Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.

BACKGROUND: Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. METHODS: We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. RESULTS: Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. CONCLUSIONS: Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.).

The association of pre-treatment neutrophil to lymphocyte ratio with overall survival in patients with glioblastoma multiforme.

Neutrophil-lymphocyte ratio (NLR) is a marker of systemic inflammatory response and its elevation has recently been shown to be a poor prognostic factor in many malignancies including colon, prostate and bladder cancer. The primary aim of this study was to assess the prognostic impact of NLR in a clinically annotated cohort of patients with glioblastoma multiforme (GBM). We hypothesised that elevated NLR would be associated with worse prognosis. Between 2004 and 2009, 137 patients had surgery for GBM and were assessed for consideration of adjuvant therapy at our institution. Of these, 84 patients with an evaluable pre-corticosteroid full blood count result were identified and included in the final analysis. Median overall survival was 9.3 months (range 0.7-82.1). On univariate analysis, age >65 years, gender, ECOG performance status ≥2, frontal tumour, extent of surgical resection, completion of adjuvant chemoradiation protocol and NLR > 4 were significantly correlated with overall survival. Patients with NLR > 4, had a worse median overall survival at 7.5 months versus 11.2 months in patients with NLR ≤ 4 (hazard ratio 1.6, 95 % CI 1.00-2.52, p = 0.048). On multivariate analysis NLR > 4 remained an independent prognostic indicator for poor outcome. These data are an important reminder of the potential relevance of host immunity in GBM. In our cohort, NLR > 4 conferred a worse prognosis independent of other well established prognostic factors. If validated in other cohorts NLR may prove to be a useful addition in predicting prognosis in GBM patients. The demonstration that host immunity plays a role in GBM biology suggests that investigation of emerging therapies which modulate host immune response are warranted in this disease.

Gain of chromosome arm 1q in atypical meningioma correlates with shorter progression-free survival.

AIMS: Atypical (World Health Organization grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Post-operative radiotherapy may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array comparative genomic hybridization to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumours show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample. METHODS: Eighty-six completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow-up was obtained. Utilizing a dual-colour interphase fluorescence in situ hybridization assay, 1q gain was assessed using Bacterial Artificial Chromosome probes directed against 1q25.1 and 1q32.1. RESULTS: The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas. CONCLUSIONS: These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.

Axial ablation versus terminal interruption of the reflux source (AAVTIRS): a randomised controlled trial.

BACKGROUND: Treatment of superficial venous reflux has been shown to improve ulcer healing time and reduce the risk of ulcer recurrence. Terminal ablation of the reflux source (TIRS) is an alternative to formal endovenous ablation or surgery which can be performed by injecting sclerosant foam into the peri-ulcer plexus of the veins. TIRS has been shown to be successful and in our experience is the option preferred by many patients, when offered as an alternative to axial ablation (AA). AIM: To determine if the proportion of ulcers healed within 6 months of endovenous treatment differs between patients undergoing AA of varicose veins or TIRS by peri-ulcer foam sclerotherapy. METHODS: AAVTIRS is an assessor-blinded randomised controlled trial. Patients will be recruited from a dedicated ulcer clinic in Roscommon University Hospital and from the vascular surgical clinics in University Hospital Galway. All patients attending the ulcer clinic will be screened for eligibility. RANDOMISATION: Random computer-generated sequence is stratified by ulcer size. Allocation will be concealed using sealed opaque envelopes. BLINDING: Assessors reviewing wounds at follow -p visits will be blinded to patient allocation. PRIMARY ENDPOINT: The proportion of ulcers healed within 6 months of enrolment. DISCUSSION: This will be the first time that TIRS has been evaluated with a properly powered randomised trial in the setting of venous ulcer management. Streamlining the management of venous ulcers has broad health economic benefits. If it is found that TIRS is superior or non-inferior to AA, then a less expensive, less invasive injection can be offered as an alternative to AA in an attempt to encourage the healing of venous ulcers. If AA is found to be superior to TIRS, then this would suggest that all patients undergoing ablation in the management of venous ulcers should have their superficial reflux fully treated, building on the evidence of the EVRA trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04484168. Registered on 23 July 2020.

Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®).

Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin-free recombinant full-length FVIII product (ADVATE(®)). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell-produced to a baby hamster kidney cell-produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.

The role of biopsy in the diagnosis of infections of the central nervous system.

