Inguinal lymph nodes agenesia in a patient with Schimmelpenning-Feuerstein-Mims syndrome with proven somatic KRAS mutation.

Schimmelpenning-Feuerstein-Mims (SFM) syndrome is a neurocutaneous disorder that can affect many body systems. The principal and most characteristic anomalies are craniofacial naevus sebaceous in association with neurological, ocular and skeletal findings. The presence of vascular malformations in this condition is unusual; nevertheless, vascular malformations have been suggested by many authors to be part of the spectrum of the same disease. Few cases have been published on the association of SFM with lymphatic malformations. This syndrome is categorized as a mosaic RASopathy due to postzygotic mutations in the HRAS, KRAS or NRAS genes. These genes are involved in the RAF-MEK-ERK signalling pathway, which is activated by mutant cells, increasing cellular proliferation. These mutations have been found only in naevus sebaceous cells, and may be also the explanation for many of the associated pathologies. We report a case of an 18-year-old boy diagnosed with SFM syndrome associated with lymphatic malformation in the legs and agenesia of the inguinal lymph nodes. The lymphatic alterations were diagnosed by gammography of the legs. The genetic diagnosis was confirmed by the presence of a KRAS postzygotic mutation in naevus sebaceous cells of a skin specimen. Genetically confirmed cases of mosaic RASopathies should be used to more accurately characterize phenotypic presentations of this syndrome and develop a future therapeutic strategy, such as molecular targeted therapy.

MRI for Response Assessment of Extensive Lymphatic Malformations in Children Treated With Sirolimus.

BACKGROUND. Extensive lymphatic malformations (LMs) may cause substantial morbidity. The mammalian target of rapamycin (mTOR) inhibitor sirolimus shows promise for treating vascular anomalies, although response assessment is not standardized. OBJECTIVE. The purpose of this study was to retrospectively characterize changes seen on MRI of children with extensive LMs treated with sirolimus. METHODS. Twenty-five children treated with sirolimus for extensive LMs were included. Baseline MRI was defined as the MRI examination performed closest to therapy initiation; follow-up MRI was defined as the most recent MRI examination performed while the patient was receiving therapy. Two pediatric radiologists independently determined MRI lesion volume by tracing lesion contours on all slices (normalized to patient body surface area expressed in square meters) and determined signal by placing an ROI on the dominant portion of the lesions (normalized to CSF signal) on baseline and follow-up T2-weighted MRI sequences. Interreader agreement was determined, and values were averaged for further analysis. Volume and signal changes were compared with patient, lesion, and treatment characteristics. RESULTS. The mean (± SD) interval between initiation of sirolimus treatment and follow-up MRI was 22.1 ± 13.8 months. The mean lesion volume index on baseline and follow-up MRI was 728 ± 970 and 345 ± 501 mL/m2, respectively (p < .001). Ninety-two percent of children showed a decrease in lesion volume index that was greater than 10% (mean volume change, -46.4% ± 28.2%). Volume change was inversely correlated with age (r = -0.466; p = .02). The mean volume change was -64.7% ± 25.4% in children younger than 2 years old versus -32.0% ± 21.6% in children 2 years old or older (p = .008). The mean volume change was -58.1% ± 24.0% for craniocervical lesions versus -35.5% ± 28.2% for lesions involving the trunk and/or extremities (p = .03). Mean lesion signal ratio on baseline and follow-up MRI was 0.81 ± 0.29 and 0.59 ± 0.26, respectively (p < .001). Mean signal ratio change was -23.8% ± 22.7%. Volume and signal changes were moderately correlated (r = 0.469; p = .02). Volume and signal changes were not associated with sex, lesion subtype, serum concentration of sirolimus, or the interval between sirolimus initiation and follow-up MRI (p > .05). Interreader agreement for volume index change was excellent (intraclass correlation coefficient, 0.983), and that for signal ratio change was moderate to good (intraclass correlation coefficient, 0.764). CONCLUSION. Sirolimus treatment of extensive LMs in children is associated with significant reductions in volume and signal on T2-weighted MRI. The decrease in volume is greater in younger children and craniocervical lesions. CLINICAL IMPACT. The results may facilitate development of standardized MRI-based criteria for assessing the response of vascular malformations to pharmacotherapy.

