Les pneumopathies interstitielles diffuses chroniques: un mariage de raison entre pathologiste, clinicien et radiologue [Diffuse parenchymal lung disease, multidisciplinary approach and role of pathology]

The diagnostic approach to diffuse parenchymal lung disease (DPLD) and especially to the idiopathic interstitial pneumonias has changed over the last two decades, mostly thanks to the development of high resolution CT. Though far from replacing pathology, this additional tool has contributed to the definition of new and more precise diagnostic criteria especially for idiopathic interstitial pneumonias, integrating data provided by the three main contributors: lung specialist, radiologist and pathologist. The purpose of this article is to review the role of histopathology in the multidisciplinary approach of the diagnosis of DPLD and idiopathic interstitial pneumonias.

Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma.

A key element for the development of suitable anti-cancer drugs is the identification of cancer-specific enzymatic activities that can be therapeutically targeted. Mucosa-associated lymphoid tissue transformation protein 1 (MALT1) is a proto-oncogene that contributes to tumorigenesis in diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) subtype, the least curable subtype of DLBCL. Recent data suggest that MALT1 has proteolytic activity, but it is unknown whether this activity is relevant for tumor growth. Here we report that MALT1 is constitutively active in DLBCL lines of the ABC but not the GCB subtype. Inhibition of the MALT1 proteolytic activity led to reduced expression of growth factors and apoptosis inhibitors, and specifically affected the growth and survival of ABC DLBCL lines. These results demonstrate a key role for the proteolytic activity of MALT1 in DLBCL of the ABC subtype, and provide a rationale for the development of pharmacological inhibitors of MALT1 in DLBCL therapy.

Hereditary diffuse leukoencephalopathy with axonal spheroids: More than just a rare disease.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a progressive white matter disease with a wide range of clinical symptoms including dementia, behavioral changes, seizures, pyramidal signs, ataxia, and parkinsonism.(1-3) Affected individuals develop symptoms in their early 40s with an average survival time of 10 years. HDLS is inherited as an autosomal dominant trait. Recently, mutations in the colony-stimulating factor 1 receptor gene (CSF-1R) were identified as the genetic cause of HDLS.(4) White matter lesions, easily demonstrated on MRI studies, involve predominantly the frontal lobes and corpus callosum with subsequent cortical atrophy. MRI abnormalities are present prior to symptom onset.(5,6) Histopathology shows widespread myelin and axon destruction with axonal dilations termed spheroids, as well as pigmented macrophages.

Single-hole GPR reflection imaging of solute transport in a granitic aquifer

Identifying transport pathways in fractured rock is extremely challenging as flow is often organized in a few fractures that occupy a very small portion of the rock volume. We demonstrate that saline tracer experiments combined with single-hole ground penetrating radar (GPR) reflection imaging can be used to monitor saline tracer movement within mm-aperture fractures. A dipole tracer test was performed in a granitic aquifer by injecting a saline solution in a known fracture, while repeatedly acquiring single-hole GPR sections in the pumping borehole located 6 m away. The final depth-migrated difference sections make it possible to identify consistent temporal changes over a 30 m depth interval at locations corresponding to fractures previously imaged in GPR sections acquired under natural flow and tracer-free conditions. The experiment allows determining the dominant flow paths of the injected tracer and the velocity (0.4-0.7 m/min) of the tracer front. Citation: Dorn, C., N. Linde, T. Le Borgne, O. Bour, and L. Baron (2011), Single-hole GPR reflection imaging of solute transport in a granitic aquifer, Geophys. Res. Lett., 38, L08401, doi: 10.1029/2011GL047152.

Diffuse nesidioblastosis with hypoglycemia mimicking an insulinoma: a case report.

