CD30 as a therapeutic target in adult haematological malignancies: Where are we now?

CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti-CD30 CAR-T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti-CD30 therapies that have emerged to date.

Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers.

Background: Peripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem-cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methods: In the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to-treat (ITT). Results: Among 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients ≤65 years old with PTCL-not otherwise specified (NOS) (N = 78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N = 123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N = 68, 25%) with partial (N = 52, 19%) or complete responses (N = 217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR = 1.02; 95% CI: 0.69-1.50 for PFS and HR = 1.08; 95% CI: 0.68-1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P = 0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. Conclusions: The present data do not support the use of ASCT for up-front consolidation for all patients with PTCL-NOS, AITL, or ALK-ALCL with partial or complete response after induction.

Control of sigma virus multiplication by the ref(2)P gene of Drosophila melanogaster: an in vivo study of the PB1 domain of Ref(2)P.

Ref(2)P has been described as one of the Drosophila proteins that interacts with the sigma virus cycle. We generated alleles to identify critical residues involved in the restrictive (inhibiting viral multiplication) or permissive (allowing viral multiplication) character of Ref(2)P. We demonstrate that permissive alleles increase the ability of the sigma virus to infect Drosophila when compared to null alleles and we confirm that restrictive alleles decrease this capacity. Moreover, we have created alleles unfunctional in viral cycling while functional for Ref(2)P fly functions. This type of allele had never been observed before and shows that fly- and virus-related activities of Ref(2)P are separable. The viral status of Ref(2)P variants is determined by the amino-terminal PB1 domain polymorphism. In addition, an isolated PB1 domain mimics virus-related functions even if it is similar to a loss of function toward fly-related activities. The evolutionary tree of the Ref(2)P PB1 domain that we could build on the basis of the natural allele sequences is in agreement with an evolution of PB1 domain due to successive transient selection waves.

Unusual variability of the Drosophila melanogaster ref(2)P protein which controls the multiplication of sigma rhabdovirus.

The ref(2)P gene of Drosophila melanogaster was identified by the discovery of two alleles, Po and Pp, respectively, permissive and restrictive for sigma rhabdovirus multiplication. A surprising variability of this gene was first noticed by the observation of size differences between the transcripts of permissive and restrictive alleles. In this paper, another restrictive allele, Pn, clearly distinct from Pp, is described: it exhibits a weaker antiviral effect than Pp and differs from Pp by its molecular structure. Five types of alleles were distinguished on the basis of their molecular structure, as revealed by S1 nuclease analysis of 17 D. melanogaster strains; three alleles were permissive and two restrictive. Comparison of the sequences of four haplotypes revealed numerous point mutations, two deletions (21 and 24 bp) and a complex event involving a 3-bp deletion, all affected the coding region. The unusual variability of the ref(2)P locus was confirmed by the high ratio of amino acid replacements to synonymous mutations (7:1), as compared to that of other genes, such as the Adh (2:42). Nevertheless, nucleotide sequence comparison with the Drosophila erecta ref(2)P gene shows that selective pressures are exerted to maintain the existence of a functional protein. The effects of this high variability on the ref(2)P protein are discussed in relation to its specific antiviral properties and to its function in D. melanogaster, where it is required for male fertility.

The BamHI fragment 9 of pseudorabies virus contains genes homologous to the UL24, UL25, UL26, and UL 26.5 genes of herpes simplex virus type 1.

The genomes of pseudorabies virus (PrV) and of herpes simplex virus type 1 (HSV1) are colinear, excepting an inversion in the unique long region, of which one extremity resides within the BamHI fragment 9. This fragment (4088 bp) encodes the counterparts of HSV1 UL24, UL25, UL26 and UL26.5 that are transcribed into four 3'-coterminal mRNAs. Multiple alignments of UL24, UL25 and UL26 protein homologs from alpha-, beta- and gamma-herpesviruses were performed. The PrV UL24 protein is shorter than its counterparts, missing the non-conserved COOH-terminal region. The region which is common to all viruses contains a basic NH2-terminus and a hydrophobic COOH-end, suggesting that UL24 may function as a matrix protein. The UL25 proteins are well conserved, particularly among the alpha-herpesviruses. All the domains involved in the proteolytic activity of theUL26 protein are highly conserved, as well as the two cleavage sites. Thus, its function and processing may be similar in PrV as in other herpesviruses. Due to the fact that in PrV the UL26 and UL44 genes are adjacent and their ends are conserved, the right border of the inversion must lie within their intergenic region.

