Microbiota modulation by teriflunomide therapy in people with multiple sclerosis: An observational case-control study.

Multiple sclerosis (MS) is a chronic immune-mediated and heterogeneous disease characterized by demyelination, axonal damage, and physical and cognitive impairment. Recent studies have highlighted alterations in the microbiota of people with MS (pwMS). However, the intricate nature of the disease and the wide range of treatments available make it challenging to identify specific microbial populations or functions associated with MS symptoms and disease progression. This study aimed to characterize the microbiota of pwMS treated with the oral drug teriflunomide (TF) and compare it with that of pwMS treated with beta interferons (IFNß), pwMS treated with no previous disease modifying therapies (naïve), and healthy controls. Our findings demonstrate significant alterations in both the composition and function of the gut microbiota in pwMS that are further influenced by disease-modifying therapies. Specifically, oral treatment with TF had a notable impact on the gut microbiota of pwMS. Importantly, the dysregulated microbial environment within the gut was associated with symptoms commonly experienced by pwMS, including fatigue, anxiety, and depression.

Bacteria-Fungi Interactions in Multiple Sclerosis.

Multiple sclerosis (MS) arises from a complex interplay between host genetic factors and environmental components, with the gut microbiota emerging as a key area of investigation. In the current study, we used ion torrent sequencing to delve into the bacteriome (bacterial microbiota) and mycobiome (fungal microbiota) of people with MS (pwMS), and compared them to healthy controls (HC). Through principal coordinate, diversity, and abundance analyses, as well as clustering and cross-kingdom microbial correlation assessments, we uncovered significant differences in the microbial profiles between pwMS and HC. Elevated levels of the fungus Torulaspora and the bacterial family Enterobacteriaceae were observed in pwMS, whereas beneficial bacterial taxa, such as Prevotelladaceae and Dialister, were reduced. Notably, clustering analysis revealed overlapping patterns in the bacteriome and mycobiome data for 74% of the participants, with weakened cross-kingdom interactions evident in the altered microbiota of pwMS. Our findings highlight the dysbiosis of both bacterial and fungal microbiota in MS, characterized by shifts in biodiversity and composition. Furthermore, the distinct disease-associated pattern of fungi-bacteria interactions suggests that fungi, in addition to bacteria, contribute to the pathogenesis of MS. Overall, our study sheds light on the intricate microbial dynamics underlying MS, paving the way for further investigation into the potential therapeutic targeting of the gut microbiota in MS management.

Biphasic papillary (biphasic squamoid alveolar) renal cell carcinoma: a clinicopathologic and molecular study of 17 renal cell carcinomas including 10 papillary adenomas.

Biphasic papillary renal cell carcinoma (synonymous with biphasic squamoid alveolar renal cell carcinoma) is considered within the spectrum of papillary renal cell carcinoma (PRCC). With < 70 reported cases of biphasic PRCC, there is limited data on the pathologic spectrum and clinical course. Seventeen biphasic PRCC cases and 10 papillary adenomas with similar biphasic morphology were assessed. The mean age of the biphasic PRCC patients was 62 years (male to female ratio of 1.8:1), from 10 partial nephrectomies, 6 radical nephrectomies, and 1 biopsy. The mean tumor size was 3.6 cm (range 1.6-8 cm), with 24% showing multifocality. Fifteen out of 17 cases were limited to the kidney (one of which was staged as pT2a but had lung metastases at diagnosis) and 2/17 cases were staged as T3a. All tumors showed typical biphasic morphology with an extent of squamoid foci widely variable from 10 to 95%. Emperipolesis was identified in 88% of cases. All biphasic PRCC tested exhibited positivity for PAX8 (16/16), keratin 7 (17/17), EMA (15/15), AMACR (17/17), and vimentin (12/12) in both large and small cells; cyclin D1 was only expressed in the large cells (16/16). The 10 papillary adenomas showed a similar immunoprofile to biphasic PRCC. NGS testing performed on 13 biphasic PRCC revealed 4 (31%) harboring MET SNVs. In 1/5 (20%) papillary adenomas, a pathogenic MET SNV was identified. Biphasic PRCC is rare with a generally similar immunoprofile to "type 1" PRCC but with notable strong positivity for cyclin D1 in the large cell component. Although most of the biphasic PRCC cases were of small size, low stage, and with an indolent behavior, one patient had metastatic disease and one patient died of the disease.

microRNA sequencing for biomarker detection in the diagnosis, classification and prognosis of Diffuse Large B Cell Lymphoma.

