Lacosamide in monotherapy in BTRE (brain tumor-related epilepsy): results from an Italian multicenter retrospective study.

PURPOSE: Lacosamide (LCM) is a third-generation anti-seizure medication (ASM) approved for focal onset epilepsy in patients aged ≥ 4.378 Previous studies have reported an efficacy of LCM as add-on treatment in brain tumor-related epilepsy (BTRE). To date, there are no studies in the literature focusing on lacosamide used in monotherapy to treat BTRE. In our retrospective study we investigated efficacy and tolerability of LCM in monotherapy in a multicenter national cohort of primary brain tumor patients. METHODS: We collected from 12 Italian Centers 132 patients with primary brain tumors who were treated with LCM in monotherapy. For each patient we evaluated seizure freedom at 3 and 6 months (primary endpoints), side effects and drop-out rate (secondary endpoints). RESULTS: Overall, LCM led to seizure freedom in 64.4% of patients at 3 months and 55% at 6 months. Patients who used two or more ASMs before LCM had a worse seizure control than patients in monotherapy with LCM as first choice. In 14 patients, we observed seizure control despite tumor progression on magnetic resonance (MRI). Multivariate analysis showed that gross-total resection at diagnosis was significantly associated with higher seizure freedom rate at 6 months. Side effects were mainly mild (grade 1-2 according to CTCAE classification) and drop-out rate was low (1.5%). Main side effects were dizziness and somnolence. CONCLUSIONS: This is the first study showing a good efficacy and tolerability of LCM when used in monotherapy in BTRE. Further prospective studies are needed to confirm these preliminary data, investigating also quality of life and neurocognitive functions.

Changes on soundscapes reveal impacts of wildfires in the fauna of a Brazilian savanna.

Wildfire is a natural process in Brazilian savannas, but human activities alter fire regimes and threaten biodiversity. In this study, we used an ecoacoustics approach to assess fauna responses and recovery after wildfire in a Brazilian savanna. Six passive acoustic monitoring devices were used to record soundscapes before and after a wildfire a at burned and non-burned sites for one year and one month (September 2012 to September 2013). Power Spectral Density and the Acoustic Complexity Index were used to track biophony. Before the fire, the two sites had similar biophonic patterns (PSD: T = 1136, Z = 1.52, P = 0.12; ACI: T = 1117, Z = 1.10, P = 0.26) and soniferous species richness (Site 1 = 52 and Site 2 = 49). However, in the first two sessions of recordings after the fire, biophony became higher at the burned site during the day (PSD: T = 211 and 233; Z = 4.13 and 6.41; ACI: T = 120 and 469, Z = 5.14 and 7.07; all P < 0.00). During the night, biophony was usually higher at the non-burned site until May 2013 (PSD: T = 0 to 453; Z = 3.30 to 5.90; ACI: T = 333 to 491, Z = 3.80 to 4.93; all P < 0.00). Biophony became similar (P = 0.17 to 0.38) at the two sites or higher (P = 0.00 to 0.01) at the burned site from July to September 2013 (PSD: T = 55 to 1167; Z = 1.35 to 6.89; ACI: T = 719 to 1365, Z = 0.87 to 3.04). After the fire, a reduction of soniferous species at the burned site was observed for insects and bats. Both biophonic activity and soniferous species showed a tendency to recover one year after the fire, but there were still less species in September 2013 (non-burned = 43 and burned = 37) when compared to September 2012 at both sites (Site 1 = 52 and Site 2 = 49). Our results showed that changes in the natural regimes of fire can negatively impact the biodiversity and reinforce the need for monitoring protocols and inspection of wildfires.

Pathology without microscope: From a projection screen to a virtual slide.

We have witnessed successive stages since the Seventies in the advancements towards digital pathology. We agree with Dr Pallua et al on the tremendous changes that are taking place in pathology, all leading toward greater role of digitalization in the field of pathology, both in terms of consultation and teaching. In particular, distance teaching using digital pathology will grow into a mainstream mode of pathology teaching, something that has been reinforced by COVID-19.

