[CAR-T cells, an innovative therapy]. / Les CAR-Tcells, une thérapie innovante.

CAR-T cell therapy for patients with hematological malignancies has been practiced at the Basse-Normandie Hematology Institute since November 2022. This treatment requires the care pathway to be coordinated by the nurse coordinator. Nurses play a key role in the early diagnosis of side effects induced by this drug. Interdisciplinary collaboration and the value of teamwork are also emphasized.

[Splenic lymphoma, diagnosis and treatment]. / Lymphomes spléniques : diagnostic et prise en charge.

Some common clinical situations, such as splenomegaly or lymphocytosis, or less common, such as autoimmune hemolytic anemia, cold agglutinin disease, or cryoglobulinemia can lead to the diagnosis of splenic lymphoma. Splenic lymphoma is rare, mainly of non-hodgkinian origin, encompassing very different hematological entities in their clinical and biological presentation from an aggressive form such as hepato-splenic lymphoma to indolent B-cell lymphoma not requiring treatment such as marginal zone lymphoma, the most frequent form of splenic lymphoma. These entities can be challenging to diagnose and differentiate. This review presents different clinical and biological manifestations suspicious of splenic lymphoma and proposes a diagnosis work-up. We extended the strict definition of splenic lymphoma (lymphoma exclusively involving the spleen) to lymphoma thant can be revealed by a splenomegaly and we discuss the differential diagnosis of splenomegaly.

Radiotherapy of lymphomas.

Radiotherapy for Hodgkin lymphomas has evolved a lot over time, but still plays an important role, almost always in addition to chemotherapy, for the management of the early stages. The major objective is to preserve the quality of life of patients who will be cured from this disease in the vast majority of cases. Also, the personalization of the indications for the purpose of de-escalating toxicity is very refined and is essentially based on the pre- and pertherapeutic assessment by FDG-PET. The indications for radiotherapy are more limited for non-Hodgkin lymphomas, but the same principles are found, regardless of the histological type. We present the update of the recommendations of the French society of oncological radiotherapy for radiotherapy of lymphomas, which remains a very evolving field in terms of therapeutic strategy and evaluation.

[HHV-8 Related immunological and hematological diseases]. / Maladies immunologiques et hématologiques liées à HHV-8.

HHV-8 is an oncogenic Gammaherpesvirinae discovered in 1994 during the HIV pandemic. It is the causative agent of Kaposi's sarcoma, and is also associated with the occurrence of several aggressive B lymphoproliferative disorders. Most of them occur in an immunosuppression setting, usually due to HIV infection. Multicentric HHV8-associated Castleman's disease and KSHV Inflammatory Cytokine Syndrome (KICS) are primarily reactive entities with prominent systemic features. They illustrate the cytokinic storm induced by HHV-8 in its cell host. On the other hand, HHV-8 can drive proliferation and lymphomagenesis of its plasmablastic cell host, and is associated with a risk to develop aggressive lymphomas with plasmacytic differenciation. Primary effusion lymphoma usually localizes in body cavities and may affect other extra-nodal sites ; its prognostic is poor. Diffuse large B-cell lymphoma HHV-8, NOS affect more commonly nodes and blood and evolve from infected cell of HHV-8 associated Castleman disease. On the contrary, germinotropic lymphoproliferative disorders presents mainly as localized adenopathy with indolent course, and show polyclonality. Histology plays a key role in distinguishing these different entities and need expert reviewing, especially since they may be associated with each other. Besides lymphoproliferative disorders, HHV8 is associated with various hematological manifestations. The aim of this review is to provide an update on the presentation, diagnosis, and management of immunologic and hematologic complications associated with HHV-8.

[Role of radiotherapy in haematology]. / Place de la radiothérapie en hématologie.

The management of myeloid and lymphoid disease is essentially based on chemotherapy and targeted therapies. Since radiotherapy could be responsible for severe late toxicities, essentially due to conventional bidimensional irradiation techniques, many trials have attempted to omit radiotherapy or to scale down the dose in their therapeutic strategy. Nevertheless, radiotherapy still plays a role for curative or symptomatic purposes.

Neuropathies périphériques associées aux syndromes lymphoprolifératifs : spectre clinique et démarche diagnostique.

