Cold urticaria as a complication of cryotherapy in the treatment of viral warts.

Cryotherapy with liquid nitrogen has been established as the first-line treatment for pediatric patients with viral warts. Cold-induced urticaria (CU) is a rare skin reaction triggered by cold stimuli. We present the case of a pediatric patient with viral warts who developed CU after receiving cryotherapy.

Using conceptual modeling to improve genome data management.

With advances in genomic sequencing technology, a large amount of data is publicly available for the research community to extract meaningful and reliable associations among risk genes and the mechanisms of disease. However, this exponential growth of data is spread in over thousand heterogeneous repositories, represented in multiple formats and with different levels of quality what hinders the differentiation of clinically valid relationships from those that are less well-sustained and that could lead to wrong diagnosis. This paper presents how conceptual models can play a key role to efficiently manage genomic data. These data must be accessible, informative and reliable enough to extract valuable knowledge in the context of the identification of evidence supporting the relationship between DNA variants and disease. The approach presented in this paper provides a solution that help researchers to organize, store and process information focusing only on the data that are relevant and minimizing the impact that the information overload has in clinical and research contexts. A case-study (epilepsy) is also presented, to demonstrate its application in a real context.

Novel CT-based parameters assessing relative cross-sectional area to guide surgical management and predict clinical outcomes in patients with acute subdural hematoma.

INTRODUCTION: Acute subdural hematoma (aSDH) is one of the most devastating entities secondary to traumatic brain injury (TBI). Even though radiological computed tomography (CT) findings, such as hematoma thickness (HT), midline shift (MLS), and MLS/HT ratio, have an important prognostic role, they suffer from important drawbacks. We hypothesized that relative cross-sectional area (rCSA) of specific brain regions would provide valuable information about brain compression and swelling, thus being a key determining factor governing the clinical course. METHODS: We performed an 8-year retrospective analysis of patients with moderate to severe TBI with surgically evacuated, isolated, unilateral aSDH. We investigated the influence of aSDH rCSA and ipsilateral hemisphere rCSA along the supratentorial region on the subsequent operative technique employed for aSDH evacuation and patient's clinical outcomes (early death and Glasgow Outcome Scale [GOS] at discharge and after 1-year follow-up). Different conventional radiological variables were also assessed. RESULTS: The study included 39 patients. Lower HT, MLS, hematoma volume, and aSDH rCSA showed a significant association with decompressive craniectomy (DC) procedure. Conversely, higher ipsilateral hemisphere rCSA along the dorso-ventral axis and, specifically, ipsilateral hemisphere rCSA at the high convexity level were predictors for DC. CT segmentation analysis exhibited a modest relationship with early death, which was limited to the basal supratentorial subregion, but could not predict long-term outcome. CONCLUSION: rCSA is an objectifiable and reliable radiologic parameter available on admission CT that might provide valuable information to optimize surgical treatment.

Task synergies in neurovascular surgery: Image-guided navigation using a thermoplastic facial mask for the resection of a symptomatic occult to MRI brain microarteriovenous malformation.

Due to the size of microarteriovenous malformations (mAVM), its precise angioarchitecture description often requires a supraselective DSA and detecting the nidus during microsurgical resection is challenging. An accurate intraoperative navigation system is desirable but available softwares which can combine DSA and MRI are not always available. The authors present here a technical note describing the use of a stereotactic thermoplastic mask with a fiducial box to guide the resection of a mAVM.

Assessment of Obsessive Thoughts About COVID-19 in 7 Latin American Countries: Structure and Measurement Invariance of the Obsession With COVID-19 Scale.

The present study aimed to evaluate the measurement invariance of the Obsession with COVID-19 Scale (OCS) among seven Latin American countries: Bolivia, Brazil, Cuba, El Salvador, Guatemala, Paraguay, and Uruguay. Although the OCS has been used in several countries and languages, there is a need for approaches that better integrate the cross-cultural equivalence of the scale. A total of 3185 people participated in the study. The results indicated the presence of a unidimensional structure and good reliability indices for the OCS in each country. The alignment method indicated that the OCS is an invariant measure of COVID-19 obsession among the populations of seven Latin American countries. The findings based on IRT analysis indicated that all OCS items had adequate discrimination and difficulty parameters. The findings contribute to the understanding of the internal structure of the scale in different countries at the same time, something that has been pending evaluation.

