrating the importance of Fcγ receptor in this process. Using this model of ADCC, we demonstrated that high-affinity FcγR3A polymorphism on NK cells was associated with better in vitro response to avelumab. In line with this result, patients from the TROPHIMMUN trial homozygous for the high affinity FcγR3A polymorphism had better clinical response to avelumab., Conclusions: Our work demonstrates that ADCC contributes to the therapeutic effect of avelumab in GTN and that the individual patient response is impacted by the FcγR3A polymorphism. The FcγR3A polymorphism could be used as a biomarker to identify patients diagnosed with monochemoresistant GTN who are most likely to respond to avelumab., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Myeloid sarcoma (MS) is a rare extra-medullary manifestation of acute myeloid leukaemia (AML) in the form of a first manifestation, progression or recurrence. Mostly located in the bones, it has the particularity of reaching the ENT sphere by mimicking common patho-logies, leading to a delay in diagnosis and treatment. The -mastoid involvement that we have encountered in our clinical -practice (clinical vignette) shows the complexity of identifying this pathology, with very few cases reported in the literature. The anamnesis, including a -history of AML, and the clinical examination help to guide the investigations. Targeted imaging, in this case CT/MRI combined with a biopsy of the lesion and a marrow puncture, is used to make the -diagnosis. Treatment with chemotherapy is indicated and rapidly initiated., Competing Interests: Les auteur-es n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Indeterminate dendritic cell histiocytosis (IDCH) is a rare and poorly understood entity characterized by accumulation of CD1a+/S100+ histiocytes (as Langerhans cell histiocytosis (LCH)), but with reduced-absent expression of Langerin/CD207. We assembled 43 cases of IDCH (defined by CD1a+/CD207<20% immunophenotypic profile) examining the clinical, pathologic, and molecular landscape. Median age at presentation was 70 years (IQR: 44-80 years) with cutaneous (31/43; 72%) and nodal (11/43; 26%) involvement predominating. Eighteen (42%) individuals had an associated non-histiocytic hematopoietic neoplasm ('secondary' IDCH) while 7 of 43 (16%) had a concurrent non-IDCH histiocytosis ('mixed' histiocytosis). Most cases exhibited morphology indistinguishable from LCH but with a CD1c+/CSF1R(CD115)-phenotype, mirroring the signature of normal indeterminate cells and conventional dendritic cell type 2. Mutational analysis revealed frequent KRAS (13/32; 41%), and BRAF p.V600E (11/36, 31%) mutations that were nearly mutually exclusive. RNAseq analysis uncovered ETV3::NCOA2 fusion in 6 other patients presenting as a sole genetic alteration without any other concurrent histiocytic or hematopoietic neoplasm. BRAF and MAP2K1 alterations were significantly associated with partial/retained (1-20%) Langerin expression (P = .005) and mixed histiocytosis (P = .002). Remarkably, myeloid alterations (DNMT3A, TET2 and SRSF2) co-occurred in IDCH tissues of several individuals. Paired sequencing of IDCH and concurrent non-IDCH hematopoietic neoplasm in four individuals revealed shared mutations. Age at diagnosis and any nodal involvement at diagnosis predicted inferior overall survival, but BRAF/RAS pathway alterations did not impact outcome. These data have implications for the diagnostic evaluation, classification, and therapeutic management of IDCH., (Copyright © 2024 American Society of Hematology.)

Chondrosarcoma (CHS), also known as malignant cartilage tumors, is the second most common bone cancer after osteosarcoma. This tumor is particularly chemo- and radioresistant, and the only therapeutic alternative is surgery with wide margins. The tumor immune microenvironment reveals an infiltration of tumor-associated macrophages (TAMs) sometimes approaching 50% of the tumor mass, mainly differentiated into M2-like phenotype and correlated with poor prognosis and metastasis. Thus, macrophage-targeting therapies could have an interest in the management of CHS. To evaluate these strategies, we propose here the development of a three-dimensional (3D) tumoroid co-culture model between two human CHS cell lines (JJ012 and CH2879) and a human leukemia monocytic cell line (THP-1) in a methylcellulose matrix. These two models were compared to the in vivo xenograft models in terms of macrophage phenotypes, proteoglycans, MMP-9, and COX-2 expression. Finally, mifamurtide, an immunomodulator acting on TAMs, was evaluated on the most in vitro relevant model: 3D co-culture CH2879 model. Our results showed that it is now possible to develop 3D models that very accurately mimic what is found in vivo with the possibility of evaluating treatments specific to a tumor cell component.

