Radiotherapy plus temozolomide in elderly patients with glioblastoma: a "real-life" report.

BACKGROUND: The optimization of the management for elderly glioblastoma patients is crucial given the demographics of aging in many countries. We report the outcomes for a "real-life" patient cohort (i.e. unselected) comprising consecutive glioblastoma patients aged 70 years or more, treated with different radiotherapy +/- temozolomide regimens. METHODS: From 2003 to 2016, 104 patients ≥ 70 years of age, consecutively treated by radiotherapy for glioblastoma, were included in this study. All patients were diagnosed with IDH-wild type glioblastoma according to pathological criteria. RESULTS: Our patient cohort comprised 51 female patients (49%) and 53 male. The median cohort age was 75 years (70-88), and the median Karnofsky performance status (KPS) was 70 (30-100). Five (5%) patients underwent macroscopic complete resection, 9 (9%) had partial resection, and 90 (86%), a stereotactic biopsy. The MGMT promoter was methylated in 33/73 cases (45%). Fifty-two (50%), 38 (36%), and 14 (14%) patients were categorized with RPA scores of III, IV, and I-II. Thirty-three (32%) patients received normofractionated radiotherapy (60 Gy, 30 sessions) with temozolomide (Stupp), 37 (35%) received hypofractionated radiotherapy (median dose 40 Gy, 15 sessions) with temozolomide (HFRT + TMZ), and 34 (33%) HFRT alone. Patients receiving only HFRT were significantly older, with lower KPSs. The median overall survival (OS; all patients) was 5.2 months. OS rates at 12, 18, and 24 months, were 19%, 12%, and 5%, respectively, with no statistical differences between patients receiving Stupp or HFRT + TMZ (P = 0.22). In contrast, patients receiving HFRT alone manifested a significantly shorter survival time (3.9 months vs. 5.9 months, P = 0.018). In multivariate analyses, the prognostic factors for OS were: i) the type of surgery (HR: 0.47 [0.26-0.86], P = 0.014), ii) RPA class (HR: 2.15 [1.17-3.95], P = 0.014), and iii) temozolomide use irrespective of radiotherapy schedule (HR: 0.54 [0.33-0.88], P < 0.02). MGMT promoter methylation was neither a prognostic nor a predictive factor. CONCLUSIONS: These outcomes agree with the literature in terms of optimal surgery and the use of HFRT as a standard treatment for elderly GBM patients. Our study emphasizes the potential benefit of using temozolomide with radiotherapy in a real-life cohort of elderly GBM patients, irrespective of their MGMT status.

[Jugal rejuvenation and jowls treatment]. / Rajeunissement jugal et traitement des bajoues.

The aim of this study is to analyze the anatomical changes leading to the appearance of jugal aging with the appearance of jowls. It is also to describe the different techniques and to highlight those that are most effective with the permanent concern of obtaining a natural result with a well-defined jawline and a harmonious distribution of jugal volumes. For this purpose, the techniques of lifting with relocation of the displaced volumes and lipostructure are often associated with the strict respect of different directional vectors for the underlying tissues and for the skin redraping. More precisely, the dissection of the pre-masseteric space makes it possible to address the specific problems posed by the jowls and the heavy labio-mental grooves. In responding to the psycho-sociological demand of our time, two major types of indications emerge with the facelift of the young patient, which makes it possible to obtain a long lasting result and a fast return to social and professional life and a later indication surgery, which requires more invasive techniques resulting in heavier surgical procedures and follow-up.

[Temporal rejuvenation]. / Rajeunissement temporal.

The temporal region has imprecise limits in the young patient. During the aging process, it becomes individualized with the appearance of a temporal fossa, the temporal, orbital and zygomatic bone margins, the ptosis of the lateral part of the brow and the appearance of the wrinkles of the crow's foot. As this area frame the look, it should be taken into consideration during the clinical examination as well as the facial and cervical stages. The rejuvenation techniques are numerous, nuanced and gradual. As long as the eyebrow ptosis is not evident and the distance of the eyebrows unaltered, the volumizing techniques and the botulinum toxin can respond effectively and harmoniously to the patients' demand. Then the surgical techniques of temporal and brow liftings must be considered and coupled with the techniques of lipostructure that are more and more practiced. It should be noted that the demand for temporal rejuvenation is increasing and precedes the demand of cervicofacial rejuvenation. This underlines the importance of this region both in terms of preventing or at least slowing down the process than in terms of curing the stigma of aging.