CNS infections require prompt appropriate therapy, but do not usually require tissue biopsy for diagnosis. We performed a 5 year audit of CNS infections which required brain or spinal biopsy to determine or confirm a diagnosis of CNS infection. Sixteen cases were identified in which clinical, radiological or additional investigations including culture, serology or PCR for the suspected specific infective agents were not diagnostic. 6 (37.5%) were bacterial abscesses presenting as space-occupying intracerebral lesions with a differential diagnosis of neoplasm. There were 3 (18.7%) cases of toxoplasmosis and 2 (12.5%) cases of aspergillosis. There was one case (6.2%) of herpes simplex encephalitis, one cysticercosis and one progressive multifocal leucoencephalopathy, all biopsied as possible neoplasms. There were 2 (12.5%) cases of spinal tuberculosis, one multifocal, mimicking neurofibromatosis. This review highlights the usefulness of targeted biopsy in the rapid diagnosis of CNS infections. It also emphasizes the lack of specificity of 'negative' culture and serology in certain cases, especially in the setting of immune-compromise.

Massive retroperitoneal ganglioneuroma presenting with small bowel obstruction 18 years following initial diagnosis.

BACKGROUND: Ganglioneuroma is a rare tumour of neural crest origin, which arises from maturation of a neuroblastoma. While previously considered to be non-functioning, they are now known to be frequently endocrinologically active. AIMS AND METHODS: We report a case of a massive retroperitoneal ganglioneuroma presenting with small bowel obstruction in an adult, 18 years after initial diagnosis. Urinary dopamine levels were elevated, but other catecholamines were within normal limits. This is the first report in the English-language literature of a retroperitoneal ganglioneuroma presenting with or causing intestinal obstruction. We also review the metabolic, radiological, and histological features of these tumours. Relevant publications were identified from a Medline search using the MeSH headings 'ganglioneuroma', 'retroperitoneal neoplasms' and 'intestinal obstruction', and also from the reference lists of retrieved articles. CONCLUSIONS: Ganglioneuroma can grow to a massive size and present in a varied manner. It should be included in the differential diagnosis of any large retroperitoneal or mediastinal mass, including those causing bowel obstruction.

Pseudoaneurysm of the occipital artery: an unusual cause of persisting headache after minor head injury.

Post-traumatic pseudoaneurysms of the extracranial arteries in the scalp are uncommon sequelae of head injury. We report on a patient who presented four weeks after a minor head injury with a tender, pulsating and enlarging mass in the course of the left occipital artery. There was associated headache radiating to the vertex. Computed tomographic angiography confirmed the lesion to be a pseudoaneurysm of the occipital artery. The lump was resected with complete resolution of symptoms.

Zidovudine therapy and HIV encephalitis: a 10-year neuropathological survey.

OBJECTIVE: To assess the effect of zidovudine on productive HIV infection of the brain. DESIGN: To correlate the incidence of HIV-specific neuropathology with zidovudine therapy. PATIENTS: We examined 192 AIDS cases neuropathologically; 97 had never been treated with zidovudine, 72 had received zidovudine for over 3 months and until death, 23 had their treatment terminated more than 1 month before death. RESULTS: The incidence of HIV encephalitis/HIV leukoencephalopathy (HIVE/HIVL) and of multinucleated giant cells (MGC) was significantly lower in patients who had received zidovudine than in those who had never received zidovudine. The yearly incidence of HIVE/HIVL increased between 1982 and 1987 probably because of improved survival, and decreased between 1987 and 1990 although the percentage of patients treated with zidovudine increased. Since 1991 the incidence of HIVE/HIVL and of MGC increased slightly. The percentage of patients treated with zidovudine until death decreased and that of patients whose treatment was terminated increased concomitantly. In 1989 and 1990, most patients whose treatment was terminated had MGC and HIVE/HIVL. In 1991 and 1992 this incidence decreased markedly, coinciding with the introduction of dideoxyinosine therapy. CONCLUSION: Zidovudine treatment significantly reduces the occurrence of productive HIV infection of the brain in AIDS. Discontinuing zidovudine therapy may favour the occurrence of HIV encephalitis. Substitution therapy with dideoxyinosine also appears to protect against HIV-specific brain pathology.

Early brain changes in HIV infection: neuropathological study of 11 HIV seropositive, non-AIDS cases.