Lymphoproliferative syndromes (multiple myeloma, Waldenström's disease, chronic lymphocytic leukemia, lymphomas) may be associated with peripheral neuropathies. The mechanism can be dysimmune, associated or not with monoclonal gammopathies; paraneoplastic; infiltrative; or more commonly, iatrogenic or due to vitamin deficiency. The diagnosis can be complex, especially when the neuropathy is the presenting manifestation, requiring a close cooperation between internists and neurologists. The positive diagnosis of the neuropathy is based on a systematic electro-clinical investigation, which specifies the topography and the mechanism of the nerve damage, sometimes reinforced by imaging examinations, in particular, nerve and/or plexus MRI. The imputability of the neuropathy to a lymphoproliferative syndrome is based on a set of arguments including the clinical context (B signs, tumour syndrome), first-line laboratory tests (hemogram, protein electrophoresis, viral serologies, complement), auto-antibodies discussed according to the neuropathy (anti-MAG, anti-gangliosides) and sometimes more invasive examinations (bone marrow or neuro-muscular biopsies).

An overview of genetic predisposition to familial hematological malignancies.

Genetic predisposition has been always noted in the context of familial hematological malignancies. Epidemiological studies have provided evidence consisting of an increased risk to develop blood cancer in relatives diagnosed with the same pathology and characterized by early age at diagnosis and higher severity compared to sporadic forms. With the emergence of new genomic testing approaches, the prevalence of familial aggregations of hematological malignancies seems to be under estimated. The heterogeneity of clinical features explains the wide number of genes' mutations reported to date and the variable penetrance of variants. Nevertheless, the genetic basis of familial hematological malignancies is still not well understood. Identifying the genetic background in familial aggregations provides a valuable tool for prognostic evaluation, personalized treatment and better genetic counseling in high-risk families. Herein, we provide an overview of genes reported in the last few years in association to hematological malignancies including familial form of Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, acute Myeloid Leukemia and acute Lymphoblastic Leukemia.

[Impact of algorithms proposed by the Cutaneous Lymphoma French Study Group for diagnosis of cutaneous lymphoproliferations]. / Impact des algorithmes du groupe français d'étude des lymphomes cutanés (GFELC) sur le diagnostic anatomopathologique des lymphoproliférations cutanées.

After a first diagnosis proposition, management of cutaneous lymphomas requires a systematic review by an expert pathologist and each case is presented to a multidisciplinary meeting in the setting of the French Study Group of Cutaneous Lymphomas to propose an adequate treatment. A retrospective study of the 2760 cutaneous lymphoproliferations retrieved between 2010 and 2011 were analyzed and demonstrated the interest of diagnostic algorithms we built with the group. The objective of our study was to compare two cohorts from 2010-2011 and 2015-2017 regarding the proportion of cases sent for validation or expertise, the concordance and mismatch rates and potential diagnostic issues using our diagnostic algorithms. Between 2015-2017, 5640 skin lymphoproliferation cases were examined. It appeared that Pathologists were more confident and effective in finding the right diagnosis. Indeed, the rate of concordant diagnosis increased from 57% to 67%. Moreover, in comparison with the 2010-2011 concordant cases sent for expertise, 73.5% of concordant cases were sent for validation in 2015-2017. 14% of cases remained discordant, mainly sent for expertise. Furthermore, half of questionable cases (26.3%) were resolved after expertise, and 12.1% cases remained unsolved. These priority cases are important to be presented at multidisciplinary meeting. The analysis of discordant and doubtful cases unveiled recurrent diagnostic problems for which we proposed appropriate diagnostic algorithms including large B cell lymphomas, CD4+ T cell lymphoproliferations, epidermotropic CD8+ T-cell lymphoproliferations and the differential diagnosis of mycosis fongoïdes/Sezary syndrome versus inflammatory dermatitis.

[Peripheral T cell lymphomas: diagnosis and treatment]. / Lymphomes T périphériques : diagnostic et prise en charge.

Peripheral T cell lymphomas are rare malignancies with aggressive course, with several different subtype described in the 2016 WHO classification. Their distribution across the world is heterogenous, with marked difference between Western and Asian country. Their clinical presentation often comprise extra-nodal involvement, B symptoms and immune system disorder which can lead to wrong diagnosis orientation. Make a right diagnosis need a experienced pathologist in close collaboration with clinical datas. Peripheral T cell lymphomas are in general associated with poor prognosis when treated with anthracyclines-based regimen, and several studies and trials focused on the use of intensified regimen or novel targeted agents, whose proper indication still remain to be clarified.