Despite being considered a single disease, Diffuse Large B Cell Lymphoma (DLBCL) presents with variable backgrounds, which results in heterogeneous outcomes among patients, with 40% of them still having primary refractory disease or relapse. Thus, novel biomarkers are needed. In addition, multiple factors regarding its pathogenesis remain unclear. In this context, recent investigations point to the relevance of microRNAs (miRNAs) in cancer. However, regarding DLBCL, there is inconsistency in the data reported. Therefore, in this work, the main goals were to determine a miRNA set with utility as biomarkers for DLBCL diagnosis, classification, prognosis and treatment response, as well as to decipher the mechanism of action of deregulated miRNAs in the origin of the disease. We analyzed miRNA expression in a cohort of 78 DLBCL patients and 17 controls using small RNA sequencing and performed a miRNA-mRNA interaction network analysis. This way, we were able to define new miRNA expression signatures for diagnosis, classification, treatment response and prognosis, and we identified plausible mechanisms of action by which deregulated miRNAs could be involved in DLBCL pathogenesis. In summary, our study remarks that miRNAs could play an important role in DLBCL.

Papillary Renal Neoplasm With Reverse Polarity: A Clinical, Pathologic, and Molecular Study of 8 Renal Tumors From a Single Institution.

CONTEXT.­: In 2019, papillary renal neoplasm with reverse polarity (PRNRP) was defined as a new neoplasm because it has a predominately tubulopapillary pattern lined by a single layer of cuboidal and eosinophilic cells with apically located round nuclei. Immunohistochemically, this neoplasm showed expression of GATA-3 and L1CAM and had recurrent KRAS mutations. OBJECTIVE.­: To estimate the incidence of PRNRP and provide 8 additional cases with some variations in the morphology. DESIGN.­: We reviewed 1627 renal tumors from our hospital during a 21-year period (2000-2020). We reexamined 196 papillary renal cell carcinomas and selected those that met the diagnostic criteria for PRNRP. RESULTS.­: We found 8 cases consistent with PRNRP. The median age of the patients was 64.75 years; 7 patients were male, and 1 was female. Two patients had end-stage renal disease. No recurrence, metastasis, or tumor-related death occurred in a mean follow-up period of 67.62 months. Tumor size ranged from 1.6 to 3.7 cm. All cases were pT1. Seven cases (7 of 8; 87.5%) had predominantly cystic changes, and 1 had solid architecture. No foamy cells, clear cell change, or psammoma bodies were seen in any cases. All cases were positive for CK7, EMA, GATA3, and L1CAM. KRAS gene mutation was detected in 5 cases (5 of 8; 62.5%). CONCLUSIONS.­: PRNRP represents 4.08% (8 of 196 cases) of papillary renal cell carcinomas and 0.49% (8 of 1627 cases) of all renal tumors in the 21-year period in our series. In our study, all cases exhibited an indolent clinical course. This supports that PRNRP has characteristic morphologic and molecular features.

Microbial dysbiosis and lack of SCFA production in a Spanish cohort of patients with multiple sclerosis.

Background: Multiple sclerosis (MS) is a chronic, demyelinating, and immune-mediated disease of the central nervous system caused by a combination of genetic, epigenetic, and environmental factors. The incidence of MS has increased in the past several decades, suggesting changes in the environmental risk factors. Much effort has been made in the description of the gut microbiota in MS; however, little is known about the dysbiosis on its function. The microbiota produces thousands of biologically active substances among which are notable the short-chain fatty acid (SCFA) excretion. Objectives: Analyze the interaction between microbiota, SCFAs, diet, and MS. Methods: 16S, nutritional questionnaires, and SCFAS quantification have been recovered from MS patients and controls. Results: Our results revealed an increment in the phylum Proteobacteria, especially the family Enterobacteriaceae, a lack in total SCFA excretion, and an altered profile of SCFAs in a Spanish cohort of MS patients. These alterations are more evident in patients with higher disability. Conclusions: The abundance of Proteobacteria and acetate and the low excretion of total SCFAs, especially butyrate, are common characteristics of MS patients, and besides, both are associated with a worse prognosis of the disease.