The challenge of managing the evolution of genomics data over time: a conceptual model-based approach.

BACKGROUND: Precision medicine is a promising approach that has revolutionized disease prevention and individualized treatment. The DELFOS oracle is a model-driven genomics platform that aids clinicians in identifying relevant variations that are associated with diseases. In its previous version, the DELFOS oracle did not consider the high degree of variability of genomics data over time. However, changes in genomics data have had a profound impact on clinicians' work and pose the need for changing past, present, and future clinical actions. Therefore, our objective in this work is to consider changes in genomics data over time in the DELFOS oracle. METHODS: Our objective has been achieved through three steps. First, we studied the characteristics of each database from which the DELFOS oracle extracts data. Second, we characterized which genomics concepts of the conceptual schema that supports the DELFOS oracle change over time. Third, we updated the DELFOS Oracle so that it can manage the temporal dimension. To validate our approach, we carried out a use case to illustrate how the new version of the DELFOS oracle handles the temporal dimension. RESULTS: Three events can change genomics data, namely, the addition of a new variation, the addition of a new link between a variation and a phenotype, and the update of a link between a variation and a phenotype. These events have been linked to the entities of the conceptual model that are affected by them. Finally, a new version of the DELFOS oracle that can deal with the temporal dimension has been implemented. CONCLUSION: Huge amounts of genomics data that is associated with diseases change over time, impacting patients' diagnosis and treatment. Including this information in the DELFOS oracle added an extra layer of complexity, but using a model-driven based approach mitigated the cost of implementing the needed changes. The new version handles the temporal dimension appropriately and eases clinicians' work.

Discerning the global phylogeographic distribution of Phyllosticta citricarpa by means of whole genome sequencing.

Phyllosticta citricarpa is a fungal pathogen causing citrus black spot (CBS). As a regulated pest in some countries, the presence of the pathogen limits the export of fruit and is therefore of agricultural and economic importance. In this study, we used high throughput sequencing data to infer the global phylogeographic distribution of this pathogen, including 71 isolates from eight countries, Argentina, Australia, Brazil, China, Cuba, Eswatini, South Africa and the United States of America. We assembled draft genomes and used a pairwise read mapping approach for the detection and enumeration of variants between isolates. We performed SSR marker discovery based on the assembled genome with the best assembly statistics, and generated genotype profiles for all isolates with 1987 SSR markers in silico. Furthermore, we identified 32,560 SNPs relative to a reference sequence followed by population genetic analyses based on the three datasets; pairwise variant counts, SSR genotypes and SNP genotypes. All three analysis approaches gave similar overall results. Possible pathways of dissemination among the populations from China, Australia, southern Africa and the Americas are postulated. The Chinese population is the most diverse, and is genetically the furthest removed from all other populations, and is therefore considered the closest to the origin of the pathogen. Isolates from Australia, Eswatini and the South African province Mpumalanga are closely associated and clustered together with those from Argentina and Brazil. The Eastern Cape, North West, and KwaZulu-Natal populations in South Africa grouped in another cluster, while isolates from Limpopo are distributed between the two aforementioned clusters. Southern African populations showed a close relationship to populations in North America, and could be a possible source of P. citricarpa populations that are now found in North America. This study represents the largest whole genome sequencing survey of P. citricarpa to date and provides a more comprehensive assessment of the population genetic diversity and connectivity of P. citricarpa from different geographic origins. This information could further assist in a better understanding of the epidemiology of the CBS pathogen, its long-distance dispersal and dissemination pathways, and can be used to refine phytosanitary regulations and management programmes for the disease.

Changes in Spanish lifestyle and dietary habits during the COVID-19 lockdown.