Mitochondrial DNA haplogroups may influence Fabry disease phenotype.

While the genetic origin of Fabry disease (FD) is well known, it is still unclear why the disease presents a wide heterogeneity of clinical presentation and progression, even within the same family. Emerging observations reveal that mitochondrial impairment and oxidative stress may be implicated in the pathogenesis of FD. To investigate if specific genetic polymorphisms within the mitochondrial genome (mtDNA) could act as susceptibility factors and contribute to the clinical expression of FD, we have genotyped European mtDNA haplogroups in 77 Italian FD patients and 151 healthy controls. Haplogroups H and I, and haplogroup cluster HV were significantly more frequent in patients than controls. However, no correlation with gender, age of onset, organ involvement was observed. Our study seems to provide some evidence of a contribution of mitochondrial variation in FD pathogenesis, at least in Italy.

The Frequencies of Different Inborn Errors of Metabolism in Adult Metabolic Centres: Report from the SSIEM Adult Metabolic Physicians Group.

BACKGROUND: There are few centres which specialise in the care of adults with inborn errors of metabolism (IEM). To anticipate facilities and staffing needed at these centres, it is of interest to know the distribution of the different disorders. METHODS: A survey was distributed through the list-serve of the SSIEM Adult Metabolic Physicians group asking clinicians for number of patients with confirmed diagnoses, types of diagnoses and age at diagnosis. RESULTS: Twenty-four adult centres responded to our survey with information on 6,692 patients. Of those 6,692 patients, 510 were excluded for diagnoses not within the IEM spectrum (e.g. bone dysplasias, hemochromatosis) or for age less than 16 years, leaving 6,182 patients for final analysis. The most common diseases followed by the adult centres were phenylketonuria (20.6%), mitochondrial disorders (14%) and lysosomal storage disorders (Fabry disease (8.8%), Gaucher disease (4.2%)). Amongst the disorders that can present with acute metabolic decompensation, the urea cycle disorders, specifically ornithine transcarbamylase deficiency, were most common (2.2%), followed by glycogen storage disease type I (1.5%) and maple syrup urine disease (1.1%). Patients were frequently diagnosed as adults, particularly those with mitochondrial disease and lysosomal storage disorders. CONCLUSIONS: A wide spectrum of IEM are followed at adult centres. Specific knowledge of these disorders is needed to provide optimal care including up-to-date knowledge of treatments and ability to manage acute decompensation.

Late-Onset Glycogen Storage Disease Type 2.

Glycogenosis II (GSDII) is an autosomal recessive lysosomal storage disorder resulting from acid alpha-glucosidase (GAA) deficiency, subsequent lysosomal accumulation of glycogen in muscles, impairment of autophagic processes and progressive cardiac, motor and respiratory failure. The infantile form usually appears in the first month of life, progresses rapidly and presents with severe cardiac involvement and complete deficiency of alpha-glucosidase activity (< 1% of normal controls). The late-onset form is characterized by great variability of the phenotypical spectrum. Main findings are muscle weakness and severe respiratory insufficiency while cardiac involvement may be completely absent. Residual GAA enzyme activity may correlate with severity of phenotype but many adult patients sharing the same mutations present with a wide variability in residual enzyme activity, age of onset and rate of disease progression, thus supporting a role for other factors, i.e., post-translational modifications and modifier genes, in modulating disease presentation. Enzyme replacement therapy (ERT) with alglucosidase alfa stabilizes the disease or improves muscle and/or respiratory function. However, efficacy of ERT may be influenced by several factors including age when ERT begins, extent of muscle damage, degree of defective autophagy, diversity in muscle fiber composition, difficulties in delivery of the therapeutic agent and antibody production. Further studies should be warranted to investigate factors determining the differences in clinical expression and therapeutic response in order to achieve better clinical and therapeutic management of these patients.

Myopathic involvement and mitochondrial pathology in Kennedy disease and in other motor neuron diseases.