In the face of climate change, Health is mobilizing to find solutions and reduce its environmental impact. The CAP (understand, act and share) sustainable hospital toolbox cited in the roadmap for the Ecological Planning of the French Health System offers 3 original, operational and complementary tools to: (1) acculturate professionals in the sector (Plan Health Faire®), (2) build the establishment strategy (2030 Agenda), and (3) take action with healthcare professionals (The Sustainable Units program)., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: The healthcare sector is a major contributor to greenhouse gas emissions, accounting for 8 % of annual French emissions. Eco-design in healthcare, which provides care with equal quality, safety, and relevance but with a lower environmental impact, is therefore a crucial lever for sustainable medical practice. This article explores the application of eco-design in anatomical and cytopathological practices (ACP) in France, in response to the country's decarbonization goals., Objectives: After demonstrating that decarbonization is possible through the chosen eco-design of care and practices in ACP, we describe the barriers to these changes and the potential real-world solutions., Discussion: We examine the challenges and solutions for integrating eco-design principles into daily ACP practice, highlighting the importance of the relevance of medical procedures to reduce unnecessary practices. We discuss the technical and human barriers in ACP, as well as the solutions: raising awareness among laboratory personnel, industrial stakeholders, research and innovation, the involvement of scientific societies, and initiatives from the collective for Ecological Transformation in ACP (TEAP). Finally, we propose financial incentives to make eco-friendly practices economically viable in ACP., Conclusion: Eco-design in ACP practices is essential to address the climate challenge and ensure the sustainability of the healthcare system., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Global warming and the disruption in ecosystems have been identified as the greatest threats to human health in the 21st century. Today, the French healthcare system accounts for 6.6% to 10% of overall greenhouse gas emissions in France. This system is currently not resilient and totally dependent on fossil fuels. Therefore, a transformation of the current system is needed in order to reduce the deterioration of populations' health. Medical education and pedagogy have been identified as a major solution for the ecological transformation of the healthcare system. The introduction of early education on ecology and environmental health in the first and second cycles of medical studies is a major lever for action. From the third cycle of medical studies, and more specifically in pathology, it is essential to teach this topic to residents and experienced pathologists, whether in "theoretical teaching" or "applied to the medical specialty". The aim of this review is to identify the educational programs and training currently available in the medical courses and at the post-graduate level, regarding ecology/environmental health and the consequences on human health. Then, we will detail more specifically the pedagogical perspectives and training opportunities for pathology residents and pathologists., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: This study describes our experience implementing a connected prescription software (NetSIG, Terascop) for molecular pathology exams., Material and Methods: NetSIG was set up for liquid biopsies and tissue testing. After registration and activation of regional pathology laboratories, NetSIG was implemented for external then internal prescriptions., Results: NetSIG allows users to follow up on all prescriptions on the website, to interact through messages and to consult reports after validation. External set up was quick (3-4 months) and comprehensive (>70%). Prescriptions were made by physicians or more often by secretaries or referring pathologists. Internal prescriptions were made by pathologists then registered in NetSIG by our secretaries. This deployment strategy has resulted in very good completeness of prescriptions (>90%)., Discussion and Conclusion: Connected prescriptions made this complex circuit more fluid and facilitated the redistribution of different administrative and technical tasks. The number of phone calls decreased sharply. Half of the prescriptions were made by pathologists and half by oncologists (physicians or secretaries). The mean dearchiving duration for blocks was one day. Mean forwarding of blocks was 2.5 days. Mean turnaround time was 8 days for targeted techniques and 13 days for Next Generation Sequencing. Physicians appreciated the interactivity of the software and the fact that they could consult it on a smartphone., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Formalin is the international gold-standard fixative in pathology laboratories. However it is not the ideal one considering its deleterious effects on individuals and the environment. Complete formalin removal or even substitution does not seem possible in the near future. In this update, we present various tools allowing to integrate the use of formalin into an ecocare approach. Among them, formalin recycling according to the protocol developed by the University Hospital of Bordeaux is simple to implement and delivers rapid and significant results, allowing pathology professionals to meet the sustainable development objectives included in the France 2030 agenda., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

While digitization and artificial intelligence represent the future of our specialty, future is also constrained by global warming and overstepping of planetary limits, threatening human health and the functioning of the healthcare system. The report by the Délégation ministérielle du numérique en santé and the French government's ecological planning of the healthcare system confirm the need to control the environmental impact of digital technology. Indeed, despite the promises of dematerialization, digital technology is a very material industry, generating greenhouse gas emissions, problematic consumption of water and mineral resources, and social impacts. The digital sector is impacting at every stage: (i) manufacture of equipment; (ii) use; and (iii) end-of-life of equipment, which, when recycled, can only be recycled to a very limited extent. This is a fast-growing sector, and the digitization of our specialty is part of its acceleration and its impact. Understanding the consequences of digitalization and artificial intelligence, and phenomena such as the rebound effect, is an essential prerequisite for the implementation of a sober, responsible, and sustainable digital pathology. The aim of this update is to help pathologists better understand the environmental impact of digital technology. As healthcare professionals, we have a responsibility to combine technological advances with an awareness of their impact, within a systemic vision of human health., (Copyright © 2024. Published by Elsevier Masson SAS.)

