Evolution of cerebrovascular imaging and associated clinical findings in children with Alagille syndrome.

PURPOSE: Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with highly variable expression. Intracranial arterial and venous anomalies have a reported prevalence of 30-40% and can increase the risk of stroke by 16%. Few reports document the frequency and evolution of cerebrovascular abnormalities (CVAs) in children with ALGS. We aimed to define the spectrum, frequency, and evolution of CVAs in a series of children with ALGS using magnetic resonance angiography (MRA). METHODS: We conducted a single-center, retrospective study in a large tertiary pediatric hospital. CVAs were grouped into 4 categories: 1) Stenosis or narrowing; 2) Aneurysms and ectasias; 3) Tortuosity; and 4) Vascular anomalies and anatomical variants. RESULTS: Thirty-two children met the inclusion criteria. The median age at initial diagnosis was 6 (3.8-10.3) years. Thirteen (40%) had follow-up MRI at a mean of 55 (31.5-66) months. Eighteen (56%) had CVAs; the most frequent fell into group 1 (n = 12, 37.5%). CVAs were stable over time, except for one patient with Moyamoya arteriopathy (MMA). One patient developed a transient ischemic attack secondary to an embolic event. Three (9.3%) had microhemorrhages at the initial diagnosis secondary to Tetralogy of Fallot. Another patient had recurrent subdural hematomas of unknown cause. CONCLUSION: CVAs were stable except in the presence of MMA. Vascular strokes, which are reported in older patients with ALGS, were not a common feature in children under 16 years of age, either at presentation or over the 31.5-66 month follow-up period.

Expanding the Imaging Spectrum of Polymorphous Low-Grade Neuroepithelial Tumor of the Young in Children.

Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) are rare brain tumors first described in 2017 and recently included in the 2021 5th World Health Organization Classification of Tumors of the Central Nervous System. They typically affect children and young adults. Few pediatric cases have been reported in the literature. The most common imaging features described, include location within the temporal lobe, involvement of the cortical/subcortical region, coarse calcifications, and well-defined margins with solid and cystic morphology, with slight-or-no enhancement. However, there is limited information on imaging features in children. We present the imaging spectrum of neuroimaging features in a series of pediatric patients with a histologically and molecularly proved PLNTY diagnosis. Coarse calcifications are uncommon in children compared with the adult literature, and they may develop with time. The transmantle-like sign can be observed, and adjacent cortical dysplasia may be seen. Seizure recurrence may occur despite gross total resection of the tumor.

T2-based magnetic resonance genitography in children with complex anorectal malformations: experience at a tertiary pediatric hospital in Latin America.

In children with anorectal malformations (ARMs), it is essential to have a diagnostic imaging method that helps with the evaluation of the internal anatomy. In patients with a persistent cloaca, an ARM variant, in which the measurement of the urethral channel and common channel determines surgical management, there are multiple options for imaging. Magnetic resonance imaging (MRI) is an excellent method for this purpose, from which accurate measurements of channel length can be obtained. Additionally, the use of volumetric/isotropic sequences allows multiplanar reformatting. We present our experience with pelvic MRI and intracavitary non-paramagnetic contrast (MR genitography). This method uses volumetric T2-weighted images and the instillation of saline solution as a contrast agent to distinguish the common channel, length of the urethra, anatomy of the vagina, and presence and location of the rectal fistula. We believe this technique to be particularly useful for those working in settings with limited MRI resources.

Erdheim-Chester Disease Due to a Novel Internal Duplication of NRAS: Response to Targeted Therapy with Cobimetinib.

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.

Computed tomography angiography features of children with ectopia cordis.

Ectopia cordis is a rare congenital defect with high mortality, and it remains challenging to radiologists, neonatologists and surgeons. CT angiography provides key information that aids in the decision-making process for possible surgical intervention. This pictorial essay describes CT angiography features in six neonates with ectopia cordis.

Is horseshoe lung a component of VACTERL spectrum? Case report and review of literature.

