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Malignant peripheral nerve sheath tumors (MPNSTs) are the leading cause of death in patients with neurofibromatosis type 1. They can result from premalignant neurofibromas, including neurofibromas with atypia and atypical neurofibromatous neoplasms of uncertain biologic potential. Some phenotypic characteristics have been described as associated with their development. The aim of this study was to outline our use of whole-body positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1, especially in the screening of asymptomatic individuals with a higher risk of developing an MPNST, and to study its impact on neurofibroma classification (malignant vs premalignant) and MPNST staging over time. Individuals with neurofibromatosis type 1 who underwent a positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging between 2017 and 2021 were included, analyzing separately the screened population. Maximum standard uptake value and diffusion-weighted imaging were assessed. Biopsy/surgery confirmed the diagnosis. In all, 345 positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging were performed in 241 patients, including 149 asymptomatic (62%) but at-risk patients. Eight MPNSTs in 8 screened individuals (5%), 6 neurofibromas with atypia in 4 individuals (3%), and 29 atypical neurofibromatous neoplasms of uncertain biologic potential in 23 individuals (15%) were diagnosed. Over time, the proportion of grade 3 MPNST and the malignant/premalignant ratio in screened individuals significantly decreased (P = .03 and P < .001, respectively). This study emphasizes the diagnostic and screening performances of whole-body positron emission tomography with 18 F-fluorodeoxyglucose/magnetic resonance imaging in adults with neurofibromatosis type 1., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P = .001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAX messenger RNA (mRNA) expression levels were assessed by PrimeFlow RNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2 expression. Ex vivo, autologous, antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2+ primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2 may be triggered by HTLV-1 infection and correlates with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (registered on https://clinicaltrials.gov as #NCT04984837)., (© 2022 by The American Society of Hematology.)