The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for pituitary neuroendocrine tumors (PitNETs) to improve the quality of their histological diagnosis. Each center performed at least 30 histological cases of PitNETs using the EPPG tools and assessed their value using a scorecard with 10 questions. For each center, the histological cases were carried out by pathologists with varying levels of expertise in pituitary pathology defined as junior, intermediate, and expert. Two hundred and ninety histological cases were collected from six French and Italian centers. The three EPPG tools were validated and regarded as helpful for a more accurate and time-efficient diagnosis. The usefulness of level 2 and level 3 of the "EPPG's multi-step approach for immunohistochemistry" including pituitary transcription factors (PIT1, TPIT, and SF1) and chromogranin, SSTRs, and P53 respectively was higher in "other non-functioning" (silent plurihormonal PIT1, silent corticotroph, and null cell): 88% vs 32%, p < 10-6 and 42% vs 14%, p = 0.002, respectively. The diagnostic algorithm proved more useful for junior pathologists (p = 0.0001) and those with intermediate experience. PIT-EASY survey confirmed the importance of a standardized approach to PitNETs for an accurate and reproducible diagnosis and served as validation of the EPPG proposal. The tool appeared to be of practical value to junior participants and staff with intermediate experience for safe routine diagnostic reporting., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described., Method: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases., Results: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM , outside of the two previously known mutational hotspots., Conclusion: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis., Objectives: We aim to describe the clinico-pathological characteristics and prognostic value of pMF., Methods: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF)., Results: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5])., Conclusion: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas., (© 2024 European Academy of Dermatology and Venereology.)

Introduction: Imlifidase is authorized for desensitization of highly sensitized adult kidney transplant candidates with a positive crossmatch (XM) against a deceased donor. Here, we report on the results for the first 9 patients transplanted in this context who had at least 3 months of follow-up., Methods: The eligibility criteria were as follows: calculated panel reactive antibodies (cPRA) ³ 98%, ³ 3 years on the waiting list, immunodominant donor-specific antibodies (DSAs) with mean fluorescence intensity (MFI) > 6000 (and < 5000 at 1:10 dilution) and a negative post-imlifidase complement-dependent cytotoxic XM (CDCXM)., Results: All 9 patients had been on dialysis for an average of 123 ± 41 months, with cPRA at 99% ( n  = 2) or 100% ( n  = 7). At transplantation, the mean number of DSAs was 4.3 ± 1.4. The median immunodominant DSA MFI was 9153 (6430-16,980). Flow cytometry XM (FCXM) and CDCXM before imlifidase were positive in 9 and 2 patients, respectively. After 1 injection of imlifidase, all were negative. Patients received polyclonal antibodies, i.v. Igs (IVIg), rituximab, tacrolimus, and mycophenolate. Five patients had a DSA rebound within the first 14 days: 2 had concomitant clinical antibody-mediated rejection (ABMR), 2 had subclinical ABMR, and 1 had isolated positive C4d staining. No ABMR was observed in patients without rebound. Chronic Kidney Disease-Epidemiology Collaboration formula estimated glomerular filtration rate (eGFR) was 56 ± 22 ml/min per 1.73 m 2 at the last follow-up (7 ± 2.8 months). No graft loss or death were observed. Four patients developed at least 1 infection., Conclusion: These real-life data demonstrate that the use of imlifidase to desensitize highly sensitized patients can have an acceptable short-term efficacy and safety profile in selected patients., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival., Methods: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group., Results: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P <0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous ( P =0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade ( P =0.977) and location ( P =0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion ( P =0.387)., Conclusion: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Chikungunya virus, an arthropod-borne pathogen is recognized by the World Health Organization as a top priority Emerging Infectious Disease and is ranked fourth in public health needs according to the Coalition for Epidemic Preparedness Innovations. Despite its substantial impact, as evidenced by an annual estimate of 120 274 disability-adjusted life years, our understanding of the chronic aspects of chikungunya disease remains limited. This review focuses on chronic chikungunya disease, emphasizing its clinical manifestations, immunopathogenesis, therapeutic options and disease burden., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians.)