Comparison of three methods of diagnosis of plasma unmeasured anions in critically ill patients.

BACKGROUND: The measurement of plasma unmeasured anions (PUA) is paramount in assessing metabolic acid base disorders. The aim of this study was to compare the accuracy of three methods in diagnosing abnormal PUA values: standard base excess (SBE), the albumin corrected anion gap (AGc), and the Stewart-Figge approach, based on unidentified anions (XAc-). METHODS: Acid-base variables were prospectively collected in ICU patients admitted January-September 2008. Whatever the method, PUA values measured two standard deviations above or below the mean of those in control subjects were considered as abnormal. RESULTS: Of the 205 consecutives patients included, 179 had an abnormal PUA value. The accuracy of AGc and XAc- in diagnosing abnormal PUA values was comparable (AUC: 0.89±0.03 and 0.89±0.03, P=0.82) but greater than that of SBE (0.67±0.06, P<0.001 and P<0.001, respectively). Of the high PUA values (n=161), 96% were diagnosed by XAc-, 88% by AGc (P<0.01) and 48% by SBE (P<0.001). Hyperlactatemia (n=111) was diagnosed equally by AGc and XAc-, (81% and 86%, P=0.37) but less by SBE (50%, P<0.001 and P<0.001, respectively). High PUA not associated with hyperlactatemia (N.=61) was more frequently diagnosed by XAc- (97%) than by AGc (84%, P=0.03). CONCLUSION: In ICU patients, AGc and the Stewart-Figge approach should be preferred over SBE for diagnosing abnormal PUA values and predicting hyperlactatemia. The Stewart-Figge approach based on unidentified anions, is the most efficient in diagnosing high PUA values not associated with hyperlactatemia.

[Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases]. / Histoire naturelle des leucodystrophies avec mutation EIF2B: étude rétrospective multicentrique de 24 cas adultes.

INTRODUCTION: The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome (CACH-VWM) was first characterized in children (2-5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. METHODS: The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. CONCLUSION: eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation.

Clinical and genetic findings in a series of Italian children with pure hereditary spastic paraplegia.

BACKGROUND: hereditary spastic paraplegias (HSP) are a group of neurodegenerative disorders characterized by progressive lower extremity spastic weakness. SPG7, SPG4 and SPG3A are some of the autosomal genes recently found as mutated in recessive or dominant forms of HSP in childhood. SPG31 is more often associated with a pure spastic paraplegia phenotype, but genotype-phenotype correlation is still unclear. The aims of the current study was: (i) to verify the mutational frequency of SPG4, SPG3A, SPG31 and SPG7 genes in our very-well-selected childhood sample, and (ii) to improve our knowledge about the clinical and electrophysiological HSP phenotypes and their possible correlation with a specific mutation. METHODS: a sample of 14 Italian children affected by pure HSP (mean age at diagnosis 5.9 years) was extensively investigated with electrophysiological, neuroradiological and genetic tests. RESULTS: three SPG4 mutations were identified in three patients: two novel missense mutations, both sporadic, and one multiexonic deletion already reported. A novel large deletion in SPG31 gene involving exons 2-5 was also detected in one young patient. No mutations in the SPG7 and in the SPG3A genes were found. CONCLUSIONS: our data confirm that HSP represent a heterogeneous group of genetic neurodegenerative disorders, also in sporadic or autosomal recessive early onset forms. Multiplex Ligation-dependent Probe Amplification-based mutation screening for SPG4 and SPG31 genes would be added to sequencing-based screening of SPG4, SPG31 and SPG3A genes in the routine diagnosis of HSP children.

