Lymphatic Vasculature: An Emerging Therapeutic Target and Drug Delivery Route.

The lymphatic system has received increasing scientific and clinical attention because a wide variety of diseases are linked to lymphatic pathologies and because the lymphatic system serves as an ideal conduit for drug delivery. Lymphatic vessels exert heterogeneous roles in different organs and vascular beds, and consequently, their dysfunction leads to distinct organ-specific outcomes. Although studies in animal model systems have led to the identification of crucial lymphatic genes with potential therapeutic benefit, effective lymphatic-targeted therapeutics are currently lacking for human lymphatic pathological conditions. Here, we focus on the therapeutic roles of lymphatic vessels in diseases and summarize the promising therapeutic targets for modulating lymphangiogenesis or lymphatic function in preclinical or clinical settings. We also discuss considerations for drug delivery or targeting of lymphatic vessels for treatment of lymphatic-related diseases. The lymphatic vasculature is rapidly emerging as a critical system for targeted modulation of its function and as a vehicle for innovative drug delivery.

[A case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) without relapse after early steroid treatment].

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a brainstem predominant lymphocytic inflammatory disease, which often relapses without oral immunosuppressants. This report describes a 37-year-old male case of CLIPPERS without relapse for 1 year after early steroid treatment. He was admitted to our hospital because of sensory disturbance in the left side of his body and ataxic gait. Gadolinium-enhanced T1-weighted MRI revealed multiple punctate and curvilinear enhancements in the pons and right middle cerebellar peduncle. We started treatment with high-dose intravenous methylprednisolone (IVMP) therapy on the 20th day of the illness. His neurological symptoms dramatically improved. Follow-up MRI showed that the enhancing lesions disappeared. We diagnosed him with CLIPPERS based on the clinical course, radiological findings, and steroid response. He did not take any oral immunosuppressant after discharge. However, there was no clinical and radiological relapse for 1 year after the IVMP therapy. Although this case requires careful follow-up because of recurrence risk, early steroid treatment was possibly related to 1-year remission.

Prevention of diffuse, minimal lymphatic "retention" with Robuvit®: a concept, supplement registry study.

BACKGROUND: The aim of this study was to evaluate the effects of the standardized supplement Robuvit® (oak wood extract) in defined diffuse, minimal lymphatic "retention" (DMLR). METHODS: Robuvit® has already been investigated in both primary and secondary (post-surgical, post chemo-radiotherapy) lymphatic insufficiency. This registry included subjects with diffuse, minimal lymphatic "retention" (DMLR). The registry management groups included women with mild-moderate limb swelling using standard management (SM) as controls. A second, comparable group used prevention with Robuvit® at the dosage of 3 cp/day (300 mg/day) for 4 weeks. RESULTS: No tolerability problems or side effects were observed with the preventive supplementation. The management groups (34 women in total), including 18 women in Robuvit® and 16 in SM were comparable in age and baseline evaluations. After 4 weeks, in the Robuvit® group, edema scale values derived from ultrasound observations decreased significantly (P<0.05) at all measurement's sites, from the proximal (inguinal) level to the more distal (ankle-foot) level. No significant changes in edema were observed in control subjects. Generally, in areas with higher level of edema (distal areas at the foot and ankle), the edema decrease was larger than in more proximal, ultrasound measurement sites. CONCLUSIONS: Preventive Robuvit® supplementation appears to be safe and effective in controlling DMLR in subjects without significant or apparent clinical conditions. This preventive, concept study should be extended to a larger population for more meaningful observations.

CLAPO syndrome: Effective response to treatment with oral rapamycin.

CLAPO syndrome (Capillary vascular malformation of the lower lip, Lymphatic malformations of the head and neck, Asymmetry and Partial or generalized Overgrowth) is a nonfrequent pathology. This syndrome is characterized by the capillary malformation (CM) of the lower lip, a very important clinical sign when diagnosing CLAPO. The aim of our report is to demonstrate that rapamycin could be a reliable and safe targeted therapy in lymphatic malformations (LMs). This drug is useful in reducing the LM's size before final surgical treatment. The clinical and radiological evolution of a patient with CLAPO syndrome is reported in this article, before and after the treatment with rapamycin.

[Diosmin in the treatment of venous disease: pharmacokinetics and pharmacodynamics (in Russian only)]. / Diosmin v lechenii venoznoi patologii: osnovy farmakokinetiki i farmakodinamiki.

The issues of absorption, bacterial intestinal metabolism and hepatic metabolism of diosmin are described. The main metabolites of the drug and the ways of their elimination are indicated. The article describes the main therapeutic targets and mechanisms of influence on the course of disease including effect on the venous wall tone and permeability, lymphatic drainage, inflammation and oxidative stress.

Lymphocutaneous nocardiosis in a kidney transplant patient successfully treated with tigecycline.