Metastatic Lymph Node Ratio (mLNR) is a Useful Parameter in the Prognosis of Colorectal Cancer; A Meta-Analysis for the Prognostic Role of mLNR.

Background and objectives: The presenting study aimed to elucidate the prognostic role of the metastatic lymph node ratio (mLNR) in patients with colorectal cancer (CRC), using a meta-analysis. Materials and Methods: Using data from 90,274 patients from 14 eligible studies, we performed a meta-analysis for the correlation between mLNR and survival rate. Besides, subgroup analyses were performed, based on tumor stage, tumor location, and mLNR. Results: A high mLNR showed significant correlation with worse overall survival and disease-free survival rates in CRC patients (hazard ratio (HR), 1.617, 95% confidence interval (CI) 1.393-1.877, and HR 2.345, 95% CI 1.879-2.926, respectively). In patients with stage III, who had regional LN metastasis, the HRs were 1.730 (95% CI 1.266-2.362) and 2.451 (95% CI 1.719-3.494) for overall and disease-free survival, respectively. According to tumor location, rectal cancer showed a worse survival rate when compared to colon cancer. In the analysis for overall survival, when mLNR was 0.2, HR was the highest across the different subgroups (HR 5.040, 95% CI 1.780-14.270). However, in the analysis for disease-free survival, the subgroup with an mLNR < 0.2 had a higher HR than the other subgroups (HR 2.878, 95% CI 1.401-5.912). Conclusions: The mLNR may be a useful prognostic factor for patients with CRC, regardless of the tumor stage or tumor location. Further studies are necessary for the detailed criteria of mLNR before its application in daily practice.

The Significance of Incidental Findings on Computed Tomography of the Chest.

BACKGROUND: Computed tomography (CT) of the chest has replaced lung scans and pulmonary angiography as the criterion standard for the diagnosis of pulmonary embolism (PE). Most of these examinations are negative for PE, but they frequently have incidental findings that may require further evaluation. OBJECTIVE: In order to examine common incidental findings and their possible clinical ramifications and required workup, we reviewed data from relevant studies in which chest CTs were performed and incidental findings discovered. DISCUSSION: The most common incidental findings on chest CT are pulmonary nodules and lymph nodes. Nodules are significantly more commonly found in smokers and are also more likely to be malignant in smokers. The recently updated 2017 Fleischner Society recommendations provide guidance to clinicians in deciding which nodules should be further evaluated. Enlarged lymph nodes similarly represent potential malignancy and most will need further evaluation with positron emission tomography scans or by transbronchial needle aspiration. CONCLUSIONS: Enlarged lymph nodes and pulmonary nodules are both common incidental findings on chest CT. Each represents the potential for malignancy, and under certain conditions requires additional workup and further evaluation. The majority will be benign, even in high-risk populations. However, because of the increasing prevalence of the chest CT and the frequency with which incidental findings will be seen, it is important that the emergency physician be aware of common features and recommended subsequent evaluation.

Lateral neck lumps: A systematic approach for the general paediatrician.

Lateral neck lumps are very common in children, and are largely benign in nature. The majority of lumps may be diagnosed on history and clinical examination alone, and further investigations are often not required. The most common pathologies in young children include reactive lymphadenopathy, lymphadenitis and atypical mycobacterial infections. A lateral neck lump is an uncommon presentation for malignancy and is largely restricted to older children and adolescents. The paediatric surgeon plays an important role in the assessment and management of lateral neck lumps, often in the form of reassurance to the patients and their carers.

ULTRASONOGRAPHIC FINDINGS IN 13 HORSES WITH LYMPHOMA.

