Spatial transcriptomics reveals segregation of tumor cell states in glioblastoma and marked immunosuppression within the perinecrotic niche.

Glioblastoma (GBM) remains an untreatable malignant tumor with poor patient outcomes, characterized by palisading necrosis and microvascular proliferation. While single-cell technology made it possible to characterize different lineage of glioma cells into neural progenitor-like (NPC-like), oligodendrocyte-progenitor-like (OPC-like), astrocyte-like (AC-like) and mesenchymal like (MES-like) states, it does not capture the spatial localization of these tumor cell states. Spatial transcriptomics empowers the study of the spatial organization of different cell types and tumor cell states and allows for the selection of regions of interest to investigate region-specific and cell-type-specific pathways. Here, we obtained paired 10x Chromium single-nuclei RNA-sequencing (snRNA-seq) and 10x Visium spatial transcriptomics data from three GBM patients to interrogate the GBM microenvironment. Integration of the snRNA-seq and spatial transcriptomics data reveals patterns of segregation of tumor cell states. For instance, OPC-like tumor and NPC-like tumor significantly segregate in two of the three samples. Our differentially expressed gene and pathway analyses uncovered significant pathways in functionally relevant niches. Specifically, perinecrotic regions were more immunosuppressive than the endogenous GBM microenvironment, and perivascular regions were more pro-inflammatory. Our gradient analysis suggests that OPC-like tumor cells tend to reside in areas closer to the tumor vasculature compared to tumor necrosis, which may reflect increased oxygen requirements for OPC-like cells. In summary, we characterized the localization of cell types and tumor cell states, the gene expression patterns, and pathways in different niches within the GBM microenvironment. Our results provide further evidence of the segregation of tumor cell states and highlight the immunosuppressive nature of the necrotic and perinecrotic niches in GBM.

Oclusión intestinal mecánica por íleo biliar. Reporte de caso

La obstrucción de la luz del intestino delgado por un cálculo biliar ubicado de forma anómala, denominada incorrectamente íleo biliar, representa del 1 al 3 % de los síndromes obstructivos intestinales. Se define como una entidad inusual, caracterizada por la obstrucción intestinal mecánica, causada por el impacto de uno o varios cálculos biliares en la luz intestinal, por lo general en el ilion terminal. El objetivo es describir el presente caso por lo infrecuente de esta entidad, describir la sistemática diagnóstica y conducta tomada, así como realizar el análisis de la literatura relacionada. Se trata de una paciente femenina de 87 años de edad, que acude por cuadro de vómitos y distensión abdominal de 20 días de evolución, con muy mal estado general. Se realiza laparotomía exploradora, donde se observa en el ilion proximal gran cálculo de aproximadamente 4 cm, que obstruye la luz en su totalidad. Se realiza enterolitotomía y resección intestinal sin intervención en la vesícula biliar o la vía biliar. Fallece al tercer día del postoperatorio mediato por descompensación de su enfermedad cardiovascular. Se concluye que el íleo biliar es una entidad infrecuente sin estudios que estandaricen un tratamiento específico, y que requiere de intervención quirúrgica. La enterotomía para extracción de cálculos es una técnica segura y eficaz, sin necesidad de intervención en la vía biliar en un primer tiempo.

Obstruction of the lumen of the small intestine by an abnormally located gallstone, incorrectly called gallstone ileus, accounts for 1% to 3% of all obstructive bowel syndromes. It is defined as an unusual entity characterized by mechanical intestinal obstruction, caused by the impact of one or several gallstones in the intestinal lumen, usually in the terminal ilium. The objective is to describe the present case due to the infrequency of this entity, to describe the diagnostic system and conduct taken, as well as to carry out the analysis of the related literature. An 87-year-old female patient presented with symptoms of vomiting and abdominal distension of 20 days of evolution, with an unusual, very poor general condition, characterized by mechanical intestinal obstruction caused by the impact of one or several gallstones in the intestinal lumen, usually in the terminal ilium. An exploratory laparotomy was performed, where a large stone of approximately 4 cm was observed in the proximal ileum which completely obstructed the lumen. Enterolithotomy and bowel resection were performed without intervention in the gallbladder or bile duct. She died on the third day of the immediate postoperative period due to decompensation of her cardiovascular disease. It is concluded that gallstone ileus is a rare entity without studies that standardize a specific treatment and that it requires surgical intervention. Enterotomy for stone removal is a safe and effective technique without the need for intervention in the bile duct in the first time.