Kennedy disease (spinal and bulbar muscular atrophy, or SBMA) is a motor neuron disease caused by a CAG expansion in the androgen-receptor (AR) gene. Increasing evidence shows that SBMA may have a primary myopathic component and that mitochondrial dysfunction may have some role in the pathogenesis of this disease. In this article, we review the role of mitochondrial dysfunction and of the mitochondrial genome (mtDNA) in SBMA, and we present the illustrative case of a patient who presented with increased CK levels and exercise intolerance. Molecular analysis led to definitive diagnosis of SBMA, whereas muscle biopsy showed a mixed myopathic and neurogenic process with "mitochondrial features" and multiple mtDNA deletions, supporting some role of mitochondria in the pathogenesis of the myopathic component of Kennedy disease. Furthermore, we briefly review the role of mitochondrial dysfunction in two other motor neuron diseases (namely spinal muscular atrophy and amyotrophic lateral sclerosis). Most likely, in most cases mtDNA does not play a primary role and it is involved subsequently. MtDNA deletions may contribute to the neurodegenerative process, but the exact mechanisms are still unclear. It will be important to develop a better understanding of the role of mitochondrial dysfunction in motoneuron diseases, since it may lead to the development of more effective strategies for the treatment of this devastating disorder.

Reproducibility of histopathologic tumor grading in penile cancer--results of a European project.

Since reliable molecular prognostic parameters for inguinal lymph metastases in penile cancer are not available, tumor grading is often used as a surrogate prognostic tool for the indication of inguinal lymphadenctomy and has been integrated into the current TNM classification for penile cancer. The reliability of tumor grading is under discussion. We examined interobserver grading variability in 90 primary penile carcinomas, assessed by 12 different uropathologists from five European countries. Tumor grading, following the CAP scheme, was compared, and interobserver variability was calculated using kappa statistics. The interobserver variability was high as reflected by an overall low kappa coefficient (mean k = 0.34) and reached a moderate level only in 26.4 % of the cases (range 0.02-0.67). The percentage of G1 tumors assigned ranged from 8.6 to 52.5 %, G2 tumors from 27.1 to 72.6 % and G3 tumors from 11.7 to 48.7 %. Only some observers assigned G4 with a range of 0.6-21.9 %. Subdivision into low and high grade according to UICC and EAU classifications differed significantly (P < 0.001). Low reproducibility of grading in penile carcinomas with the favored method does not allow a reliable prognostication of tumor aggressiveness. Inclusion of histological grading into the TNM classification currently seems not to be a benefit.

Targeting prostate-specific membrane antigen for personalized therapies in prostate cancer: morphologic and molecular backgrounds and future promises.

Prostate-specific membrane antigen (PSMA) is an integral, non-shed membrane glycoprotein that is highly expressed on prostate epithelial cells and strongly upregulated in prostate cancer (PCa). Prostatic neoplastic transformation results in the transfer of PSMA from the apical membrane to the luminal surface of the ducts. However, the role of PSMA in tumor angiogenesis and carcinogenesis is poorly understood. PSMA is characterized by folate hydrolase and carboxypeptidase activity and internalization function, and its levels are directly correlated to androgen independence, metastasis and PCa progression. As largely substantiated by preclinical and clinical findings, PSMA could represent a promising target for Positron Emission Tomography (PET) radiopharmaceuticals for PCa imaging. Furthermore, PSMA could prove an important target for the development of new therapeutic approaches, including PSMA-based aptamers, peptides, antibody-drug conjugated therapy, as well as radiotherapy and immunotherapy. This review will summarize the role of PSMA in PCa development and progression and its potential role in the diagnosis and treatment of patients with initial and advanced PCa.

Pathology of upper tract urothelial carcinoma with emphasis on staging.