[Atypical Sézary syndrome in a young subject]. / Syndrome de Sézary atypique chez un sujet jeune.

INTRODUCTION: Sézary syndrome accounts for 5% of cutaneous T-cell lymphomas, with mean age of onset of 60 years. Erythroderma associated with palmoplantar keratoderma and lymphadenopathy is the usual clinical presentation, but the disease has potentially confusing polymorphic clinical features. PATIENTS AND METHODS: We report the case of a 27-year-old patient with no notable disease history, presenting generalized non-pruritic dermatosis for 3 months, with erythema and papules, and follicular distribution, localized to the limbs, the trunk and the face. Palmoplantar keratoderma was associated with acral edema. The clinical presentation was initially evocative of pityriasis rubra pilaris. Laboratory tests showed hyperlymphocytosis with Sézary cells in the blood. A diagnosis of grade IVA Sézary syndrome was made based on the skin biopsy results and the PET scan. Screening for KIR3DL2 on T-cells in blood was positive. Extracorporeal photochemotherapy was initiated but cutaneous relapse occurred, leading to combined treatment with bexarotene, which proved ineffictive. Despite numerous chemotherapies (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone, then dexamethasone, oxaliplatin and cytarabine, associated with brentuximab, vedotin, and, ultimately, clofarabine and endoxan), the patient died after 9 months. DISCUSSION: Our case illustrates an atypical clinical presentation of cutaneous lymphoma in a young patient. With a fatal outcome in 9 months despite 5 different lines of treatment, our case highlights the aggressive nature of Sézary syndrome as well as the difficulties involved in treating this disease. CONCLUSION: A diagnosis of Sézary syndrome must be considered in the event of atypical dermatosis in patients of all ages. The presence of lymphomatous clonal cells and Sézary cells in the blood, immunophenotyping of lymphocytes in blood and marrow, and a second reading of the cutaneous biopsy results enabled us to make a diagnosis of Sezary syndrome.

Population-based incidence of lymphomas in the French Nord-Pas-de-Calais region between 2001 and 2005: Annual estimations and spatial analysis.

BACKGROUND: Non-Hodgkin's lymphomas (NHL) are the seventh most commonly diagnosed cancer in France. Nord-Pas-de-Calais is ranked as the region with the highest incidence of cancers and deaths by cancer in France. With its rich industrial past and its contrasted population densities between urban and rural territories, Nord-Pas-de-Calais represents a geographic area of interest to study the overall incidence of NHL and examine spatial variation of NHL incidence between the 170 cantons of the region. METHODS: LYMPHONOR was a population-based multicentre retrospective study of patients residing in the Nord-Pas-de-Calais region and diagnosed with NHL between January 2001 and December 2005. Spatial distribution of NHL incidence in Nord-Pas-de-Calais was explored using two complementary approaches: adjusted smoothed standardised incidence ratio (SIR) and spatial scan statistics (detection of atypical clusters). RESULTS: Between 2001 and 2005, 2132 new cases of NHL were diagnosed in the Nord-Pas-de-Calais region. In 2005, age-standardised NHL incidence rates were 10.2 and 7.0 cases per 100,000 person-years in male and female residents, respectively. No significant spatial disparities in NHL incidence were found within the Nord-Pas-de-Calais region. The age-adjusted smoothed SIR varied from 0.82 to 1.25 between cantons. Consistently, spatial scan statistics did not detect any significant atypical cluster of high NHL incidence. CONCLUSION: Comparison with national data collected during the same period does not show an overincidence of NHL in the Nord-Pas-de-Calais region. In addition, no evidence for spatial heterogeneity and clustering of NHL incidence was found within this region. Future epidemiological research using large-scale registries is needed to better appraise spatial variation of NHL incidence in France and to investigate possible reasons for significant clusters.

[Primary skin lymphomas: Current therapy]. / Lymphomes cutanés primitifs : actualités thérapeutiques.

