Genomic profiling of Mycosis Fungoides identifies patients at high risk of disease progression.

Mycosis fungoides (MF) is the most prevalent primary cutaneous T-cell lymphoma, with an indolent or aggressive course and poor survival. The pathogenesis of MF remains unclear, and prognostic factors in the early stages are not well-established. Here, we characterized the most recurrent genomic alterations using whole-exome sequencing of 67 samples from 48 patients from Lille University Hospital (France), including 18 sequential samples drawn across stages of the malignancy. Genomic data were analyzed on the Broad Institute's Terra bioinformatics platform. We found that gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), or mutations in JUNB and TET2 are associated with high-risk disease stages. Furthermore, gain7q, gain10p15.1 (IL2RA and IL15RA), del10p11.22 (ZEB1), and del6q16.3 (TNFAIP3) are coupled with shorter survival. Del6q16.3 (TNFAIP3) was a risk factor for progression in low-risk patients. By analyzing the clonal heterogeneity and the clonal evolution of the cohort, we defined different phylogenetic pathways of the disease with acquisition of JUNB, gain10p15.1 (IL2RA and IL15RA), or del12p13.1 (CDKN1B) at progression. These results establish the genomics and clonality of MF and identify potential patients at risk of progression, independent of their clinical stage.

Targeting CCR4 with mogamulizumab in refractory CD3-CD4+ lymphocytic-variant hypereosinophilic syndrome.

Not available.

Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.

Lymph node excisions provide more precise lymphoma diagnoses than core biopsies: a French Lymphopath network survey.

According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying ∼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10-6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB.

Profuse telangiectasias in an immunocompetent patient misleading presentation revealing a hepatosplenic-Tγδ-cell lymphoma.

Here we present the case of an hepato-splenic-Tγδ-cell lymphoma interestingly occurring in a non-immunocompromised patient, with profuse telangiectasias giving originally misleading orientation towards the diagnosis of B angiotropic lymphoma.

Hidden in the Eyes-Recurrence of Systemic Hemopathies Reportedly "In Remission": Six Cases and Review of Literature.

Background and Objectives: Secondary ocular localizations of hematological malignancies are blinding conditions with a poor prognosis, and often result in a delay in the diagnosis. Materials and Methods: We describe a series of rare cases of ocular involvement in six patients with hematological malignancies, reportedly in remission, who presented secondary ocular localizations, challenging to diagnose. Two patients had an acute lymphoblastic leukemia (ALL) and developed either a posterior scleritis or a pseudo-panuveitis with ciliary process infiltration. One patient had iris plasmacytoma and developed an anterior uveitis as a secondary presentation. Two patients had a current systemic diffuse large B-cell lymphoma (DLBCL) and were referred either for intermediate uveitis or for papilledema and vitritis with secondary retinitis. Finally, one patient with an acute myeloid leukemia (AML) presented a conjunctival localization of a myeloid sarcoma. We herein summarize the current knowledge of ophthalmologic manifestations of extramedullary hematopathies. Results: Inflammatory signs were associated with symptomatic infiltrative lesions well displayed in either the iris, the retina, the choroid, or the cavernous sinus, from the admission of the patients in the ophthalmological department. These findings suggest that patients with ALL, AML, systemic DLBCL, and myeloma can present with ophthalmic involvement, even after having been reported as in remission following an effective systemic treatment and/or allograft. Conclusions: Early detection of hidden recurrence in the eyes may permit effective treatment. Furthermore, oncologists and ophthalmologists should be aware of those rare ocular malignant locations when monitoring patient's progression after initial treatment, and close ophthalmologic examinations should be recommended when detecting patient's ocular symptoms after treatment.

Fatal Enterovirus-related Myocarditis in a Patient with Devic's Syndrome Treated with Rituximab.

Enteroviruses are a frequent source of infection and among the most common central nervous system viral pathogens. Enteroviruses - in particular, the Coxsackie B viruses - are a known cause of myocarditis. Rituximab is a genetically engineered chimeric anti-CD20 monoclonal antibody. Many reports in the literature suggest a higher risk of infection following repeated rituximab therapy, including viral infection. However, observations of enterovirus-related myocarditis in the context of rituximab treatment are scarce. The authors describe the case of a patient with neuromyelitis optica spectrum disorder who developed severe and fatal enterovirus-related myocarditis after rituximab therapy with a difficult differential diagnosis of autoimmune or giant-cell myocarditis. This case highlights the importance of complete diagnostic workup in difficult cases of myocarditis, including endomyocardial biopsies.

Micronodular thymic carcinoma with lymphoid hyperplasia: relevance of immunohistochemistry with a small panel of antibodies for diagnosis-a RYTHMIC study.