Factores pronósticos y la influencia en la supervivencia de operados de cáncer de pulmón en el Hospital Universitario General Calixto García / Prognostic Factors and their Influence of Patients Operated on for Lung Cancer at Hospital Universitario General Calixto García

Introducción: El cáncer de pulmón ocupa el primer lugar entre las causas de mortalidad por cáncer a nivel mundial y solamente el 15,6 por ciento de los que padecen esta enfermedad sobreviven los 5 años. Objetivo: Evaluar la influencia de los factores pronósticos en la supervivencia de operados por cáncer de pulmón. Métodos: Estudio observacional descriptivo, tipo serie de casos de 107 enfermos operados en el Hospital Universitario General Calixto García en el período 2015-2020. Se utilizaron las variables tipo histológico, estadio clínico, estado físico e intervención quirúrgica. Resultados: Predominó el sexo masculino en edades entre 60-69 años, con antecedentes de hipertensión arterial y tabaquismo. Los síntomas que predominaron fueron la disnea, la tos y el dolor torácico. Las etapas clínicas más frecuentes fueron en orden: IIIA, IIB, IIA y las variantes histopatológicas adenocarcinoma y epidermoide. La técnica quirúrgica más empleada fue la lobectomía. Conclusiones: Los factores pronósticos de mayor significación estadística son la comorbilidad, la presencia de síntomas y el diagnóstico tardío. Los factores pronósticos relacionados con el tumor y el tratamiento quirúrgico con adyuvancia tienen una alta repercusión en la supervivencia(AU)

Introduction: Lung cancer ranks first among the causes of cancer mortality worldwide and only 15.6 percent of those with this disease survive the 5 years. Objective: To assess the influence of prognostic factors on the survival of patients operated on for lung cancer. Methods: A descriptive observational study of case series was carried out with 107 patients operated on at Hospital Universitario General Calixto García in the period 2015-2020. The variables histological type, clinical stage, physical condition and surgical intervention were used. Results: There was a predominance of the male sex, aged 60-69 years, with a history of arterial hypertension and smoking. The predominant symptoms were dyspnea, cough and chest pain. The most frequent clinical stages were IIIA, IIB, IIA, in that order; and the predominant histopathological variants were adenocarcinoma and epidermoid. The most commonly used surgical technique was lobectomy. Conclusions: The prognostic factors of greatest statistical significance are comorbidity, presence of symptoms and late diagnosis. Prognostic factors related to the tumor or the adjuvant surgical treatment have a high impact on survival(AU)

Impacto de la COVID-19 en los enfermos con diagnóstico de cáncer de pulmón en el Hospital Universitario General Calixto García / Impact of COVID-19 on Ill Patients Diagnosed with Lung Cancer at Hospital Universitario General Calixto García

Introducción: En enero de 2020 la Organización Mundial de la Salud declara el estado de pandemia por COVID-19. Los enfermos con cáncer de pulmón tienen gran vulnerabilidad ante esta enfermedad. Objetivo: Evaluar el impacto de la COVID-19 en los enfermos con diagnóstico de cáncer de pulmón. Método: Se realizó un estudio descriptivo, retrospectivo y longitudinal en 273 enfermos con cáncer de pulmón, discutidos en el Grupo Multidisciplinario de Tórax del Hospital Universitario General Calixto García desde el 2019 hasta el 2021. Se analizaron diferentes variables y se aplicaron análisis estadísticos, tales como porcentaje, desviación estándar y media. Resultados: El mayor número de enfermos operados discutidos en el grupo multidisciplinario fue durante el 2019 (21 para un 19,45 porciento). La etapa clínica II predominó en el año 2019, en 10 pacientes. La lobectomía fue la técnica más empleada y predominó en el 2019 en 16 enfermos (76,2 porciento), mientras que durante el 2020-2021 fueron 7. En estos años se diagnosticaron con COVID-19 un total de 17 individuos no operados y fallecieron 11. Conclusiones: Durante el período 2020-2021 disminuyó el número de casos discutidos por cáncer de pulmón en el Grupo Multidisciplinario de Tórax del Hospital Universitario General Calixto García. La mayoría no tuvo criterio de cirugía. La lobectomía fue la técnica quirúrgica más empleada, aunque se redujo su realización durante el 2020-2021. La mayoría de los enfermos que contrajeron COVID-19 no fueron operados y más de la mitad de ellos fallecieron(AU)