Horseshoe lung (HL) is a rare congenital anomaly that has been classically associated with Scimitar syndrome. Very few cases have been described in the context of the VACTERL spectrum. We present a case of a newborn girl with mesocardia, tracheoesophageal fistula, and imperforated anus, who required O2 support at birth and during hospitalization. A chest CT angiography revealed a HL as an incidental finding. We suspect that HL and the VACTERL spectrum, are not separated entities but likely a further expansion of VACTERL-associated symptoms. HL might be underdiagnosed in asymptomatic patients as Chest CT angiography is not part of the routine work up for patients with VACTERL association.

Diagnostic performance of two serological assays for the detection of SARS-CoV-2 specific antibodies: surveillance after vaccination.

Massive vaccination programs are being carried out to limit the SARS-CoV-2 pandemic that started in December 2019. Serological tests are of major importance as an indicator of circulation of the virus and to assess how vaccine-induced immunity progresses. An Enzyme-Linked Immunosorbent Assay (ELISA) and a Lateral Flow Assay (LFA) have been developed based on the SARS-CoV-2 recombinant Receptor Binding Domain (RBD) and the combination of Spike and Nucleoprotein, respectively. The validation with 1272 serum samples by comparison with INgezim COVID 19 DR showed good diagnostic performance (sensitivity: 93.2%-97.2%; specificity: 98.3%-99.3%) for detection of previous contact with SARS-CoV-2. Moreover, according to our results, these assays can help in the serosurveillance during and after vaccination, by detecting the humoral immune response as soon as 15 days postvaccination and identifying low-respondents. Hence, these tests could play a key role in the progression to a COVID-19 free world, helping to adjust future vaccination protocols.

Receptor-binding domain-based immunoassays for serosurveillance differentiate efficiently between SARS-CoV2-exposed and non-exposed farmed mink.

During the COVID-19 pandemic, infection of farmed mink has become not only an economic issue but also a widespread public health concern. International agencies have advised the use of strict molecular and serosurveillance methods for monitoring the SARS-CoV2 status on mink farms. We developed 2 ELISAs and a duplex protein microarray immunoassay (MI), all in a double-recognition format (DR), to detect SARS-CoV2 antibodies specific to the receptor-binding domain (RBD) of the spike protein and to the full-length nucleoprotein (N) in mink sera. We collected 264 mink serum samples and 126 oropharyngeal samples from 5 Spanish mink farms. In both of the ELISAs and the MI, RBD performed better than N protein for serologic differentiation of mink from SARS-CoV2-positive and -negative farms. Therefore, RBD was the optimal antigenic target for serosurveillance of mink farms.

Large-scale study on virological and serological prevalence of SARS-CoV-2 in cats and dogs in Spain.

The disease produced by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is currently one of the primary concerns worldwide. Knowing the zoonotic origin of the disease and that several animal species, including dogs and cats, are susceptible to viral infection, it is critical to assess the relevance of pets in this pandemic. Here, we performed a large-scale study on SARS-CoV-2 serological and viral prevalence in cats and dogs in Spain in order to elucidate their role and susceptibility. Samples from animals in contact with COVID-19 positive people and/or compatible symptoms (n = 492), as well as from random animals (n = 1024), were taken. Despite the large number of animals analyzed, only 12 animals (eight dogs and four cats), which represents 0.79% of the total analyzed animals (n = 1516), were positive for viral SARS-CoV-2 RNA detection by reverse transcription quantitative PCR (RT-qPCR) in which viral isolation was possible in four animals. We detected neutralizing antibodies in 34 animals, four of them were also positive for PCR. This study evidences that pets are susceptible to SARS-CoV-2 infection in natural conditions but at a low level, as evidenced by the low percentage of positive animals detected, being infected humans the main source of infection. However, the inclusion of animals in the surveillance of COVID-19 is still recommended.

Vitiligo-like Depigmentation in a Patient Undergoing Treatment with Nivolumab for Advanced Renal-cell Carcinoma.