Micronodular thymic carcinoma with lymphoid hyperplasia (MNTCLH) is a rare form of thymic carcinoma. We present the experience of RYTHMIC, the French national network devoted to the treatment of thymic epithelial tumors through multidisciplinary tumor boards with a review of all tumors by pathologists for classification and staging. Six cases of MNTCLH were diagnosed during a review of 1007 thymic epithelial tumors. Histologically, epithelial cells with atypia and mitoses formed micronodules that were surrounded by an abundant lymphoid background with follicles. There was neither obvious fibro-inflammatory stroma nor necrosis. Spindle cells areas were common. Initial diagnosis was micronodular thymoma in two cases, cellular atypia being overlooked, eclipsed by the micronodular pattern. Immunohistochemistry with a panel of five antibodies showed that cytokeratins (AE1-AE3) and p63-positive epithelial cells also expressed CD5 and that there was no TdT-positive cells within the tumors. CD20 highlighted the lymphoid hyperplasia. Additionally epithelial cells also expressed CD117 and diffusely Glut 1. Twenty-seven micronodular thymomas with lymphoid stroma diagnosed during the same period did not show the CD5 and CD117 positivities seen in MNTCLH and contained TdT-positive lymphocytes. Three of the 6 patients with MNTCLH had adjuvant radiotherapy. Three patients with follow-up information were alive without recurrence at 38, 51, and 95 months. Our study shows that immunohistochemistry, such as that used in the RYTHMIC network with a small panel of antibodies, may easily help to confirm the correct diagnosis of MNTCLH, a rare and low-aggressive form of thymic carcinoma, and avoid the misdiagnosis of micronodular thymoma.

Aerobic fitness and isokinetic knee strength of semi-professional rugby union players: a comparison between backs and forwards.

BACKGROUND: This study aimed to describe the physical fitness characteristics of semi-professional rugby union (RU) players using VO2max (mL. min-1. kg-1), knee peak torque (PT), mean power (MP), hamstring: quadriceps (H:Q) ratio and basic anthropometrics characteristics and to compare backs and forwards across these same characteristics. METHODS: VO2max and ventilatory threshold (VT) as a percentage of VO2max were measured using the Bruce protocol maximal graded test. Knee strength test PT, MP and H:Q were analyzed using the isokinetic dynamometer test. Basic anthropometrics measures were obtained by measures of body mass, height (from Tanita Body Composition Analysis; Tanita Corp., Tokyo, Japan). While fat mass was measured using skinfold thicknesses taking from different body parts. Twenty-five semi-professional players aged (26.3±0.9 years) from the same team were recruited for the study. Mean experimental values from maximal graded test and isokinetic dynamometer test were analyzed using t-tests from the SigmaStat 3.11 program (Systat Software Inc., San Jose, CA, USA). RESULTS: The results showed that forwards were significant taller (P=0.036), heavier (P=0.01), with greater fat mass (P=0.001) than backs. Backs had a greater VO2max (P=0.02) than forwards. With forwards having a greater (P=0.01) eccentric H PT. CONCLUSIONS: This study presents important information for players and athletic coordinators as to the differences between backs and forwards across physiological and strength measures. This information can greatly inform the individualized training protocol and preparation of current and future players across different positions and different levels.

Paraffin Immunofluorescence Increases Light-Chain Detection in Extra-Renal Light Chain Amyloidosis and Other Light-Chain-Associated Diseases.

CONTEXT.­: Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases. OBJECTIVES.­: To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain-associated diseases. DESIGN.­: First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing. RESULTS.­: In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure. CONCLUSIONS.­: We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain-related diseases.

Key performance indicators in Tour de France sailing.

This study aimed to determine the key performance indicators of inshore sailing during the sailing Tour de France. Technical and physical parameters were investigated to determine the discriminating factors between successful and less successful international level sailors. Measurements from 21 sailors (mean ± SD; age = 23.81 ± 4.18 years) were conducted prior to the sailing Tour de France. Global Positioning System data of all participating teams (n = 23) was analysed. Sailors were divided into two groups (i.e. successful and less successful) according to qualifying performance percentage. The differences between successful and less successful sailors were explored by means of independent t-tests. Results indicate that successful boats displayed higher maximal speed, higher average speed and more efficient starting performance per race than less successful boats. Successful sailors have stronger handgrip strength, higher isometric maximal voluntary force relative to bodyweight (isometric mid-thigh pull) and more powerful submaximal pulling (bench pull) actions than their less successful counterparts. The results of this study suggest that multiple sailing, physical and physiological variables are related to sailing performance in inshore sailing. Therefore, we emphasize the importance of integrating specific testing protocols to evaluate the performance potential of inshore sailors participating in the sailing Tour de France.