Ultrasonography and radiography are commonly used for staging of lymphoma in horses, however there is little published information on imaging characteristics for horses with confirmed disease. The purpose of this retrospective, case series study was to describe ultrasonographic and radiographic findings for a group of horses with a confirmed diagnosis of lymphoma. A total of 13 horses were sampled. Lymphadenopathy (8/13), peritoneal effusion (6/13), splenic (6/13), and hepatic (5/13) lesions were the most frequently identified. The predominant splenic and hepatic ultrasonographic lesions were hypoechoic nodules, organomegaly, and changes in echogenicity. Digestive tract lesions were detected in three horses and these included focal thickening and decreased echogenicity of the small (2/13) and large intestinal (2/13) wall. Thoracic lesions were predominantly pleural effusion (4/13), lymphadenopathy (4/13), and lung parenchymal changes (3/13). Enlarged lymph nodes were detected radiographically (4/13) and/or ultrasonographically (2/13) in the thorax and ultrasonographically in the abdomen (7/13) and in the caudal cervical region (4/13). Findings supported the use of abdominal and thoracic ultrasonography for lymphoma staging in horses. Ultrasound landmarks for localizing cecal and caudal deep cervical lymph nodes were also provided.

[Venous aneurysms associated with lymphatic malformations]. / Aneurismas venosos asociados a malformaciones linfáticas.

OBJECTIVES: To analyze and describe the association between the development of venous aneurysms of the mayor vessels in patients with lymphatic malformations. MATERIAL AND METHODS: Retrospective review of patients diagnosed with both VA and LM from 1993 to 2014 and a descriptive analysis of clinical course was performed. RESULTS: We found 6 patients, 50% females, who had LM and VA confirmed with imaging techniques. All were diagnosed between 20 weeks- 12 years of age. LM were found within the thoracic cavity (n= 4), intrathoracical-cervical area (n= 1) and lower extremities (n= 1). In most cases the dilated veins were near the LM and thus, the mediastinal vessels were most commonly affected (superior vena cava-innominated (n= 1), venous jugulosubclavian confluence (n= 2), superior vena cava (n= 2) and popliteal vein (n= 1)). A total of 4 patients required surgical treatment of the LM with complete excision in 2 of the cases. Patients with a prenatal diagnosis of lymphatic malformation were most likely to present venous aneurysms at birth (n= 2), however the remaining patients (without prenatal diagnosis) developed them later on (average 6 years). Unlike lower extremity aneurysms, none of these aneurysms grew or required antiplatelet therapy; local thrombosis developed in one which resulted in pulmonary thromboembolism and one developed mitral valve insufficiency (regurgitation?) which required valve replacement. CONCLUSION: VA is extremely rare, and there is not therapeutic algorithm, therefore treatment should be individualized.

OBJETTIVOS: Analizar y describir la asociación entre el desarrollo de aneurismas venosos (AV) de grandes troncos en pacientes con malformaciones linfáticas (ML). MATERIAL Y METODOS: Estudio retrospectivo de los pacientes de nuestro centro entre 1993-2014, y análisis descriptivo de la asociación AV y ML. RESULTADOS: Se identificaron 6 pacientes, 50% mujeres, con una ML confirmada mediante prueba de imagen y una dilatación aneurismática de un tronco venoso. Los pacientes tenían edades entre 20 semanas-12 años y las ML se encontraban intratorácicas (n= 4), intratorácicas-cervical (n= 1) y en miembro inferior (n= 1); y las venas dilatadas en sus proximidades, siendo afectadas con mayor frecuencia los grandes vasos mediastínicos (vena cava superior- innominada (n= 1), confluencia venosa subclavioyugular (n= 2), vena cava superior (n= 2) y la vena poplítea (n= 1)). Se intervinieron n= 4, no pudiéndose extirpar completamente en 2 casos. Los niños que presentaron un diagnóstico prenatal de la malformación linfática presentaban una dilatación aneurismática de una gran vena en el control neonatal de la malformación (n= 2). En cambio, los pacientes con diagnóstico tardío de ML no presentaban dilatación vascular hasta pasados varios años (media 6 años). Ningún AV ha iniciado tratamiento antiagregante, y no han aumentado bruscamente su tamaño, uno desarrolló un trombo y posteriormente un tromboembolismo pulmonar, y otro debutó una insuficiencia mitral necesitando un recambio valvular mitral. CONCLUSION: El AV es una entidad poco común, y no existe algoritmo terapéutico, siendo una máxima el tratamiento individualizado de cada paciente.