Autoimmune GFAP astrocytopathy presenting with remarkable CNS hyperexcitability and oculogyric crises.

The autoimmune GFAP astrocytopathy has been associated with meningoencephalomyelitis that usually responds to glucocorticoids. We report a 20-year-old man that developed an acute and severe meningoencephalomyelitis with remarkable CNS hyperexcitability and oculogyric crises. CSF analysis showed hypoglycorrhachia, pleocytosis, elevated ADA, and CSF-immunofluorescence characteristic of autoimmune GFAP astrocytopathy. MRI showed lesions at thalamus, corpus-callosum, dorsal pons and dentate nucleus with associated myelitis. Immunotherapy led to a full recovery, although MRI activity was observed at follow-up. CNS hyperexcitability, typically seen in other immune-mediated syndromes, represents a novel presenting form to be included as part of the clinical spectrum of this entity.

ABO blood group distributions in multiple sclerosis patients from Basque Country; O- as a protective factor.

BACKGROUND: The relation between ABO/Rh groups and multiple sclerosis (MS) has been proposed in several studies, however there is a controversy about the role of these groups in the disease. Although it has been reported that some groups can be protective or risk factors, there is no consensus and discordant reports can be found in the literature. OBJECTIVES AND METHODOLOGY: In this short report, we analyze the ABO/Rh distribution in a MS cohort of 265 patients and compare these frequencies with the results obtained from the Basque Blood Donors bank (17,796 individuals) of the same region. RESULTS AND CONCLUSIONS: From our data, the absence of immune antigens (A, B or Rhesus +) defined by the group O- seems to be protective in the MS group with an odds ratio of 0.49 (95% confidence interval 0.309-0.796), while the presence of Rh+ plus A or B seems to be a risk in developing multiple sclerosis.

Methylation of CpG sites in BCL2 major breakpoint region and the increase of BCL2/JH translocation with aging.

The BCL2 breakage mechanism has been shown to be highly dependent on DNA methylation at the major breakpoint region (MBR) CpG sites. We recently described an increased frequency of BCL2/ JH translocation with aging. It is known that methylation levels change with aging. The present study aimed to determine whether methylation alterations at CpG sites of BCL2 MBR were the cause of increased breakages with aging. We analyzed the methylation levels of three CpG sites on the region by pyrosequencing and studied if methylation levels and/or polymorphisms affecting CpG sites were associated with an increase of translocations. We observed that although the methylation levels of MBR CpG sites were higher in individuals with BCL2/JH translocation, in contrast to our expectations, these levels decreased with the age. Moreover, we show that polymorphisms at those CpG sites leading to absence of methylation seem to be a protective factor for the apparition of translocations.

[Smoking and multiple sclerosis]. / Tabaco y esclerosis múltiple.

INTRODUCTION: Multiple sclerosis (MS) is a complex autoimmune disease of unknown etiology, in which genetic and environmental factors interact and determine the disease susceptibility. In recent years, smoking effect has been one of the emerging environmental factors in the study of MS and has been associated with an increased susceptibility and an increase in disease progression. AIM: To review the current evidence on the role of smoking in MS. DEVELOPMENT: The review includes an update of studies that have analyzed different aspects of tobacco in MS, including the potential pathogenic pathways involved, association of smoking and risk of MS, interactions with other risk factors and the effect of smoking in the disease course. CONCLUSIONS: Observational studies show that smoking significantly increases the risk of MS (odds ratio~1.5) and is an independent risk factor. However, MS is a complex disease and this risk may be modified depending on the interaction with other genetic and environmental factors. The role of smoking as a progression factor is more controversial, with confronted results and highly variable studies, making it difficult to draw any conclusion. The mechanisms by which smoking may modify the risk and progression of the disease have to be further investigated.

