Vemurafenib skin phototoxicity is indirectly linked to ultraviolet A minimal erythema dose decrease.

BACKGROUND: Vemurafenib, an anti-rapidly accelerated fibrosarcoma kinase B (BRAF) molecule, improves survival among patients with metastatic BRAF-mutated melanoma. Photosensitivity, a frequent cutaneous adverse effect induced by vemurafenib, can lead to cessation of treatment. OBJECTIVES: To investigate photosensitivity mechanisms in patients treated with vemurafenib for metastatic melanoma. METHODS: In a prospective study of 12 patients, photobiological explorations with measurements of ultraviolet A (UVA) minimal erythema dose (MED) and polychromatic MED were performed over 3 days in all 12 patients. UVA MED and polychromatic MED were also assessed for four patients before treatment. We then performed spectrophotometric analyses of (i) serum and faeces in these four patients, before and after introduction of vemurafenib; (ii) the lyophilized form of vemurafenib without excipient added; and (iii) the lyophilized form of vemurafenib added to serum and faeces before treatment. RESULTS: Photosensitivity was present in 92% of the patients. UVA MED was normal before treatment and decreased after treatment, while polychromatic MED remained normal. The same three peaks (210, 260 and 310 nm) were identified in the spectrum for UVB and UVC but not for UVA on spectrophotometric analyses for each condition (lyophilized vemurafenib; serum and faeces after introduction of vemurafenib; and lyophilized vemurafenib added to serum and faeces before treatment). The peaks were different before treatment. CONCLUSIONS: Our study confirms that photosensitivity under vemurafenib treatment was a UVA phototoxicity reaction, and our results suggest that a metabolite of vemurafenib rather than the parent molecule is involved in this phototoxicity.

[Haematological malignancies (HM) in Basse-Normandie (BN): incidence and clinical and biological characteristics over the period 1997-2005 in patients less than 25 years old]. / Épidémiologie des hémopathies malignes en Basse-Normandie : incidence et caractéristiques cliniques et biologiques chez l'enfant et l'adulte jeune de moins de 25ans (1997-2005).

BACKGROUND: The study was designed to present the incidence of all the haematological malignancies (HM) in Basse-Normandie (BN) over the period 1997 to 2005 in patients less than 25 years old. BN is an administrative region in the North-West of France, composed of three departments: Calvados, Manche and Orne. We extracted data from the Registre régional des hémopathies malignes de Basse-Normandie, a French registry which belongs to the Association of the French Cancer Registries (Francim). METHODS: All the HM were coded using the third edition of the International classification for oncologic diseases (ICD-O-3). We compared the clinical and biological descriptive data in patients less than 15 years old to those of young adults (15-24 years old). RESULTS: A total of 305 new cases of HM were recorded over the period 1997 to 2005. HM were more frequent in men (168 cases) than in women (137 cases). Patients less than 25 years old accounted for 4.1% of all HM cases, whereas patients less than 15 years old and young adults (15-24 years old) represented 2.2% and 1.9% of all cases, respectively. In patients less than 25 years old, the overall world-standardized incidence rates (WSR) were 7.67/100,000 (95% CI: 6.31-9.04) in BN (8.08 [6.15-10.02] for men and 7.24 [5.31-9.17] for women). In patients less than 15years, the overall WSR was 7.38/100,000 (6.23-8.52), with no difference between boys (7.57) and girls (7.17). Acute lymphoblastic leukaemia (ALL) was the most frequent HM, WSR=4.02/100,000 (3.16-4.88) (4.30 [3.08-5.53] in men, 3.73 [2.52-4.93] in women), with similar clinical and biological criteria between patients less than 15 years and young adults. In young adults, the overall WSR was 8.21/100,000 (7.47-8.96), similar between men and women (9.02 [7.93-10.12] and 7.37 [6.35-8.38], respectively). Their highest WSR was obtained for Hodgkin lymphomas (HL): 3.37/100,000 (2.89-3.85), similar between men (3.49 [2.8-4.17]) and women (3.25 [2.58-3.93]). The study did not show any significant difference between the Calvados, Manche and Orne departments (except for HL, which seems more frequent in Manche department for 15-24 years old cases). There was no evidence of an increased risk for ALL in the subdistricts Beaumont-Hague and Les Pieux, which respectively have a nuclear waste reprocessing plant and a nuclear power plant on their territory. The subtype of HM was dependent on age whereas clinical and biological data were the same, whatever the age. CONCLUSION: These results contribute to HM monitoring in an area where the nuclear industry is present and to improve the organization and follow-up of medical care.

Evaluation of Flow Cytometry for Cell Count and Detection of Bacteria in Biological Fluids.