Bacterial translocation in alymphoplasia (aly/aly) mice.

Bacterial translocation (BTL) is defined as the passage of viable bacteria from the gastrointestinal tract to the organs. This study was to elucidate the roles of Peyer's patches (PPs) and/or mesenteric lymph nodes (MLNs) in BTL. Alymphoplastic mutant mice and phenotypically normal heterozygous micewere dominantly colonized with streptomycin-resistant Escherichia coli and BTL was examined. In PP- and MLN-competent mice, BTL to MLNs was detected in 100% of mice, but BTL to organs was rare (25%). On the other hand, in PP- and MLN-deficientmice, BTL to organs was detected in 91% of mice. The results clearly indicate that PPs are not the only site for bacterial entry.

[Abdominal lymphatic malformation (ALM). Our experience]. / Malformación linfática abdominal (MLA). Nuestra experiencia.

INTRODUCTION: Lymphatic malformations are congenital lesions usually placed in the head and neck, the abdominal location is infrequent. OBJECTIVES: Analyze our experience in ALM management. METHOD: Retrospective study of pediatric patients with ALM from 1996 to 2011. It is a descriptive analysis of clinical, diagnostic and therapeutic features. RESULTS: 10 patients with ALM were treated (6 girls: 4 boys), with a median age of 4.03 years (3 days-13 years). Acute abdomen was the most common presenting feature (40%). Ultrasound was carried out in all these cases, completing the study with CT (9 cases), MRI (1) or both (1). Treatment was surgical, excepting one case that presented infection of the ALM. The approach by laparotomy allowed total resection in all cases, involving bowel resection in 6. The mass was located in small bowel mesentery (6), mesocolon (1), liver (1), and in retroperitoneum (1). The final pathologic diagnosis showed an error in diagnostic imaging of 60%.The mean follow-up was 18 months (SD: 12.8), with not recurrences. CONCLUSIONS: ALM often manifests in a non-specific form and it may remain silent. Imaging studies guide the diagnosis, but only the histology provides a definitive result. Total resection is the best option to prevent recurrences and minimize complications.

Classification of lymphatic-system malformations in primary lymphoedema based on MR lymphangiography.

OBJECTIVES: The study aims to investigate lymphatic-system malformations and proposes a classification of primary lymphoedema based on comprehensive imaging data of both lymph vessel- and lymph-node abnormalities. MATERIALS AND METHODS: A total of 378 patients with primary lymphoedema of the lower extremity were examined with magnetic resonance lymphangiography (MRL) using gadobenate dimeglumine as contrast agent. Lymph vessels and drainage lymph nodes were evaluated, leading to the proposal of the classification of primary lymphoedema and the relative proportions. RESULTS: A total of 63 (17%) patients exhibited defects of the inguinal lymph nodes with mild or moderate dilatation of afferent lymph vessels. A total of 123 (32%) patients exhibited lymphatic anomalies as lymphatic aplasia, hypoplasia or hyperplasia with no obvious defect of the drainage lymph nodes. The involvement of both lymph vessel- and lymph-node abnormalities in the affected limb was found in 192 (51%) patients. The primary lymphoedema was classified as three major types as: (1) lymph nodes affected only; (2) lymph vessel affected only with three subtypes and (3) both lymph vessel and lymph node affected with subgroups. CONCLUSIONS: A comprehensive classification of lymphatic-system malformation in primary lymphoedema is proposed, which clearly defines the location and pathologic characteristics of both lymphatics and lymph node and may lead to further study of the aetiology as well as rational treatment of the disease.

Isolated femoral osseous megalymphatics with chylous reflux: case report and review of the literature.

We report here the clinical and imaging findings of marked dilatation of the intraosseous lymphatic vessels, "megalymphatics," with chylous reflux presenting with pain and extensive lytic changes in a femoral bone of a child. Multimodality imaging findings, including radiographs, magnetic resonance imaging, ultrasound, scintigraphy and percutaneous osseous lymphangiography are described.

Tularemia: A rare cause of pediatric lymph nodes adenitis.