PURPOSE: The COVID-2019 pandemic forced many governments to declare the "to stay at home" which encouraged social distancing and isolation among citizens. The aim of this study was to assess the dietary and lifestyle habit changes that occurred during home confinement in Spain. METHODS: An European online survey was launched in April 2020. This included 70 questions on sociodemographic characteristics, lifestyle, dietary habits, including key Mediterranean diet (MedDiet) foods. A total of 945 Spanish adults from 1268 European that completed the online survey were included in the analysis. RESULTS: Most of the Spanish participants adopted healthier dietary habits during home lockdown, which was translated to a higher MedDiet adherence. However, a negative impact on physical activity levels, sleep quality or smoking rates was observed. Low MedDiet adherence was associated with a higher risk of weight gain (OR = 1.53, CI 1.1-2.1; p = 0.016), while no snacking between meals reduced the risk by 80% (OR = 0.20, CI 0.09-0.45, p < 0.001) and eating more quantity, considering portion size, increased body weight gain risk almost sixfold more. CONCLUSION: To conclude, although dietary habits were improved during home lockdown, certain unhealthy behaviours (e.g. increased snacking between meals, increased food intake, and an increase in sedentary behaviour) were increased.

Electrocardiographic predictors of atrial fibrillation in patients with cryptogenic stroke.

BACKGROUND: Empiric anticoagulation is not routinely indicated in patients with cryptogenic stroke without documentation of atrial fibrillation (AF). Therefore, identification of patients at increased risk of AF from this vulnerable group is vital. OBJECTIVES: To identify electrocardiographic (ECG) predictors of AF in patients with cryptogenic stroke or transient ischemic attack (TIA) undergoing insertion of an implantable cardiac monitor (ICM). METHODS: In this single-center study, 48 patients with cryptogenic stroke or TIA had an ICM implanted for detection of AF between January 2013 and September 2019. Patients with and without AF were compared in terms of p-wave duration and a novel index (MVP score). RESULTS: During a mean follow-up of 16 ± 14 months, AF was detected in seven patients (15%). Diagnosis of AF was made after a mean of 10 ± 14 months, with time to first AF detection ranging between 1 and 40 months. Patients with AF had a longer p-wave duration (136 ± 9 ms vs. 116 ± 10 ms; p = .0001) and a higher MVP score (4.5 ± 1.2 vs. 2.0 ± 0.9, p = .0001) than those without AF. Advanced interatrial block (IAB) was observed in 43% of patients with ICM evidence of AF and 0% of those without AF (p = .002). Age, LA size or LVEF were not predictors of AF. CONCLUSION: An increased p-wave duration, advanced IAB and high MVP score are associated with AF occurrence in patients with cryptogenic stroke. Identifying patients with these markers may be helpful as they may benefit from more exhaustive and prolonged monitoring.

Clinical improvement after cranioplasty and its relation to body position and cerebral hemodynamics.

Cranioplasty after decompressive craniectomy (DC) has been found to improve the neurological condition. The underlying mechanisms are still unknown. The aim of this study is to investigate the roles of the postural changes and atmospheric pressure (AP) in the brain hemodynamics and their relationship with clinical improvement. Seventy-eight patients were studied before and 72 h after cranioplasty with cervical and transcranial color Doppler ultrasound (TCCS) in the sitting and supine positions. Craniectomy size, shape, and force exerted by the AP (torque) were calculated. Neurological condition was assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Barthel index. Twenty-eight patients improved after cranioplasty. Their time elapsed from the DC was shorter (214 vs 324 days), preoperative Barthel was worse (54 vs 77), internal carotid artery (ICA) mean velocity of the defect side was lower while sitting (14.4 vs 20.9 cm/s), and torque over the craniectomy was greater (2480.3 vs 1464.3 N*cm). Multivariate binary logistic regression showed the consistency of these changes. TCCS findings were no longer present postoperatively. Lower ICA (defect side) velocity in the sitting position correlates significantly with clinical improvement. Greater torque exerted by the AP might explain different susceptibilities to postural changes, corrected by cranioplasty.

Transplantation of hematopoietic progenitors in myelofibrosis.

The objective of this work is to generate recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles published between 1999 and 2015 (January) was used as a source of scientific evidence. The recommendations were produced through a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and the European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention, and management of post-transplant relapse. Patients with intermediate-2 or high-risk disease and age < 70 years should be considered candidates for allo-SCT. Patients with intermediate-risk 1 disease and age < 65 years should be considered candidates if they have refractory transfusion-dependent anemia, or a peripheral blood (PB) blast percentage > 2%, or adverse cytogenetics. Splenectomy before transplantation must be decided on a case-by-case basis. Patients with intermediate-2 or high-risk disease who lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor should be enrolled in a protocol that uses HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for transplants from HLA-matched unrelated donors and siblings. The optimal intensity of the conditioning regimen has yet to be defined. Strategies such as discontinuation of immunosuppressive drugs, infusion of donor lymphocytes, or both were considered adequate to prevent clinical relapse. In conclusion, we provide consensus-based recommendations aimed at optimizing allo-SCT in PMF. Unmet clinical needs were highlighted.