Background: T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables., Methods: We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression., Findings: CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS., Interpretation: In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination., Funding: This research received no external funding., Competing Interests: Declaration of interests JT has received honoraria as a speaker and/or in an advisory role from AMGEN, Astellas, Astra Zeneca, BMS, Merck KGaA, MSD, Novartis, ONO pharmaceuticals, Pierre Fabre, Roche Genentech, Sanofi and Servier. CL has received honoraria as a speaker and/or in an advisory role from AMGEN, AAA-Novartis, Takeda, Deciphera, Pierre Fabre, Servier. FG's institution has received grants or contracts from Astra, consulting fees from Roche, AMGEN and MSD, honoraria as a speaker from Merck and support for attending meetings and/or travel from AMGEN. FB has received honoraria for lectures, speakers, presentations, manuscript writing or educational events from MSD, Pierre Fabre, Sanofi, BMS, Incyte, Servier and Astellas and support for attending meetings and/or travel from AMGEN, Pierre Fabre and MSD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19) affects the respiratory system. Studying the clinical characteristics of this infection has revealed its tropism to the nervous system, which is responsible for neurological and sensory damage, in particular, dizziness and hearing loss. To determine the frequency and characteristics of the neurological impairment represented by dizziness and hearing loss in healthcare professionals (HCP) with COVID-19. Cross-sectional descriptive study conducted among HCP at Charles Nicolle Hospital (CNH) in Tunis affected by COVID-19 during the period from September 2020 to December 2020. Data collection was carried out by regular telephone follow-up of COVID-19 symptoms in these HCPs during the period of sanitary isolation. A total of 482 HCPs with COVID-19 were collected. The average age of the population was 41 ± 10 years, of which 111 were men (23%) and 371 were women (77%). The main neurological manifestations were: headache (71.2%), anosmia (60%), dizziness (21.8%), and hearing loss (1.5%). Patients with vertigo were significantly older (P=0.035), female (P=0.003), obese (P=0.014), suffering from more comorbidities (P=0.004), and having greater professional seniority (P=0.009). Dizziness was significantly associated with fever (P=0.001), abdominal pain (P=0.001), and desaturation (P=0.039). Neurological symptoms including dizziness and hearing loss may be the only sign with which a case of COVID-19 could be recognized. Raising awareness of such a presentation of COVID-19 patients is crucial during this pandemic period to prevent infectious spread, especially in hospitals., Competing Interests: Les auteurs ne déclarent aucun conflit d´intérêts., (Copyright: Bahri Ghada et al.)

Introduction: Hairy-cell leukemia (HCL) is a rare B-cell chronic lymphoproliferative disorder (B-CLPD), whose favorable prognosis has changed with the use of purine nucleoside analogs (PNAs), such as cladribine (CDA) or pentostatin (P). However, some patients eventually relapse and over time HCL becomes resistant to chemotherapy. Many discoveries have been made in the pathophysiology of HCL during the last decade, especially in genomics, with the identification of the BRAF V600E mutation and cellular biology, including the importance of signaling pathways as well as tumor microenvironment. All of these new developments led to targeted treatments, especially BRAF inhibitors (BRAFis), MEK inhibitors (MEKis), Bruton's tyrosine kinase (BTK) inhibitors (BTKis) and recombinant anti-CD22 immunoconjugates., Results: The following major changes or additions were introduced in these updated guidelines: the clinical relevance of the changes in the classification of splenic B-cell lymphomas and leukemias; the increasingly important diagnostic role of BRAF V600E mutation; and the prognostic role of the immunoglobulin (IG) variable (V) heavy chain (H) ( IGHV ) mutational status and repertory. We also wish to insist on the specific involvement of bones, skin, brain and/or cerebrospinal fluid (CSF) of the disease at diagnosis or during the follow-up, the novel targeted drugs (BRAFi and MEKi) used for HCL treatment, and the increasing role of minimal residual disease (MRD) assessment., Conclusion: Here we present recommendations for the diagnosis of HCL, treatment in first line and in relapsed/refractory patients as well as for HCL-like disorders including HCL variant (HCL-V)/splenic B-cell lymphomas/leukemias with prominent nucleoli (SBLPN) and splenic diffuse red pulp lymphoma (SDRPL)., Competing Interests: JP: Incyte, Kite/Gilead. CT: Janssen, AstraZeneca, Abbvis, Beigene, Lipomed. XT: Abbvie, Beigene, Deciphera, Hikma, Lipomed. All other authors declare no conflicts of interest.