Classification of upper tract urothelial preneoplastic and neoplastic lesions mirrors that of the urinary bladder, with all lesions of the bladder urothelium being possible in the upper tract and vice versa. There are three major groups of non-invasive urothelial neoplasms: flat, papillary, and inverted. These three groups share a similar morphological spectrum of intraurothelial changes, ranging from hyperplasia to dysplasia to carcinoma in situ. However, they differ in terms of architectural growth pattern compared to the surrounding non-neoplastic mucosal surface. Infiltrating urothelial carcinoma is defined as a urothelial tumor that invades beyond the basement membrane. Unlike in non-invasive papillary urothelial neoplasms (pTa), the role of histologic grade in pT1 and higher stage tumors has been suggested to be of only relative importance. The vast majority of tumors of the upper urinary tract are urothelial carcinoma. More commonly seen, however, are foci of squamous differentiation and, less frequently, glandular differentiation. Pure urothelial carcinomas also display a wide range of variant morphologies, and recognition of these morphologies is important for diagnosis, classification, and prognosis.

Karyometry and quantitative immunohistochemical analysis of the urothelium in tissue sections: a feasibility study based on chromatin remodeler DAXX immunostaining.

The aim of this study was to investigate the feasibility of applying a software traditionally used in the field of engineering to pathology, in particular to tissue sections from normal urothelium (NU) immuno-stained for the chromatin remodeler DAXX (death domain-associated protein). The study included 5 cases of NU. Images were recorded with a Nikon digital camera. The nuclear area and the intensity of nuclear staining were analyzed with a software package developed in LabVIEW environment. The nuclear size is 14.8 plus or minus 6.5 square microns. The nuclei in the cells adjacent to the stroma are slightly smaller than in the intermediate cells by a factor of 0.86. The mean nuclear area of the nuclei in the superficial cell layer in NU is identical to the nuclei in the intermediate cell layers. For each nucleus intensity of nuclear staining is calculated based on the gray value of the individual picture elements in the green color plane. The mean and standard deviation of nuclear gray value are 106 plus or minus 15. The mean value in the nuclei adjacent to the stroma is slightly greater by a factor 1.02 and 1.04 compared to the intermediate and superficial cell layers. In conclusion, this exploratory study shows that karyometry and quantitative immunohistochemical analysis can be done accurately by using a digital camera commonly available to pathologists and an image analysis software routinely used in the field of engineering.

[A case of acute renal failure secondary to late-onset McArdle's disease]. / Un caso di insufficienza renale acuta secondaria a malattia di McArdle ad esordio tardivo.

INTRODUCTION: Mc Ardles disease, also known as Type V glycogen storage disease, is a rare deficiency of the enzyme glycogen phosphorylase in muscle cells, inherited as an autosomal recessive trait. In the absence of this enzyme, muscles cannot break down glycogen during exercise, so in patients affected by McArdles disease even moderate physical activity produces cramps, pain and fatigue. Anaerobic activity leads to severe fixed contractures and rhabdomyolisis with myoglobinuria and raised serum creatine-kinase, which, in turn, can lead to acute renal failure. Disease onset is usually in early childhood, although diagnosis is often not made until the second or third decade. CASE REPORT: We present the case of a 68-year-old man who presented to the Emergency Room with fatigue, vertigo, diarrhea and oliguria. The patient underwent five daily hemodialysis sessions, diuresis reappeared and there was progressive recovery of renal function. The patient described episodes of fatigue and muscular pain occurring since childhood: the positive personal history, together with persistently raised CPK levels in the absence of any infective or toxic cause of myositis, led us to suspect the presence of this rare metabolic disease, which was subsequently confirmed by muscle biopsy. CONCLUSION: To date, there is no specific treatment for type V glycogenosis, although a diet rich in protein and saccarose, vitamin B6 supplementation and creatine administration are generally recommended. Moderate physical activity can help manage symptoms by improving exercise tolerance and blood supply to the muscles, ensuring provision of glucose and free fatty acids for the muscle fibers.