TITLE: Tabaco y esclerosis multiple.Introduccion. La esclerosis multiple (EM) es una enfermedad autoinmune de etiologia compleja, hoy por hoy desconocida, en la que factores geneticos y ambientales determinan la susceptibilidad. En los ultimos años, el efecto del tabaco ha sido uno de los factores ambientales que ha emergido en la EM, y se ha asociado tanto a un aumento de la susceptibilidad como a un aumento de la progresion. Objetivo. Revisar la evidencia actual sobre el papel del tabaco en la EM. Desarrollo. Se incluye una actualizacion de los estudios publicados que han analizado distintos aspectos del tabaco en la EM: vias patogenicas implicadas, asociacion del tabaco y riesgo de EM, interaccion con otros factores de riesgo y efecto del tabaco en el curso de la enfermedad. Conclusiones. Los estudios observacionales demuestran que el tabaquismo incrementa de forma significativa el riesgo de EM (odds ratio ~ 1,5) y es un factor de riesgo independiente. Sin embargo, la EM es una enfermedad compleja y el aumento de riesgo por el tabaco puede diferir en funcion de la interaccion con otros factores geneticos y ambientales. El papel del tabaco como factor de progresion es mas controvertido, con resultados contradictorios y estudios de gran variabilidad, lo que dificulta establecer una conclusion firme. Los mecanismos por los que el tabaquismo modifica el riesgo y posiblemente la progresion de la enfermedad no son aun conocidos.

Lack of association between deficient mismatch repair expression and outcome in endometrial carcinomas of the endometrioid type.

OBJECTIVE: Endometrial carcinomas of the endometrioid type (EEC) are associated with a good prognosis. However, about 20% of them recur and new prognostic markers are needed. Microsatellite instability (MSI), associated with mismatch repair (MMR) deficiency, is a frequent alteration in EECs that has been associated with prognosis. However, its prognostic impact on EECs remains unclear. The aim of the present study was to clarify the relationship between MMR deficiency and outcome in a large cohort of well classified EECs. METHODS: A total of 212 EEC samples were analyzed by immunohistochemistry for the MMR genes MLH-1, MSH-2, MSH-6 and PMS-2. Kaplan-Meier survival analysis and log-rank tests were performed to study the prognostic significance of dMMR taking into account clinical and pathological parameters. RESULTS: We observed no association between MMR deficiency and OS or PFS in our 212 EEC patients (p-value=0.6565 and 0.4380, respectively). When we performed the analysis in different FIGO-stage groups, we did not find association between MMR and OS or PFS in stages I, I/II or III/IV. When we analyzed the specific group of patients with lymphatic invasion separately, MMR expression was not associated with OS or PFS either. CONCLUSIONS: MMR deficiency does not seem to be a good prognostic marker in endometrioid type endometrial carcinomas.

[Cognitive performance and quality of life in multiple sclerosis in Gipuzkoa]. / Rendimiento cognitivo y calidad de vida de la esclerosis múltiple en Gipuzkoa.

INTRODUCTION: Cognitive impairment and the presence of depressive symptoms, which are commonly found in patients with multiple sclerosis, affect the patients' quality of life. AIM. To describe the quality of life, cognitive compromise and levels of depression, in relation to other clinical variables, in patients with multiple sclerosis in the province of Gipuzkoa. PATIENTS AND METHODS: A total of 114 patients were submitted to neuropsychological evaluation. The MSQoL-54 and Beck's Depression Inventory were applied to evaluate the quality of life and levels of depression. Three main analyses were performed: a comparison of cognitive performance among subtypes, an analysis of the correlation among clinical, neuro-psychological and quality of life variables, and an analysis of the effects of gender on cognitive performance. RESULTS: A neuropsychological pattern is found in multiple sclerosis that is characterised by a slowing of the processing of information and attentional difficulties. Quality of life is related with depressive syndromes and with overall cognitive performance but not with clinical factors such as the rate of attacks or the length of time the disease lasts. The data confirm the existence of poorer cognitive performance in males, above all in terms of verbal auditory memory. CONCLUSIONS: Gender is presented as a factor that modulates the impact of the disease on cognitive performance, which reinforces the interest in conducting studies that clarify the origin of such differences. Furthermore, the quality of life displays a greater relationship with the degree of adaptation to the disease than with its symptoms.