Introduction: In January 2020, the World Health Organization declares a pandemic status due to the COVID-19. Lung cancer patients are highly vulnerable to this disease. Objective: To evaluate the impact of COVID-19 in patients diagnosed with lung cancer. Methods: A descriptive, retrospective and longitudinal study was carried out in 273 patients with lung cancer, discussed in the multidisciplinary thorax group at Hospital Universitario General Calixto García from 2019 to 2021. Different variables were analyzed and statistical analyses were applied, such as percentage, standard deviation and mean. Results: The highest number of operated patients discussed in the multidisciplinary group was reported during 2019 (21, accounting for 19.45 percent). The clinical stage II predominated in 2019, with 10 patients. Lobectomy was the most used technique and the predominant in 2019, with 16 patients (76.2 percent), while 7 were reported during 2020-2021. A total of 17 nonoperated individuals were diagnosed with COVID-19 in these years and 11 died. Conclusions: During 2020-2021, there was a decrease in the number of lung cancer cases discussed in the multidisciplinary thorax group at Hospital Universitario General Calixto García decreased. Most of them did not have surgery criteria. Lobectomy was the most used surgical technique, although its realization was reduced during 2020-2021. Most of the patients who contracted COVID-19 were not operated and over half of them died(AU)

Psychometric properties of the self-efficacy scale for chronic disease management (SEMCD-S) in older Colombian adults.

BACKGROUND: Self-efficacy alludes to personal competence in an individual's effectiveness when facing stressful situations. This construct has been related to different domains of the health field, finding that high levels of self-efficacy benefit human functioning and enhance well-being. METHODS: The present study aimed to determine the psychometric properties of the self-efficacy scale for managing chronic diseases (SEMCD-S) by assessing factorial, convergent and divergent validity, reliability, and measurement invariance. Likewise, the comparison of self-efficacy according to socio-demographic characteristics was proposed by contrasting latent factors. An instrumental, transactional, descriptive, and non-experimental design study was carried out with the participation of 325 Colombian senior citizens. RESULTS: The findings suggest that the scale has appropriate psychometric properties. The one-factor structure exhibited a satisfactory fit, the mean-variance extracted reported acceptable figures and the correlation analysis with other constructs supported this instrument's convergent and discriminant validity. Likewise, it was invariant to the different socio-demographic aspects examined, while the internal consistency figures were high. Differences in the means of the latent factors were only detected in the academic grade. In this case, older adults with a primary school level attained higher self-efficacy values than those who had completed high school or university studies. CONCLUSIONS: It is concluded that the self-efficacy scale for chronic disease management is a valid and reliable instrument that can be used in the Colombian context to measure and compare this construct.

Polio virotherapy targets the malignant glioma myeloid infiltrate with diffuse microglia activation engulfing the CNS.

BACKGROUND: Malignant gliomas commandeer dense inflammatory infiltrates with glioma-associated macrophages and microglia (GAMM) promoting immune suppression, evasion, and tumor progression. Like all cells in the mononuclear phagocytic system, GAMM constitutively express the poliovirus receptor, CD155. Besides myeloid cells, CD155 is widely upregulated in the neoplastic compartment of malignant gliomas. Intratumor treatment with the highly attenuated rhino:poliovirus chimera, PVSRIPO, yielded long-term survival with durable radiographic responses in patients with recurrent glioblastoma (Desjardins et al. New England Journal of Medicine, 2018). This scenario raises questions about the contributions of myeloid versus neoplastic cells to polio virotherapy of malignant gliomas. METHODS: We investigated PVSRIPO immunotherapy in immunocompetent mouse brain tumor models with blinded, board-certified neuropathologist review, a range of neuropathological, immunohistochemical, and immunofluorescence analyses, and RNAseq of the tumor region. RESULTS: PVSRIPO treatment caused intense engagement of the GAMM infiltrate associated with substantial, but transient tumor regression. This was accompanied by marked microglia activation and proliferation in normal brain surrounding the tumor, in the ipsilateral hemisphere and extending into the contralateral hemisphere. There was no evidence for lytic infection of malignant cells. PVSRIPO-instigated microglia activation occurred against a backdrop of sustained innate antiviral inflammation, associated with induction of the Programmed Cell Death Ligand 1 (PD-L1) immune checkpoint on GAMM. Combining PVSRIPO with PD1/PD-L1 blockade led to durable remissions. CONCLUSIONS: Our work implicates GAMM as active drivers of PVSRIPO-induced antitumor inflammation and reveals profound and widespread neuroinflammatory activation of the brain-resident myeloid compartment by PVSRIPO.