El objetivo de este trabajo es generar recomendaciones sobre el manejo del trasplante alogénico de células madre (alo-SCT) en la mielofibrosis primaria (MFP). Se utilizó una revisión sistemática integral de artículos publicados entre 1999 y 2015 (enero) como fuente de evidencia científica. Las recomendaciones se produjeron mediante un proceso Delphi en el que participó un panel de 23 expertos designados por la European LeukemiaNet y el European Blood and Marrow Transplantation Group. Las preguntas clave incluyeron la selección de pacientes, la selección de donantes, el manejo previo al trasplante, el régimen de acondicionamiento, el manejo posterior al trasplante, la prevención y el manejo de la recaída después del trasplante. Los pacientes con enfermedad de riesgo intermedio 2 o alto y edad < 70 años deben ser considerados candidatos para alo-SCT. Los pacientes con enfermedad de riesgo intermedio 1 y edad < 65 años deben ser considerados candidatos si presentan anemia refractaria dependiente de transfusiones, o un porcentaje de blastos en sangre periférica > 2%, o citogenética adversa. La esplenectomía previa al trasplante debe decidirse caso por caso. Los pacientes con enfermedad de riesgo intermedio 2 o alto que carecen de un hermano compatible con el antígeno leucocitario humano (HLA) o de un donante no emparentado deben inscribirse en un protocolo que utilice donantes no idénticos de HLA. PB se consideró la fuente más apropiada de células madre hematopoyéticas para trasplantes de hermanos y donantes no emparentados compatibles con HLA. La intensidad óptima del régimen de acondicionamiento aún debe definirse. Se consideraron adecuadas estrategias como la suspensión de los fármacos inmunosupresores, la infusión de linfocitos del donante o ambas para evitar la recaída clínica. En conclusión, proporcionamos recomendaciones basadas en consenso destinadas a optimizar el alo-SCT en MFP. Se destacaron las necesidades clínicas insatisfechas.

Essential thrombocythaemia.

Essential thrombocythemia (ET) is a chronic Philadelphia-negative myeloproliferative neoplasm that has its main involvement in the megakaryopoietic lineage, generating sustained thrombocytosis in peripheral blood and an increase in the number of mature megakaryocytes in the bone marrow. In addition to marked thrombocytosis, it is characterized by increased thrombotic or hemorrhagic risk and the presence of constitutional symptoms. Patients with ET have a low but known risk of disease progression to myelofibrosis and/or acute leukemia. The diagnosis is made based on the 2016 WHO criteria. At present, available treatments for patients with ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding.

La trombocitemia esencial (TE) es una neoplasia mieloproliferativa crónica Filadelfia negativa que tiene su principal involucro en la línea megacariopoyética, generando trombocitosis sostenida en la sangre periférica y un incremento en el número de megacariocitos maduros en médula ósea. Además de una marcada trombocitosis, se caracteriza por un mayor riesgo trombótico o hemorrágico y la presencia de síntomas constitucionales. Los pacientes con TE tienen un riesgo bajo, pero conocido, de evolución de la enfermedad a mielofibrosis y/o leucemia aguda. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. Los tratamientos actualmente disponibles para los pacientes con TE están dirigidos principalmente a minimizar el riesgo de trombosis y/o hemorragia.

Pregnancy in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are associated with a significant risk of thrombosis and the hypercoagulable environment of pregnancy increases this risk. The most frequent gestational complications consist of spontaneous abortion, thrombosis, bleeding, and hypertensive disease of pregnancy. Treatment depends on thrombotic risk, gestational trimester, and myeloproliferative neoplasm.

Las neoplasias mieloproliferativas (NMP) están asociadas a un riesgo notable de trombosis y el entorno de hipercoagulabilidad propio del embarazo aumenta este riesgo. Las complicaciones gestacionales más frecuentes consisten en: aborto espontáneo, trombosis, sangrado y enfermedad hipertensiva del embarazo. El tratamiento depende del riesgo trombótico, trimestre gestacional y neoplasia mieloproliferativa.