Impact of expert pathologic review of thymic epithelial tumours on diagnosis and management in a real-life setting: A RYTHMIC study.

BACKGROUND: Classification of thymic epithelial tumours (TETs) is known to be challenging; however, the level of discordances at a nationwide level between initial and expert diagnosis and their clinical consequences are currently unknown. RYTHMIC is a national network dedicated to the management of TET based on initial histological diagnosis, followed by an additional expert review of all cases. Our aim was to evaluate the discordances between initial and expert diagnoses and whether they would have led to different clinical management. PATIENTS AND METHODS: We conducted a retrospective analysis of the cohort of patients discussed at RYTHMIC tumour board from January 2012 to December 2016. Assessment of disagreement was made for histological typing and for staging. The discordances were classified as major or minor based on whether they would have changed or not the proposed therapeutic strategy, respectively. Follow-up of the patients with major discordances was conducted until December 2018. RESULTS: Four hundred sixty-seven patients were reviewed, and 183 (39%) discordances were identified either related to histological subtype (132) and/or stage (72). Major discordances were identified in 27 patients (6%). They included 16 patients with TET for whom treatment recommendation based on the central review would have been post-operative radiotherapy, whereas it had not been the case. However, follow-up did not show any progression among the 15 patients with high-grade histology and/or stage resected thymomas. On the other hand, among the remaining 11 patients including 7 with a diagnosis other than TET, the overall management or follow-up would have been completely different with the expert diagnosis. CONCLUSION: Our real-life cohort reveals a high level of discordances considering TET diagnosis and supports expert review for optimal clinical management.

[Thymoma and squamous thymic carcinoma diagnosis; experience from the RYTHMIC network]. / Diagnostic des thymomes et carcinomes thymiques malpighiens ; expérience du réseau RYTHMIC.

The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases.

[Intravascular large B cell lymphoma pathological findings led by positron emission tomography findings: About one case]. / Diagnostic histologique de lymphome intravasculaire guidé par une hyperfixation corticale rénale à la tomographie par émission de positons : à propos d'un cas.

Intravascular large B cell lymphoma is a rare non-Hodgkin large B cell lymphoma disease, with heterogeneous clinical manifestation and difficult pathological diagnosis. Positron emission tomography may be helpfull in this context and has already been reported. A 45-year-old woman was admitted for persistent high fever, inflammatory syndrome and unexplained haemophagocytic syndrome. Bilateral cortical renal hypermetabolism at positron emission tomography initially misled to pyelonephritis diagnosis and secondarily led to kidney biopsy, which showed intravascular large B cell lymphoma. Renal involvement in intravascular large B cell lymphoma is rare and is usually characterized by acute renal failure and proteinuria. Global hypermetabolism at positron emission tomography has already been described in this context, but cortical hypermetabolism has never been associated with pathological findings. In front of persistent high fever without etiology, this positron emission tomography feature must lead to intravascular large B cell lymphoma suspicion and to kidney biopsy to obtain pathological proof.

Training load quantification of high intensity exercises: Discrepancies between original and alternative methods.

The purpose of this study was to quantify training loads (TL) of high intensity sessions through original methods (TRIMP; session-RPE; Work-Endurance-Recovery) and their updated alternatives (TRIMPcumulative; RPEalone; New-WER). Ten endurance athletes were requested to perform five sessions until exhaustion. Session 1 composed by a 800m maximal performance and four intermittent sessions performed at the 800m velocity, three sessions with 400m of interval length and work:recovery ratios of 2:1, 1:1 and 1:2 and one with 200m intervals and 1:1. Total TL were quantified from the sessions' beginning to the cool-down period and an intermediate TL (TL800) was calculated when 800m running was accumulated within the sessions. At the end of the sessions high and similar RPE were reported (effect size, η2 = 0.12), while, at the intermediate 800m distance, the higher interval distances and work:recovery ratios the higher the RPE (η2 = 0.88). Our results show marked differences in sessions' total TL between original (e.g., lowest TL for the 800m and highest for the 200m-1:1 sessions) and alternative methods (RPEalone and New-WER; similar TL for each session). Differences appear in TL800 notably between TRIMP and other methods which are negatively correlated. All TL report light to moderate correlations between original methods and their alternatives, original methods are strongly correlated together, as observed for alternative methods. Differences in TL quantification between original and alternative methods underline that they are not interchangeable. Because of high exercise volume influence, original methods markedly enhance TL of sessions with higher exercise volumes although these presented the easiest interval distances and work-recovery ratios. Alternative methods based on exhaustion level (New-WER) and exertion (RPEalone) provided a new and promising point of view of TL quantification where exhaustion determines the highest TL whatever the exercise. This remains to be tested with more extended populations submitted to wider ranges of exercises.