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell-mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52 ± 17 months posttransplant with severe concomitant acute T cell-mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (κ = 0.2, p = .005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade≥II mucosal rejection and grade 0/I skin rejection) (n = 55 [70%]) and concordant (grade≥II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p = .08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Since the first successful facial transplantation in 2005, the benefits of this procedure in terms of aesthetics, functionality, and quality of life have been firmly established. However, despite immunosuppressive treatment, long-term survival of the allograft might be compromised by chronic antibody-mediated rejection (CAMR), leading to irreversible necrosis of the tissue. In the absence of therapeutic options, this complication is inevitably life-threatening., Methods: We report facial retransplantation in a man, 8 years after his first facial transplantation because of extensive disfigurement from type 1 neurofibromatosis and 6 weeks after complete loss of his allograft due to severe CAMR. We describe the chronology of immune-related problems that culminated in allograft necrosis and the eventual loss of the facial transplant, the desensitisation protocol used for this highly immunosensitised recipient, the surgical technicalities of the procedure, the specific psychological management of this patient, and the results from follow-up at 30 months., Findings: Although the patient had a complicated postoperative course with numerous immunological, infectious, cardiorespiratory, and psychological events, he was discharged after a hospital stay of almost 1 year. He has since been able to re-integrate into his community with acceptable restoration of his quality of life., Interpretation: This clinical report of the first documented human facial retransplantation is proof-of-concept that the loss of a facial transplant after CAMR can be mitigated successfully by retransplantation combined with an aggressive desensitisation process., Funding: Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome frequently secondary to infectious disease, especially in immuno-compromised patients. We report a HLH secondary to disseminated nocardiosis and Streptomyces spp pulmonary infection., Case Report: A 69-years-old women had recent subcutaneous nodules of the forearms and loins associated with peripheral neuropathy and pulmonary nodule of the right upper lobe. Cutaneous biopsy revealed granuloma. Cutaneous lesions worsened and the patient developed a HLH with probable cardiac and neurological involvement, associated with cutaneous granulomatosis and diffuse polyclonal lymphocyte proliferation. Nocardia PCR was positive in cutaneous biopsy. Pulmonary samples revealed Streptomyces in culture and Nocardia in PCR. The evolution under antibiotic treatment was favorable., Conclusion: Recent diagnosis of HLH without obvious etiology should lead to etiological investigation, including the search for infections with slow-growing bacteria such as Nocardia or Streptomyces spp., (Copyright © 2019 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma associated with chemoresistance and a poor prognosis. Various nonsynonymous mutations in the R172 residue of IDH2 are present in 20% to 30% of AITL patients. In addition to their diagnostic value, these mutations are potentially targetable, especially by isocitrate dehydrogenase (IDH) 2 inhibitor, and therefore their identification in a routine setting is clinically relevant. However, in AITL, the neoplastic cells may be scarce, making the identification of molecular anomalies difficult. We evaluated the diagnostic value of different methods to detect IDH2 mutations in formalin-fixed, paraffin-embedded tumor samples. Immunohistochemistry with an anti-IDH2 R172K antibody, Sanger sequencing, high-resolution melting PCR, allele-specific real-time quantitative PCR, and next-generation sequencing (NGS) were applied to biopsy specimens from 42 AITL patients. We demonstrate that the IDH2 R172K antibody is specific to this amino acid substitution and highly sensitive for the detection of the IDH2 R172K variant, the most frequent substitution in this disease. In our study, NGS and allele-specific real-time quantitative PCR displayed a good sensitivity, detecting 96% and 92% of IDH2 mutations, respectively, in contrast to Sanger sequencing and high-resolution melting PCR, which showed a significantly lower detection rate (58% and 42%, respectively). These results suggest that a combination of immunohistochemistry and AS-PCR or NGS should be considered for the identification of IDH2 mutations in AITL in a routine setting., (Copyright © 2018 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Background: More than 30 face transplantations have been done worldwide since 2005 but no documented long-term follow-up has been reported in the literature. We aimed to answer remaining question about the long-term risks and benefits of face transplant., Methods: In this single-centre, prospective, open study, we assessed 20 patients presenting with facial defects. Ten patients were selected, and, after three were secondarily excluded, seven were transplanted: two with neurofibromatosis 1, one with a burn, and four with self-inflicted facial gunshot injuries. We report the long-term outcomes of six face allotransplant recipients at an average of 6 years (range 3·4-9 years) after the transplantation. All admissions to hospital except for planned revisions and immunosuppressive follow-up therapy were reported as adverse events (safety endpoint). Predefined immunological, metabolic, surgical, and social integration endpoints were collected prospectively. Patients underwent quantitative health-related quality of life assessments through Short Form 36 health questionnaires. This study was registered with ClinicalTrials.gov, number NCT00527280., Findings: Two of seven patients died: one at 65 days due to transplant destruction with concomitant pseudomonas infection and the second at 3·4 years after transplantation by suicide. The six patients alive at long-term follow-up presented with functional transplants. Safety endpoints were related to infection in the first month, acute rejection from 1 day to 7 years after transplantation, or side-effects of immunosuppressive therapy. Recurrent rejection episodes justified maintenance therapy with high-dose steroids at high levels in all patients at last follow-up, yet none of the patients developed diabetes. Three patients were found to have hypertension with one requiring therapy. All patients had a noticeable reduction in glomerular filtration rate. All recipients and their families accepted their transplant. Improvements in social integration and quality of life were highly variable among the patients and depended on baseline levels and psychiatric comorbidities., Interpretation: These long-term results show the crucial effect of patients' social support and pre-existing psychiatric conditions on the risk-benefit ratio of facial transplantation. Careful preoperative patient selection and long-term postoperative follow-up programmes under strict institutional review board controls should be used for any future grafts of this type., Funding: Protocole Hospitalier de Recherche Clinique (PHRC) National., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Hidradenitis suppurativa (HS) is a chronic, inflammatory, debilitating, follicular disease of the skin. Despite a high prevalence in the general population, the physiopathology of HS remains poorly understood. The use of antibiotics and immunosuppressive agents for therapy suggests a deregulated immune response to microflora. Using cellular and gene expression analyses, we found an increased number of infiltrating CD4(+) T cells secreting IL-17 and IFN-γ in perilesional and lesional skin of patients with HS. By contrast, IL-22-secreting CD4(+) T cells are not enriched in HS lesions contrasting with increased number of those cells in the blood of patients with HS. We showed that keratinocytes isolated from hair follicles of patients with HS secreted significantly more IL-1β, IP-10, and chemokine (C-C motif) ligand 5 (RANTES) either constitutively or on pattern recognition receptor stimulations. In addition, they displayed a distinct pattern of antimicrobial peptide production. These findings point out a functional defect of keratinocytes in HS leading to a balance prone to inflammatory responses. This is likely to favor a permissive environment for bacterial infections and chronic inflammation characterizing clinical outcomes in patients with HS., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