Update on selected renal cell tumors with clear cell features. With emphasis on multilocular cystic clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (CCRCC) is the most common malignant tumor of renal epithelial origin and, with the exception of some rare tumors, the most deadly. The exception is represented by the multilocular cystic CCRCC, whose prognosis is excellent with survival rates of 100% when diagnosis is made according to the WHO definition. For this reason a proposal has been made to rename this tumor as multilocular cystic renal cell neoplasms of low malignant potential. Another exemption could be the clear cell (tubulo) papillary renal cell carcinoma/clear cell papillary renal cell carcinoma (CCPRCC), a tumor with tubulopapillary architecture and clear cytoplasm. Published data indicates that these are neoplasms with indolent clinical behavior. No cases with metastasis have been reported. Neoplasms meeting criteria for CCPRCC will subsequently be reclassified as of "low malignant potential" rather than carcinoma. The stroma of CCPRCC not infrequently demonstrates smooth muscle metaplasia. It should be remembered, however, that smooth muscle stromal metaplasia and proliferation are not entirely specific to this entity. Hence, it is suggested that smooth muscle metaplasia in the kidney may be a nonspecific common reaction to a variety of stimuli. Xp11 translocation renal cell carcinomas are a group of neoplasms distinguished by chromosomal translocations with breakpoints involving the TFE3 transcription factor gene, which maps to the Xp11.2 locus. The most distinctive histologic pattern of the Xp11 translocation renal cell carcinoma is that of a neoplasm with both clear cells and papillary architecture, and abundant psammoma bodies. TFE3 immunohistochemical staining is reported to be sensitive and specific for a diagnosis of translocation-associated carcinoma as long as the labeling is strong, diffuse, and nuclear. This immunostaining is particularly useful if the differential diagnosis includes CCRCC and CCPRCC. In conclusion, recognition of CCRCC and differentiation from other renal cell neoplasms with clear cytoplasm is important not only for prognostication but also for treatment-related reasons.

Treatment effects in prostate cancer following traditional and emerging therapies.

Treatment options for prostate cancer consist of radical prostatectomy, hormonal therapy and radiation therapy. Hormonal and radiation therapy have well-known, often profound, effects on the histological appearance of benign and malignant prostate tissue. Novel therapies including focal ablative treatments, chemotherapies and targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments at the tissue level. As such, knowledge of treatment-related changes and access to clinical information are essential to ensure accurate interpretation and reporting of post-treatment prostate specimens by pathologists.

A contemporary update on pathology reporting for urinary bladder cancer.

Providing the best management for patients with bladder cancer relies on close cooperation among uro-oncologists and pathologists. The pathologist is involved in the diagnosis and assessment of prognostic and therapeutic factors in bladder biopsies, transurethral resection (TUR) and cystectomy specimens. The pathologist must report accurately the key features using terms that are well understood by clinicians. Adequate clinical information is important to pathologists in deciding the best approach in handling and processing the surgical specimens.

Immunohistochemical expression and localization of somatostatin receptors in normal prostate, high grade prostatic intraepithelial neoplasia and prostate cancer and its many faces.

Data on the immunohistochemical expression and localization of the five somatostatin receptors (SSTRs) have been obtained by our group in separate studies concerning the many faces of prostate cancer (PCa), its precursor high grade prostatic intraepithelial neoplasia (HGPIN) and normal epithelium (Nep). This publication highlights the key findings, with special reference to: normal prostate epithelium; untreated HGPIN and PCa, both clinically and incidentally detected; PCa with NE differentiation; HGPIN and PCa following complete androgen ablation (CAA); and hormone refractory (HR) PCa. Taken together, the data obtained in these investigations demonstrate that SSTR profiling in individual patients with HGPIN and the multifaceted PCa is feasible and is of relevance to better tailor the somatostatin analogue-based treatment.

Is there a role for prostate tumour overexpressed-1 in the diagnosis of HGPIN and of prostatic adenocarcinoma? A comparison with alpha-methylacyl CoA racemase.