INTRODUCTION: We describe a case of diffuse nesidioblastosis in an adult patient who presented with exclusively fasting symptoms and a focal pancreatic 111In-pentetreotide uptake mimicking an insulinoma. CASE PRESENTATION: A 23-year-old Caucasian man had severe daily fasting hypoglycemia with glucose levels below 2mmol/L. Besides rare neuroglycopenic symptoms (confusion, sleepiness), he was largely asymptomatic. His investigations revealed low venous plasma glucose levels, high insulin and C-peptide levels and a 72-hour fast test that were all highly suggestive for an insulinoma. Abdominal computed tomography and magnetic resonance imaging did not reveal any lesions. The sole imagery that was compatible with an insulinoma was a 111In-somatostatin receptor scintigraphy that showed a faint but definite focal tracer between the head and the body of the pancreas. However, this lesion could not be confirmed by endoscopic ultrasonography of the pancreas. Following duodenopancreatectomy, the histological findings were consistent with diffuse nesidioblastosis. Postoperatively, the patient continued to present with fasting hypoglycemia and was successfully treated with diazoxide. CONCLUSION: In the absence of gastrointestinal surgery, nesidioblastosis is very rare in adults. In addition, nesidioblastosis is usually characterized by post-prandial hypoglycemia, whereas this patient presented with fasting hypoglycemia. This case also illustrates the risk for a false positive result of 111In-pentetreotide scintigraphy in the case of nesidioblastosis. Selective arterial calcium stimulation and venous sampling is the most reliable procedure for the positive diagnosis of insulinoma or nesidioblastosis and should be used to confirm any suspicion based on imaging modalities.

Estimation of the correlation structure of crustal velocity heterogeneity from seismic reflection data

Numerous sources of evidence point to the fact that heterogeneity within the Earth's deep crystalline crust is complex and hence may be best described through stochastic rather than deterministic approaches. As seismic reflection imaging arguably offers the best means of sampling deep crustal rocks in situ, much interest has been expressed in using such data to characterize the stochastic nature of crustal heterogeneity. Previous work on this problem has shown that the spatial statistics of seismic reflection data are indeed related to those of the underlying heterogeneous seismic velocity distribution. As of yet, however, the nature of this relationship has remained elusive due to the fact that most of the work was either strictly empirical or based on incorrect methodological approaches. Here, we introduce a conceptual model, based on the assumption of weak scattering, that allows us to quantitatively link the second-order statistics of a 2-D seismic velocity distribution with those of the corresponding processed and depth-migrated seismic reflection image. We then perform a sensitivity study in order to investigate what information regarding the stochastic model parameters describing crustal velocity heterogeneity might potentially be recovered from the statistics of a seismic reflection image using this model. Finally, we present a Monte Carlo inversion strategy to estimate these parameters and we show examples of its application at two different source frequencies and using two different sets of prior information. Our results indicate that the inverse problem is inherently non-unique and that many different combinations of the vertical and lateral correlation lengths describing the velocity heterogeneity can yield seismic images with the same 2-D autocorrelation structure. The ratio of all of these possible combinations of vertical and lateral correlation lengths, however, remains roughly constant which indicates that, without additional prior information, the aspect ratio is the only parameter describing the stochastic seismic velocity structure that can be reliably recovered.

Expression of MYC, IgM, As Well As Non-Germinal Centre B-Cell Like Immunophenotype and Positive Immunofish Index Predict a Worse Progression Free Survival and Overall Survival in a Series of 670 De Novo Diffuse Large B-Cell Lymphomas Included in Clinical Trials: A GELA Study of the 2003 Program