Dear Editor, Nivolumab is a fully human monoclonal antibody that targets the programmed cell death 1 (PD-1) immune checkpoint. It has been approved for its use in several types of advanced solid tumors, including melanoma, lung cancer, and renal cell carcinoma (RCC). The inhibition of PD-1 leads to an enhanced adaptive immune response against tumor cells through the activation of T-cells. Vitiligo-like depigmentation (VLD) is a well-known side-effect in patients with melanoma that are being treated with anti PD-1 therapies (1). However, its development in patients undergoing treatment with nivolumab for cancers other than melanomas has been described very rarely. To our knowledge, herein we report the second case of nivolumab-induced VLD in a patient with metastatic RCC (2). The patient was a 63-year-old man who had a medical history of advanced RCC. He had initially undergone nephrectomy, and three months later he presented with local relapse and lung metastases. He had then received different treatment regimes, presenting with progression each time, until he finally started treatment with nivolumab. Five months after its introduction, the patient developed a disseminated hypochromic eruption. No other drugs were started over that period. He had no personal or family history of vitiligo or other autoimmune disorders. Dermatological examination revealed multiple, symmetrical, well-demarcated, depigmented macules involving his face, neck, torso, hands, and forearms. (Figure 1, a). Preservation of pigment in hair follicles could be seen on the dorsal aspect of his hands (Figure 1, b). Two 4-mm punch biopsies were taken, one from one from a depigmented patch and another from normally pigmented skin. In the first one, immunohistochemical analysis with Melan-A immunostaining demonstrated the absence of melanocytes, whereas melanocytes were present in the second one. A CD-8+ positive infiltrate was present in both biopsies, especially in the first one (Figure 2). The patient was diagnosed with VLD associated with nivolumab therapy. Since the patient was asymptomatic, no treatment was prescribed. He was advised to protect the achromic areas from sun exposure. In our patient, a causal association between the onset of VLD and the treatment with nivolumab cannot be completely ruled out. However, the clinical presentation with flecked macules in sun-exposed areas was consistent with what has been described in other patients presenting with VLD after starting treatment with this chemotherapeutic agent. The time to onset in our case was also within the limits which have been previously reported for this side-effect (16-52 weeks) (3). Therefore, we believe that a causal association is very probable. In patients with advanced melanoma who are treated with PD-1 inhibitors, the development of vitiligo-like lesions has been proved to be associated with improved progression-free and overall survival rates (4,5). This mechanism is not fully understood, but it has been suggested that inhibition of PD-1 could cause a loss of tolerance to melanocytic antigens, thus leading to a CD-8 T-cell dependent destruction of melanocytes present in the melanoma as well as in healthy skin (3,5). The presence of CD8 T-lymphocytes in our patient's biopsies supports this theory. However, the development of this condition in patients suffering from non-melanoma cancers suggests that different mechanisms, independent from melanoma, could also be involved. Larger studies are needed in order to determine if VLD also correlates with better survival rates in patients treated with nivolumab for non-melanoma malignancies. In conclusion, new checkpoint inhibitors can cause VLD not only in patients suffering from melanoma but also in those affected by other tumors. We believe dermatologists should play a key role in the management of this side-effect. Therefore, we ought to be familiar with it in order to be able to identify and treat it appropriately without discontinuation of anticancer treatment.

High prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 outbreak.