Objective: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes., Methods: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes., Results: The cohort exhibited a large genetic heterogeneity, with the identification of 172 distinct genes and 253 novel variants. Among children, a notable prevalence of pathogenic variants in genes associated with oxidative phosphorylation (OXPHOS) functions and mitochondrial translation was observed. In adults, pathogenic variants were primarily identified in genes linked to mtDNA maintenance. Additionally, a substantial proportion of patients (54% (42/78) and 48% (13/27) in children and adults, respectively), undergoing WES or WGS testing displayed PMD mimics, representing pathologies that clinically resemble mitochondrial diseases., Interpretation: We reported the largest French cohort of patients suspected of PMD with pathogenic variants in nuclear genes. We have emphasized the clinical complexity of PMD and the challenges associated with recognizing and distinguishing them from other pathologies, particularly neuromuscular disorders. We confirmed that WES/WGS, instead of panel approach, was more valuable to identify the genetic basis in patients with "possible" PMD and we provided a genetic testing flowchart to guide physicians in their diagnostic strategy., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

We created valrubicin-loaded immunoliposomes (Val-ILs) using the antitumor prodrug valrubicin, a hydrophobic analog of daunorubicin. Being lipophilic, valrubicin readily incorporated Val-lLs that were loaded with specific antibodies. Val-ILs injected intravenously rapidly reached the bone marrow and spleen, indicating their potential to effectively target cancer cells in these areas. Following the transplantation of human pediatric B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML) in immunodeficient NSG mice, we generated patient-derived xenograft (PDX) models, which were treated with Val-ILs loaded with antibodies to target CD19, CD7 or CD33. Only a small amount of valrubicin incorporated into Val-ILs was needed to induce leukemia cell death in vivo, suggesting that this approach could be used to efficiently treat acute leukemia cells. We also demonstrated that Val-ILs could reduce the risk of contamination of CD34 + hematopoietic stem cells by acute leukemia cells during autologous peripheral blood stem cell transplantation, which is a significant advantage for clinical applications. Using EL4 lymphoma cells on immunocompetent C57BL/6 mice, we also highlighted the potential of Val-ILs to target immunosuppressive cell populations in the spleen, which could be valuable in impairing cancer cell expansion, particularly in lymphoma cases. The most efficient Val-ILs were found to be those loaded with CD11b or CD223 antibodies, which, respectively, target the myeloid-derived suppressor cells (MDSC) or the lymphocyte-activation gene 3 (LAG-3 or CD223) on T4 lymphocytes. This study provides a promising preclinical demonstration of the effectiveness and ease of preparation of Val-ILs as a novel nanoparticle technology. In the context of hematological cancers, Val-ILs have the potential to be used as a precise and effective therapy based on targeted vesicle-mediated cell death., (© 2024. The Author(s).)

Chondroblastoma is a rare benign cartilaginous tumor mostly confined to the epiphyses and apophyses. Cases outside the epiphyseal region are exceedingly rare. Extramedullary chondroblastomas are exceptional; to our knowledge, only two cases qualified as "periosteal chondroblastoma" have been described in the literature. We report two cases of metaphyseal periosteal chondroblastoma both located on the inferior surface of the femoral neck. Both cases were paucicellular with an unusual dense sclerotic reaction. The diagnosis of chondroblastoma was supported by the expression of histone 3.3, K36M mutant in tumor cells., (© 2023. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Background: Ovarian pseudomyxoma peritonei (OPMP) are rare, without well-defined therapeutic guidelines. We aimed to evaluate cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat OPMP., Methods: Patients from the French National Network for Rare Peritoneal Tumors (RENAPE) database with proven OPMP treated by CRS/HIPEC and with histologically normal appendix and digestive endoscopy were retrospectively included. Clinical and follow-up data were collected. Histopathological and immunohistochemical features were reviewed., Results: Fifteen patients with a median age of 56 years were included. The median Peritoneal Cancer Index was 16. Following CRS, the completeness of cytoreduction (CC) score was CC-0 for 9/15 (60%) patients, CC-1 for 5/15 (33.3%) patients, and CC-2 for 1/15 (6.7%) patients. The median tumor size was 22.5 cm. After pathological review and immunohistochemical studies, tumors were classified as Group 1 (mucinous ovarian epithelial neoplasms) in 3/15 (20%) patients; Group 2 (mucinous neoplasm in ovarian teratoma) in 4/15 (26.7%) patients; Group 3 (mucinous neoplasm probably arising in ovarian teratoma) in 5/15 (33.3%) patients; and Group 4 (non-specific group) in 3/15 (20%) patients. Peritoneal lesions were OPMP pM1a/acellular, pM1b/grade 1 (hypocellular) and pM1b/grade 3 (signet-ring cells) in 13/15 (86.7%), 1/15 (6.7%) and 1/15 (6.7%) patients, respectively. Disease-free survival analysis showed a difference (p = 0.0463) between OPMP with teratoma/likely-teratoma origin (groups 2 and 3; 100% at 1, 5, and 10 years), and other groups (groups 1 and 4; 100%, 66.6%, and 50% at 1, 5, and 10 years, respectively)., Conclusion: These results suggested that a primary therapeutic strategy using complete CRS/HIPEC for patients with OPMP led to favorable long-term outcomes., (© 2024. The Author(s).)