Introduction: Diffuse large B-cell lymphomas (DLBCL) represent a heterogeneous disease with variable clinical outcome. Identifying phenotypic biomarkers of tumor cells on paraffin sections that predict different clinical outcome remain an important goal that may also help to better understand the biology of this lymphoma. Differentiating non-germinal centre B-cell-like (non-GCB) from Germinal Centre B-cell-like (GCB) DLBCL according to Hans algorithm has been considered as an important immunohistochemical biomarker with prognostic value among patients treated with R-CHOP although not reproducibly found by all groups. Gene expression studies have also shown that IgM expression might be used as a surrogate for the GCB and ABC subtypes with a strong preferential expression of IgM in ABC DLBCL subtype. ImmunoFISH index based on the differential expression of MUM-1, FOXP1 by immunohistochemistry and on the BCL6 rearrangement by FISH has been previously reported (C Copie-Bergman, J Clin Oncol. 2009;27:5573-9) as prognostic in an homogeneous series of DLBCL treated with R-CHOP. In addition, oncogenic MYC protein overexpression by immunohistochemistry may represent an easy tool to identify the consequences of MYC deregulation in DLBCL. Our aim was to analyse by immunohistochemistry the prognostic relevance of MYC, IgM, GCB/nonGCB subtype and ImmunoFISH index in a large series of de novo DLBCL treated with Rituximab (R)-chemotherapy (anthracyclin based) included in the 2003 program of the Groupe d'Etude des Lymphomes de l'Adulte (GELA) trials. Methods: The 2003 program included patients with de novo CD20+ DLBCL enrolled in 6 different LNH-03 GELA trials (LNH-03-1B, -B, -3B, 39B, -6B, 7B) stratifying patients according to age and age-adjusted IPI. Tumor samples were analyzed by immunohistochemistry using CD10, BCL6, MUM1, FOXP1 (according to Barrans threshold), MYC, IgM antibodies on tissue microarrays and by FISH using BCL6 split signal DNA probes. Considering evaluable Hans score, 670 patients were included in the study with 237 (35.4%) receiving intensive R-ACVBP regimen and 433 (64.6%) R-CHOP/R-mini-CHOP. Results: 304 (45.4%) DLBCL were classified as GCB and 366 (54.6%) as non-GCB according to Hans algorithm. 337/567 cases (59.4%) were positive for the ImmunoFISH index (i.e. two out of the three markers positive: MUM1 protein positive, FOXP1 protein Variable or Strong, BCL6 rearrangement). Immunofish index was preferentially positive in the non-GCB subtype (81.3%) compared to the GCB subtype (31.2%), (p<0.001). IgM was recorded as positive in tumor cells in 351/637 (52.4%) DLBCL cases with a preferential expression in non-GCB 195 (53.3%) vs GCB subtype 100(32.9%), p<0.001). MYC was positive in 170/577 (29.5%) cases with a 40% cut-off and in 44/577 (14.2%) cases with a cut-off of 70%. There was no preferential expression of MYC among GCB or non-GCB subtype (p>0.4) for both cut-offs. Progression-free Survival (PFS) was significantly worse among patients with high IPI score (p<0.0001), IgM positive tumor (p<0.0001), MYC positive tumor with a 40% threshold (p<0.001), ImmunoFISH positive index (p<0.002), non-GCB DLBCL subtype (p<0.0001). Overall Survival (OS) was also significantly worse among patients with high IPI score (p<0.0001), IgM positive tumor (p=0.02), MYC positive tumor with a 40% threshold (p<0.01), ImmunoFISH positive index (p=0.02), non-GCB DLBCL subtype (p<0.0001). All significant parameters were included in a multivariate analysis using Cox Model and in addition to IPI, only the GCB/non-GCB subtype according to Hans algorithm predicted significantly a worse PFS among non-GCB subgroup (HR 1.9 [1.3-2.8] p=0.002) as well as a worse OS (HR 2.0 [1.3-3.2], p=0.003). This strong prognostic value of non-GCB subtyping was confirmed considering only patients treated with R- CHOP for PFS (HR 2.1 [1.4-3.3], p=0.001) and for OS (HR 2.3 [1.3-3.8], p=0.002). Conclusion: Our study on a large series of patients included in trials confirmed the relevance of immunohistochemistry as a useful tool to identify significant prognostic biomarkers for clinical use. We show here that IgM and MYC might be useful prognostic biomarkers. In addition, we confirmed in this series the prognostic value of the ImmunoFISH index. Above all, we fully validated the strong and independent prognostic value of the Hans algorithm, daily used by the pathologists to subtype DLBCL.