BACKGROUND: Many cutaneous manifestations have been described in possible association with the COVID-19 pandemic, including acral lesions resembling chilblains. The underlying pathomechanisms of COVID-19 chilblains are not fully understood. The aim of this study was to describe the clinical, pathological, and laboratory findings of a series of patients who developed chilblains during the COVID-19 outbreak and to investigate the possible factors that could be involved in the pathogenesis of these lesions. METHODS: We conducted a prospective cohort study that included 54 patients who presented with chilblains during the highest peak in the incidence of COVID-19 in Cantabria (northern Spain). Skin biopsies were performed on 10 of these patients who presented with recent lesions. Laboratory investigations, including immunological analysis, serological studies, and the assessment of cryoproteins, were also performed. RESULTS: Most patients presented erythematous plaques located on the toes and/or purpuric macules located on the feet. Histopathological findings were compatible with those of idiopathic chilblains. Immunohistochemical evaluation showed C3d and C4d deposits in the vessel walls in seven cases. The autoimmunity panel was negative in most of our series. Cryoprotein testing showed positive cryofibrinogen in two-thirds (66.7%) of the patients assessed. On follow-up, most patients presented almost complete resolution, although six patients required prednisone and antiaggregant drug treatment. CONCLUSIONS: This study shows, for the first time to our knowledge, a high prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 pandemic. Cryofibrinogenemia could be implicated in the pathogenesis of chilblains related to COVID-19.

Two serological approaches for detection of antibodies to SARS-CoV-2 in different scenarios: a screening tool and a point-of-care test.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected more than 8 million people worldwide, becoming a pandemic. Detecting antibodies against SARS-CoV-2 is of utmost importance and a good indicator of exposure and circulation of the virus within the general population. Two serological tools based on a double recognition assay [enzyme-linked immunosorbent assay (DR-ELISA) and lateral flow assay (DR-LFA)] to detect total antibodies to SARS-CoV-2 have been developed based on the recombinant nucleocapsid protein. A total of 1065 serum samples, including positive for COVID-19 and negative samples from healthy donors or infected with other respiratory pathogens, were analyzed. The results showed values of sensitivity between 91.2% and 100%, and specificity of 100% and 98.2% for DR-LFA and DR-ELISA, respectively. No cross-reactivity against seasonal coronavirus (HCoV-NL63, HCoV-229E, HCoV-HKU1, HCoV-OC43) was found. These results demonstrate the importance of serology as a complementary tool to polymerase chain reaction for follow-up of recovered patients and identification of asymptomatic individuals.

The presence of Merkel cell carcinoma polyomavirus is associated with a distinct phenotype in neoplastic Merkel cell carcinoma cells and their tissue microenvironment.

AIMS: Merkel cell carcinoma (MCC) is an aggressive primary neuroendocrine tumor of the skin, associated with Merkel cell polyomavirus (MCPyV) in 49-89% of cases, depending on the country of origin and the techniques of detection. The presence of MCPyV defines heterogeneity in MCC; MCPyV-negative cases bear a much higher mutational load, with a distinct ultraviolet signature pattern featuring C > T transitions, as a consequence of exposure to ultraviolet light radiation. MCC stroma has not been thoroughly studied, although MCC patients benefit from therapy targeting PD1/PDL1. METHODS AND RESULTS: In this study, using Tissue Microarrays and immunohistochemistry, we have analyzed a series of 219 MCC cases in relation to the presence of MCPyV, and confirmed that the presence of MCPyV is associated with changes not only in the neoplastic cells, but also in the composition of the tumor stroma. Thus, MCPyV, found in 101/176 (57,4%) analyzable cases, exhibits changes in its tumor morphology, the density of the inflammatory infiltrate, the phenotype of the neoplastic cells, and the cell composition of the tumor stroma. MCPyV presence is negatively correlated with a higher level of p53 expression, and associated with a very high frequency (86%) of HLA-I expression loss, a higher apoptotic index, and a stroma richer in T-cells, cytotoxic T-cells, macrophages, PDL1-positive macrophages, and B-cells. CONCLUSIONS: Our findings provide evidence of the basic heterogeneity of MCC, supporting the hypothesis that the presence of MCPyV may induce a rich inflammatory response, which is at least partially avoided through loss of HLA-I antigen expression. On the other hand, MCPyV-negative cases show a much higher frequency of stronger p53 expression and, probably, p53 alterations.

COVID-19 patients with psoriasis and psoriatic arthritis on biologic immunosuppressant therapy vs apremilast in North Spain.