Adenopathy in pediatrics can have many different causes: infectious, tumoral, and inflammatory. We report the case of an 8-year-old patient with a febrile popliteal ulceration associated with an inflammatory satellite inguinal lymph node adenitis. Serological tests and polymerase chain reaction analyses confirmed the diagnosis of ulceroglandular tularemia. An appropriate antimicrobial therapy led to a full recovery. This case reminds us to consider tularemia as a potential emergent disease in children presenting with subacute to chronic lymphadenopathy and thereby to choose the correct diagnostic tool and appropriate antimicrobial therapy.

Alymphoplasia (aly)-type nuclear factor kappaB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system.

Alymphoplasia (aly) mice, which carry a point mutation in the nuclear factor kappaB-inducing kinase (NIK) gene, are characterized by the systemic absence of lymph nodes and Peyer's patches, disorganized splenic and thymic architectures, and immunodeficiency. Another unique feature of aly/aly mice is that their peritoneal cavity contains more B1 cells than normal and aly/+ mice. Transfer experiments of peritoneal lymphocytes from aly/aly mice into recombination activating gene (RAG)-2(-/-) mice revealed that B and T cells fail to migrate to other lymphoid tissues, particularly to the gut-associated lymphatic tissue system. In vivo homing defects of aly/aly peritoneal cells correlated with reduction of their in vitro chemotactic responses to secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC). The migration defect of aly/aly lymphocytes was not due to a lack of expression of chemokines and their receptors, but rather to impaired signal transduction downstream of the receptors for SLC, indicating that NIK is involved in the chemokine signaling pathway known to couple only with G proteins. The results showed that the reduced serum levels of immunoglobulins (Igs) and the absence of class switch to IgA in aly/aly mice are due, at least in part, to a migration defect of lymphocytes to the proper microenvironment where B cells proliferate and differentiate into Ig-producing cells.

[Treatment of lymphatic malformations with OK-432 sclerosis. Our experience]. / Tratamiento de las malformaciones linfáticas mediante esclerosis con OK-432. Nuestra experiencia.

INTRODUCTION: The elective treatment of lymphatic malformations has always been surgical resection. However sclerotherapy with a variety of substances is being used as an alternative to surgery specially in the last years. The aim of this essay is to present our results using sclerosis with OK-432. MATERIALS AND METHODS: We have reviewed all patients affected by lymphatic malformation that have been treated by sclerosis with OK-432. Each procedure was performed under general anesthesia by a radiologist and a pediatric surgeon. RESULTS: Fifteen patients have been treated. On the whole, 36 procedures have been performed, with a mean of 2.4 for each patient. The mean amount of OK-432 injected was 1.5 milligrams (mg) in each procedure. 73% of the patients showed nearly complete or complete response. There were two complications; one of them was a limited bleeding and the other one, a case of high fever resolved by antipyretics and antibiotics. Microcystic or mixed malformations required a higher number of procedures and presented poorer response. CONCLUSION: Sclerotherapy with OK-432 is an effective and safe treatment for lymphatic malformation specially the macrocystic ones, therefore it should be considered as first line therapeutic option.

Lymphedema and Lymphovenous Bypass: Perioperative Nursing Implications.

Lymphedema-the accumulation of fluid in tissues, usually in the upper and lower extremities-often results from lymph node dissection or radiation and can cause painful and debilitating swelling that may interfere with a patient's daily living activities and quality of life. The goal of treatment for lymphedema is to reduce the volume of fluid in the affected area. Lymphedema is staged according to presenting characteristics, and interventions may be surgical or nonsurgical, such as complex decongestive therapy. Lymphovenous bypass is a surgical procedure performed for the management of lymphedema and involves rerouting microvascular channels to allow for the drainage of fluid that has accumulated in the lymphatic tissue of the upper or lower extremities. It requires supermicrosurgery techniques because of the small size of the vessels being anastomosed. Perioperative nursing implications for lymphovenous bypass include OR preparation and providing emotional support for patients living with lymphedema.

Doxycycline sclerotherapy of an intraosseous femoral lymphatic malformation: case report and literature review.