Prostate Tumour Overexpressed-1 (PTOV1) was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer (PCa). Alpha-Methyl-CoA racemase (AMACR) mRNA was identified as being overexpressed in PCa. PTOV1 and racemase were immunohistochemically evaluated in PCa, high-grade prostatic intraepithelial neoplasia (HGPIN), atrophy and normal-looking epithelium (NEp) in 20 radical prostatectomies (RPs) with pT2a Gleason score 6 prostate cancer with the aim of analyzing the differences in marker expression between PTOV1 and AMACR. The level of expression of PTOV1 and AMACR increased from NEp and atrophy through HGPIN, away from and adjacent to prostate cancer, to PCa. With the ROC curve analysis the overall accuracy in distinguishing PCa vs HGPIN away from and adjacent to cancer was higher for AMACR than for PTOV1. In conclusion, AMACR can be considered a more accurate marker than PTOV1 in the identification of HGPIN and of PCa. However, PTOV1 may aid in the diagnosis of PCa, at least to supplement AMACR as another positive marker of carcinoma and to potentially increase diagnostic accuracy.

Fine-needle aspiration cytology of adrenal masses: a re-assessment with histological confirmation.

BACKGROUND: Fine-needle aspiration (FNA) of adrenal masses is a method currently indicated in lesions suspected of being extra-adrenal in origin; even though its diagnostic reliability has already been determined in many studies, few have used histological examination obtained after adrenalectomy for diagnostic confirmation. AIM: To analyze the diagnostic performance of adrenal FNA in subjects with an available histological confirmation. SUBJECTS AND METHODS: Fifty subjects (26 benign adrenal lesions, 9 primary malignant lesions, and 15 metastatic lesions) who had undergone ultrasound (US)-guided adrenal FNA and then adrenalectomy were re-analyzed retrospectively. RESULTS: FNA guaranteed a sensitivity of 85.7% and a specificity of 100% in all subjects; after having divided the subjects into oncologic and non-oncologic groups, the sensitivity of the test in oncologic patients (100%) increased significantly compared to non-oncologic (57.1%) with no difference in specificity (100% in both groups). Considering also non-diagnostic samples in our analysis (no.=11; 22% of all samples studied), FNA correctly diagnosed malignancy only in 75% of the cases and benignancy only in 66.6%; however, even after including non-diagnostic samples, the percentage of correct malignancy diagnosis remained significantly higher in oncologic (93.3%) than in non-oncologic patients (44.4%) without significant statistical difference between the 2 groups regarding the percentage of correct benignancy diagnosis (respectively 100% and 63.6%). CONCLUSIONS: Our study, based on histological confirmation, underlines the low discriminant value of US-guided adrenal FNA, though the method may have value in oncologic patients.

Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis.

Papillary urothelial neoplasia of low malignant potential (PUNLMP) recurs in approximately 35% of patients. Conventional histopathological assessment does not distinguish non-recurrent from recurrent PUNLMP. The aim of this study is to explore the differences in global histone acetylation and global DNA methylation between non-recurrent and recurrent PUNLMP. Acetylated histone H3 lysine 9 (AcH3K9) and 5-methylcytosine (5MeC) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). The total optical density of the nuclear staining was measured photometrically in at least 40 nuclei separately for the basal, intermediate and luminal positions in each case. Concerning the total optical density values for both acetylation and methylation, a decrease in staining is observed from non-recurrent PUNLMP to recurrent PUNLMP, at all nuclear locations. For acetylation the mean value in non-recurrent PUNLMP, intermediate between NU and UC, is closer to the former than to latter. The mean value in recurrent PUNLMP is closer to UC than to NU. In NU, non-recurrent and recurrent PUNLMP, the acetylation to methylation ratio decreased from the nuclei in basal position to those in the surface, the average for the above groups being 1.491, 1.611 and 1.746, respectively. Setting the observed values for NU at each sampling location to unity, acetylation shows a steady decrease, the percentages of changes in this nuclear location compared to NU being -5% in non-recurrent PUNLMP, -15% in recurrent PUNLMP and -24% in UC. Concerning methylation, there is a slight increase in non-recurrent PUNLMP (+5%), a decrease in recurrent PUNLMP (-19%) followed by a sharp rise for the UC (+61%). In conclusion, there are differences in global histone acetylation and DNA methylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed to elucidate the complex interplay between chromatin structure, its modifications and recurrence of PUNLMP.