Therapeutic progress in primary cutaneous lymphomas continues to be largely dominated by the T-cell lymphomas, towards which the great majority of recent therapeutic innovations have been directed. The latter include local treatments consisting either of relatively classical but "revamped" approaches involving different pharmaceutical forms (example: chlormethine gel) or else lower but seemingly equally effective dosages (electron therapy), or of more innovative approaches (example: UVA-1, dynamic phototherapy, imiquimod, resimiquimod). However, significant progress has been made chiefly in terms of systemic treatments with the emergence of "targeted" drugs that directly and specifically target tumour cells (monoclonal antibodies directed against CD30, CCR4 or CD158k) and the further development of "small" molecules such as histone deacetylase inhibitors and new cytostatics. Immunotherapies, which have proven so effective in other areas of oncodermatology, are also of great interest, while allogeneic haematopoietic stem-cell transplantation has clearly shown its superiority over autologous transplantation and now constitutes a significant component of the therapeutic arsenal in advanced disease. While the innovations in terms of B-cell lymphomas are certainly less significant, mention must also be made of the value of rituximab combined with polychemotherapy (CHOP) and of lenalidomide (as second-line therapy) in primary cutaneous diffuse large B-cell lymphoma, leg type, along with the development of localized (very) low-dose radiotherapy in unilesional or paucilesional indolent forms.

[CAR-T cells: Lymphocytes that express a chimeric antigen receptor]. / CAR-T cells : lymphocytes exprimant un récepteur chimérique à l'antigène.

CAR-T cells are genetically modified human lymphocytes and gene therapy medicinal products. They are developed to treat cancers that express a membrane antigen targeted by the CAR. The FDA approved the two first-in-class medicinal products in 2017 and EMA in August 2018; both are autologous CAR-T cells targeting CD19 that is expressed at the surface of normal B-cells throughout their differentiation, and on B-cell lymphoid malignancies. Clinical efficacy was demonstrated for B-cell acute lymphoblastic leukemias, non-Hodgkin's lymphoma and chronic lymphocytic leukemia, although the marketing authorizations are less liberal in terms of indications. Manufacturing of these personalized treatments necessitates that a novel organization and supply chain be set in place, to ensure product preservation, patient safety and compliance with complex regulatory requirements. Side effects are commensurate with clinical efficacy and can be life-threatening: proper management imposes tight coordination between various specialists, particularly between hematologists and intensive care practitioners. High pricing for these treatments is part of a long-term trend for increasing costs of innovations in hematology and oncology; it questions the ability of healthcare systems to sustain their reimbursement.

Radiotherapy of relapse-refractory follicular lymphoma.

PURPOSE: To assess the efficacy of treatment and outcomes of patients with relapsed or refractory follicular lymphoma treated with external beam irradiation. PATIENTS AND METHODS: Fifteen patients who received external beam radiotherapy for relapsed or refractory follicular lymphoma were studied. The median age was 68.3 years (range: 37.9-87.08 years) with four men and 11 women. Seven patients had early stage (I or II); eight advanced stage (III or IV). Median FLIPI score was 2. Two patients had high tumour bulk disease. Six patients had extranodal invasion, with five patients having bone marrow invasion. RESULTS: The median time of follow-up after relapse or first-line treatment in case of refractory disease was 61.9 months (range: 9.1-119.7 months). Complete response after external beam radiotherapy was seen in 11 cases (73%) and partial response in two (13%), with a median dose of 30Gy (range: 2-40Gy) and median number of fractions of 15 (range: 2-20). Eight patients (53%) relapsed after external beam radiation therapy in a median of 20.2 months, mostly out of irradiated volumes. Most patients (66%) had a disease control after one or two courses of external beam radiation therapy. At last follow-up, 86% of patients were in remission including those with salvage chemotherapy. The toxicity profile was favourable with toxicity higher than grade 1. In univariate analysis, a Follicular Lymphoma International Prognostic Index (FLIPI) score above 2 was the only predicting factor for non-control disease. CONCLUSION: For relapsed and refractory follicular lymphoma, external beam radiotherapy should be considered as an effective modality when integrated in a multimodality approach. Randomised studies are warranted to validate this strategy.

[Primary lymphoma of the skull: Case report and literature review]. / Lymphome primitif de la voûte crânienne : cas clinique et revue de la littérature.

Primitive lymphomas of the bone are exceptional tumors, representing 4% of all non-Hodgkin lymphomas. The location at the skull remains the rarest. We report the case of a 56 year old patient with lytic lesions in the skull of a small cell lymphoma B, treated with primary chemotherapy and intensity-modulated radiotherapy in arctherapy with a dose of 30Gy in 15 fractions. With a follow-up time of 18 months after the end of treatment, the patient has no sign of disease evolution.