The analysis of biological fluids is crucial for the diagnosis and monitoring of diseases causing effusions and helps in the diagnosis of infectious diseases. The gold standard method for cell count in biological fluids is the manual method using counting chambers. The microbiological routine procedures consist of Direct Gram staining and culture on solid or liquid media. We evaluate the analytical performance of SYSMEX UF4000 (Sysmex, Kobe, Japan) and Sysmex XN10 (Sysmex, Kobe, Japan) in comparison with cytological and microbiological routine procedures. A total of 526 biological fluid samples were included in this study (42 ascitic, 31 pleural, 31 peritoneal, 125 cerebrospinal, 281 synovial, and 16 peritoneal dialysis fluids). All samples were analyzed by flow cytometry and subsequently processed following cytological and/or microbiological routine procedures. With regard to cell counts, UF4000 (Sysmex, Kobe, Japan) showed a performance that was at least equivalent to those of the reference methods and superior to those of XN10 (Sysmex, Kobe, Japan). Moreover, the bacterial count obtained with UF4000 (Sysmex, Kobe, Japan) was significantly higher among culture or Direct Gram stain positive samples. We established three optimal cutoff points to predict Direct Gram stain positive samples for peritoneal (465.0 bacteria/µL), synovial (1200.0 bacteria/µL), and cerebrospinal fluids (17.2 bacteria/µL) with maximum sensitivity and negative predictive values. Cell count and detection of bacteria by flow cytometry could be used upstream cytological and microbiological routine procedures to improve and accelerate the diagnosis of infection of biological fluid samples. IMPORTANCE The analysis of biological fluids is crucial for the diagnosis and monitoring of diseases causing effusions and helps in the diagnosis of infectious diseases. The possibility of carrying out cytological and microbiological analyses of biological fluid samples on the same automated machine would simplify the sample circuit (addressing the sample in a single laboratory, 24/7). It would also minimize the quantity of sample required. The performance of cytological and microbiological analysis by the flow cytometer UF 4000 (Sysmex, Kobe, Japan) has never been evaluated yet. This study has shown that bacterial count by flow cytometry using UF4000 (Sysmex, Kobe, Japan) could be used upstream of microbiological routine procedures to improve and to accelerate the diagnosis of infection of biological fluid samples.

[Haematological malignancies: incidence in Basse-Normandie, France, for 1997-2004]. / Epidémiologie des hémopathies malignes en Basse-Normandie.

BACKGROUND: The study was designed to present the incidence of all the haematological malignancies in Basse-Normandie over the period 1997-2004. We extracted the data from the "Registre régional des hémopathies malignes de Basse-Normandie (RRHMBN)", a French registry which belongs to the Association of the French Cancer Registries (FRANCIM). All the malignant haematological diseases were coded using the third edition of the International Classification for Oncologic Diseases (ICD-O-3) and the ADICAP classification, a special version adapted in 2001 for haematology. Five thousand five hundred and ten new cases of malignant haematological disorders were registered over the period 1997-2004. Whatever the department constituting the Basse-Normandie (Calvados, Manche and Orne), no significant difference of incidence was detected. In men, the more frequent malignant disorders were non-Hodgkin's malignant lymphomas (NHML) followed by chronic lymphocytic leukemia and other mature neoplasms, myelodysplastic syndromes (MDS), multiple myeloma (MM), myeloproliferative disorders (MPD), acute myeloid leukemias (AML), Hodgkin's lymphomas (HL), Waldenström's macroglobulinemia (WM) and acute lymphoblastic leukemia (ALL). In women, MM is the third more frequent haematological disorders after NHML and lymphocytic leukaemia and other mature neoplasms, MPD, MDS, AML, Hodgkin's lymphomas, WM and ALL. The other haematological disorders are very rare. We provide the incidence for the main haematological disorders and for the first time we also present the incidence of the different subtypes of the Hodgkin's and non-Hodgkin's malignant lymphomas, mature lymphoid neoplasms, MPD and also MDS. These results are useful for the organization and follow-up of medical care. The development of specialized haematology and active protocols can optimize the management of the older patients. A high quality of the collected data remains necessary for a continuous watching and research on patients with malignant haematological diseases.

Localised impedance monitoring device for the remote clinical assessment of home-based dialysis patients.

BioImpedance Spectroscopy (BIS) has been clinically used to determine the hydrational status of patients undergoing haemodialysis (HD). In the present project we are developing a calf-localised, integrated impedimetric device to periodically and conveniently measure and transmit information on the hydrational status of home-based patients to a remote clinic. Surprisingly, we have found that simple postural changes before or during measurement lead to significant fluid shifts in the lower leg that are as important and as long lasting as the effects of haemodialysis. These must be taken into account if potentially hazardous errors are not to be made in assessing a patient's hydrational status.

[Fortuitously discovered neutropenia in children: diagnosis and follow-up]. / Neutropénies de découverte fortuite chez l'enfant : diagnostic et suivi.