Sensitivity and specificity of decreased CSF asialotransferrin for eIF2B-related disorder.

OBJECTIVE: This is a study estimating diagnostic accuracy of CSF asialotransferrin to transferrin ratio measurement in eIF2B related disorders by using clinical evaluation and EIF2B mutation analysis as the reference standard. eIF2B-related disorder is a relatively common leukodystrophy with broad phenotypic variation that is caused by mutations in any of the five EIF2B genes. There is a need for a simple and clinically valid screening tool for physicians evaluating patients with an unclassified leukodystrophy. METHODS: CSF two-dimensional gel (2DG) electrophoresis analyses to measure asialotransferrin to transferrin ratios were performed in 60 subjects including 6 patients with documented EIF2B gene mutations, patients with other types of leukodystrophy, and patients with no leukodystrophy. RESULTS: All six patients with mutation proven eIF2B-related disease showed low to nearly undetectable amounts of asialotransferrin in their CSF when compared to 54 unaffected controls by CSF 2DG analyses in this study. eIF2B-like patients, with clinically similar presentations but no mutations in EIF2B1-5, were distinguished from patients with mutations in EIF2B1-5 by this biomarker. Patients with mutations in EIF2B1-5 had asialotransferrin/transferrin ratio levels significantly different from the group as a whole (p < 0.001). Using 8% asialotransferrin/transferrin ratio as a cutoff, this biomarker has a 100% sensitivity (95% CI = 52-100%) and 94% specificity (95% CI = 84-99%). CONCLUSION: Decreased asialotransferrin/transferrin ratio in the CSF of patients with eIF2B-related disorder is highly sensitive and specific. This rapid (<48 hours) and inexpensive diagnostic tool for eIF2B-related disorders has the potential to identify patients with likely eIF2B-related disorder for mutation analysis.

Exon deletion in the non-catalytic domain of eIF2Bepsilon due to a splice site mutation leads to infantile forms of CACH/VWM with severe decrease of eIF2B GEF activity.

The CACH/VWM syndrome is an autosomal recessive leukodystrophy characterized by a broad spectrum of clinical presentations and by diffuse cavitary degeneration of the white matter on MRI. Mutations responsible for this disorder are missense or frameshift mutations occurring in the five genes (EIF2B1-5) that encode the translation eukaryotic initiation factor eIF2B. We found that a patient with infantile CACH/VWM carries a mutation in the acceptor splice site of EIF2B5 exon 6. In lymphoblastoid cells of the patient, we detected an abnormal EIF2B5 transcript in which exon 6 was absent, however, the predicted protein product lacking part of the non-catalytic domain encoded by exon 6 was not detected. The eIF2B GEF activity was severely decreased. These data support the importance of the non-catalytic domain of the eIF2Bepsilon subunit in the eIF2B complex formation and activity.

Skin and platysma muscle anchoring.

Anatomically, the platysma muscle is composed of two parts: a facial part and a cervical part. This observation allows a better understanding of the modifications due to aging. The correction of platysma bands needs nearly vertical directional vectors at the facial level. The periosteum of the malar bone and the anterior border of the parotid fascia are two solid structures that are not modified during aging. They allow the anchoring of the ptotic tissues including premalar fat pads, jowls, and platysma bands. The connections between the skin and the platysma muscle are not affected, although most of the described techniques need a detachment of the platysma muscle from the skin and a suture of the anterior border via a submental approach. Furthermore, the posterior border of the platysma muscle is not modified by aging. This explains why it is useless to detach this structure. The principles of the proposed technique are fundamentally different. Lore's fascia is used as a guide for approaching the trunk of the facial nerve. Labbé and colleagues have done an anatomic study of this procedure. It allows a solid anchoring of the platysma muscle, which is not detached from the skin. This is the key to the operation because the skin and the muscle are elevated en bloc. The author demonstrates that the absence of separation between skin and muscle, particularly at the cervical level, is a very efficient means for correcting platysma bands and for obtaining good definition of the cervicomental angle.