Ganglioglioma deep transcriptomics reveals primitive neuroectoderm neural precursor-like population.

Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy-confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.

Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Caracterización de enfermos con cáncer de tiroides operados en el Hospital Clínico Quirúrgico General "Freyre de Andrade" / Characterization of Patients with Thyroid Cancer Operated on in "Freyre de Andrade" General Clinical Surgical Hospital

Introducción: El cáncer de tiroides es el tumor más común de los malignos originados en órganos endocrinos (más del 92 por ciento) y comprende un grupo de tumores que son diferentes clínicamente, epidemiológicamente y en cuanto a pronóstico. Objetivo: Caracterizar a los enfermos con cáncer de tiroides operados en el Hospital Clínico Quirúrgico General "Freyre de Andrade". Métodos: Se realizó un estudio descriptivo, retrospectivo de corte longitudinal en el Hospital Clínico Quirúrgico General "Freyre de Andrade" en el período 2014-2019. El universo estuvo constituido por 32 enfermos operados de cáncer de tiroides. Fueron analizadas variables sociodemográficas, clasificación de Bethesda, diagnóstico histológico, técnica quirúrgica empleada y complicaciones. Resultados: El cáncer de tiroides predominó en mujeres (87,5 por ciento) entre 51 - 60 años (25,0 por ciento). Según la clasificación de Bethesda prevaleció la categoría VI (15,62 por ciento). Predominó el carcinoma papilar (65,62 por ciento). A todos los enfermos se le realizó una tiroidectomía total y las complicaciones fueron el hematoma posoperatorio (6,25 por ciento) y el granuloma (6,25 por ciento). Conclusiones: El cáncer tiroideo predomina en mujeres entre la quinta y sexta década de la vida. La técnica quirúrgica que se utiliza es la tiroidectomía total con baja morbilidad. Predomina la variante histológica del carcinoma papilar(AU)

Introduction: Thyroid cancer is the most common malignant tumor originating in endocrine organs (more than 92 percent) and comprises a group of clinically, epidemiologically and prognostically different tumors. Objective: To characterize patients with thyroid cancer operated on at Freyre de Andrade General Clinical Surgical Hospital. Methods: A descriptive, retrospective and longitudinal study was carried out at Freyre de Andrade General Clinical Surgical Hospital in the period 2014-2019. The universe consisted of 32 patients operated on for thyroid cancer. Sociodemographic variables, Bethesda classification, histological diagnosis, used surgical technique and complications were analyzed. Results: Thyroid cancer predominated in women (87.5 percent) between 51 and 60 years of age (25.0 percent). According to the Bethesda classification, category VI prevailed (15.62 percent). Papillary carcinoma predominated (65.62 percent). All patients underwent total thyroidectomy, while the complications were postoperative hematoma (6.25 percent) and granuloma (6.25 percent. Conclusions: Thyroid cancer predominates in women between the fifth and sixth decades of life. The used surgical technique is total thyroidectomy, reporting low morbidity. The histological variant of papillary carcinoma predominates(AU)

Eosinophilic globules in a classic ependymoma: evidence of a possible secretory role.

A number of neoplasms of the central nervous system can demonstrate diffuse eosinophilic globules, known to be secretory products of the corresponding cell type, but they have not been a salient feature in descriptions of classic ependymoma. Here, we present a case of a posterior fossa ependymoma demonstrating glassy PAS-positive, diastase-resistant, eosinophilic globules with light microscopic and ultrastructural features resembling Reissner fiber, the secretory product of the subcommissural organ. While there has been a single published description of an ependymoma with intra- and extracellular granulofibrillary material suggested to be evidence of secretory differentiation, ours is the first case to demonstrate diffuse eosinophilic globules in an ependymoma. The extent of globules allowed full study by electron microscopy to provide new insight into the secretory material and the surrounding structures. Our findings suggest that neoplastic ependymal cells can recapitulate the secretory capacity of the subcommissural organ.

Proinflammatory cytokines and ARDS pulmonary edema fluid induce CD40 on human mesenchymal stromal cells-A potential mechanism for immune modulation.