TITLE: Rendimiento cognitivo y calidad de vida de la esclerosis multiple en Gipuzkoa.Introduccion. El deterioro cognitivo y la presencia de sintomas depresivos, comunes en los pacientes con esclerosis multiple, inciden en la calidad de vida de los pacientes. Objetivo. Describir la calidad de vida, la afectacion cognitiva y los niveles de depresion, en relacion con otras variables clinicas, en los pacientes con esclerosis multiple de la provincia de Gipuzkoa. Pacientes y metodos. Se evaluo neuropsicologicamente a 114 pacientes. Se incluyeron el MSQoL-54 y el inventario de depresion de Beck para evaluar la calidad de vida y los niveles de depresion. Se emprendieron tres analisis principales: comparacion del rendimiento cognitivo entre subtipos, analisis de correlacion entre variables clinicas, neuropsicologicas y de calidad de vida, y analisis sobre los efectos del genero en el rendimiento cognitivo. Resultados. Se halla en la esclerosis multiple un patron neuropsicologico caracterizado por enlentecimiento en el procesamiento de la informacion y dificultades atencionales. La calidad de vida se relaciona con sintomas depresivos y con el rendimiento cognitivo global pero no con factores clinicos como la tasa de brote o la duracion de la enfermedad. Los datos confirman un peor rendimiento cognitivo en los hombres, sobre todo en la memoria auditiva verbal. Conclusiones. El genero se presenta como un factor modulador en el impacto de la enfermedad sobre el rendimiento cognitivo, que refuerza el interes de estudios que clarifiquen el origen de dichas diferencias. Ademas, la calidad de vida muestra una mayor relacion con la adaptacion a la enfermedad que con sus sintomas.

The Presence of Mutations in the K-RAS Gene Does Not Affect Survival after Resection of Pulmonary Metastases from Colorectal Cancer.

Introduction. Our objective was to identify mutations in the K-RAS gene in cases of pulmonary metastases from colorectal cancer (CRC) and determine whether their presence was a prognostic factor for survival. Methods. We included all patients with pulmonary metastases from CRC operated on between 1998 and 2010. K-RAS mutations were investigated by direct sequencing of DNA. Differences in survival were explored with the Kaplan-Meier method log-rank tests and multivariate Cox regression analysis. Results. 110 surgical interventions were performed on 90 patients. Factors significantly associated with survival were disease-free interval (P = 0.002), age (P = 0.007), number of metastases (P = 0.001), lymph node involvement (P = 0.007), size of the metastases (P = 0.013), and previous liver metastasis (P = 0.003). Searching in 79 patients, K-RAS mutations were found in 30 cases. We did not find statistically significant differences in survival (P = 0.913) comparing native and mutated K-RAS. We found a higher rate of lung recurrence (P = 0.040) and shorter time to recurrence (P = 0.015) in patients with K-RAS mutations. Gly12Asp mutation was associated with higher recurrence (P = 0.022) and lower survival (P = 0.389). Conclusions. The presence of K-RAS mutations in pulmonary metastases does not affect overall survival but is associated with higher rates of pulmonary recurrence.

[Acute herpes simplex virus type 1 retinal necrosis three years after herpes simplex encephalitis]. / Necrosis retiniana aguda por virus herpes simple tipo 1 a los tres años de una encefalitis herpética.

TITLE: Necrosis retiniana aguda por virus herpes simple tipo 1 a los tres años de una encefalitis herpetica.

Determination of a low risk group for having metastatic nodules not detected by computed tomography scan in lung metastases surgery.