Neutropenia seems to be quite frequent in current pediatric practice and can confuse the clinician since it may result from a severe cause. The aim of this study was to provide a prospective description of episodes of neutropenia in children to assess its clinical relevance in a general pediatric cohort consulting and/or hospitalized in a French university hospital. In this prospective observational and monocentric study conducted from April 2012 to April 2013, we included all the patients under 18 years of age who presented neutropenia (defined as an absolute neutrophil count [ANC] below 1×10(9)/L before 1 year of age and below 1.5×10(9)/L beyond) on a whole blood count (WBC) performed in our hospital. Patients treated with chemotherapy were not included. Medical records were regularly checked for at least 1 year after inclusion, and clinical and biological data were collected prospectively to compare transient episodes of neutropenia (<3 months) with persistent episodes of neutropenia (>3months). Of 55,018 consultations and 13,967 hospitalizations (chemotherapy excluded), 8966 blood counts were performed and 250 episodes of neutropenia were found in 238 patients. Data concerning clinical progression were available in 195 cases of which 136 had at least one subsequent WBC. Two hundred thirty-one episodes corresponded to new episodes, while neutropenia preexisted before inclusion in the others. The median follow-up was 12.8 months. Most episodes of neutropenia occurred in children <2 years of age (52%), with a median age of 22.2 months. Mean ANC was 0.943×10(9)/L (±0.340) and a few episodes of neutropenia were below 0.5×10(9)/L (9.2%). Neutropenia persisted more than 3 months in only 13.2% of cases. When neutropenia was below 0.5×10(9)/L, it significantly persisted (RR=3.08; 95% CI [1.31-7.22]). Other factors associated with persistent neutropenia were thrombocytopenia, monocytopenia, a CRP more than 70mg/L, significant abnormality on the clinical exam, and age over 24 months. However, multivariate analysis showed that only an ANC below 0.5×10(9)/L was significantly associated with persistence. While etiology could not be determined in 32% of cases, neutropenia resulted mostly from infectious causes (37.8%), with other causes being more anecdotal. The majority of infectious episodes of neutropenia were viral (90.3%). Like other studies, this investigation suggests that most episodes of neutropenia concern young children, are transient, are benign and often due to infectious diseases. Although it may not reflect the medullar stock or the real capacity of neutrophils to fight bacterial infections, it seems that neutropenia below 0.5×10(9)/L is more likely to persist and be complicated, as previous studies also suggest. To conclude, neutropenia is not exceptional in children and, even if it often results from viral infections and mostly evolves favorably, the clinician should closely monitor these patients, especially when neutrophils are below 0.5×10(9)/L.

Evaluation of a new impedancemeter to independently measure extracellular, intracellular and total body water volumes: application to the measurement of hydration.

The objective of this study was to evaluate the accuracy of independent hydric data for the quantification of total body water (V t), extracellular water (V e) and intracellular water (V i), obtained by a multifrequency impedancemeter Z-Métrix(®) (ZM), in standing and lying position, with respect to the Xitron reference. In a second step, the aim was to consider whether it is possible to quantify daily hydration. The average repeatability error of the ZM impedancemeter is less than 0.5 %. For total body water (V t), we note a low R (2) dispersion with an average of 0.9 for men and 0.6 for women. The estimation of extracellular water is equivalent to a maximum error of 3.1 % in standing position for women against 2.97 % for men in the same position. The estimation of the total body water by direct measurement and by summing the volumes of extracellular and intracellular water obtained by the Z-Metrix(®) shows very low dispersions with R (2) = 0.89 and average error from 1.3 % for healthy women in lying position to 3.9 % for healthy women in standing position. Finally, despite the impact of events on the daily measurements, it is viable to track a subject's overall hydration.

[Intrapericardial congenital ectasias of the left atrium]. / Les ectasies congénitales intrapéricardiques de l'auricule gauche

Congenital intrapericardial dilatation of the left atrium is an abnormality which is either very rare (16 cases reported in the literature) or one that is easily missed. The clinical features are unhelpful, and the diagnosis is suggested by the outline on X ray and confirmed by angiocardiography. The great importance of this abnormality lies in its natural history. Disorders of rythm (9 cases out of 16) and embolism (5 cases out of 16) are amongst the complications to be weighed up when deciding the treatment policy. Operative treatment, which is straightforward, seems to us to be indicated in all cases.

[Levocardia with ventricular inversion and a single atrium in normal position]. / Lévocardie avec inversion ventriculaire et oreillette unique en position normale

A 12-year child had complete heart block, an abdominal situs inversus with laevocardia. Further investigation demonstrated in addition an inferior vena cava ending into an azygos vein, a shunt at the atrial level and a pulmonary valve stenosis. At operation there was a lone atrium in normal position, a ventricular inversion without transposition of the great vessels. In spite of a corrective operation of the Mustard type, the child died the following day through haemorrhage and low output.