Human mesenchymal stem/stromal cells (hMSCs) are a promising therapy for acute respiratory distress syndrome (ARDS) and other inflammatory conditions. While considerable research has focused on paracrine effects and mitochondrial transfer that improve lung fluid balance, hMSCs are well known to have immunomodulatory properties as well. Some of these immunomodulatory properties have been related to previously reported paracrine effectors such as indoleamine-2,3-dioxygenase (IDO), but these effects cannot fully account for cell-contact dependent immunomodulation. Here, we report that CD40 is upregulated on hMSCs under the same conditions previously reported to induce IDO. Further, CD40 transcription is also upregulated on hMSCs by ARDS pulmonary edema fluid but not by hydrostatic pulmonary edema fluid. Transcription of CD40, as well as paracrine effectors TSG6 and PTGS2 remained significantly upregulated for at least 12 hours after withdrawal of cytokine stimulation. Finally, induction of this immune phenotype altered the transdifferentiation of hMSCs, one of their hallmark properties. CD40 may play an important role in the immunomodulatory effects of hMSCs in ARDS and inflammation.

Wireless Sensing of Concrete Setting Process.

An RFID-based wireless system to measure the evolution of the setting process of cement-based materials is presented in this paper. The system consists of a wireless RFID temperature sensor that works embedded in concrete, and an external RFID reader that communicates with the embedded sensor to extract the temperature measurement conducted by the embedded sensor. Temperature time evolution is a well known proxy to monitor the setting process of concrete. The RFID sensor consisting of an UWB Bow Tie antenna with central frequency 868 MHz, matched to the EM4325 temperature chip through a T-match structure for embedded operation inside concrete is fully characterized. Results for measurements of the full set up conducted in a real-scenario are provided.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Frequent Mutations of POT1 Distinguish Pulmonary Sarcomatoid Carcinoma From Other Lung Cancer Histologies.

INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer (NSCLC) harboring mutations in many canonical NSCLC-driver genes (eg, TP53, KRAS, MET). Protection of telomeres 1 (POT1) mutations are observed in angiosarcoma and chronic lymphocytic leukemia, but their frequency in other solid tumors, including NSCLC subtypes, has not been rigorously explored. MATERIALS AND METHODS: We analyzed next-generation sequencing data from 62,368 tumors, including 11,134 NSCLCs and 100 PSCs. We performed logistic regression to identify associations between POT1 mutation frequency and tumor histology across 184 tumor categories, adjusting for tumor mutational burden. We further explored co-occurring gene mutations in genes previously reported to underlie PSC tumorigenesis. RESULTS: Across 184 tumor categories, POT1 mutations were most frequent in PSC and were 14 times more common in PSC (28%) than in other tumor types (P = 1.23 × 10-31) and 6.7 times more common in PSC than other NSCLCs (P = 5.1 × 10-17). PSCs harboring KRAS mutations were significantly more likely to harbor POT1 mutations (P = 1.3 × 10-3), whereas those with TP53 mutations were less likely to harbor POT1 mutations (P = .037). One-fourth of POT1-mutated PSCs harbored a second POT1 mutation. Across all PSCs, 83% of POT1 mutations were in the OB1/OB2 (DNA-binding) domain (P = 1.5 × 10-5), an enrichment not observed in other tumor types. CONCLUSION: We report an unanticipated association between POT1 mutation and PSC. Unlike other molecular alterations that are frequent across NSCLC subtypes, POT1 mutations are largely unique to PSC. This finding may help to develop disease-defining molecular subgroups within PSC and presents opportunities for molecularly stratified prognostication and therapy.

Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report.

BACKGROUND: Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors. CASE PRESENTATION: A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis. CONCLUSION: Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.

Escala RIPASA para el diagnóstico de apendicitis aguda en el Hospital "General Freyre de Andrade" / RIPASA scale for the diagnosis of acute appendicitis in the Hospital "General Freyre de Andrade"