Molecular characterization of 6 unrelated Italian patients with 5alpha-reductase type 2 deficiency.

Steroid 5alpha-reductase (5alphaR) deficiency (OMIM number #264600) is a rare 46,XY disorder of sex differentiation caused by mutations in the 5alphaR type 2 gene (SRD5A2) resulting in dihydrotestosterone deficiency during fetal development. We report on the analysis of the SRD5A2 gene in 6 unrelated 46,XY Italian patients with external genitalia morphology ranging from predominantly female to nearly completely male. Three subjects were seen and assessed at birth, 1 patient was referred to us before puberty, and 2 at postpubertal age. Six different causative mutations (5 missense and 1 nonsense) and a rare polymorphism were identified. Four patients presented homozygous single-base substitutions. These SRD5A2 mutations were located in exon 2 (variant Cys133Gly), exon 4 (Gly196Ser and Ala207Asp) and exon 5 (Tyr235Phe). A fifth subject was a compound heterozygote who carried a nonsense mutation in exon 1 (Trp53X) and a second SRD5A2 alteration in exon 5 (Tyr235Phe). The final patient presented a mutation in only 1 allele (Gly34Trp) together with the Ala49Thr variant. The molecular characterization of these patients made it possible to identify novel mutations and to confirm, before gender assignment or any surgical approach, the suspected 5alphaR deficiency in 2 newborns, 1 of whom had inconclusive hormonal data. 5alphaR deficiency in subjects without parental consanguinity and the presence of compound heterozygotic patients suggest that SRD5A2 mutations carrier frequency may be higher than previously thought.

[Monoclonal IgM interference with immunoturbidimetric determination of ferritin and transferrin]. / Perturbation de la détermination immunoturbidimétrique de la ferritine et de la transferrine due à la présence d'une IgM monoclonale.

When they are present in important blood concentration, the monoclonal immunoglobulins are known to interfere with many immuno-analyze assays. We report the case of a patient presenting a Waldenstrom macroglobulinemia, for which the determination of some parameters of the martial assessment was impossible because of the presence of IgM kappa. The analysis of analytical alarms of the automat as well as the installation of simple and fast pre-treatment protocol of the interference enabled us to quickly make a result useful for the management of this patient.

[CACH/VWM syndrome and leucodystrophies related to EIF2B mutations]. / Le syndrome CACH/VWM et les leucodystrophies liées à des mutations EIF2B.

A new leukoencephalopathy, the CACH syndrome (Childhood Ataxia with Central nervous system Hypomyelination) or VWM (Vanishing White Matter) was identified on clinical and MRI criteria. Classically, this disease is characterized by (1) an onset between 2 and 5 years of age, with a cerebello-spastic syndrome exacerbated by episodes of fever or head trauma leading to death after 5 to 10 years of disease evolution, (2) a diffuse involvement of the white matter on cerebral MRI with a CSF-like signal intensity (cavitation), (3) a recessive autosomal mode of inheritance, (4) neuropathologic findings consistent with a cavitating orthochromatic leukodystrophy with increased number of oligodendrocytes with sometimes "foamy" aspect. A total of 148 cases have been reported so far. This disease is linked to mutations in the five EIF2B genes encoding the five subunits of the eukaryotic initiation factor 2B (eIF2B), involved in the protein synthesis and its regulation under cellular stresses. Clinical symptoms are variable, from fatale infantile forms (Cree leukoencephalopathy) and congenital forms associated with extra-neurological affections, to juvenile and adult forms (ovarioleukodystrophy) characterized by cognitive and behaviour dysfunctions and by a slow progression of the disease, leading to the term of eIF2B-related leukoencephalopathies. Prevalence of these remains unknown. Diagnosis lays on the detection of EIF2B mutations, affecting predominantly the EIF2B5 gene. A decrease in the intrinsic activity of the eIF2B factor (the guanine exchange activity, GEF) in lymphoblasts from patients seems to have a diagnostic value. The patho-physiology of the disease would involve a deficiency in astrocytes maturation leading to an increased susceptibility of the white matter to cellular stress. No specific treatment exists except the "prevention" of cellular stress. Corticosteroids sometimes proved to be useful in acute phases. Prognosis seems to correlate with the age of onset, the earliest forms being more severe.