CD160 is expressed by human and mouse natural killer (NK) cells and other cytotoxic lymphocyte subpopulations. CD160 is mostly expressed as a trimeric 83 kDa glycosylphosphatidylinositol (GPI)-anchored activating NK receptor, cleaved upon IL-15 stimulation in a secreted trimeric soluble form (sCD160) that binds to major histocompatibility complex (MHC) class I molecules, while a transmembrane isoform appears. sCD160 exhibits immunoregulatory function as it inhibits CD8(+) T-lymphocyte cytotoxic activity. We show that human mast cells (MCs) express CD160. In human and mouse skin, resident MCs expressed CD160, whereas in C57BL/6-Kit(W-sh/W-sh) mice, CD160(+) cells were only identified at the site of reconstitution with syngeneic cultured MCs. In the human mast cell line, HMC-1, we only identified the transcripts of the GPI-anchored CD160 isoform. Furthermore, CD160 was identified in HMC-1 and mouse MC supernatants, suggesting that MCs release sCD160. Supporting this hypothesis, HMC-1 express the GPI-specific phospholipase D variant 2 involved in the NK lymphocyte membrane cleavage of CD160, and morphological studies highlighted a relative loss of CD160 expression in inflammatory skin sites, where MC degranulation is expected to occur. We also demonstrated an inhibition of T-cell cytotoxicity by HMC-1 supernatant that was partially reversed by anti-CD160 mAb. In conclusion, sCD160, produced by MCs, may have a role in T-cell-MC interactions in vivo.

Composite tissue allotransplantations can be indicated when autologous transfers fail to restore human appearance. We report the reproducibility, difficulties, serious adverse events and outcomes of our patients. Five patients were included in a registered clinical research protocol after thorough screenings assessed by an independent expert committee systematically discussing the alternative options. One patient suffered from plexiform neurofibromas, two from third degree burns and two from gunshot injuries. They were included on a national waiting list with a dedicated face procurement procedure. Transplants were harvested from heart beating brain-dead donors before other tissues and organs. Induction immunosuppressive therapy included antithymocyte globulins, steroids, mycophenolate mophetil and tacrolimus. Maintenance therapy included the last three ones associated with extracorporeal-photopheresis. Four patients were transplanted with 7- to 38-month follow-up. One could not due to multiple panel reactive antibodies after 18 months on waiting list. Acute cellular rejections were controlled by conventional treatment. Opportunistic infections affected all patients and lead one patient to die two month after the transplantation. Voluntary facial activity appeared from 3 to 5 month. Face transplantation has been reproducible under conventional immunosuppression. Major improvements in facial aesthetic and function allowed patients to recover social relations and improved their quality of life., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The risk to benefit ratio of face transplantation with a composite tissue allograft remains debatable, although this procedure is technically feasible. We report here a 1-year follow-up of a patient who underwent face transplantation with a composite tissue allograft., Methods: On Jan 21, 2007, a 29-year-old man with neurofibromatosis type 1 underwent resection of a massive plexiform neurofibroma diffusely infiltrating the middle and lower part of his face. The main goal was to restore both the cutaneous appearance and function of the face, including, in particular, control of orbicularis oculi and oris muscle contraction. The issues of immunosuppressive therapy, psychological outcome, and social reintergration were addressed, together with the monitoring of graft rejection by biopsies of the skin and mucosa., Findings: The initial postoperative course was uncomplicated. Two episodes of clinical rejection occurred on days 28 and 64. The second episode was associated with cytomegalovirus infection. Both episodes resolved favourably, with no further clinical signs of rejection, making the reduction of immunosuppressive treatment possible. A year after surgery, the functional outcome was very good, with successful sensory and motor reinnervation in the transplanted territory. Psychological recovery was excellent, with complete social reintegration., Interpretation: This case demonstrates the feasibility of surgically removing a large part of the face and replacing it with a composite tissue allograft. This facial repair procedure, which seems to have a satisfactory risk to benefit ratio, could be offered in rare and selected cases.

The distinction between Sézary syndrome (SS) and benign erythrodermic inflammatory diseases (EID) is difficult to make both clinically and on skin biopsies, since histomorphology can provide nonspecific results. New markers of circulating malignant Sézary cells have been recently described, especially CD158k/KIR3DL2 and T-plastin, but it has not been yet determined whether they could help in the diagnosis of erythroderma in skin samples. In this study, 13 frozen skin specimens from 10 SS patients and 26 from EID were analyzed for CD158k/KIR3DL2 expression using immunohistochemistry with AZ158 mAb, which also recognizes the monomeric CD158e/KIR3DL1 receptor. Although positive in all SS samples, immunohistochemistry appeared to not reliably discriminate between SS and EID. Therefore in all samples disclosing a significant staining with AZ158 mAb, CD158k/KIR3DL2, CD158e/KIR3DL1 and T-plastin mRNA expression were analyzed on the same skin specimen using conventional and/or quantitative real-time reverse transcription (RT)-PCR. Interestingly, only CD158k/KIR3DL2 transcripts were found to be significantly overexpressed in skin biopsies from patients with SS (P<0.0001), including when normalization to CD3 expression was achieved (P=0.0003). In light of these findings, CD158k/KIR3DL2 transcripts appear to be a unique molecular marker of SS in skin samples, allowing differential diagnosis with benign EID in routine practice.