Immunosuppressive and immunomodulatory treatments are critical for the management of inflammatory and autoimmune conditions such as psoriasis or psoriatic arthritis. Similar to those illnesses, the lung injury and acute respiratory distress shown in coronavirus disease 2019 (COVID-19) patients are the result of a disruption in the balance of pro- and anti-inflammatory cytokines. This hyperinflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), associated with the severity of the coronavirus disease, is called the cytokine storm. There is a growing concern regarding how patients on immunosuppressant biologic therapies might be at higher risk of being infected and whether they need to discontinue their treatment preemptively. Clinical data on COVID-19-infected patients with psoriasis or psoriatic arthritis are still scarce. Here, we presented seven cases of these type of patients. The patient infected with COVID-19 on apremilast and the one on apremilast with infected spouse showed the best safety profile and mildest symptoms. One of the secukinumab patients also presented a relatively good outcome. Infliximab patients and the one with serious comorbidities showed the worst outcome. Even though more clinical data are yet needed to draw strong conclusions, apremilast could be a safer alternative for dermatology and rheumatology patients in case of clinically important active infection.

[Burkitt's lymphoma of the skull calotte: a case report]. / Linfoma de Burkitt de la calota craneana: a propósito de un caso.

Introduction: Burkitt's lymphoma is a non- Hodgkin B-cell lymphoma whose cranial location is extremely rare. Clinical case: The case of a 35-year-old Peruvian man with a progressive parietal left cranial tumor is described. A biopsy with immunohistochemistry was performed for the diagnostic confirmation of Burkitt's lymphoma. First-line outpatient treatment with CODOX-M/IVAC was initiated, however, he stopped attending his treatment for 2 months. He returns, he is shown progression of the disease and is treated with rituximab, ifosfamide carboplatin and etoposide. Does not respond satisfactorily and dies. Conclusions: Burkitt's lymphoma is a very aggressive tumor that, if not treated in a timely manner, has high mortality, as happened with the patient in the case.

Introducción: El linfoma de Burkitt es un linfoma no Hodgkin de células B cuya ubicación craneal es extremadamente rara. Caso clínico: Se describe el caso de un hombre peruano de 35 años con una tumoración craneal parietal izquierda de crecimiento progresivo. Para la confirmación diagnóstica de linfoma de Burkitt se realizó una biopsia con inmunohistoquímica. Se inició tratamiento ambulatorio de primera línea con CODOX-M/IVAC, sin embargo, deja de acudir a su tratamiento por 2 meses. Retorna, se le evidencia progresión de la enfermedad y se le trata con rituximab, ifosfamida carboplatino y etopósido. No responde de forma satisfactoria y fallece. Conclusiones: El Linfoma de Burkitt es un tumor muy agresivo que si no es tratado oportunamente presenta alta mortalidad, tal como ocurrió con el paciente del caso.

Tocilizumab in giant cell arteritis: differences between the GiACTA trial and a multicentre series of patients from the clinical practice.

OBJECTIVES: A potential point of concern among clinicians is whether results derived from the clinical trials can be reasonably applied or generalised to a definable group of patients seen in real world. It can be the case of the GiACTA study that is a phase III randomised controlled trial of tocilizumab (TCZ) in giant cell arteritis (GCA). To address this question, we compared the clinical features and the responses to TCZ from the GiACTA trial patients with those from a series of GCA seen in the daily clinical practice. METHODS: Comparative study of clinical features between patients from the GiACTA trial (overall n=251) and those from a multicentre series of real-world GCA patients undergoing TCZ therapy (n=134). The diagnosis of GCA in the GiACTA trial was established by the ACR modified criteria whereas in the series of real-world patients it was made by using the ACR criteria, a positive biopsy of temporal artery or the presence of imaging techniques consistent with large-vessel vasculitis in individuals who presented cranial symptoms of GCA. GiACTA trial patients received subcutaneous TCZ (162 mg every 1 or 2 weeks) whereas those from the clinical practice series were treated using standard IV dose (8 mg/kg/month) or subcutaneous (162 mg/week). RESULTS: Real-life patients undergoing TCZ were older with longer disease duration and higher values of ESR and had received conventional immunosuppressive therapy (mainly methotrexate) more commonly than those included in the GiACTA trial. Despite clinical differences, TCZ was equally effective in both GiACTA trial and clinical practice patients. However, serious infections were more commonly observed in GCA patients recruited from the clinical practice. CONCLUSIONS: Despite clinical differences with patients recruited in clinical trials, data from real-life patients confirm the efficacy of TCZ in GCA.

