Primary Vitreoretinal Lymphoma: Current Diagnostic Laboratory Tests and New Emerging Molecular Tools.

Primary vitreoretinal lymphoma (PVRL), a rare aggressive malignancy primarily involving the retina and/or the vitreous, is a major diagnostic challenge for clinicians (who commonly misdiagnose it as chronic uveitis) as well as for pathologists (for biological and technical reasons). Delays in diagnosis and treatment are responsible for visual impairments and life-threatening consequences, usually related to central nervous system involvement. The identification of lymphoma cells in vitreous fluid, obtained by vitrectomy, is required for diagnosis. Of note, the scarcity of neoplastic cells in small volumes of vitreous sample, and the fragility of lymphoma cells with degenerative changes caused by previous steroid use for presumed uveitis makes diagnosis based on cytology plus immunophenotyping difficult. Interleukin levels, immunoglobulin heavy chain or T-cell receptor gene rearrangements, and MYD88 mutation are applied in combination with cytology to support diagnosis. We aim to describe the current laboratory technologies for PVRL diagnosis, focusing on the main issues that these methods have. In addition, new emerging diagnostic strategies, such as next-generation sequencing analysis, are discussed. The genetic profile of PVRL remains largely unexplored. Better knowledge of genetic alterations is critical for precision medicine interventions with target-based treatments of this lymphoma for which no standardised treatment protocol currently exists.

Pediatric Thymoma: A Review and Update of the Literature.

Pediatric thymomas are extremely rare and slow-growing malignant tumors. The recent publication of the first Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) stage classification and updated treatment guidelines for thymomas has prompted us to perform a review of the literature on pediatric thymomas. A search of English-language articles in the PubMed, Cochrane, Web of Science, and Embase databases was conducted. Additional articles were identified through reference lists of retrieved publications. Thirty-two articles involving 82 pediatric thymomas were included. Males comprised 60% of patients, and 13% manifested myasthenia gravis (MG). Histotype B1 (45%) and stage I (52% Masaoka-Koga and 71% UICC/AJCC TNM) were the most frequent. Of note is the possibility that the lack of cases with mixed histologies in the reviewed publications might be related to a sampling issue, as it is well known that the more sections are available for review, the more likely it is that the majority of these neoplasms will show mixed histologies. Both staging systems showed a gradual increase in the percentage of cases, with more advanced stages of disease moving from type A to B3 thymomas. Complete surgical resection (R0) was the main therapeutic approach in Masaoka-Koga stage I (89%) and UICC/AJCC TNM stage I (70%) thymomas. Advanced stages of disease and incomplete surgical resection were most often associated with recurrence and death. An association between stage and outcome, and completeness of resection and outcome, was found. Interestingly, though an association between histotype and staging was found, this does not take into account the possibility of mixed histologies which would reduce the clinical impact of histologic subtyping over staging.

T-Cell Lymphoblastic Lymphoma Arising in the Setting of Myeloid/Lymphoid Neoplasms with Eosinophilia: LMO2 Immunohistochemistry as a Potentially Useful Diagnostic Marker.

BACKGROUND: Rarely, T-lymphoblastic lymphoma (T-LBL) may develop in the setting of myeloid/lymphoid neoplasms with eosinophilia (M/LNs-Eo), a group of diseases with gene fusion resulting in overexpression of an aberrant tyrosine kinase or cytokine receptor. The correct identification of this category has relevant therapeutic implications. LIM domain only 2 (LMO2) is overexpressed in most T-LBL, but not in immature TdT-positive T-cells in the thymus and in indolent T-lymphoblastic proliferations (iT-LBP). METHODS AND RESULTS: We retrospectively evaluated 11 cases of T-LBL occurring in the context of M/LNs-Eo. Clinical, histological, immunohistochemical and molecular features were collected and LMO2 immunohistochemical staining was performed. The critical re-evaluation of these cases confirmed the diagnosis of T-LBL with morphological, immunohistochemical and molecular features consistent with T-LBL occurring in M/LNs-Eo. Interestingly, LMO2 immunohistochemical analysis was negative in 9/11 cases, whereas only 2 cases revealed a partial LMO2 expression with a moderate and low degree of intensity, respectively. CONCLUSIONS: LMO2 may represent a potentially useful marker to identify T-LBL developing in the context of M/LNs-Eo. In this setting, T-LBL shows LMO2 immunohistochemical profile overlapping with cortical thymocytes and iT-LBP, possibly reflecting different molecular patterns involved in the pathogenesis of T-LBL arising in the setting of M/LNs-Eo.

Clinical, pathological and molecular features of plasmablastic lymphoma arising in the gastrointestinal tract: A review and reappraisal.

Plasmablastic lymphoma (PBL) is a CD20-negative large B-cell lymphoma with a plasmacytic phenotype and a dismal prognosis, which has been defined as a distinct entity only in the 2008 WHO Classification of Haematopoietic and Lymphoid Tissue and confirmed in the 2017 Edition. Current knowledge of the biological, clinical and prognostic features of PBL is mostly limited, resulting in diagnostic issues, as well as in lack of standard of care and effective therapeutic options. PBL commonly affects the oral cavity of HIV-positive individuals, however the gastrointestinal (GI) tract is the most common extraoral site, and in this location most patients are HIV-negative. In this review, we focus on the clinical, morphological and prognostic features of PBL arising in the GI tract, in order to improve knowledge on this rare, but aggressive disease.

Determination of Mesothelin Levels in Pleural Effusion Does Not Help Predict Survival of Patients With Malignant Pleural Mesothelioma.

AIM: This study evaluated the prognostic value of soluble mesothelin-related protein (SMRP) levels in pleural effusions (PE) from patients with pleural mesothelioma (MPM). PATIENTS AND METHODS: SMRP level in PE was tested using an enzyme-linked immunosorbent assay (ELISA) in 109 patients with MPM at diagnosis before any treatment. The Kaplan-Meier method and the Cox regression were applied to compare overall survival probabilities across tertile categories of SMRP level. RESULTS: No significant differences in Kaplan-Meier overall survival probabilities among the SMRP categories were found. A statistically non-significant trend for increased death rate ratio (RR) was computed (p=0.327) when the higher (>46.5 nM, RR=1.38) and intermediate (8.5-46.5 nM, RR=1.18) SMRP categories were compared to the lower category (<8.5 nM, RR=1.00). Cox regression modelling including a restricted cubic spline showed a moderately rising non-linear trend in death rate. CONCLUSION: The SMRP level in PE does not appear to have prognostic significance and its detection is not recommended in routine clinical management of patients with MPM.

Continuous versus intermittent physiological monitoring for acute stroke.

BACKGROUND: Explanations for the effectiveness of stroke units compared with general wards in reducing mortality, institutionalisation and dependence of people with stroke remain undetermined, and the discussion on the most effective stroke unit model is still up for debate. The intensity of non-invasive mechanical monitoring in many western countries is one of the main issues regarding the different models. This is because of its strong impact on the organisation of the stroke unit in terms of the number of personnel, their expertise, the infrastructure and costs. OBJECTIVES: To assess whether continuous intensive monitoring compared with intermittent monitoring of physiological variables in people with acute stroke can change their prognosis in terms of mortality or disability. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (November 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (1966 to November 2012), EMBASE (1980 to November 2012), CINAHL (1982 to November 2012) and the British Nursing Index (1985 to November 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registers (November 2012) and reference lists, handsearched conference proceedings and contacted trial authors. SELECTION CRITERIA: We included all randomised, cluster randomised and quasi-randomised controlled trials comparing continuous monitoring with intermittent monitoring in people within three days of stroke onset. We excluded studies confounded by the delivery of care in different settings (that is studies in which the location of the intervention was not in the same ward in the two arms of the trial). DATA COLLECTION AND ANALYSIS: Three review authors independently selected studies for inclusion, assessed methodological quality and extracted data. We sought original data from trialists in two trials and verified the inclusion criteria in another four trials (three presented at conferences and one was from the Chinese Clinical Trial Registry). Where possible, we extracted data on the threshold level of abnormality that triggered intervention for a given physiological variable, the specific intervention given to correct the abnormality and compliance with the allocated therapy. MAIN RESULTS: Three studies, involving a total of 354 participants, met our inclusion criteria for the primary outcome. Compared with intermittent monitoring, continuous monitoring significantly reduced death and disability at three months or discharge (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.13 to 0.56) and was associated with a non-significant reduction in deaths from any cause at discharge (OR 0.72, 95% CI 0.28 to 1.85). These significant results depend on one study that has a high risk of bias.Continuous monitoring was associated with a non-significant reduction of dependency (OR 0.79, 95% CI 0.30 to 2.06), death from vascular causes (OR 0.48, 95% CI 0.10 to 2.39), neurological complications (OR 0.81, 95% CI 0.46 to 1.43), length of stay (mean difference (MD) -5.24, 95% CI -10.51 to 0.03) and institutionalisation (OR 0.83, 95% CI 0.04 to 15.72) (secondary outcomes). For the last two outcomes we detected consistent heterogeneity across trials.Cardiac complications (OR 8.65, 95% CI 2.52 to 29.66), fever (OR 2.17, 95% CI 1.22 to 3.84) and hypotension (OR 4.32, 95% CI 1.68 to 14.38) were detected significantly more often in participants who received continuous monitoring (surrogate outcomes).We detected no significant increase in adverse events due to immobility (pneumonia, other infections or deep vein thrombosis) in participants who were continuously monitored compared with those allocated to intermittent monitoring. AUTHORS' CONCLUSIONS: Continuous monitoring of physiological variables for the first two to three days may improve outcomes and prevent complications. Attention to the changes in physiological variables is a key feature of a stroke unit, and can most likely be aided by continuous monitoring without complications related to immobility or to treatments triggered by the relief of abnormal physiological variables. Well-designed, high-quality studies are needed because many questions remain open and deserve further research. These include when to start continuous monitoring, when to interrupt it, which people should be given priority, and which treatments are most appropriate after the identification of abnormalities in physiological variables.

Language disturbances as a side effect of prophylactic treatment of migraine.

BACKGROUND: Language disturbances have been previously described as word-finding difficulties in epileptic patients. These disturbances have been recently reported in migraineurs in treatment with topiramate but they have never been defined and assessed in these patients with the aid of neuropsychological testing. OBJECTIVE: To verify the occurrence of language disturbances as a side effect of topiramate treatment in episodic and chronic migraine patients. METHODS: Language disturbances were recorded on the basis of spontaneous reports of 30 migraine patients treated with topiramate and 2 control groups (20 patients treated with other prophylactic drugs and 20 patients without prophylactic treatment) and were explored with neuropsychological tests. Psychiatric comorbidity was assessed using Zung Anxiety and Depression Scales. RESULTS: Language disturbances were referred by 26.7% (n=8) of patients during topiramate treatment but by none of the patients in the 2 control groups. All patients in the topiramate group had a worse performance on all tests compared to patients of the 2 control groups. Moreover, in the topiramate group, patients with referred language disturbances had higher scores for all neuropsychological test variables, indicative of a worse performance. Some language functions (Trail Making Tests A and B) seemed to be influenced by the concomitant presence of psychiatric comorbidities, particularly anxiety and depression. CONCLUSION: It can be hypothesized that a disorder such as migraine, which involves numerous cortical and subcortical circuits implicated in the transmission and behavioral and emotional processing of pain, represents a facilitated substrate for the occurrence of language disturbances due to topiramate. This could be the expression of a more generalized impairment of cognitive processing. These aspects should be investigated in prospective studies involving larger migraine patient samples.

Endocannabinoids in platelets of chronic migraine patients and medication-overuse headache patients: relation with serotonin levels.

BACKGROUND: Chronic migraine (CM) and medication-overuse headaches (MOH) are well-recognized disabling conditions affecting a significant portion of the headache population attending centers specialized in treating headaches. A dysfunctioning of the serotonergic system has been demonstrated in MOH and CM patients. Here we report on our assessment of the dysfunctioning of the endocannabinoid system as a potential underlying factor in pathogenic mechanisms involved in CM and MOH. METHOD: To test the hypothesis of an impairment in the endocannabinoid system in patients with MOH and CM and to assess its relationship with any disruption of the serotonergic system, we determined the levels of the two main endogenous cannabinoids, anandamide (AEA) and 2-acylglycerol (2-AG), in platelets of 20 CM patients, 20 MOH patients and 20 control subjects and also measured the platelet serotonin levels in the same patients. RESULTS: We found that 2-AG and AEA levels were significantly lower in MOH patients and CM patients than in the control subjects, without significant differences between the two patient groups. Serotonin levels were also strongly reduced in the two patient groups and were correlated with 2-AG levels, with higher values for MOH patients. CONCLUSION: These data support the potential involvement of a dysfunctioning of the endocannabinoid and serotonergic systems in the pathology of CM and MOH. These systems appear to be mutually related and able to contribute to the chronification of both CM and MOH.

Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome.

UNLABELLED: All data obtained in experimental animal pain models support the role of nerve growth factor (NGF) as a putative candidate intervening in the pathogenesis of chronic pain, including chronic daily headache (CDH). Few studies have been carried out to establish its role in maintaining pain states in humans. The present study was aimed at investigating cerebrospinal fluid (CSF) levels of NGF and brain-derived neurotrophic factor (BDNF), both measured by sensitive immunoassay, in 20 chronic migraine (CM) patients and 20 patients affected by primary fibromyalgia syndrome (PFMS), compared with those of 20 age-matched control subjects. Significantly higher levels of both neurotrophins and glutamate were found. A significantly positive correlation emerged between CSF values of BDNF and those of NGF (r = .61, P < .001; r = .53, P < .01) and glutamate (r = .44, P < .02; r = .51, P < .01) in CM and PFMS patients, respectively. These findings suggest the possibility of a NGF-mediated up-regulation of BDNF involved in the pathophysiological events underlying long-term neuroplastic changes in persistent chronic painful conditions, such as CM and fibromyalgia. NGF might indirectly exert its effect through enhancing glutamatergic transmission via BDNF. The above mechanisms could account for sustained central sensitization in both chronic pain states. PERSPECTIVE: This article presents findings of higher NGF and BDNF levels correlated to increased glutamate levels in the CSF of both chronic migraine and fibromyalgia patients. This opens new insights into the pathogenic mechanisms of chronic pain and offers clinicians new therapeutic perspectives targeting the above mechanisms in both painful disorders.

Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms.

Migraine and epilepsy share several clinical features, and epilepsy is a comorbid condition of migraine. Clinical studies have shown that some antiepileptic drugs are effective at preventing migraine attacks. A rationale for their use in migraine prophylaxis is the hypothesis that migraine and epilepsy share several common pathogenetic mechanisms. An imbalance between excitatory glutamate-mediated transmission and GABA-mediated inhibition in specific brain areas has been postulated in these two pathological conditions. Moreover, abnormal activation of voltage-operated ionic channels has been implicated in both migraine and epilepsy. Cortical spreading depression has been found to be involved in the pathophysiology of epilepsy, in addition to the generation of migraine aura.

Application of the ICHD-II criteria to the diagnosis of primary chronic headaches via a computerized structured record.

BACKGROUND: The authors recently developed a software program designed to analyze clinical data from patients affected by primary headache. The program is based exclusively on the International Classification of Headache Disorders 2nd edition (ICHD-II) criteria. This software examines all the diagnoses of primary headaches on the basis of the variables needed to fulfill these mandatory criteria. METHODS: We tested the software, Primary Headaches Analyser 1.0 INT (PHA), by entering and analyzing clinical data from 200 consecutive patients affected by primary chronic headaches and evaluating the corresponding output diagnoses. RESULTS: The diagnosis of chronic migraine (1.5.1) was obtained in 68 cases (34 %) and that of probable chronic migraine (1.6.5) plus probable medication-overuse headache (8.2.8) in 46 (23%). Chronic tension-type headache (2.3) and probable chronic tension-type headache (2.4.3) plus probable medication-overuse headache (8.2.8) were diagnosed in 24 (12%) and 2 (1%) patients, respectively. Moreover, 4 and 12 patients, respectively, received both the diagnosis of chronic migraine (1.5.1) plus chronic tension-type headache (2.3) and of probable migraine (1.6.1) without aura plus chronic tension-type headache (2.3). In the remaining 44 cases (22%), none of the chronic primary headaches disorders defined by ICHD-II received an output diagnosis from the program. This was due mainly to the fact that the criteria fulfilled were insufficient for the diagnoses of migraine without (1.1) aura plus chronic migraine or, more infrequently, chronic tension-type headache. CONCLUSIONS: Our software program permitted diagnoses of chronic migraine, chronic tension-type or their probable forms (with or without MOH) in 78% of 200 patients with headache 15 or more days per month. In the remaining cases the inability to provide a specific diagnosis may be explained in part by the fact that the criteria for both diagnoses are too stringent and do not accurately reflect variations of the headache pattern in these chronic forms.

Endocannabinoids in chronic migraine: CSF findings suggest a system failure.

Based on experimental evidence of the antinociceptive action of endocannabinoids and their role in the modulation of trigeminovascular system activation, we hypothesized that the endocannabinoid system may be dysfunctional in chronic migraine (CM). We examined whether the concentrations of N-arachidonoylethanolamide (anandamide, AEA), palmitoylethanolamide (PEA), and 2-arachidonoylglycerol (2-AG) in the CSF of patients with CM and with probable CM and probable analgesic-overuse headache (PCM+PAOH) are altered compared with control subjects. The above endocannabinoids were measured by high-performance liquid chromatography (HPLC), and quantified by isotope dilution gas-chromatography/mass-spectrometry. Calcitonin gene-related peptide (CGRP) levels were also determined by RIA method and the end products of nitric oxide (NO), the nitrites, by HPLC. CSF concentrations of AEA were significantly lower and those of PEA slightly but significantly higher both in patients with CM and PCM+PAOH than in nonmigraineur controls (p<0.01 and p<0.02, respectively). A negative correlation was found between AEA and CGRP levels in CM and PCM+PAOH patients (r=0.59, p<0.01 and r=-0.65, p<0.007; respectively). A similar trend was observed between this endocannabinoid and nitrite levels. Reduced levels of AEA in the CSF of CM and PCM+PAOH patients may reflect an impairment of the endocannabinoid system in these patients, which may contribute to chronic head pain and seem to be related to increased CGRP and NO production. These findings support the potential role of the cannabinoid (CB)1 receptor as a possible therapeutic target in CM.

Proinflammatory cytokines, adhesion molecules, and lymphocyte integrin expression in the internal jugular blood of migraine patients without aura assessed ictally.

OBJECTIVE: The aim of the present research was to verify the levels of the soluble adhesion molecules sL- and sE-selectins, intercellular adhesion molecule (sICAM)-1, and vascular cell adhesion molecule-1 in serial samples of internal jugular venous blood taken from migraine patients without aura (MWoA) during attacks. The expression of leukocyte function antigen (LFA)-1 and very late activation antigen (VLA)-4 was also assessed on lymphocytes obtained from jugular venous blood. Levels of certain proinflammatory cytokines (tumor necrosis factor-alpha[TNF-alpha], interleukin-1beta[IL-1beta], IL-4, and IL-6) were also determined and correlated with those of adhesion molecules. PATIENTS AND METHODS: Seven MWoA patients were admitted in the hospital during attacks and blood samples were taken immediately after catheter insertion, at 1, 2, and 4 hours after attack onset, and within 2 hours after its termination. The levels of adhesion molecules and cytokines were measured with ELISA method. The expression of LFA-1 and VLA-4 was assessed by flow cytometry. RESULTS: A parallel transient increase of sICAM-1, TNF-alpha, and IL-6 was observed in the first 2 hours after attack onset compared with the time of catheter insertion (P < .0001, <.001, and <.003, respectively). The proportion of CD4+ and CD8+ T-cells expressing high levels of LFA-1 showed instead a progressive down-regulation with significantly lower percentages at 2 and 4 hours after attack onset (P < .01 and <.022, respectively). No variation in the percentage of VLA-4 expressing cells was observed at any time of the study. CONCLUSIONS: The transient increase in sICAM-1 and TNF-alpha found in the internal jugular blood of MWoA patients assessed ictally can be induced by sensory neuropeptides released from activated trigeminal endings. The progressive decrease in sICAM-1 levels during attacks and the down-regulation of LFA-1 expression by lymphocytes could antagonize their transvascular migration, supporting the hypothesis of sterile inflammation in the dura mater during migraine attacks.