Background: The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status., Methods: The study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS)., Results: We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with SeqOne assay and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68-1.42) and 1.05 (95% CI; 0.70-1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay., Conclusion: The SeqOne assay offers a clinically validated approach to detect HRD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Declaration of interest of the paper entitled “Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer”. D. Bertrand, N. Duforet, C. Gottin, N. Philippe, and J. Ruzicka have filed a patent application with the European Patent Office on June 24, 2022 (application number EP 22181091.4) and an international patent application with the WIPO on June 23, 2023 (application number PCT/EP2023/067179), entitled "DEVICE FOR DETERMINING AN INDICATOR OF PRESENCE OF HRD IN A GENOME OF A SUBJECT". M. Blum, C. Gottin, J. Ruzicka, T. Delhomme, J. Audoux, N. Duforet-Frebourg, D. Bertrand, N. Philippe are employees of SeqOne Genomics. M.-P. Wissler is employed by Cypath. She received consulting fees from AstraZeneca and she was a speaker for seminars sponsored by Amgen, AstraZeneca, MSD, Roche, and Servier. A. Jeanniard is employed by Agilent. E. Pujade Lauraine was a member of advisory boards for AstraZeneca, GSK, and Roche. He was on the IDMC board at Agenus and Incyte. He is employed by ARCAGY-research. I. Vergote discloses financial relationships with Agenus, Akesobio, AstraZeneca, Bristol Myers Squibb, Deciphera Pharmaceuticals, Eisai, Elevar Therapeutics, Exelixis, F. Hoffmann-La Roche, Genmab, GSK, Immunogen, Jazzpharma, Karyopharm, Mersana, MSD, Novocure, Novartis, Oncoinvent, OncXerna, Regeneron, Sanofi, Seagen, Sotio, Verastem Oncology, Zentalis, Oncoinvent AS, Amgen, Roche, Karyopharm, Genmab, Novocure. A. J. Gonzalez Martin discloses financial relationship with Alkermes, Amgen, Astrazeneca, Clovis, Eisai, Genmab, Gsk, Hederadx, Illumina, Inmunogen, Macrogenics, Mersana, MSD, Novartis, Novocure, Oncoinvent, Pharmamar, Regeneron, Roche, Sotio, Sutro, Takeda, Zaylab. He has also non-financial relationships with Aravive, GSK, MSD, Novartis, and Roche. N. Colombo received Grants or contracts from AstraZeneca, PharmaMar and Roche. She received payment or honoraria for lectures, presentations, or educational events from AstraZeneca, Tesaro, Novartis, Clovis Oncology, Merck Sharp and Dohme, GlaxoSmithKline and Eisai. She participated on a Data Safety Monitoring Board or Advisory Board for Roche, PharmaMar, AstraZeneca, Clovis Oncology, Merck Sharp and Dohme, GlaxoSmithKline, Tesaro, Pfizer, BioCad, Immunogen, Mersana, Eisai, Oncxema and Nuvation Bio. P. Alexandre received paid honoraria from GSK and Roche. K. Fujiwara received consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, and Takeda Pharmaceutical Company, receiving grant support from Immunogen, Oncotherapy, and Regeneron, and receiving consulting fees from Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, and NanoCarrier. J. Mäenpää received honoraria from AstraZeneca and GSK. K. Fujiwara received consulting fees and grant support from Pfizer, Eisai, Merck Sharp & Dohme, Taiho, Zeria, Chugai Pharmaceutical, Genmab, Takeda Pharmaceutical Company, Novartis, Kyowa Hakko Kirin, Daiichi Sankyo, Mochida Pharmaceutical, and NanoCarrier, and received a grant support from Immunogen, Oncotherapy, and Regeneron. P. Harter discloses grant supports from AstraZeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Clovis. He did consulting activities for AstraZeneca. He was a member of advisory councils for AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, and Eisai. He did lectures for Amgen, AstraZeneca, GSK, Roche, Sotio, Stryker, Zai Lab, MSD, Clovis, Eisai. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 μmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Megacystis-microcolon-hypoperistalsis-syndrome (MMIHS) is a rare and early-onset congenital disease characterized by massive abdominal distension due to a large non-obstructive bladder, a microcolon and decreased or absent intestinal peristalsis. While in most cases inheritance is autosomal dominant and associated with heterozygous variant in ACTG2 gene, an autosomal recessive transmission has also been described including pathogenic bialellic loss-of-function variants in MYH11. We report here a novel family with visceral myopathy related to MYH11 gene, confirmed by whole genome sequencing (WGS). WGS was performed in two siblings with unusual presentation