Polycythemia vera.

Polycythemia vera (PV) is mainly characterized by erythrocytosis, thrombotic and hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. The diagnosis is made based on the 2016 WHO criteria. The treatment of PV focuses on rapidly reducing the erythrocyte mass, either by means of phlebotomies or with cytoreductive treatment, and the reduction of thrombotic risk by correcting cardiovascular risk factors and the use of platelet antiaggregants.

La policitemia vera (PV) se caracteriza principalmente por eritrocitosis, predisposición trombótica y hemorrágica, una variedad de síntomas y riesgos acumulativos de progresión fibrótica y/o evolución leucémica a lo largo del tiempo. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. El tratamiento de la PV se centra en reducir rápidamente la masa eritrocitaria, ya sea por medio de flebotomías o con tratamiento citorreductor, y la disminución del riesgo trombótico mediante la corrección de factores de riesgo cardiovascular y el uso de antiagregantes plaquetarios.

Risks in invasive procedures.

Patients with myeloproliferative neoplasms have an increased risk of thrombosis and bleeding. This risk must be identified, as well as individualizing the therapeutic strategy before invasive procedures; adequate cytoreduction reduces the risk of complications.

Los pacientes con neoplasias mieloproliferativas tienen un riesgo incrementado de trombosis y sangrado. Se debe identificar dicho riesgo, así como individualizar la estrategia terapéutica previo a los procedimientos invasivos; una adecuada citorreducción disminuye el riesgo de complicaciones.

Symptom control.

In addition to symptoms secondary to splenomegaly, microvascular abnormalities, and thrombohemorrhagic complications, patients with MPN may experience a significant symptom burden attributed to an increase in circulating inflammatory cytokines. These symptoms can be severe and limit quality of life. Therefore, in addition to the prevention of complications, one of the objectives of the treatment of MPN is the control of symptoms.

Además de la sintomatología secundaria a la esplenomegalia, a las alteraciones microvasculares y a las complicaciones trombohemorrágicas, los pacientes con neoplasias mieloproliferativas (NMP) pueden experimentar una importante carga sintomática atribuida a un aumento de citocinas inflamatorias circulantes. Estos síntomas pueden ser severos y limitar la calidad de vida. Por ello, además de la prevención de las complicaciones, uno de los objetivos del tratamiento de las NMP es el control de los síntomas.

Thrombotic events.

Major thrombotic complications in myeloproliferative neoplasms (MPNs) represent an important clinical problem due to their high morbidity, the complexity of their management, and their associated mortality. The appearance of a thrombosis implies a high thrombotic risk stratification of the MPN and determines the initiation or optimization of cytoreductive treatment and the use of antiplatelet or anticoagulant therapy as secondary prophylaxis. The incidence of thrombosis at the time of diagnosis is higher than during the course of the disease, being located in the arterial territory in 60-70% of cases. Once thrombosis has occurred, up to 20-33% of patients experience thrombotic recurrence in the same initial vascular territory.

Las complicaciones trombóticas mayores en las neoplasias mieloproliferativas (NMP) representan un importante problema clínico debido a su elevada morbilidad, la complejidad de su manejo y su mortalidad asociada. La aparición de una trombosis comporta una estratificación de alto riesgo trombótico de la NMP y determina el inicio o la optimización del tratamiento citorreductor y el uso de terapia antiplaquetaria o anticoagulante como profilaxis secundaria. La incidencia de trombosis en el momento del diagnóstico es mayor que durante la evolución de la enfermedad, localizándose en territorio arterial en el 60-70% casos. Una vez se ha producido una trombosis, hasta el 20-33% de los pacientes sufre una recurrencia trombótica en el mismo territorio vascular inicial.

First inter-institutional consensus on Chronic Myeloproliferative Neoplasms.

The objective of the consensus is to make available to the professionals of the different public health institutions in our country, who are in charge of these diseases, the most relevant and up-to-date information about their diagnosis and treatment in clinical practice. With this inter-institutional consensus we hope to contribute to improving the quality of care for patients with chronic myeloproliferative neoplasms throughout the Mexican Republic, to unify criteria in both diagnosis and treatment of the different myeloproliferative diseases.