The left border of the genomic inversion of pseudorabies virus contains genes homologous to the UL46 and UL47 genes of herpes simplex virus type 1, but no UL45 gene.

The genome of pseudorabies virus (PrV) is collinear with the herpes simplex virus type 1 (HSV1) genome, except for an inversion in the unique long region, the right extremity of which resides within the BamHI fragment 9 and the left within the BamHI fragment 1. We previously sequenced the right border of the inversion which is situated next to the UL44-gC gene and found that it encodes the UL24, UL25, UL26 and UL26.5 gene counterparts of HSV1. We have now sequenced 5317 base pairs of the BamHI fragment 1, upstream of the UL27-gB gene. We found two open reading frames homologous to UL46 and UL47 of HSV1 yet UL45 was absent and replaced by a set of strictly repeated sequences. PrV UL46 and UL47 are transcribed into two 3' co-terminal messenger RNAs with early and late kinetics, respectively. Comparison of the PrV UL46 and UL47 protein sequences with their counterparts from alphaherpesviruses indicated a strong similarity. The genome is rearranged in this region with respect to HSV1 and the inversion must have taken place, on the left side, within the UL46-UL27 intergenic region. Thus, the inversion should include genes UL27 to UL44.

[Early and middle latency auditory evoked potentials in vertebrobasilar strokes]. / Potentiels évoqués auditifs précoces et de latence moyenne dans les accidents vasculaires vertébrobasilaires.

Brainstem auditory evoked potentials (BAEPs) and middle-latency auditory evoked potentials (MLAEPs) have been recorded in 67 patients who had a stroke in well-defined territories of the vertebral and basilar arteries. Either CT scan or MRI have been performed in all cases. BAEPs were abnormal in 41/67 patients and MLAEPs were abnormal in 25/39 patients. BAEPs abnormalities were either bilateral (29/41 cases) or unilateral (12/41 cases). All components of BAEPS were unilaterally absent in four cases and bilaterally in one case. Pa component of MLAEPs was unilaterally delayed or reduced in five cases and bilaterally in 20 cases. Considering the topography of the infarct as shown by CT scan or MRI: medulla oblongata (13 cases): BAEPSs were normal in nine cases; pons (24 cases): BAEPs were abnormal in 16 cases; MLAEPs were abnormal in ten of 15 patients whose BAEPs were abnormal as well; mesencephalon (seven cases): BAEPs were abnormal in only two cases, and MLAEPs were abnormal in two cases one of which BAEPs were normal; in patients with diffuse infarctions either BAEPs or MLAEPs or both were abnormal in all cases. Stimulation of the ear ipsilateral to the lesion disclosed more BAEPs or MLAEPs abnormalities than stimulation of the contralateral ear.

[Agrypnia (organic insomnia)]. / Les agrypnies.

The word agrypnia, ie, organic insomnia, was first used to describe a patient with a Morvan fibrillary chorea, which is an ill-delineated syndrome. This review considers the experimental insomnia created by raphe nuclei, anterior hypothalamic, or thalamic lesions. There are some papers reporting REM and non-REM sleep reduction in man after vascular, traumatic or degenerative lesion of the pons. There is only one case of agrypnia due to a bilateral stereotatic thalamic injury. Infectious agrypnia (trypanosomiasis, Von Economo) may exist but has not been documented by polygraphic means. Fatal familial insomnia induces a precocious agrypnia and leads to death with vegetative and motor disturbances. It is associated with an abnormal prion-protein which may interfere with gabaergic synapses. Finally agrypnia in humans corresponds to either lesionnal or infra microscopic synaptic prion linked disorders.

Preliminary evaluation of medical outcomes (including quality of life) and costs in incident RA cases receiving hospital-based multidisciplinary management.

A six-month, prospective descriptive study of medical outcomes (including quality of life) and costs was conducted in 20 incident cases of rheumatoid arthritis (RA). Multidisciplinary management was started during an inpatient stay at the beginning of the study. Patients were evaluated on a day-hospital basis three and six months later. The following parameters were studied: quality-of-life scores on a generic scale (the Nottingham Health Profile [NHP]) and two specific scales (Health Assessment Questionnaire [HAQ] and the short-form Arthritis Impact Measurement Scale [AIMS]), pain severity, disease activity assessed by the patient and physician, painful and swollen joint counts, erythrocyte sedimentation rate, and C-reactive protein level. The following costs were evaluated: laboratory tests, plain radiographs, other investigations, physician care (by rheumatologists or other specialists), second-line drug therapy and monitoring for its side effects, care by nurses, physical therapy, and occupational therapy. All patients showed significant improvement three months after initiation of multidisciplinary management. This effect was sustained through the sixth month. Quality-of-life scores improved, with the exceptions of the social isolation subscore on the NHP and the psychological impact, social activity, and occupational activity subscores on the short-form AIMS. Mean total cost for the six-month period was 3429 +/- 880 euros (1 euro = 6.6 FF). Laboratory tests contributed the largest portion of the total cost (39%), followed by rheumatologist care (16%); the other costs accounted for 7.6 to 9.2% of the total cost. This prospective medical and economic study is preliminary. Comparative studies are needed.