of MMIHS and their two healthy parents. The 38 years-old brother had severe bladder dysfunction and intestinal obstruction, whereas the 30 years-old sister suffered from end-stage kidney disease with neurogenic bladder and recurrent sigmoid volvulus. WGS was completed by retrospective digestive pathological analyses. Compound heterozygous variants of MYH11 gene were identified, associating a deletion of 1.2 Mb encompassing MYH11 inherited from the father and an in-frame variant c.2578&#95;2580del, p.Glu860del inherited from the mother. Pathology analyses of the colon and the rectum revealed structural changes which significance of which is discussed. Cardiac and vascular assessment of the mother was normal. This is the second report of a visceral myopathy corresponding to late-onset form of MMIHS related to compound heterozygosity in MYH11; with complete gene deletion and a hypomorphic allele in trans. The hypomorphic allele harbored by the mother raised the question of the risk of aortic disease in adults. This case shows the interest of WGS in deciphering complex phenotypes, allowing adapted diagnosis and genetic counselling., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Somatic cells that have been partially reprogrammed by the factors Oct4, Sox2, Klf4, and cMyc (OSKM) have been demonstrated to be potentially tumorigenic in vitro and in vivo due to the acquisition of cancer-associated genomic alterations and the absence of OSKM clearance over time. In the present study, we obtained partially reprogrammed, SSEA1-negative cells by transducing murine hepatocytes with Δ1Δ3-deleted adenoviruses that expressed the 4 OSKM factors. We observed that, under long-term 2D and 3D culture conditions, hepatocytes could be converted into LGR5-positive cells with self-renewal capacity that was dependent on 3 cross-signaling pathways: IL6/Jak/Stat3, LGR5/R-spondin, and Wnt/β-catenin. Following engraftment in syngeneic mice, LGR5-positive cells that expressed the cancer markers CD51, CD166, and CD73 were capable of forming invasive and metastatic tumors reminiscent of intrahepatic cholangiocarcinoma (ICC): they were positive for CK19 and CK7, featured associations of cord-like structures, and contained cuboidal and atypical cells with dissimilar degrees of pleomorphism and mitosis. The LGR5+-derived tumors exhibited a highly vascularized stroma with substantial fibrosis. In addition, we identified pro-angiogenic factors and signaling pathways involved in neo-angiogenesis and vascular development, which represent potential new targets for anti-angiogenic strategies to overcome tumor resistance to current ICC treatments., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Non-invasive subtyping of hepatocellular adenomas (HCA) remains challenging for several subtypes, thus carrying different levels of risks and management. The goal of this study is to devise a multivariable diagnostic model based on basic clinical features (age and sex) combined with MRI-radiomics and to evaluate its diagnostic performance., Methods: This single-center retrospective case-control study included all consecutive patients with HCA identified within the pathological database from our institution from January 2003 to April 2018 with MRI examination (T2, T1-no injection/injection-arterial-portal); volumes of interest were manually delineated in adenomas and 38 textural features were extracted (LIFEx, v5.10). Qualitative (i.e., visual on MRI) and automatic (computer-assisted) analysis were compared. The prognostic scores of a multivariable diagnostic model based on basic clinical features (age and sex) combined with MRI-radiomics (tumor volume and texture features) were assessed using a cross-validated Random Forest algorithm., Results: Via visual MR-analysis, HCA subgroups could be classified with balanced accuracies of 80.8 % (I-HCA or ß-I-HCA, the two being indistinguishable), 81.8 % (H-HCA) and 74.4 % (sh-HCA or ß-HCA also indistinguishable). Using a model including age, sex, volume and texture variables, HCA subgroups were predicted (multivariate classification) with an averaged balanced accuracy of 58.6 %, best=73.8 % (sh-HCA) and 71.9 % (ß-HCA). I-HCA and ß-I-HCA could be also distinguished (binary classification) with a balanced accuracy of 73 %., Conclusion: Multiple HCA subtyping could be improved using machine-learning algorithms including two clinical features, i.e., age and sex, combined with MRI-radiomics. Future HCA studies enrolling more patients will further test the validity of the model., Competing Interests: 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., (© 2024 The Authors.)