We examined 11 brains of human immunodeficiency virus (HIV) seropositive cases who died from unnatural causes (10 intravenous drug abusers who died from heroin overdose and 1 homosexual dead from a gunshot injury); 10 brains of HIV seronegative heroin addicts who died from overdose and 1 seronegative drug abuser who died from gunshot injury served as controls. Complete postmortem examination did not show evidence of acquired immune deficiency syndrome (AIDS) or AIDS related complex. Terminal changes including nerve cell ischemia, edema and diffuse vascular congestion were observed in all cases. Perivascular pigment deposition with macrophages was a constant finding in drug addicts and was probably related to chronic intravenous injection. In contrast, cerebral vasculitis was significantly more frequent and marked in HIV seropositive cases and was often associated with lymphocytic meningitis. Granular ependymitis, myelin pallor with reactive astrocytosis and microglial proliferation were also more frequent and more severe in HIV seropositive cases. Immunocytochemistry was negative for HIV antigens. Our study further supports the view that early central nervous system changes occur in HIV infection.

Clinical characteristics of a family with chromosome 17-linked disinhibition-dementia-parkinsonism-amyotrophy complex.

We studied the clinical features, pathology, and molecular genetics of a family (Mo) with an autosomal dominant disinhibition, frontal lobe dementia, parkinsonism, and amyotrophy. We examined seven affected members and gathered clinical information on another six. The mean onset was at age 45 years. Personality and behavioral changes (disinhibition, withdrawal, alcoholism, hyperphagia) were the first symptoms in twelve. There was early memory loss, anomia, and poor construction with preservation until late of orientation, speech, and calculations. All affected members examined had rigidity, bradykinesia, and postural instability. Mean duration to death was 13 years. We studied the neuropathology of six individuals, five of whom had been examined in life. There was atrophy and spongiform change in the frontotemporal cortex, and neuronal loss and gliosis in the substantia nigra and amygdala. Two individuals, including one with fasciculations and muscle wasting, had anterior horn cell loss. There were no Lewy bodies, neurofibrillary tangles, or amyloid plaques. We call this disorder the "disinhibition-dementia-parkinsonism-amyotrophy complex" (DDPAC), based on the clinical syndrome found in this family and linkage to chromosome 17.

Fatal vertebral giant cell arteritis.

Death due to giant cell arteritis (GCA) is rare, and is usually caused by coronary or vertebral arteritis in the acute phase of the disease. A case of fatal GCA is reported in a woman with a normal erythrocyte sedimentation rate, who had been treated for temporal arteritis for eight months. Post mortem examination showed a dissection and thrombosis of the intracranial portion of the left vertebral artery caused by giant cell arteritis. Focal coronary artery GCA was also found. As far as is known, this is the only case in which dissection of the vertebral artery attributable to GCA has been reported.

Neuropathy due to podophyllin intoxication.

A 22-year-old man developed a severe sensorimotor neuropathy following ingestion of podophyllin, which had been prescribed for genital condylomata. The initial toxic symptoms were vomiting and diarrhoea, followed by peripheral neuropathy. The neuropathy was still present 18 months later. Nerve conduction studies and sural nerve biopsy confirmed the presence of axonal degeneration.

Extensive form of progressive multifocal leucoencephalopathy associated with laryngeal carcinoma.

A case is reported of the rare association between progressive multifocal leucoencephalopathy and carcinoma. A 66-year-old man underwent a laryngectomy for carcinoma. Four years later he developed a local recurrence. Simultaneously there were behavioural disturbances and a left motor neglect followed by dense hemiplegia and coma. The patient died a further 5 months later. Anergy was demonstrated by skin tests. CT scan showed asymmetrical non-enhancing low-density areas in the hemispheric white matter, brain-stem and cerebellum and neuropathological examination confirmed extensive myelin loss with typical papovavirus inclusions in oligodendrocytes identified by electron microscopy.

Motor nerve transplantation.

The motor nerve transplantation (MNT) technique is used to transfer an intact nerve into a denervated muscle by harvesting a neurovascular pedicle of muscle containing motor endplates from the motor endplate zone of a donor muscle and implanting it into a denervated muscle. Thirty-six adult New Zealand White rabbits underwent reinnervation of the left long peroneal (LP) muscle (fast twitch) with a motor nerve graft from the soleus muscle (slow twitch). The right LP muscle served as a control. Reinnervation was assessed using microstimulatory single-fiber electromyography (SFEMG), alterations in muscle fiber typing and grouping, and isometric response curves. Neurofilament antibody was used for axon staining. The neurofilament studies provided direct evidence of nerve growth from the motor nerve graft into the adjacent denervated muscle. Median motor endplate jitter was 13 microsec preoperatively, and 26 microsec at 2 months, 29.5 microsec at 4 months, and 14 microsec at 6 months postoperatively (p < 0.001). Isometric tetanic tension studies showed a progressive functional recovery in the reinnervated muscle over 6 months. There was no histological evidence of aberrant reinnervation from any source outside the nerve pedicle. Isometric twitch responses and adenosine triphosphatase studies confirmed the conversion of the reinnervated LP muscle to a slow-type muscle. Acetylcholinesterase studies confirmed the presence of functioning motor endplates beneath the insertion of the motor nerve graft. It is concluded that the MNT technique achieves motor reinnervation by growth of new nerve fibers across the pedicle graft into the recipient muscle.