MRI anatomy of the acoustic-facial bundle in vivo.

In this study performed on 5 healthy volunteers the authors used oblique axial, coronal and sagittal MRI sections suitable to be anatomical configuration of the acoustic-facial bundle and were able to individualize the nerves forming this bundle throughout their course, with the sole exception of the intermediate nerve (VII2). They also analysed the relations of these nerves between themselves and with the other elements of the cerebellopontine angle. In addition, a proton-density sequence (SE, 6,000/30 ms) made it possible to differentiate in vivo between the grey matter and the white matter sufficiently to individualize the principal nuclei and tracts of the brain stem, and in particular the main vestibulo-cochlear central pathways.

[Progressive supranuclear paralysis. Quantification of dopamine D2 receptors using radionuclide tomography]. / Paralysies supra-nucléaires progressives. Quantification des récepteurs dopaminergiques D2 par tomoscintigraphie.

Progressive supranuclear palsy (PSP) may sometimes be misdiagnosed as Parkinson's disease in its early stages, hence an early positive diagnosis of PSP based on dopamine D2 receptor density could be extremely valuable. In the present case report, the absence of dopamine D2 receptors was clearly demonstrated in the striatum using 123I-iodobenzamide (IBZM) tomoscintigraphy. This illustrates the potential use of IBZM tomoscintigraphy to identify Parkinson-like's disease presenting with decreased dopamine D2 receptor density; and hence to predict L-Dopa effectiveness. Further studies are needed to evaluate the vaue of IBZM tomoscintigraphy in the different Parkinson's like diseases.

[Non-traumatic vertebro-epidural radiculo-spinal cord compressions: value of x-ray computed tomography coupled with myelography for lesion evaluation and therapeutic indications]. / Compressions médullo-radiculaires vertébro-épidurales non traumatiques: intérêt de l'étude tomodensitométrique couplée à la myélographie pour le bilan lésionnel et les indications thérapeutiques.

About 37 cases of non-traumatic spinal cord and cauda-equina compression, the authors emphasize the value of CT-scan study after intra-thecal injection of water-soluble contrast-medium. This exploration gives accurate informations about the involvement of both spinal and para-spinal spaces. These data are helpful diagnosis purpose and for the choice of therapeutic especially when surgical procedure is decided.

[The new imaging technics: theoretical principles, limitations and some ideas on costs]. / Les nouvelles techniques d'imagerie: principes théoriques, limites, notions de coût.

The new imaging techniques modify the diagnostic, or even sometimes therapeutic, decision lines. Their efficiency is much greater than that of the old techniques, while pretium doloris and side-effects are considerably reduced. Such advances are not without a major disadvantage: the ever increasing cost of imaging explorations. Radiological guidance (with conventional radiology, ultrasounds and computerized tomography) facilitates percutaneous procedures for diagnostic (biopsy) or therapeutic purposes (emptying of abscesses, chemonucleolysis of herniated lumbar disc, etc.).

Sequences of the N and M genes of the sigma virus of Drosophila and evolutionary comparison.

The genome of the sigma rhabdovirus of Drosophila melanogaster consists of six genes in the order 3' N-2-3-4-G-L 5'. The nucleotide sequences of the N and of the fourth genes were determined from cDNA clones. Each gene contained a single long open reading frame encoding polypeptides with predicted MW of 50 and 25 kDa, respectively. Evidence that these genes encode the nucleocapsid N and the matrix M proteins were obtained using antibodies raised against recombinant proteins derived from the cloned genes and expressed in Escherichia coli. The M and N predicted amino acid sequences were compared with those of other rhabdoviruses. The M protein of sigma virus shared a similar domain arrangement to the other M proteins, but it showed very little sequence conservation. The N protein of sigma virus showed no significant homology with its counterpart in SYNV or IHNV and VSHV; it did, however, show sequence homology with the N of four vesiculoviruses and two lyssaviruses. The extent of amino acid identity suggests that sigma virus occupies an intermediate evolutionary position between these two genera. Some conserved motifs in the M and N proteins were deduced from the comparisons.