Cutaneous nocardiosis is an infrequent infection which has been increasingly reported in immunocompromised patients. Although trimethoprim-sulfamethoxazole is considered to be the agent of choice for treatment of nocardiosis, newer antimicrobials such as tigecycline have been proven to be effective in vitro, as well. We report the first case of primary cutaneous nocardiosis in a renal transplant recipient having corresponded well to treatment with tigecycline.

Calcified peripancreatic lymph nodes in pancreatic and hepatic tuberculosis mimicking pancreatic malignancy: A case report and review of literature.

RATIONALE: Tuberculosis remains a serious menace to the health of people. Isolated hepatic tuberculosis is rare and pancreatic tuberculosis is extremely rare. The preoperative diagnosis of pancreatic tuberculosis remains a great challenge. PATIENT CONCERNS: A 58-year-old Asian woman was referred to our hospital for evaluation of low back pain for 4 years and abdominal pain for 1 month. DIAGNOSES: Computed tomography (CT) of the abdomen showed a hypodense mass in the pancreatic head and neck with abundant calcifications, a hypodense lesion in the liver without calcification, peripancreatic lymphadenopathy, calcifications in some lymph nodes. CT-guided fine needle aspiration biopsy of the hepatic lesion was carried out and the cytological examination revealed hepatic tuberculosis. INTERVENTIONS: The patient was treated with antituberculous therapy for 1 year. OUTCOMES: Low back pain and abdominal pain disappeared 3 months after initial treatment and after 2 year of follow-up, the patient was asymptomatic. LESSONS: Our data hint that calcifications in both pancreatic lesions and peripancreatic lymph nodes may suggest pancreatic tuberculosis rather than pancreatic malignancy.

Intralymphatic histiocytosis treated with intralesional triamcinolone acetonide and pressure bandage.

Intralymphatic histiocytosis is a rare disorder associated with a variety of inflammatory conditions. We report the case of an 89-year-old woman with a history of a right knee replacement and a ruptured popliteal cyst who developed an erythematous indurated plaque over the surgical scar. Histopathology revealed fibrosis, chronic inflammation, and histiocytes within the lymphatics consistent with intralymphatic histiocytosis. The plaque flattened following intralesional injection of triamcinolone acetonide 10 mg/cc×1.6 cc once monthly for 2 consecutive months and application of a pressure bandage, with no recurrence after 4 months. This treatment may be useful for recalcitrant disease.

Intralymphatic Histiocytosis: A Report of 2 Cases. / Histiocitosis intralinfática, a propósito de 2 casos.

Intralymphatic histiocytosis is a benign condition characterized by poorly defined erythematous plaques (sometimes forming a reticular pattern) as well as the presence of nodules and vesicles. Its etiology and pathogenesis appear to be related to chronic inflammation in the affected area, prior surgery, or systemic disease, particularly rheumatoid arthritis. We report on 2 new cases, both associated with joint surgery in the affected area and osteoarticular disease (primary synovial osteochondromatosis and rheumatoid arthritis). This is a chronic disease and there is no specific treatment. Different treatment options were chosen in the 2 cases described. A spectacular response to treatment with oral pentoxifylline and topical tacrolimus was observed in 1 of the patients.

Adult onset Still's disease with dermatopathic lymphadenopathy.

Adult onset Still's disease (AOSD) is a chronic inflammatory disorder involving multiple systems. The symptoms mimic those of lymphomas, therefore, the diagnosis of lymphoma needs to be excluded prior to establishing the diagnosis of AOSD. Another similar condition is dermatopathic lymphadenopathy (DL). In DL, the histopathological appearance of lymph node biopsy may also mimic AOSD. The DL is associated with several systemic pathologies, such as malignant lymphomas, and rarely AOSD. We present a case of a 43-year-old male presented with 3 months history of fatigue, fever, and lymphadenopathy. Initial work-up satisfactorily met the criteria for diagnosis of AOSD. But considering the well-known association of DL with hematological malignancies, detailed pathological studies were considered, including tumor markers to rule out  the possibility of malignancy. The patient was started on steroids and showed remarkable recovery within 2 weeks. Evaluation of malignant lymphomas in a patient with DL is important, in order to diagnose AOSD and rule out hematological malignancy.

Nonsteroidal Anti-Inflammatory Drugs Quickly Resolve Symptoms Associated with EBV-Induced Infectious Mononucleosis in Patients with Atopic Predispositions.

