P. Cougoul

Cryofibrinogénémie : étude monocentrique au CHU de Toulouse

PURPOSE Cryofibrinogenemia is an unknown disorder and studies dedicated to it are limited. The aim of our study was to report on the incidence, clinical manifestations and associated diseases in patients with isolated cryofibrinogenemia. METHODS This is a retrospective single-center study. Patients included in this study had a positive and isolated detection of cryofibrinogen between January 1st, 2011 and December 31st, 2012. Identification was possible through the database of the laboratory of immunology. RESULTS Two hundred and eighty-one consecutive orders of cryofibrinogenemia were identified. Seventy-three patients had a positive detection of cryofibrinogenemia. Among them, 12 had an isolated cryofibrinogenemia and sixty-one patients (84%) had concomitant cryofibrinogenemia and cryoglobulinemia. The mean age was 59±19years. Seven patients were female (58%). Cutaneous manifestations were present in half case. Peripheral nerve involvement was present in 5 cases (42%) and rheumatic manifestations in 4 patients (33%). A thrombotic event was reported in 7 patients (58%). Renal impairment was present in 7 patients. The median cryofibrinogen concentration was 254±304mg/L. Five patients had a secondary cryofibrinogenemia. The most often prescribed treatment was corticosteroids. CONCLUSION Cryofibrinogenemia is an unknown disorder. Testing for cryoglobulinemia is more frequent than for cryofibrinogenemia whereas clinical manifestations are similar. Detection of cryofibrinogen is positive in most of the cases, with an important prevalence of thrombotic events in this population. This study confirms the importance of conducting prospective studies on cryofibrinogenemia.

Acquired epidermodysplasia verruciformis, a new opportunistic infection related to bendamustine

Dear Editor, We read with interest the recent article of Garcia-Munoz et al. [1] who reported a significant impairment of lymphocyte recovery in patients treated with bendamustine plus rituximab. Authors suggested the higher risk of opportunistic infections in this context, linked to secondary low CD4+ T cell counts. As an illustration, we report here a case of an acquired epidermodysplasia verruciformis (EV) in a patient treated with bendamustine as monotherapy. The progressive development of this opportunistic infection seemed strictly correlated to the persistent decrease of the absolute lymphocyte counts (Fig. 1a). A 40-year-old female patient had been followed up for 7 years for stage IIIB Hodgkin lymphoma with initial lymph node and gall bladder involvement. She had been successively treated with BEACOPP regimen with radiotherapy, CEPP regimen and 17 cycles of vinblastine. Due to new progression of the disease, bendamustine monotherapy was introduced in April 2012 with injections every 3 weeks during 6 cycles (70 mg/m), then every 2 months. The patient was HIV negative with no other medical condition. Absolute lymphocyte count was 2600 (cells/μl) at baseline and progressively decreased in parallel with the successive cycles of bendamustine. After 18 months of treatment, a severe lymphopenia with (grade 3 or 4) low CD4+ cell counts was reported (Fig. 1a). Concomitantly, we noticed the progressive development of red brownwart-like flat papules on the forehead, the shoulders and the pubic area, associated with pityriasis versicolor-like lesions on the chest (Fig. 1b, c). Skin biopsy revealed a hyperkeratotic and acanthotic epidermis containing large keratinocytes. Anti-HPV immunoperoxydase staining revealed a strong positivity of nuclei of superficial keratinocytes (Fig. 1d, e), enabling to confirm the diagnosis of acquired EV. The patient also presented several bacterial and viral infections during the same period (Fig. 1a). Bendamustine was stopped in June 2014; however, severe grade 3 lymphopenia persisted for 6 months after interruption of bendamustine treatment. In parallel, lesions of acquired EV slightly improved but patient developed a new opportunistic infection presenting as a necrotizing HSV retinitis. The dose-l imit ing toxici ty of bendamustine is myelosuppression with rapid depression of CD4/CD8/ CD19+ T cell compartments and lymphocytopenia, either during the treatment of lymphoproliferative disorders or solid tumours [1–3]. Severe infections can affect almost 10 % of treated patients [4, 5] including opportunistic infections, mainly in the form of pneumocystis pneumonia, candida infections, Herpes zoster or EBV and CMV reactivations [1–3, 6]. To our knowledge, acquired epidermodysplasia verruciformis had never been described neither with bendamustine nor in association with P. Cougoul :K. Delavigne :O. B. Rauzy Department of Internal Medicine, Institut Universitaire du Cancer, Toulouse, Oncopole, France