Whole anterior segment proton beam radiotherapy for diffuse iris melanoma.

AIM: To report the results of whole anterior segment proton beam radiotherapy (PBR) for diffuse iris melanoma. METHODS: Between 2000 and 2011, 12 patients with iris melanoma received PBR to the entire iris and ciliary body. RESULTS: Patients had a mean age of 57 years and a median follow-up of 3.5 years (range 1-11.6 years). Tumour iris involvement was 1-4 h in five patients, 5-8 h in four and 9-12 h in three. Angle involvement was 6-8 h in five patients and 9-12 h in seven. The visual acuity (VA) before treatment was 6/5-6/6 in six patients, 6/8-6/9 in three and 6/18-6/38 in three. No tumour recurrence occurred during the follow-up period. Glaucoma treatment was required in 11 of 12 patients. The visual acuity at the last follow-up was 6/5-6/9 in five patients, 6/18-6/24 in three, 6/60-1/60 in two and no light perception in two. Four patients developed varying non-severe degrees of limbal stem cell deficiency, which was treatable with conservative measures. CONCLUSIONS: Whole anterior segment PBR is a useful alternative to enucleation for diffuse iris melanoma. Most patients will need treatment for glaucoma and some may require treatment for tear-film instability and/or stem cell failure.

Geostatistical inversion of seismic and GPR reflection images: what can we actually resolve?

Estimation of the spatial statistics of subsurface velocity heterogeneity from surface-based geophysical reflection survey data is a problem of significant interest in seismic and ground-penetrating radar (GPR) research. A method to effectively address this problem has been recently presented, but our knowledge regarding the resolution of the estimated parameters is still inadequate. Here we examine this issue using an analytical approach that is based on the realistic assumption that the subsurface velocity structure can be characterized as a band-limited scale-invariant medium. Our work importantly confirms recent numerical findings that the inversion of seismic or GPR reflection data for the geostatistical properties of the probed subsurface region is sensitive to the aspect ratio of the velocity heterogeneity and to the decay of its power spectrum, but not to the individual values of the horizontal and vertical correlation lengths.

Ostéomyélite sclérosante diffuse de la mandibule et SAPHO [Diffuse sclerosing osteomyelitis of the mandible and SAPHO].

Diffuse sclerosing osteomyelitis of the mandible may be the presenting manifestation of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome. We report an additional case of such a presentation.

Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution's experience

Objective: To demonstrate our institutional experience in the treatment ofdiffuse intrinsic pontine glioma (DIPG) with an hypofractionated external beam radiotherapy schedule.Materials and Methods: Between April 1996 and January 2004, 22 patients, ages 2.9-12.5 years, with newly diagnosed DIPG were treated by hypofractionated radiation therapy delivering a total dose of 45 Gy in daily fraction of 3 Gy, given over 3 weeks. No other treatment was applied concomittently.Results: Fourteen of the 22 patients received the prescribed dose of 45 Gy in 15 fractions of 3 Gy, two patients received a total dose of 60 and 45 Gy with a combination of two different beams (photons and neutrons), in 5 cases the daily fraction was modified to 2 Gy because of bad tolerance and one patient died due to serious intracranial hypertension after 2 fractions of 3 Gy and one of 2 Gy. Fourteen patients of 22 patients/of the total showed a clinical improvement, usually starting in the second week of treatment. No grade 3 or 4 acute toxicity from radiotherapy was observed. No treatment interruption was needed. In six patients, steroids could be discontinued within one month after the end of radiotherapy. The median time to progression and the median overall survival were 5.7 months and 7.6 months, respectively.Conclusion: External radiotherapy with a radical hypofractionated regimen is feasible and well tolerated in children with newly diagnosed DIPG. This regimen does not seem however to change the overall survival in this setting. It could represent an alternative option of short duration to more protracted regimens.