Lymphatic malformations of the femur are rare benign conditions, with few published reports in the literature. Herein is presented an ambulatory 19-year-old male subject with a painful lymphatic malformation of the distal femur characterized by a serpiginous intraosseous and extraosseous extent. Laboratory and physical examination were unremarkable except for a right knee joint effusion and patellar grind. The malformation was sclerosed twice with doxycycline, resulting in patient-reported decreased associated pain from an intensity of 9 of 10 at presentation to 2 of 10 at 9-month follow-up.

The prolactin inducible protein/gross cystic disease fluid protein-15 deficient mice develop anomalies in lymphoid organs.

The Prolactin Inducible Protein (PIP) is a 15 kDa protein secreted by normal apocrine glands, including salivary, lacrimal and sweat glands. PIP levels are normally low in the mammary glands of healthy individuals, but high levels have been observed in pathological conditions of the breast such as benign breast cystic disease and breast cancer. While the function of PIP is not well elucidated, accumulating evidence strongly point to a role in both innate and adaptive immunity. Using PIP deficient mice (Pip-/- mice) our laboratory demonstrated that loss of PIP function led to impaired T helper type 1 response and cell mediated immunity. In the present study we provide additional supporting evidence showing abnormal lymphocytic distribution in primary and secondary lymphoid organs of Pip-/- mice. Significant morphological changes in the Eustachian tube, an immune-protected site where PIP is normally found, were also associated with the absence of PIP. Collectively, these results further support an immuno-regulatory role for PIP and have implications for a spectrum of immune-related illnesses including otitis media and hearing loss as well as breast cancer.

The absence of cutaneous lymph nodes results in a Th2 response and increased susceptibility to Leishmania major infection in mice.

Lymph nodes (LNs) are important sentinel organs where antigen-presenting cells interact with T cells to induce adaptive immune responses. In cutaneous infection of mice with Leishmania major, resistance depends on the induction of a T-helper-cell-1 (Th1)-mediated cellular immune response in draining, peripheral LNs. We investigated whether draining, peripheral LNs are absolutely required for resistance against L. major infection. We investigated the course of experimental leishmaniasis in wild-type (wt) mice lacking peripheral LNs (pLNs), which we generated by in utero blockade of membrane-bound lymphotoxin, and in mice lacking pLNs or all LNs due to genetic deletion of lymphotoxin ligands or receptors. wt mice of the resistant C57BL/6 strain without local skin-draining LNs were still able to generate specific T-cell responses, but this yielded Th2 cells. This switch to a Th2 response resulted in severe systemic infection. We also confirmed these results with mice lacking pLNs due to genetic depletion of lymphotoxin-beta. The complete absence of LNs due to a genetic depletion of the lymphotoxin-beta receptor also resulted in a marked deterioration of disease and a Th2 response. Thus, in the absence of pLNs, an L. major-specific Th2 response is induced in the remaining secondary lymphoid organs, such as the spleen and non-skin-draining LNs. This indicates a critical requirement for pLNs to induce protective Th1 immunity and suggests that whether Th1 or Th2 priming to the same antigen occurs depends on the site of the primary antigen recognition.

An ENU-induced mutation in the lymphotoxin alpha gene impairs organogenesis of lymphoid tissues in C57BL/6 mice.

The TNF family is critical for development of lymphoid organs and plays significant roles in regulation of innate and adoptive immune responses. Here, we describe a novel N-ethyl-N-nitrosourea (ENU)-induced mutant strain, HLB382, with a point mutation in the Lta gene, which encodes lymphotoxin (LT) alpha, a member of the TNF family. Mutant mice had no lymph nodes and no Peyer's patches. Microscopically, the spleens had disordered follicles and no germinal centers or discernible marginal zones (MZ). While the development of T cells and follicular B cells was normal, the numbers of NK and MZ B cells were significantly reduced. Interestingly, the numbers of peritoneal B1b cells were significantly increased. Genomic DNA sequences revealed a single base pair insertion in the coding region of Lta resulting in a frame shift and a premature stop codon. This new strain provides opportunities for understanding the full range of Lta gene function on a pure C57BL/6 background.