Re: Severe Primary Autoimmune Thrombocytopenia (ITP) in Pregnancy: a national cohort study Primary immune thrombocytopenia management during pregnancy. A French study

Sir, We welcome the letter by Algeri et al. and their insightful reflections about a particular subset of non-tubal ectopic pregnancies reported in our recently published series. As highlighted by the Italian group, cornual–interstitial pregnancies are especially challenging, from achieving the correct diagnosis to choosing the best treatment option. We should be aware that uncertainty in the diagnosis may potentially lead to overtreatment and unnecessary morbidity. Some of these cases will be nonviable pregnancies that will resolve spontaneously or be amenable to uterine curettage, as illustrated in the first and second cases presented. Moreover, a precise differential diagnosis with an angular pregnancy will avoid intervention in a normal ongoing pregnancy that is only implanted eccentrically in the uterine cavity. This was suspected following the second ultrasound in the third case presented, but later dismissed based on magnetic resonance imaging findings. Cases classified as angular pregnancies are not ectopic pregnancies and, as such, have not been included in our series. Nonetheless, in keeping with the experience reported, we are occasionally confronted with the same diagnostic dilemma. At our centre we do have access to three-dimensional/ mutiplanar transvaginal ultrasound and we agree that obtaining a true coronal view of the uterus is helpful in some cases. In our experience, for the asymptomatic and haemodynamically stable patient, sequential examinations performed by the same team of experienced examiners are essential to determine whether the pregnancy is growing towards the cavity or into the interstitial space with further ballooning of this region. Again here, there are no codified practice guidelines and the balance is thin between early intervention to minimise risks and an expectant approach to avoid an unnecessary procedure. We are glad to hear that ultrasoundguided injection will be considered as an option by more centres following the publication of our series and that this is acknowledged as an effort to provide evidence-based guidance in the choice of treatment options for nontubal ectopic pregnancies.&

Cryofibrinogenemia and risk of cancer in cryoglobulinemic patients without vasculitis criteria

Cryofibrinogen is a cryoprotein that forms only in plasma and not in serum. In patients screened for a cryopathy, prevalence of cryofibrinogenemia varies from 12% to 51% [1–3]. Most studies concerning essential and secondary cryofibrinogenemia excluded patients with concomitant cryoglobulinemia [1]. In cryoglobulinemic patients, the presence of cryofibrinogenemia has been shown to be associated with cryoglobulinemia vasculitis [4,5]. Moreover, we found that patients with both cryoproteins had more frequently a cancer than patients with isolated cryoglobulinemia [5]. In routine practice, about half of the patients with a positive cryglobulinemia do not fulfil cryoglobulinemia vasculitis criteria. The present study aimed to determine the characteristics associated with the presence of cryofibrinogenemia in cryoglobulinemic patients without cryoglobulinemia vasculitis. We retrospectively included all cryoglobulinemic patients who were also tested for cryofibrinogenemia at the Immunology Laboratory of Toulouse University Hospital between January 2011 and December 2012. Toulouse University Hospital Research Ethics Committee approval was obtained for anonymous retrospective medical chart review. Patients who fulfilled cryoglobulinemia vasculitis criteria previously used in the CryoVas Cohort were excluded [6]. Medical files were reviewed. Baseline clinical and laboratory findings at the time of cryoprotein testing were recorded. Renal involvement was defined by a creatininemia N130 μmol/L or a glomerular filtration rate b60 ml/min/1.73 m (Modification of Diet in Renal Disease (MDRD) Study equation) or hematuria or proteinuria N500 mg/24 h. Blood was collected in citrated tubes for cryofibrinogenemia and in anticoagulant-free tubes for cryoglobulinemia. Both sera and plasma were kept at 37°C until centrifugation, which was performed within one hour for plasma and within 12 h for sera. Samples were kept at 4°C for 72 h for sera and 8 days for plasma and were then tested for the presence or absence of precipitate. Both cryoprecipitates were quantified by optic density absorbance at 280 nm. Presence of cryofibrinogen and of cryoglobulin was confirmed by western blotting, as previously described [2,5]. The study included 75 patients, 43 being cryoglobulin-positive/ cryofibrinogen-positive (CF-positive group) patients and 32 being cryoglobulin-positive/cryofibrinogen-negative (CF-negative group).