Androgenetic alopecia, the most prevalent type of hair loss, is characterized by a receding hairline in men and diffuse thinning of hair in women. Despite being considered a benign condition, it can exert a considerable psychological toll, especially on women and young men. Despite its high prevalence, only a limited number of medications have received approval for its treatment. In this article, we review the available treatment options, assessing their efficacy and potential side effects. Additionally, we explore minimally-invasive strategies such as photobiomodulation, micro-needling and platelet-rich plasma therapy. Furthermore, we delve into discussions on hair transplantation and camouflage methods., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: While opportunistic infections are a frequent and challenging problem in kidney transplant recipients, their long-term epidemiology remains hardly known., Methods: Opportunistic infections were recorded in 1144 recipients transplanted in our center between 2004 and 2015. Incidence rates and baseline risk factors were determined using joint frailty models., Results: After a median follow-up of 5.6 years, 544 opportunistic infections occurred in 373/1144 (33%) patients, dominated by viral infections (396/544, 72%), especially cytomegalovirus (CMV) syndromes and diseases (213/544, 39%). One-third of the infected patients experienced at least two opportunistic infections. The incidence of opportunistic infections was 10 times higher during the first year post-transplantation than after that (34.7 infections for 100 patient-years vs 3.64). Opportunistic infections associated with the age of the donor (P = .032), the age of the recipient (P = .049), the CMV serostatus (P < 10-6), a higher class II HLA mismatch (P = .032) and an induction treatment including rabbit anti-thymocyte globulins (P = .026). Repeated opportunistic infections associated with each other (P < 10-6) and with renal death (P < 10-6)., Conclusion: Opportunistic infections occur with a two-period incidence pattern and many susceptible patients suffer from repeated episodes. This knowledge may help tailor new prevention and follow-up strategies to reduce the burden of opportunistic infections and their impact on transplantation outcome., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: Legionnaires disease (LD) is a rare, life-threatening opportunistic bacterial infection that poses a significant risk to patients with impaired cell-mediated immunity such as solid organ transplant recipients. However, the epidemiologic features, clinical presentation, and outcomes of LD in this population are poorly described., Research Question: What are the clinical manifestations, radiologic presentation, risk factors for severity, treatment, and outcome of LD in solid organ transplant recipients?, Study Design and Methods: In this 10-year multicenter retrospective cohort study in France, where LD notification is mandatory, patients were identified by hospital discharge databases. Diagnosis of LD relied on positive culture findings from any respiratory sample, positive urinary antigen test (UAT) results, positive specific serologic findings, or a combination thereof. Severe LD was defined as admission to the ICU., Results: One hundred one patients from 51 transplantation centers were eligible; 64 patients (63.4%) were kidney transplant recipients. Median time between transplantation and LD was 5.6 years (interquartile range, 1.5-12 years). UAT results were positive in 92% of patients (89/97). Among 31 patients with positive culture findings in respiratory samples, Legionella pneumophila serogroup 1 was identified in 90%. Chest CT imaging showed alveolar consolidation in 98% of patients (54 of 57), ground-glass opacity in 63% of patients (36 of 57), macronodules in 21% of patients (12 of 57), and cavitation in 8.8% of patients (5 of 57). Fifty-seven patients (56%) were hospitalized in the ICU. In multivariate analysis, severe LD was associated with negative UAT findings at presentation (P = .047), lymphopenia (P = .014), respiratory symptoms (P = .010), and pleural effusion (P = .039). The 30-day and 12-month mortality rates were 8% (8 of 101) and 20% (19 of 97), respectively. In multivariate analysis, diabetes mellitus was the only factor associated with 12-month mortality (hazard ratio, 3.2; 95% OR, 1.19-8.64; P = .022)., Interpretation: LD is a late and severe complication occurring in solid organ transplant recipients that may present as pulmonary nodules on which diabetes impacts its long-term prognosis., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Recent advances in the field of immuno-oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high-throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi-marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)