The large spectrum of eIF2B-related diseases.

eIF2B (eukaryotic initiation factor 2B) is a GEF (guanine nucleotide-exchange factor) that plays, with its substrate eIF2, a key regulatory role in the translation initiation phase of protein synthesis. The importance of correct control of eIF2 and eIF2B for normal physiology is underlined by the recent involvement of the five genes that encode the five eIF2B subunits in a severe autosomal recessive neurodegenerative disease, described in young children as CACH (childhood ataxia with central nervous system hypomyelination)/VWM (leukoencephalopathy with vanishing white matter) syndrome. The syndrome is characterized by episodes of rapid deterioration during febrile illnesses or following head trauma and symmetrical demyelination of the brain white matter with cavitation aspects, leading to a progressive vanishing of the white matter replaced by CSF (cerebrospinal fluid). However, a wide clinical spectrum has been observed in the 148 patients presently reported, from congenital forms with rapid death to adult-onset forms with slow mental decline and progressive motor dysfunction, sometimes associated with congenital eye abnormalities or ovariodysgenesis. So far, 77 different mutations in each of the five EIF2B genes (EIF2B1-5), encoding subunits eIF2Balpha-epsilon, have been found, with two-thirds affecting the eIF2Bepsilon subunit. The correlation found between the level of GEF activity of eIF2B in the mutated white blood cells and the age at disease onset suggests a direct role of the abnormal translation control in the pathophysiology of the disease.

Nonhomologous Robertsonian translocations (NHRTs) and uniparental disomy (UPD) risk: an Italian multicentric prenatal survey.

OBJECTIVES: The risk of uniparental disomy (UPD) occurrence associated with the prenatal finding of balanced nonhomologous Robertsonian translocations (NHRTs) has been estimated only on limited empirical data. The aim of the study was to verify the estimate of the general risk, to get narrower confidence intervals by cumulating the data and to obtain risk estimates for specific translocation types. METHODS: We tested for UPD 160 prenatal specimens referred to the participant centers after the cytogenetic finding of NHRT. RESULTS: One case of upd(14)mat was found, associated with a 45,XX,der(14;22)mat fetal karyotype. The general empirical risk of UPD occurrence in NHRT carrier fetuses, corrected for the actual number of chromosomes analyzed, was 0.76% (95% CI 0.02-4.25%). Cumulative data with previous studies gives a general risk of UPD associated with NHRT of 0.80% (95% CI 0.17-2.34%). The UPD risk for the specific NHRT der(13;14) did not significantly differ from that of the other NHRTs taken together. CONCLUSION: The present survey confirms the previously estimated risk of occurrence of UPD in offspring of NHRT carriers as a low, but not negligible risk, worth being investigated in prenatal diagnosis.

The effect of genotype on the natural history of eIF2B-related leukodystrophies.

BACKGROUND: Recessive mutations in the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of variable age at onset and severity. OBJECTIVES: To evaluate the clinical spectrum of eIF2B-related disorders and search for a phenotype-genotype correlation. METHODS: Ninety-three individuals (78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis. RESULTS: Eighty-nine percent of individuals with MRI criteria of CACH/VWM have a mutation in one of the eIF2B beta to epsilon subunits. For 83 individuals (68 families), 46 distinct mutations (90% missense) in four of the five eIF2B subunits (beta, gamma, delta, epsilon) were identified. Sixty-four percent were in the epsilon subunit, a R113H substitution was found in 71% of eIF2B epsilon-mutated families. A large clinical spectrum was observed from rapidly fatal infantile to asymptomatic adult forms. Disease severity was correlated with age at onset (p < 0.0001) but not with the type of the mutated subunit nor with the position of the mutation within the protein. Mutations R113H in the epsilon subunit and E213G in the beta subunit were significantly associated with milder forms. CONCLUSIONS: The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders.