T-Cell Monoclonality in the Blood and the Skin Correlates With Poor Response to Treatment in Mycosis Fungoides.

BACKGROUND: The prognostic value of skin and blood T-cell receptor clonality in mycosis fungoides is a matter of debate. Our aim was to ascertain the relation between the presence of a monoclonal T-cell population in the blood and in the skin with response to treatment in patients with mycosis fungoides. PATIENTS AND METHODS: Clinical features and follow-up data were retrospectively collected and analyzed in 94 patients with mycosis fungoides seen at a cutaneous lymphoma clinic in a single tertiary center. All patients had results of polymerase chain reaction analysis of T-cell receptor gamma gene rearrangement in lesional skin and in peripheral blood at time of diagnosis. Association of response to treatment with clonality in the tissue and in the blood was assessed. RESULTS: T-cell monoclonality was detected in the skin in 30 of 94 patients, in the blood in 12 of 94 cases and the same clone was found in both tissues in 6 of 94 patients. The presence of a polyclonal T-cell population in the circulation was associated with complete response (P = .006). Lack of response to treatment (stable disease or progression of disease) was associated with T-cell clonality in skin (P = .009), in blood (P = .002) and in both tissues (P < .001). A multivariate analysis showed that T-cell monoclonality in the skin is independently associated with lack of response of mycosis fungoides to therapy. CONCLUSION: Blood and skin should be studied for T-cell clonality as part of the routine initial workup, even in patients with early-stage disease.

Segmental Pigmentation Disorder: Clinical Manifestations and Epidemiological Features in 144 patients, a Retrospective Case-control Study.

Segmental pigmentation disorder (SPD) is characterized by hypo- or hyper-pigmented patches segmentally distributed, present in infancy, more prominently in darker-skinned children. The aim of this study was to define the demographic and clinical characteristics of SPD in a large series of patients. This was a retrospective case-control study at 2 paediatric dermatology centres in Israel. Data were collected through a telephone questionnaire and medical records. The study group consisted of 144 individuals with SPD and 144 individuals visiting the same institutions matched for age and sex. Median age of onset of SPD was near birth; 51% of patients were Sephardic Jews, and patients were followed up for a median period of 27 years. The patches were located on the torso (43%), mostly hypopigmented (52%), and remained of the same intensity and size in 55% and 41% of cases, accordingly. No differences in extracutaneous morbidities were found between SPD and control patients. This study delineates the demographic and clinical characteristics of SPD, confirms that cutaneous findings in SPD are more prominent in darker skin, tends not to expand in size or accentuate throughout the years, nor to be associated with extracutaneous morbidities.

Superimposed type 2 segmental atopic dermatitis: case series and review of the literature.

Generalized acquired dermatoses can seldom manifest more prominently or exclusively along the lines of Blaschko. Six individuals with segmental atopic dermatitis (AD) have been reported to date. We present three additional cases of segmental cutaneous manifestations superimposed on generalized AD, and review the relevant literature.

CRP Levels as a Prognostic Factor in Mycosis Fungoides.

Mycosis Fungoides (MF) and Sézary syndrome (SS) are the most common forms of cutaneous T-cell lymphomas. Few validated prognostic factors have been reported in MF/SS, especially when compared with non-cutaneous lymphomas. Increased C-reactive protein (CRP) levels have recently been associated with poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of serum CRP levels at diagnosis in patients with MF/SS. This retrospective study included 76 patients with MF/SS. Stage was assigned according to the ISCL/EORTC guidelines. The follow-up period was 24 months or more. Disease course and response to treatment were determined using quantitative scales. Wilcoxon's rank test and multivariate regression analysis were used to analyze the data. Increased CRP levels correlated significantly with advanced stages (Wilcoxon's test, P>0.0001). Furthermore, increased CRP levels were associated with a lower treatment response rate (Wilcoxon's test, P=0.0012). Multivariate regression analysis showed that CRP is an independent predictor of advanced clinical stage at diagnosis.The present data suggest that elevated CRP levels could serve as a useful prognostic factor in MF/SS and may assist in guiding treatment choices.

Patch testing versus interferon-gamma release assay in evaluation of drug eruptions.

Delayed-onset T-cell-mediated cutaneous adverse drug reactions are an uncommon but potentially serious result of medication exposures. Identification of culprit medications is crucial, but clinical diagnosis is often difficult. Patch tests and interferon-gamma release assays (IFNγ-RA) were previously reported as potentially useful ancillary tests, while rechallenges remain the reference standard test. We compared the number of positive test results with patch testing and IFNγ-RA for drugs implicated as possible causes of cutaneous reactions. Fifty-one patients with a suspected cutaneous drug eruption underwent patch testing and IFNγ-RA for suspected drugs. Participants were followed up at least 9 months after the onset of the rash with results compared with the clinical diagnosis. Forty-two patients presented with morbilliform/eczematous eruptions; five were diagnosed with fixed drug eruption (FDE) and four with erythema multiforme. None had positive patch testing to the drugs tested. A total of 8/51 (15.6%) patients had positive reaction by the IFNγ-RA, and an additional 11 (21.6%) patients had borderline results. Positive or borderline results were more likely in patients with FDE (80%) than morbilliform/eczematous eruptions (30.9%) or erythema multiforme (25%). Our study emphasizes the necessity of additional effective ancillary tests in the evaluation of drug eruptions and supports the use of IFNγ-RA for drug testing as a tool for identifying medications associated with cutaneous drug eruptions.

Paroxysmal slow wave events predict epilepsy following a first seizure.

OBJECTIVE: Management of a patient presenting with a first seizure depends on the risk of additional seizures. In clinical practice, the recurrence risk is estimated by the treating physician using the neurological examination, brain imaging, a thorough history for risk factors, and routine scalp electroencephalogram (EEG) to detect abnormal epileptiform activity. The decision to use antiseizure medication can be challenging when objective findings are missing. There is a need for new biomarkers to better diagnose epilepsy following a first seizure. Recently, an EEG-based novel analytical method was reported to detect paroxysmal slowing in the cortical network of patients with epilepsy. The aim of our study is to test this method's sensitivity and specificity to predict epilepsy following a first seizure. METHODS: We analyzed interictal EEGs of 70 patients admitted to the emergency department of a tertiary referral center after a first seizure. Clinical data from a follow-up period of at least 18 months were available. EEGs of 30 healthy controls were also analyzed and included. For each EEG, we applied an automated algorithm to detect paroxysmal slow wave events (PSWEs). RESULTS: Of patients presenting with a first seizure, 40% had at least one additional recurring seizure and were diagnosed with epilepsy. Sixty percent did not report additional seizures. A significantly higher occurrence of PSWEs was detected in the first interictal EEG test of those patients who were eventually diagnosed with epilepsy. Conducting the EEG test within 72 h after the first seizure significantly increased the likelihood of detecting PSWEs and the predictive value for epilepsy up to 82%. SIGNIFICANCE: The quantification of PSWEs by an automated algorithm can predict epilepsy and help the neurologist in evaluating a patient with a first seizure.

An Uncommon Presentation of Darier-White Disease with Hystrix-like Palmoplantar Keratoderma.

Darier-White disease is a relatively common autosomal dominant genodermatosis caused by mutation in the ATP2A2 gene. It is characterized by multiple warty papules coalescing into plaques in the seborrheic areas and by specific histological skin changes. Palm and sole involvement in Darier-White disease is usually mild, mainly featuring discrete and small keratotic papules. We present a unique case of Darier-White disease presenting with a diffuse, mutilating hystrix-like palmoplantar keratoderma.

FOXP3 Predicts Response to Treatment in Mycosis Fungoides.

BACKGROUND: The role of the T-regulatory cells (Tregs) marker forkhead box Protein 3 (FOXP3) in mycoses fungoides (MF) pathogenesis is unclear and the results of previous studies are inconclusive. OBJECTIVE: We aimed at ascertaining the possibility that FOXP3 expression may serve to predict MF stage and response to therapy. PATIENTS AND METHODS: Immunohistochemistry staining for FOXP3 was performed on 30 skin biopsies from patients with MF, and FOXP3 expression level was quantitatively graded. Disease stage, progression, and response to treatment were determined based on clinical and imaging evidence, and association with FOXP3 expression was assessed. RESULTS: FOXP3 expression in the dermis correlated with poor response to treatment (P=0.047). A negative non-significant relationship between epidermal FOXP3 expression and clinical stage severity was observed (P=0.17). CONCLUSIONS: Dermal FOXP3 expression in MF lesions could be used to predict response to treatment in patients with MF.

Primary Cutaneous B-Cell Lymphomas in Children and Adolescents: A SEER Population-Based Study.

BACKGROUND: Although primary cutaneous B-cell lymphomas (PCBCL) comprise 25% of all cutaneous lymphomas, their incidence in the pediatric population is unknown, and the information on pediatric PCBCL has mostly been gathered from individual case reports or series from single centers. PATIENTS AND METHODS: This was a population-based, retrospective cohort study of patients in 18 cancer registries in the United States diagnosed between 2000 to 2016 through the Surveillance, Epidemiology, and End Results (SEER) program. Age-adjusted incidence rates were calculated for PCBCL in pediatric (<20 years) and adult (≥20 years) populations. Demographic, clinical, and pathological characteristics of PCBCL were compared between the two groups. RESULTS: A total of 48 pediatric and 5128 adult PCBCL cases were included. Median age at diagnosis was 16.5 years and 65 years in the two groups, respectively. The major histologic subtypes of pediatric cases were marginal zone lymphoma (77.1%), followed by diffuse large B-cell lymphoma (12.5%) and follicle center lymphoma (10.4%), which were equally distributed in adults. The age-adjusted pediatric PCBCL incidence rate (per 1,000,000 person-years) was 0.12 (95% CI 0.09-0.16). The incidence in the adult population was approximately 40-fold higher than the one observed in the pediatric group (IRR 41.4, 95% CI 31.2-56.2). All 48 pediatric cases were alive during a median follow-up time of 48 months. CONCLUSIONS: Pediatric PCBCL is a very rare disease affecting mostly adolescents of both sexes. The major histologic subtype is marginal zone lymphoma, and the prognosis is favorable.

Reducing SAR in 7T brain fMRI by circumventing fat suppression while removing the lipid signal through a parallel acquisition approach.

Ultra-high-field functional magnetic resonance imaging (fMRI) offers a way to new insights while increasing the spatial and temporal resolution. However, a crucial concern in 7T human MRI is the increase in power deposition, supervised through the specific absorption rate (SAR). The SAR limitation can restrict the brain coverage or the minimal repetition time of fMRI experiments. In the majority of today's studies fMRI relies on the well-known gradient-echo echo-planar imaging (GRE-EPI) sequence, which offers ultrafast acquisition. Commonly, the GRE-EPI sequence comprises two pulses: fat suppression and excitation. This work provides the means for a significant reduction in the SAR by circumventing the fat-suppression pulse. Without this fat-suppression, however, lipid signal can result in artifacts due to the chemical shift between the lipid and water signals. Our approach exploits a reconstruction similar to the simultaneous-multi-slice method to separate the lipid and water images, thus avoiding undesired lipid artifacts in brain images. The lipid-water separation is based on the known spatial shift of the lipid signal, which can be detected by the multi-channel coils sensitivity profiles. Our study shows robust human imaging, offering greater flexibility to reduce the SAR, shorten the repetition time or increase the volume coverage with substantial benefit for brain functional studies.

The superiority of 72 h leukocyte descent over CRP for mortality prediction in patients with sepsis.

BACKGROUND: Detection of an eventful course in the early days of sepsis treatment is clinically relevant. The white blood cell count (WBCC) and C-reactive protein (CRP) are used in daily practice to monitor the intensity of the inflammatory response associated with sepsis. It is not entirely clear which of the two might better discriminate the outcomes of patients with sepsis. METHODS: 30-day mortality was assessed in a cohort of patients who were hospitalized with sepsis in the departments of Internal Medicine in a tertiary medical center. Admission and 72-hour time points were analyzed to discriminate between patients with increased versus decreased 30 days mortality risk. RESULTS: The study included 195 patients. Higher 72 h CRP, WBCC, neutrophil counts and neutrophils to lymphocyte ratio were associated with increased mortality (p < 0.02). Baseline WBCC and CRP failed to discriminate between patients who died and those who survived (AUC = 0.551, 0.479). In multivariate analysis of the 72 h tests, higher WBCC count (OR = 1.12, 95%CI 1.05-1.20, p = 0.001), was associated with increased mortality whereas CRP was not (OR = 1.004, 95%CI 0.998-1.01, p = 0.146). CONCLUSION: Patients who presented a 72-hour leukocyte descent had a better outcome and in this regard, WBCC was superior to 72-hour CRP in predicting 30 days mortality.

A second C-reactive protein (CRP) test to detect inflammatory burst in patients with acute bacterial infections presenting with a first relatively low CRP.