[Radiotherapy in localized stages of follicular and diffuse non-Hodgkin's lymphomas]. / Radiothérapie des lymphomes malins non hodgkiniens ganglionnaires folliculaires et diffus de stade limité.

Treatment with monoclonal antibodies, especially rituximab, is more and more frequent and questions the interest of radiotherapy in limited stages of diffuse B-cell large cell and follicular non-Hodgkin's lymphomas. From a review of literature, it appears that radiotherapy is of interest in bulky disease, patients with incomplete metabolic response, elderly patients receiving short chemotherapy and those with recurrence after exclusive chemotherapy. Finally, this article gives recommendations on available techniques of radiotherapy and doses to be delivered.

[Radiotherapy of lymphomas]. / Radiothérapie des lymphomes.

Radiotherapy for Hodgkin's lymphoma has evolved over time but retains a dominant position in the treatment of early stage tumours. Its indications are more limited for non-Hodgkin's lymphomas, but the techniques follow the same principles whatever the histological type. This review presents the French recommendations in terms of preparation and choice of irradiation techniques.

[Radiotherapy of skin cancers]. / Radiothérapie des cancers cutanés.

The indications of radiotherapy for skin cancers are not clearly defined because of the lack of randomised trials or prospective studies. For basal cell carcinomas, radiotherapy frequently offers a good local control, but a randomized trial showed that surgery is more efficient and less toxic. Indications of radiotherapy are contra-indications of surgery for patients older than 60, non-sclerodermiform histology and occurring in non-sensitive areas. Adjuvant radiotherapy could be proposed to squamous cell carcinomas, in case of poor prognostic factors. Dose of 60 to 70Gy are usually required, and must be modulated to the size of the lesions. Adjuvant radiotherapy seems beneficial for desmoplastic melanomas but not for the other histological types. Prophylactic nodal irradiation (45 to 50Gy), for locally advanced tumours (massive nodal involvement), decreases the locoregional failure rate but do not increase survival. Adjuvant radiotherapy (50 to 56Gy) for Merckel cell carcinomas increases also the local control rate, as demonstrated by meta-analysis and a large epidemiological study. Nodal areas must be included, if there is no surgical exploration (sentinel lymph node dissection). Kaposi sarcomas are radiosensitive and could be treated with relatively low doses (24 to 30Gy). Also, cutaneous lymphomas are good indications for radiotherapy: B lymphomas are electively treated with limited fields. The role of total skin electron therapy for T-lymphomas is still discussed; but palliative radiotherapy is very efficient in case of cutaneous nodules.

[Malignant tumours of the eye: Epidemiology, diagnostic methods and radiotherapy]. / Tumeurs malignes ophtalmologiques : indications de la radiothérapie et techniques.

Malignant tumours of the eye are not common, barely representing 1 % of all cancers. This article aims to summarise, for each of the main eye malignant diseases, aspects of epidemiology, diagnostic methods and treatments, with a focus on radiation therapy techniques. The studied tumours are: eye metastasis, intraocular and ocular adnexal lymphomas, uveal melanomas, malignant tumours of the conjunctive, of the lids, and retinoblastomas. The last chapter outlines ocular complications of radiation therapy and their management.

[What's new in skin cancers?]. / Quoi de neuf en cancérologie cutanée?

The present "what's new in oncology in 2014?" is in keeping with data reported in the past years. Indeed, metastatic melanoma still keeps the lion's share. The results of the combinations schedules with BRAF and MEK inhibitors showed an improvement in progression-free survival. Otherwise, resistance mechanisms to MAPKinase pathway inhibitors are of interest worldwide. Nevertheless, more fundamental and transversal researches are currently being investigated than validated schedules in daily clinical practice. Following anti-CTLA-4 drugs, second-generation immunotherapies, including anti-PD1 and PD-L1 molecules, confirmed their results in extended cohorts. In the setting of localized melanoma, the final results from MLST-1, Morton's study, regarding the sentinel node procedure versus observation alone, prompted a new enhancement in the sentinel node controversy. From another point of view, "what is not new in oncology in 2014?" In this area, the absence of original investigations on the primary melanoma detection in France and the absence of innovations in the adjuvant treatment of melanoma after surgery should be mentioned. While recent revolutionary drugs, i.e. targeted therapies and immunotherapies, will know advances under the resistance pressure in a near future, a revolution is still awaited in melanoma earlier stages.