[Myxoma of the right ventricle in monozygotic twins: surgical ablation]. / Myxome du ventricule droit chez des jumeaux monozygotes. Ablation chirurgicale.

Monozygotic twins aged 23 underwent surgery, at an interval of 4 months from each other, for a myxomatous tumour of the right ventricle which had been completely asymptomatic until then. The authors present the clinical, electrocardiographic and angiographic findings, together with details of the operation and of the histological findings. They recall how rare a site this is, and summarise some of the observations which have been made on familial myxomas.

[Secondary coronary fistulas]. / Les fistules coronaires secondaires.

These fistulae are very rare: 8 to 11 p. 100 of all coronary fistulae. Three types are recognised: right coronaro-ventricular, left coronaro-ventricular, and coronao-pulmonary. The two first types are found most frequently in association with a sigmoid atresia on the orifice, and with ventricular hypoplasia in the presence of a functional atrio-ventricular valve. The fistula then serves as a means of ventricular ejection. Of the secondary fistulae, the right coronaro-ventricular type is the most common (73 p. 100). The authors have found 30 cases in the published literature, and add 2 of their own. They have also reviewed the clinical features and the findings on coronary arteriography and post mortem studies on such fistulae. They discuss their etiology, pathogenesis, and physiopathology. Surgical correction involves repairing the fistula in one stage. Fistulae of the left coronaro-ventricular type are exceptions to this rule (9 p. 100), as they are always associated with a rapidly fatal hypoplasia of the left side of the heart. Coronaro-pulmonary fistulae (18 p. 100) are usually found in association with extreme forms of Fallot's tetralogy, and a relatively simple surgical correction can form part of the total correction of the tetralogy.

Hematogones: an overview.

Hematogones were initially described as mysterious cells in bone marrow smears more than 70 years ago. These cells are normal bone marrow B-lymphocyte precursors with properties that overlap those of lymphoblasts. Their morphological and immunological features are described here with an update on the knowledge of hematogones in hematological and non-hematological disorders.

Guidance for storing blood samples in laboratories performing complete blood count with differential.

INTRODUCTION: The complete blood count (CBC) with differential leukocyte count (DIFF) is an important part of clinical laboratory analyses and provides crucial data for clinicians. Delivery time after blood collection and conditions of storage is known to affect the reliability of results of some hematologic parameters. The aim of this study was to assess the variations of hematologic parameters over time and the influence of storage temperature. METHODS: Blood samples were randomly selected from hospitalized patients and stored at room temperature and at 4 °C. CBC and DIFF were performed on an automated hematology analyzer and the results between the two groups were compared. RESULTS: Samples stored at room temperature showed an important increase in mean corpuscular volume and hematocrit and a decrease in mean corpuscular hemoglobin concentration. Neutrophil counts tended to increase, whereas monocyte counts tended to decrease. CONCLUSION: Storing samples at 4 °C improved reproducibility over time of all quantitative and qualitative parameters. We also observed that NEUT-X, a routine parameter useful in detecting myelodysplastic syndrome, became unreliable when analyzed 24 h after sample collection. Our results led us to recommend that samples should be analyzed within 6 h, particularly if samples are transported at room temperature. We also recommend storing samples at 4 °C in case of remote CBC analysis, especially in the context of clinical trials.

Performance evaluation of the body fluid mode on the platform Sysmex XE-5000 series automated hematology analyzer.

We evaluated the performance of the automated body fluid mode of the Sysmex XE-5000 series automated haematology analyzer and compared the performance of the automated method for obtaining white blood cell (WBC), red blood cell (RBC) counts and WBC differential counts with microscopic method. One hundred and seventy-four samples were analysed: 81 ascitic fluid, 32 cerebrospinal fluid (CSF), 26 pleural fluid (PF), 18 synovial fluid (SF), 13 peritoneal fluid (PeF) and 4 other types. The agreement between the automated method and the manual reference showed high correlation, with Pearson correlation coefficients greater than 0.9 for all types of body fluids. We also demonstrate that the automated body fluid analysis on the XE-5000 is an acceptable alternative to the microscopic reference method as far as ascitic fluid, peritoneal dialysis fluid, SF or PF are concerned. Conversely, results for body fluid samples from oncology patients with leukaemia or tumours showed significant differences between both methods, as XE-5000 counted blast cells and neoplastic cells in mononuclear cell count. XE-5000 could represent an attractive method for the automated analysis of WBC, RBC, mononuclear cell count (MNC) and polymorphonuclear (PMN) cells of most body fluids. However, CSFs from patients with leukaemia or lymphoma should be processed with the microscopic reference method in order to detect abnormal leukaemic cells.