A first C-reactive protein (CRP) test, as often performed by clinicians during the presentation of patients with an acute bacterial infection, might be misleading. The aim of our study was to explore the dynamic between a second CRP test taken within 12 hours from admission CRP test in a cohort of patients diagnosed with acute bacterial infection in comparison to CRP in a control group of apparently healthy individuals.This was a historical cohort study comprised of all patients admitted to the Sourasky Tel-Aviv Medical Center, Israel, between July 2007 and March 2016. The study cohort included adult patients who were diagnosed as having an infection, assumed to be of bacterial etiology (cellulitis and erysipelas, pneumonia, cholecystitis, pyelonephritis, or septicemia), who had a CRP test during the first 6 hours of hospital admission (baseline CRP), and a successive CRP test up to 12 hours from the first one (recurrent CRP). The control group was of healthy subjects who attended our medical center for a routine annual check-up.The study included 950 patients. Baseline CRP ranged from 0.04 to 454 mg/L. The median CRP velocity was 0.53 mg/L/h. Patients were grouped by baseline CRP into 4 groups (CRP < 10, 10-74.9, 75-199.9, ≥200). There was an increase in median CRP velocity between the first (0.48 mg/L/h) and the second (0.93 mg/L/h) groups, which then was decreased in the next 2 groups (0.46 and -2.58 mg/L/h, respectively). In 45 of 103 (44%) patients of the group of baseline CRP concentration less than 10 mg/dL with bacterial diagnosis, there was a complete overlap with CRP values of apparently healthy individuals during their routine annual checkup.A first single low CRP result cannot exclude the presence of a significant bacterial infection. Patients with acute bacterial infection might present with a relatively low CRP value that at times correspond to normal limit CRP concentrations. A second test, obtained within 12 hours of admission, might serve as an important tool to identify patient with an evolving inflammatory burst commonly seen during acute bacterial infection.

[LINEAR MYCOSIS FUNGOIDES IN A BLASCHKOID DISTRIBUTION].

INTRODUCTION: Mycosis fungoides (MF) is the most common type of primary cutaneous T cell lymphoma. Many clinicopathological variants of MF have been described in the literature, though only a few presented in a segmental pattern. There are several unique patterns of distribution of skin diseases, one of which is the Blaschko Lines. Congenital skin diseases develop in a Blaschkoid pattern due to mosaicism. In contrast, according to Happle, the development of acquired skin diseases in a similar pattern is explained by superimposed segmental manifestation - a process which involves mosaicism overlapping a preexisting congenital mutation. The theories by which previous case reports explained the segmental appearance of MF did not cover the molecular basis for their development. We report a case of a patient who presented with MF in a unique segmental distribution consistent with the Blaschko lines. The patient was found to have an acquired mosaic mutation in GNAS gene exclusively in the involved skin which represents a superimposed segmental manifestation according to Happle's theory. This case demonstrates the hidden potential of these rare cases which allows a better understanding of the pathogenesis by which acquired diseases develop. This is a basis for further research that could help identify new therapeutic targets for MF and other diseases that share its genetic etiology.

Paroxysmal slow cortical activity in Alzheimer's disease and epilepsy is associated with blood-brain barrier dysfunction.

A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer's disease (AD) and has major therapeutic implications. Here, we analyzed electroencephalogram (EEG) data from patients with AD and found an EEG signature of transient slowing of the cortical network that we termed paroxysmal slow wave events (PSWEs). The occurrence per minute of the PSWEs was correlated with level of cognitive impairment. Interictal (between seizures) PSWEs were also found in patients with epilepsy, localized to cortical regions displaying blood-brain barrier (BBB) dysfunction, and in three rodent models with BBB pathology: aged mice, young 5x familial AD model, and status epilepticus-induced epilepsy in young rats. To investigate the potential causative role of BBB dysfunction in network modifications underlying PSWEs, we infused the serum protein albumin directly into the cerebral ventricles of naïve young rats. Infusion of albumin, but not artificial cerebrospinal fluid control, resulted in high incidence of PSWEs. Our results identify PSWEs as an EEG manifestation of nonconvulsive seizures in patients with AD and suggest BBB pathology as an underlying mechanism and as a promising therapeutic target.

Glutathione S-transferase polymorphisms in patients with photosensitive and non-photosensitive drug eruptions.

BACKGROUND: Glutathione S-transferases (GSTs) play a critical role in cellular protection against oxidative damage. Polymorphisms in three major GST loci have been described. A number of studies have looked for an association between GSTs and skin diseases. PURPOSE: To ascertain the possibility that polymorphisms in the GSTM1, GSTT1, and GSTP1 genes may predict the development of photo-induced and non-photo-induced drug eruptions. METHODS: A cohort of 40 patients with drug eruptions, 10 of whom had developed a photo-induced drug reaction, and matched controls (116 for GSTM1 and GSTT1, 120 for GSTP1) were studied. Genotyping was conducted using direct sequencing and polymerase chain reaction. RESULTS: The GSTP1 Val/Val genotype was significantly associated with non-photosensitive drug eruptions (OR = 3.64, P value = 0.038), whereas associations observed between GSTP1, GSTM1, GSTT1 polymorphisms and photosensitive drug eruptions did not reach statistical significance. CONCLUSIONS: Variations in GSTP1 may affect the risk to develop non-photo-induced drug eruptions. These results warrant confirmatory studies in a larger patient sample.