Neuropathology and neurodegeneration in human immunodeficiency virus infection. Pathogenesis of HIV-induced lesions of the brain, correlations with HIV-associated disorders and modifications according to treatments.

A variety of HIV-induced lesions of the central nervous system (CNS) have been described, including HIV encephalitis, HIV leukoencephalopathy, axonal damage, and diffuse poliodystrophy with neuronal loss of variable severity resulting, at least partly, from an apoptotic process. However, no correlation could be established between these changes and HIV dementia (HIVD). From our study of HIV infected patients, it appeared that neuronal apoptosis is probably not related to a single cause. Microglial and glial activation, directly or indirectly related to HIV infection, plays a major role in neuronal apoptosis possibly through the mediation of oxidative stress. In our patients with full-blown AIDS, this mechanism predominated in the basal ganglia and correlated well with HIVD. Axonal damage, either secondary to microglial activation, or to systemic factors also contributes to neuronal apoptosis. Although massive neuronal loss may be responsible for HIVD in occasional cases, we conclude that neuronal apoptosis is a late event and does not represent the main pathological substrate of HIVD. The dementia more likely reflects a specific neuronal dysfunction resulting from the combined effects of several mechanisms, some of which may be reversible. Introduction of highly active antiretroviral therapy dramatically improved patient survival, however, its impact on the incidence and course of HIVD remains debatable. In our series, the incidence of HIVE has dramatically decreased since the introduction of multitherapies, but a number of cases remain whose cognitive disorders persist, despite HAART. The poor CNS penetration of many antiretroviral agents is a possible explanation, but irreversible "burnt out" HIV-induced CNS changes may also be responsible.

Spinal cord infarction caused by cartilage embolus to the anterior spinal artery.

Cartilaginous embolization of spinal vessels is a rare cause of spinal cord infarction. A 63-year-old woman developed sudden onset of painful, fatal paraparesis following a valsalva-like maneuver. Autopsy demonstrated recent nonhemorrhagic infarction of the caudal thoracic spinal cord secondary to complete occlusion of the anterior spinal artery by cartilage. The literature pertaining to 28 previously reported cases is briefly reviewed.

[Hereditary cerebral amyloid angiopathies]. / Les angiopathies amyloïdes cérébrales héréditaires.

Cerebral amyloid angiopathies are defined by the presence of amyloid substance in the walls of cerebral vessels. All amyloid substances have a particular physico-chemical structure, which imparts certain specific staining properties, but the biochemical composition of different amyloid types varies. Different forms of cerebral amyloid angiopathy have been identified, based on the biochemical nature of the protein deposited (e.g. beta-amyloid, cystatin C, transthyretin, gelsolin, amyloid protein Bri, prion protein). Some cerebral amyloid angiopathies are familial; these prompted genetic studies which in turn led to a better understanding of the genes coding for different amyloid proteins. As a group, cerebral amyloid angiopathies have certain neuropathological lesions in common. Infiltration by amyloid substance results in weakening of the small vessel walls and secondary complications responsible for changes such as microinfarcts and miliary haemorrhages in the cerebral cortex, lobar haemorrhages and/or leucoencephalopathy. These changes form the basis of the neurological complications: meningeal and cerebral haemorrhages, transient ischaemic episodes, vascular dementia. However each type of hereditary cerebral amyloid angiopathy has individual clinical and histopathological features reflecting the severity of arterial involvement, the extent of amyloid deposition within or outside the central nervous system, and the association with other neurodegenarative changes.

Intra abdominal rupture of first trimester cervical pregnancy.

A case of cervical pregnancy resulting in intra abdominal rupture in the first trimester is reported. The clinical features of this rare cause of uterine rupture are outlined. Pathological examination of the uterus showed placenta percreta.