OBJETIVO: El objetivo del consenso es poner a disposición de los profesionales de las diferentes instituciones de salud pública en nuestro país, quienes se encuentran a cargo de estas enfermedades, la información más relevante y actualizada acerca de su diagnóstico y tratamiento en la práctica clínica. Con este consenso interinstitucional esperamos contribuir a mejorar la calidad de la atención de los pacientes con neoplasias mieloproliferativas crónicas a todo lo ancho y largo de la República Mexicana, con el fin de unificar criterios tanto en diagnóstico como en tratamiento de las diferentes enfermedades mieloproliferativas.

Myelofibrosis: diagnosis and treatment.

Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK) 2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. Although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.

La mielofibrosis (MF) es una neoplasia mieloproliferativa negativa para BCR-ABL1 caracterizada por mieloproliferación clonal, señalización de cinasa desregulada y liberación de citocinas anormales. En los últimos años se han realizado importantes avances en el conocimiento de la biología molecular y la valoración pronóstica de la MF. El tratamiento convencional tiene un impacto limitado en la supervivencia de los pacientes; incluye un enfoque de espera para pacientes asintomáticos, agentes estimulantes de la eritropoyesis, andrógenos o agentes inmunomoduladores para la anemia, fármacos citorreductores como la hidroxiurea para la esplenomegalia y los síntomas constitucionales, y esplenectomía o radioterapia en pacientes seleccionados. El descubrimiento de la mutación Janus cinasa (JAK) 2 desencadenó el desarrollo de la terapia dirigida molecular de la MF. Los inhibidores de JAK son efectivos tanto en MF con JAK2 positivo como con JAK2 negativo; uno de ellos, el ruxolitinib, es la mejor terapia disponible actualmente para la esplenomegalia y los síntomas constitucionales de la MF. Sin embargo, aunque el ruxolitinib ha cambiado el escenario terapéutico de la MF, no hay indicios claros de un efecto modificador de la enfermedad. El alotrasplante de células madre sigue siendo la única terapia curativa de la MF, pero debido a su morbilidad y mortalidad asociadas, generalmente se restringe a pacientes elegibles con MF de riesgo alto e intermedio 2. Para mejorar los resultados terapéuticos actuales, actualmente se está probando la combinación de inhibidores de JAK con otros agentes y se están investigando fármacos más nuevos.

Heterotypic clustering of circulating tumor cells and circulating cancer-associated fibroblasts facilitates breast cancer metastasis.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are recruited to the tumor microenvironment (TME) and are critical drivers of breast cancer (BC) malignancy. Circulating tumor cells (CTCs) travel through hematogenous routes to establish metastases. CTCs circulate both individually and, more rarely, in clusters with other cell types. Clusters of CTCs have higher metastatic potential than single CTCs. Previously, we identified circulating CAFs (cCAFs) in patients with BC and found that while healthy donors had no CTCs or cCAFs, both were present in most Stage IV patients. cCAFs circulate individually, as cCAF-cCAF homotypic clusters, and in heterotypic clusters with CTCs. METHODS: In this study, we evaluate CTCs, cCAFs, and heterotypic cCAF-CTC clusters in patients with stage I-IV BC. We evaluate the association of heterotypic clusters with BC disease progression and metastasis in a spontaneous mouse model. Using previously established primary BC and CAF cell lines, we examine the metastatic propensity of heterotypic cCAF-CTC clusters in orthotopic and tail vein xenograft mouse models of BC. Using an in vitro clustering assay, we determine factors that may be involved in clustering between CAF and BC cells. RESULTS: We report that the dissemination of CTCs, cCAFs, and clusters is an early event in BC progression, and we find these clusters in all clinical stages of BC. Furthermore, cCAFs-CTC heterotypic clusters have a higher metastatic potential than homotypic CTC clusters in vivo. We also demonstrate that the adhesion and stemness marker CD44, found on a subset of CTCs and CAF cells, is  involved in heterotypic clustering of these cells. CONCLUSION: We identify a novel subset of circulating tumor cell clusters that are enriched with stromal CAF cells in BC patient blood and preclinical mouse models of BC metastasis. Our data suggest that clustering of CTCs with cCAFs augments their metastatic potential and that CD44 might be an important mediator of heterotypic clustering of cCAFs and BC cells.