Comparative Study of Frozen and Paraffin-Embedded Sections: Evaluation of Inflammatory Dermatoses.

BACKGROUND: Frozen section (FS) is often performed when histopathological evaluations are urgently required for implementation of therapeutic measures. In dermatology, this method is most commonly used to evaluate excision margins of tumors. FS are also routinely employed to differentiate toxic epidermal necrolysis from staphylococcal scalded skin syndrome. However, little is currently known about the performance of FS in the diagnosis of inflammatory dermatoses. OBJECTIVES: To compare histopathological diagnoses in a series of patients with a clinical diagnosis of an inflammatory dermatosis for which FS and paraffin-section (PS) specimens were obtained on the same day. METHODS: We conducted a single-center retrospective analysis of 43 cases. All histological slides were reviewed by a single dermato-pathologist. Concordance was calculated between FS and PS. RESULTS: Patients were divided into three groups according to diagnosis: papulosquamous diseases (group I), drug eruptions (group II), and a heterogeneous group (group III) that included cases of bullous vasculitis and Sweet syndrome. Among the three groups, the results of FS and of PS were discordant only in five cases (5/43, 11.6%). Compared to PS, FS had a sensitivity of 92.9% [95% confidence interval (95%CI) 64.17-99.63%] and a specificity of 100% in group I, sensitivity of 90.9% (95%CI 57.12-99.52%) and specificity of 100% in group II, and sensitivity of 83.33% (95%CI 60.78-94.16%) and specificity of 100% in group III. The degree of agreement between the results of the FS and of the PS was almost perfect (kappa = 0.95, 0.93 and 0.85 respectively). CONCLUSIONS: This study suggests that FS is a valid approach for the rapid diagnosis of inflammatory dermatoses. This method is as specific as PS, although it is less sensitive.

Electrical stimulation of the posterior tibial nerve reduces neuropathic pain in patients with polyneuropathy.

Peripheral neuropathic pain (PNP) is caused by neuronal damage to the peripheral nervous system and usually affects the distal extremities. This open-label study examined the effect of short-term peripheral nerve stimulation (PNS) on individuals with PNP due to polyneuropathy. A total of 12 patients (mean age, 63.0 ± 10.0 years, 41.7% male) with daily bilateral PNP for at least 6 months (mean duration, 7.4 ± 7.8 years) received a total of six direct electrical stimulation therapies to the posterior tibial nerve at 3-4-day intervals. Eight patients completed the study and were included in the efficacy analysis. The average pain at baseline was 36.6 ± 3.80 estimated by the Short-Form McGill Pain Questionnaire. After the last stimulation, pain was significantly reduced by 85.5% to 4.88 ± 3.1 (p = 0.008). Six patients (75%) had over 50% decrease in pain after the first stimulation therapy and 99.2% after the final stimulation therapy. The patients also reported statistically significant decreases in pain level (measured by visual analog scale), ranging from 54.85% to 87.50% after each of the stimulations as compared to the pain experienced prior to the stimulations. The procedure was safe without any serious adverse events. PNS has demonstrated excellent efficacy and improvement of PNP symptoms. Further studies in larger patient populations are warranted.

Altered Local Spatiotemporal Consistency of Resting-State BOLD Signals in Patients with Generalized Tonic-Clonic Seizures.

The purpose of this study was to evaluate the spatiotemporal Consistency of spontaneous activities in local brain regions in patients with generalized tonic-clonic seizures (GTCS). The resting-state fMRI data were acquired from nineteen patients with GTCS and twenty-two matched healthy subjects. FOur-dimensional (spatiotemporal) Consistency of local neural Activities (FOCA) metric was used to analyze the spontaneous activity in whole brain. The FOCA difference between two groups were detected using a two sample t-test analysis. Correlations between the FOCA values and features of seizures were analyzed. The findings of this study showed that patients had significantly increased FOCA in motor-related cortex regions, including bilateral supplementary motor area, paracentral lobule, precentral gyrus and left basal ganglia, as well as a substantial reduction of FOCA in regions of default mode network (DMN) and parietal lobe. In addition, several brain regions in DMN demonstrated more reduction with longer duration of epilepsy and later onset age, and the motor-related regions showed higher FOCA value in accompany with later onset age. These findings implicated the abnormality of motor-related cortical network in GTCS which were associated with the genesis and propagation of epileptiform activity. And the decreased FOCA in DMN might reflect the intrinsic disturbance of brain activity. Moreover, our study supported that the FOCA might be potential tool to investigate local brain spontaneous activity related with the epileptic activity, and to provide important insights into understanding the underlying pathophysiological mechanisms of GTCS.