Application of ICHD 2nd edition criteria for primary headaches with the aid of a computerised, structured medical record for the specialist.

We tested the computerised, structured medical record by entering and analysing the consecutive clinical sheets of primary headaches in the episodic forms (200) and chronic headache (200) and the corresponding output diagnoses of patients attending our Headache Centre. A diagnosis of one of the primary headache forms was obtained in 67.9% of cases. A certain diagnosis of primary headache plus that of a probable form was obtained in 24.4% of cases (12.7% represented by chronic migraine (CM) or chronic tension-type headache (CTTH)+probable medication overuse headache). Only probable forms were diagnosed in the remaining 7.3% (as single probable diagnosis in 5.8% of cases or multiple diagnoses of probable forms in the remaining ones). The percentage of certain diagnoses mainly in the chronic headache group (28.4%), and to a lesser extent tension-type headache (6.5%), were obtained in 34.9% of cases. A certain diagnosis of one chronic form plus that of a probable form was obtained in 50.8% of cases (26.9% represented by probable medication-overuse headache). Only probable forms were diagnosed in 13.46% (as single probable diagnosis in 8.73% of cases or multiple diagnoses of probable forms in the remaining ones). In the other cases, the ICHD-II classification does not allow the diagnoses of CM, CTTH or probable forms and medication overuse headache because the mandatory criteria for the diagnoses are too stringent and do not reflect modifications of the headache pattern in relation to its chronicity. These preliminary results underscore the usefulness of a computerised device based on the ICHD 2nd edition for diagnostic purposes in tertiary centres dedicated to headaches in clinical practice as well as its relevance for research. This computerised device may help to validate the new diagnostic criteria and to answer some emerging questions from the application of the new classification version, the relevance of which should be verified in clinical practice.

Application of the 1988 International Headache Society diagnostic criteria in nine Italian headache centers using a computerized structured record.

BACKGROUND: The actual application of the current International Headache Society (IHS) diagnostic criteria in clinical practice has not been investigated thoroughly. OBJECTIVES: To develop a computerized, structured, medical record based exclusively on the IHS classification system. DESIGN AND METHOD: We tested the computerized structured record by entering and analyzing data reported on the case sheets of 500 consecutive patients attending nine headache centers in Italy. All clinical diagnoses in the study were made according to current IHS criteria. The rate of concordance between the diagnosis provided by the computerized structured record and that reported by clinicians on the case sheets was calculated, and reasons for any discrepancies between the two diagnoses were analyzed. RESULTS: Concordance between the two diagnoses was found in 345 of 500 cases examined (69%). In the remaining 155 cases, diagnoses reached with the computerized structured record and case sheets were impossible or discordant with respect to the diagnoses made by the clinician. In 144 of these cases (28.8%), this was due to missing information or errors in the diagnosis recorded by the clinicians on the patient case sheet. In particular, the diagnosis could not be reached using the computerized structured record in 105 cases (20.6%) because of a lack of one or more data needed in formulating a correct diagnosis according to the IHS operational criteria for one of the primary headache disorders. In the remaining 41 cases some data were missing, but the data available were sufficient to reach a diagnosis according to the IHS criteria. Moreover, the diagnoses reached using the computerized structured record were not in agreement with those made by the clinicians in another 39 cases (7.9%) due to an incorrect interpretation by the clinicians of the data reported on the patients' case sheets. In only 2.2% of the cases (n = 11) misdiagnoses were due to errors of the program that were promptly corrected. CONCLUSIONS: The present study suggests that incorrect application of IHS criteria for the diagnosis of primary headache may occur in as many as one third of patients attending headache centers and that use of a computerized structured record based exclusively on current IHS criteria may overcome this deficiency.