INTRODUCTION: In recent years, there has been debate regarding the diagnostic accuracy of computed tomography (CT) in the identification of lung metastases and the need for lung palpation to determine the number of metastatic nodules. The aim of this study was to determine in which patients the CT scan was more effective in detecting all metastases. METHODS: We studied all patients who underwent curative thoracotomy for pulmonary metastasis between 1998 and 2012. All cases were reviewed by two expert pulmonary radiologists before surgery. Statistical analyses were performed using Systat version 13. RESULTS: The study included 183 patients (63.6% male) with a mean age of 61.7 years who underwent 217 interventions. The CT scan was correct in 185 cases (85.3%). Discrepancies observed: 26 patients (11.9%) with more metastases resected than observed and 6 cases (2.8%) with fewer metastases. In patients with one or two metastases of colorectal origin or a single metastasis of any other origin, the probability of finding extra nodules was 9.5%. In the remaining patients, the probability was 27.8%, with statistically significant differences (P=.001). The mean age of the patients in whom no unobserved nodules were detected was 62.9 years compared to 56.5 years on average in patients who were free from any metastases (P=.001). CONCLUSIONS: Patients older than 60 years, with one or two metastases of colorectal origin or a single metastasis from any other origin were considered to be the group with low probability of having more metastases resected than observed.

Clinical response to thalidomide in the treatment of intracranial tuberculomas: case report.

We describe a patient with multiple intracranial tuberculomas resistant to standard care with antituberculosis drugs and corticosteroids who responded well to thalidomide. Adjunctive thalidomide may have a role in the management of refractory intracranial tuberculomas, although it should be used conservatively owing to its potential adverse events.

[Response to treatment with corticoids in a case of inflammatory amyloid angiopathy without performing a biopsy]. / Respuesta al tratamiento con corticoides en un caso de angiopatía amiloide inflamatoria sin realización de biopsia.

INTRODUCTION: Inflammatory amyloid angiopathy (IAA) is an infrequent presenting symptom of the recently recognised cerebral amyloid angiopathy and its definitive diagnosis is reached by means of pathological analyses. AIM: We report the case of a male patient with IAA and good clinical, neuropsychological and neuroimaging response to treatment with corticoids; a biopsy of brain tissue was not considered necessary. CASE REPORT: The patient, 68 years old and diagnosed with Alzheimer's disease, suffered from generalised seizures followed by a language disorder and hemiparesis of the right-hand side. A magnetic resonance imaging scan showed a lesion displaying infiltrating behaviour in the left hemisphere and multiple instances of microbleeding. Clinical and radiological features suggested IAA and treatment was established with corticoids. Neuroimaging and neuropsychological tests revealed a notable improvement at 30 days after beginning treatment with immunosuppressants. The genotype was ApoE e4/e4. The need to perform a biopsy of brain tissue was ruled out. CONCLUSIONS: The case described here suggests that, in individualised cases with clinical and radiological features that are characteristic of IAA, it may be possible to establish an empirical treatment with corticoids with a probability diagnosis and perform a biopsy of brain tissue in the event of a lack of response to treatment.

Bcl-2 and BLIMP-1 expression predict worse prognosis in gastric diffuse large B cell lymphoma (DLCBL) while other markers for nodal DLBCL are not useful.

AIMS: Previous studies have identified clinicopathological and immunohistochemical differences among diffuse large B cell lymphomas (DLBCL) as a function of disease location. Nevertheless, there is a continuing tendency to generalize the prognostic value of various identified markers without taking into account tumour site. Accordingly, we analysed the prognostic value of several of the immunohistochemical markers that have been proposed for nodal DLBCL in a group of patients with gastric DLBCL. METHODS AND RESULTS: Using histochemical methods, CD10, Bcl-6, Gcet1, MUM-1, Bcl-2 and BLIMP-1 expression was investigated in 43 cases of gastric DBLCL. As in nodal DLBCLs, expression of BLIMP-1, and of Bcl-2 in non-germinal centre B cell-like (non-GCB) patients, was associated with a worse prognosis. However, unlike nodal DBLCL, there was no significant association of prognosis with expression of CD10, Bcl-6, Gcet1 or MUM-1, or with categorization according to Hans or Muris algorithms. CONCLUSIONS: Although most markers of prognosis in nodal DLBCL are not useful indicators for gastric DLBCL, Bcl-2 or BLIMP-1 expression does correlate with worse prognosis. These data support the notion that clinicopathological features in DLBCL vary according to the disease location.