[Tomographic characteristics of solid-pseudopapillary neoplasms (Frantz tumor).] / Características tomográficas del tumor sólido pseudopapilar de páncreas (tumor de Frantz).

Introduction: Solid-pseudopapillary neoplasms (SPN), or Frantz tumor, is a rare, low-grade neoplasm that occurs mainly in young women. It was described in 1959 by Virginia Frantz and constitutes 0.2-2.7 % of all pancreatic tumors. Computed tomography (CT) plays an important role in the diagnosis of this pathology of scarce reporting. The objective of the present study is to describe the epidemiological and tomographic characteristics of the SPN in the Instituto Nacional de Enfermedades Neoplásicas (INEN) of Peru. Methods: Descriptive cross-sectional study performed with medical records of all patients diagnosed with SPN between 2004 and 2014. The variables described were tumor size, location, shape, borders, thickness of the capsule, composition, calcifications and uptake of contrast. The categorical variables were expressed in absolute and relative frequencies; while the numerical variables were described with median and interquartile deviation (ID). Statistical support STATA Version 12.0 was used. Results: Of all pancreatic cystic tumors (PCT), 51.9% corresponded to confirmed cases of TSP. The median age was 23.5 years. The isolated location in the head predominated (33.3%); the most frequent mixed location was body and tail (16.7%); diameter was more frequent between 5.1-10 cm and the content of the majority was predominantly solid. 30.0% of the NSP presented calcifications. Conclusion: Most cases of INP SPN (2004-2014) have similar characteristics to those reported in the international literature.

Introducción: El tumor sólido pseudopilar de páncreas (TSP), o tumor de Frantz, es una neoplasia rara de bajo grado que acontece principalmente en mujeres jóvenes. Fue descrita en 1959 por Virginia Frantz y constituye del 0.2-2.7% de todos los tumores pancreáticos. La tomografía computada (TC) desempeña un papel importante en el diagnóstico de esta patología de escaso reporte. El objetivo del presente estudio es describir las características epidemiológicas y tomográficas del TSP en el Instituto Nacional de Enfermedades Neoplásicas (INEN) del Perú. Métodos: Estudio transversal descriptivo realizado con historias clínicas (HC) de todos los pacientes con diagnóstico de TSP entre los años 2004 y 2014. Las variables descritas fueron tamaño del tumor, ubicación, forma, bordes, grosor de la cápsula, composición, calcificaciones y captación de contraste. Las variables categóricas fueron expresadas en frecuencias absolutas y relativas; mientras que las variables numéricas fueron descritas con mediana y desviación intercuartílica (DIC). Se utilizó como soporte estadístico STATA Versión 12.0. Resultados: De todos los tumores quísticos de páncreas (TQP), el 51.9 % correspondió a casos confirmados de TSP. La mediana de la edad fue 23.5 años. Predominó la ubicación aislada en cabeza (33.3 %); la ubicación mixta más frecuente fue la de cuerpo y cola (16.7 %); fue más frecuente el diámetro entre 5.1-10 cm y el contenido de la mayoría fue a predominio sólido. El 30.0 % de los TSP presentaron calcificaciones. Conclusión: La mayoría casos de TSP del INEN (2004-2014) tienen características similares a lo reportado en la literatura internacional.