RESUMEN Introducción: La escala RIPASA fue elaborada para el diagnóstico de apendicitis aguda y ha demostrado buena sensibilidad y precisión diagnóstica, sobre todo en poblaciones asiáticas. Objetivo: Determinar la utilidad de la escala RIPASA para el diagnóstico de la apendicitis aguda. Métodos: Estudio observacional, analítico y prospectivo con 70 pacientes ingresados y operados con diagnóstico presuntivo de apendicitis aguda en el Hospital "General Freyre de Andrade" entre septiembre de 2015 y diciembre de 2017. Resultados: El 91,4 por ciento de los casos presentaron apendicitis por diagnóstico histológico. El síntoma, el signo y el dato de laboratorio más frecuentes fueron el dolor en fosa ilíaca derecha (97,1 por ciento), el rebote positivo (100 por ciento), y la leucocitosis (87,1 por ciento), respectivamente. Las diferencias entre los casos con y sin apendicitis para la puntuación de la escala fueron estadísticamente significativas. Predominaron los casos con puntajes altos (62,8 por ciento). A los 7,5 puntos la sensibilidad fue de 94 por ciento, la especificidad de 33 por ciento, la razón de verosimilitud positiva de 1,41, la razón de verosimilitud negativa de 0,19, y la precisión diagnóstica de 88,6 por ciento. El área bajo la curva de Características Operativas del Receptor fue de 0,81. Conclusiones: La escala RIPASA tuvo una buena sensibilidad y una moderada razón de verosimilitud negativa que permitirían descartar casos negativos con puntuaciones bajas. También exhibió una precisión diagnóstica y un desempeño discriminativo general aceptable. Sin embargo, la pobre especificidad y muy baja razón de verosimilitud positiva la hacen poco útil como medio diagnóstico único para la apendicitis aguda(AU)

ABSTRACT Introduction: The RIPASA scale was developed for the diagnosis of acute appendicitis and has shown good sensitivity and diagnostic precision, especially in Asian populations. Objective: To determine the utility of the RIPASA scale for the diagnosis of acute appendicitis. Methods: Observational, analytical and prospective study with 70 patients admitted and operated on with a presumptive diagnosis of acute appendicitis at the Hospital "General Freyre de Andrade" between September 2015 and December 2017. Results: 91.4 percent of the cases presented appendicitis due to histological diagnosis. The most frequent symptom, sign and laboratory data were pain in the right iliac fossa (97.1 percent), positive rebound (100 percent), and leukocytosis (87.1 percent), respectively. The differences between the cases with and without appendicitis for the scale score were statistically significant. Cases with high scores predominated (62.8 percent). At 7.5 points the sensitivity was 94 percent, the specificity was 33 percent, the positive likelihood ratio was 1.41, the negative likelihood ratio was 0.19, and the diagnostic precision was 88.6 percent. The area under the Receiver Operating Characteristics curve was 0.81. Conclusions: The RIPASA scale had good sensitivity and a moderate negative likelihood ratio that would allow us to rule out negative cases with low scores. It also exhibited diagnostic accuracy and acceptable overall discriminatory performance. However, the poor specificity and very low positive likelihood ratio make it of little use as a single diagnostic means for acute appendicitis(AU)

POT1 mutation spectrum in tumour types commonly diagnosed among POT1-associated hereditary cancer syndrome families.

BACKGROUND: The shelterin complex is composed of six proteins that protect and regulate telomere length, including protection of telomeres 1 (POT1). Germline POT1 mutations are associated with an autosomal dominant familial cancer syndrome presenting with diverse malignancies, including glioma, angiosarcoma, colorectal cancer and melanoma. Although somatic POT1 mutations promote telomere elongation and genome instability in chronic lymphocytic leukaemia, the contribution of POT1 mutations to development of other sporadic cancers is largely unexplored. METHODS: We performed logistic regression, adjusted for tumour mutational burden, to identify associations between POT1 mutation frequency and tumour type in 62 368 tumours undergoing next-generation sequencing. RESULTS: A total of 1834 tumours harboured a non-benign mutation of POT1 (2.94%), of which 128 harboured a mutation previously reported to confer familial cancer risk in the setting of germline POT1 deficiency. Angiosarcoma was 11 times more likely than other tumours to harbour a POT1 mutation (p=1.4×10-20), and 65% of POT1-mutated angiosarcoma had >1 mutations in POT1. Malignant gliomas were 1.7 times less likely to harbour a POT1 mutation (p=1.2×10-3) than other tumour types. Colorectal cancer was 1.2 times less likely to harbour a POT1 mutation (p=0.012), while melanoma showed no differences in POT1 mutation frequency versus other tumours (p=0.67). CONCLUSIONS: These results confirm a role for shelterin dysfunction in angiosarcoma development but suggest that gliomas arising in the context of germline POT1 deficiency activate a telomere-lengthening mechanism that is uncommon in gliomagenesis.