BACKGROUND: Infectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus (EBV) infection. In adults, the symptoms can often be severe and prolonged, sometimes causing serious complications. Analgesic or antipyretic drugs are normally used to relieve the symptoms. However, there is no causal treatment for the disease. CASE REPORT: Two cases of adult patients with atopic predispositions developed nocturnal fever, general fatigue, pharyngitis and lymphadenopathy after an exacerbation of atopic symptoms or those of allergic rhinitis. Due to the positive results for EBV viral-capsid antigen (VCA) IgM and negative results for EBV nuclear antigen (EBNA) IgG, diagnoses of infectious mononucleosis induced by EBV were made in both cases. Although oral antibiotics or acetaminophen alone did not improve the deteriorating symptoms, including fever, headache and general fatigue, nonsteroidal anti-inflammatory drugs (NSAIDs), such as tiaramide or loxoprofen, completely improved the symptoms quickly after the initiation. CONCLUSIONS: In these cases, given the atopic predispositions of the patients, an enhanced immunological response was likely to be mainly responsible for the pathogenesis of the symptoms. In such cases, NSAIDs, that are known to reduce the activity of EBV, may dramatically improve the deteriorating symptoms quickly after the initiation. In the present cases, the immunosuppressive property of these drugs was considered to suppress the activity of lymphocytes and thus provide the rapid and persistent remission of the disease.

IFN beta 1a as Glucocorticoids-Sparing Therapy in a Patient with CLIPPERS.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of the central nervous system, distinguished by brainstem- and spinal cord-centered lesions with a characteristic contrast enhancement on MRI, a lymphocytic perivascular infiltrate on pathological exam, and a dramatic response to and dependence on steroids therapy. Since its initial description in 2010, different glucocorticoid-sparing agents, mostly immunosuppressant drugs, have been used to minimize the dosage, but these therapies also carry the risk of important secondary effects. We present the first reported case of CLIPPERS treated with interferon beta 1a as add-on therapy. CASE REPORT: A previously healthy 31-year-old man presented with gait ataxia and dysarthria. MRI showed pons-centered hyperintense patchy lesions on T2-weighted images. Additional tests ruled out other possible diagnoses and symptoms reversed with intravenous methylprednisolone. Over the years the patient presented with several episodes of deterioration each year, which were partly reversed with glucocorticoid therapy, but leaving him with growing sequelae. Four years after the initial event, treatment with interferon-beta-1a was initiated, achieving reduced frequency of the relapses to 1 every 4 years, which were no longer associated to increasing disability. This allowed reducing glucocorticoids to 30 mg of Deflazacort every other day. CONCLUSIONS: Interferon beta-1a could be an alternative to corticosteroid-combined therapy in CLIPPERS and its more benign profile of secondary effects compared to immunosuppressants could make it an attractive choice.

A Case of a Central Conducting Lymphatic Anomaly Responsive to Sirolimus.

The study of vascular anomalies is a rapidly progressing field in medicine. The development of new knowledge in the pathology and management of these disease processes are exemplified in the treatment of hemangiomas with propranolol and generalized lymphatic malformations with sirolimus. Central conducting lymphatic anomalies have traditionally been refractory to medical and surgical interventions. We report a case of a central conducting lymphatic anomaly that was responsive to sirolimus. A 14-year-old boy presented with chylothorax and chyluria with a lymphangiogram demonstrating abnormal lymphatic flow and reflux along the entire course of the central channels. Traditionally, medical management has been limited to somatostatin and low-fat diet with poor response and surgical interventions that are palliative. Sirolimus allows a new medical option that could improve management of this unresponsive population.

Intrathoracic Involvements of Immunoglobulin G4-Related Sclerosing Disease.

To investigate clinical and radiological features of IgG4-related disease (IgG4-RD) patients with intrathoracic involvement. A prospective cohort study was performed and IgG4-RD patients were enrolled from January 2011 to March 2015 in Peking Union Medical College Hospital, in which the clinical and radiological characteristics of IgG4-RD patients with intrathoracic involvement were summarized. Out of total 248 cases with IgG4-RD, 87 cases had intrathoracic lesions, including 58 male cases and 29 female cases, with average age of 54.19 ±â€Š13.80 years. Hilar and mediastinal lymphadenopathy were the most common manifestations of IgG4-related intrathoracic disease, accounting for 52.9% (46/87). Other imaging findings of pulmonary disease included: solid nodular (25.3%), round-shaped ground-glass opacities (9.2%), alveolar-interstitial type (20.7%), bronchovascular type (23.0%), pleural effusion (4.6%), and pleural nodules or thickening (16.1%). Only 27 patients presented with respiratory symptoms, including cough, breathless, chest pain, and asthma. Compared with patients without intrathoracic disease, IgG4-related intrathoracic disease had higher IgG4 and C-reactive protein level, and higher incidence of allergy, fever, and multi-organ involvement. Most of lung interstitial disease, mediastinal mass, and bronchial thickening were sensitive to corticosteroid and immunosuppressant therapy, while 36.3% (8/22) of solitary nodular lesions were unresponsive to treatment. Eight patients were on no treatment, with 5 cases remained stable, 2 patients improved spontaneously, and 1 patient was lost follow-up. Intrathoracic lesions are not rare in patients with IgG4-RD, involving bronchial thickening, nodules, ground glass opacity, pleural thickening/effusion, lymphadenopathy, etc. Efficacy of corticosteroid and immunosuppressant therapy were noted in most of patients with lung interstitial disease, mediastinal mass, and bronchial thickening.