CD160 is a glycosylphosphatidylinositol-anchored cell surface molecule expressed by human circulating cytotoxic lymphocytes that correspond to the majority of natural killer cell (NK) expressing CD56(dim), TCRgammadelta lymphocytes, and to a minor CD8 T-cell subset. CD160 engagement by major histocompatibility complex class I molecules triggers by itself both cytotoxic function and cytokine production in NK lymphocytes, whereas it provides co-activating signals to TCR-induced proliferation in T CD8+ lymphocytes. In this study, we analyzed by immunohistochemistry the phenotype of lymphocytes infiltrating normal skin and inflammatory skin lesions of atopic dermatitis, contact dermatitis, and psoriasis. We identified a minor original subset of CD4+ CD160+ T cells infiltrating inflammatory lesions. We found that this lymphocyte subset localization is not restricted to the skin, as we demonstrated that CD160 transcripts could be induced in IL-2 or IL-15-activated CD4+ peripheral blood lymphocytes. Finally, we report that CD160 acts as a co-activator receptor for CD3-induced proliferation of CD4+ CD160+ T cells isolated from inflammatory skin lesions. Thus, we hypothesize that the unique CD4+ CD160+ lymphocyte subset plays a role in the pathogenesis of skin inflammation.

Identification of malignant Sézary cells by T-cell receptor (TCR) clonality studies is routinely used for the diagnosis of Sézary syndrome, but T-cell clones expressed in a single patient have never been accurately characterized. We previously reported that CD158k expression delineates Sézary syndrome malignant cells, and, more recently, we identified vimentin at the surface membranes of Sézary cells and normal activated lymphocytes. In the present study, T-cell clones from 13 patients with Sézary syndrome were identified by immunoscopy and further characterized in the blood according to their TCR Vbeta, CD158k, and vimentin cell-surface expression. We found in most patients a unique malignant T-cell clone that coexpressed CD158k and vimentin and that, when patients were tested, was also present in the skin. However, in some patients we detected the presence of a nonmalignant circulating clone expressing high amounts of vimentin and lacking CD158k. These results indicate that clonal expansion may originate from circulating malignant and nonmalignant CD4(+) T cell populations in patients with Sézary syndrome. Identification of the malignant cells in Sézary syndrome cannot be achieved by T-cell clonality studies or by TCR Vbeta monoclonal antibody (mAb) analysis alone; it also relies on CD158k phenotyping.

Patients with advanced cutaneous T cell lymphoma (CTCL) exhibit profound defects in cell-mediated immunity. Although it has been suggested that Sezary syndrome (SS) patients have a decreased natural killer (NK) lymphocyte activity, nothing has been reported concerning the sensitivity of Sezary cells to NK lymphocyte-mediated cytotoxicity. Peripheral blood NK cells from healthy donors were tested against Sezary tumoral cell lines as well as against freshly isolated Sezary cells. Further, we studied their ability to exhibit antibody -dependent cell-mediated cytotoxicity using either the murine anti-CD158k/KIR3DL2 monoclonal antibody (moAb) AZ158 that specifically recognizes Sezary cells, or the anti-CD52 monoclonal antibody alemtuzumab. The results show that Sezary cell lines are susceptible to NK lymphocyte lysis. More importantly, we found that freshly isolated malignant cells are killed either by IL-2 activated allogeneic NK lymphocytes or when the tumor lymphocyte targets are incubated with an anti-MHC class I F(ab)'2 antibody. Further, anti-KIR3DL2 and anti-CD52 moAb can enhance the NK lysis. Finally, we report that NK lymphocytes isolated from SS patients are potentially cytotoxic lymphocytes against autologous malignant Sezary cells. These findings indicate that antitumor-mediated NK lymphocyte cytotoxic activity can be triggered in patients with CTCL and raise the possibility of developing novel therapeutic strategies by stimulating their innate immunity.

CD158k molecules belong to the family of killer cell immunoglobulin-like receptors (KIR) that are expressed on a minor population of circulating NK and CD8+ T lymphocytes. Here, we report a strong positive correlation between the percentage of CD158k+ blood lymphocytes analyzed by flow cytometry and the percentage of atypical circulating cells (Sezary cells) determined by cytomorphology in a large group of patients with Sezary syndrome. Moreover, we show that circulating CD4+CD158k+ lymphocytes correspond to the malignant clonal cell population. Our findings suggest that the CD158k marker could be a useful tool for the evaluation of the circulating tumoral burden and the follow-up of patients with Sezary syndrome.