Lymphatic Ring Research Articles

Mapping of SARS-CoV-2 in Waldeyer’s lymphatic ring and visceral biopsies: the age and the illness duration’s impact

ObjectiveTo study the impact of age and the interval between disease diagnosis and death on the organotropism of SARS-CoV-2. MethodPatients underwent post-mortem biopsies from lungs, Waldeyer ring, heart, liver, kidneys and bone marrow between 2020‒2021. SARS-CoV-2 organotropism was mapped by using molecular RT-PCR analyses for SARS-CoV2 targeting the Envelope gene (E), the RNA Polymerase Gene (RdRp), and the Nucleocapsid gene (N). Statistical and linear regression analysis was performed to study the impact of age and illness duration in SARS-CoV-2 organotropism. ResultsWe performed 158 postmortem biopsies in 21 patients, with a mean age of 76 years old. The mean interval between the diagnosis of the infection to the death was 23 days. The RNA of the SARS-CoV-2 was detected in 100% of lung biopsies, 76%‒82% of Waldeyer’s ring biopsies, 55% of heart biopsies, 40% of kidney biopsies, 33% of liver and 25% of bone marrow biopsies. Patients who died before the day 9, presented extensive visceral dissemination of SARS-CoV-2 RNA. Most of the patients older than 80 years (90%) presented visceral dissemination of SARS-CoV-2 RNA, while among younger patients, only 3/11 patients presented visceral dissemination of the virus. The relationship between “age” and “illness duration” and multitropism of the virus was statistically significant (p<0.001). ConclusionDisease interval and age were factors that were significantly associated with RT-PCR positive results in multiple organs. Critical COVID-19 patients have multiorganic viral dissemination in early stages. In the critical older patients, multiorganic viral dissemination is the rule. Level of evidence4. Case Series.

Waldeyer ring microbiome in relation to chemoradiation-induced oral mucositis in patients with nasopharyngeal carcinoma.

Waldeyer lymphatic ring surrounds the nasopharynx and oropharynx, and no study to date has correlated its microbiome with the severity of oral mucositis (OM) in patients with nasopharyngeal carcinoma (NPC) receiving chemoradiotherapy. We performed 16S rRNA sequencing to characterize bacterial microbiome in tumor-affected nasopharynx and the surrounding normal oropharynx. We plotted the abundance and diversity of bacterial taxa and their phylogenetic distance and networks to visualize and compare the differences in pretreatment overall bacterial communities between the nasopharynx and oropharynx in patients with NPC with varying degrees of chemoradiotherapy-induced OM and quality of life. We found microbial signatures in nasopharynx around NPC were not only dissimilar to those in the surrounding oropharynx but were almost unique to each patient. The genetic distance metrics further showed that different tumor microbiota distributions in the nasopharynx among patients with NPC were well-correlated with OM severity and quality of life during chemoradiotherapy. At Waldeyer ring, the tumor-associated microbiome risk profiles of the respiratory region of nasopharynx, but not commensal microbiota of the alimentary region of oropharynx, could be noninvasive biomarkers for OM susceptibility and might include drug targets for the prevention of chemoradiation-induced OM in patients with Waldeyer ring-derived NPC.

Analysis of chronic pathology of the pharynx according to the results of pathohistological findings

Objective. To analyze the incidence of lymphoid structures of the pharynx among the adult population during the period from January 2021 to August 2022 in three nosological forms: chronic decompensated tonsillitis (CDT), hypertrophy of pharyngeal tonsils (HPT), hypertrophy of lingual tonsillitis (HLT). To determine the relationship of the above pathology between the age and sex of patients at the present stage. To evaluate the role of mycobiota in the structure of pharyngeal morbidity.Materials and methods. The object of the study was 96 patients with chronic pathology of the lymphoid structures of the pharynx aged from 17 to 70 years, who were on inpatient treatment at the Gomel Regional Clinical Hospital (GRCH) during the period from January 2021 to August 2022. All patients underwent surgical intervention followed by an assessment of the pathohistological conclusions of postoperative samples of pharyngeal lymphatic formations. The patients were divided into 3 nosological study groups: CDT; HPT; HLT. Statistical data processing was performed using software: MS Excel and the programming language for statistical data analysis R (version 4.2.1), packages tidyverse (version 1.3.1), rstatix (version 0.7.0), ggstatsplot (version 0.9.5).Results. The study revealed the most common nosological groups among patients with pathology of the pharyngeal lymphatic ring of Pirogov-Waldeyer: CDT (44%) and HPT (38%). A significant difference was revealed between the incidence rates of pathology of the Pirogov-Waldeyer pharyngeal lymphatic ring in the study age groups from 17 to 25 years (p=0.0008); from 26 to 35 years (p=0.0021); 56 years and older (p=0.008). The median age of patients in the study group was 35 years (LQ 24.0; UQ 48.5), whereas in some nosological forms: CDT – 30 years (LQ 23.0; UQ 41.0), namely 28 years among women and 36 years among men; HРT – 32.5 years (LQ 24.0; UQ 43.25), namely 34.5 years among women and 31.5 years among men; HLT – 57 years (LQ 49.0; UQ 63.0), and it is 56.5 years among women and 57 years among men. Morphological examination revealed only 2 (2%) cases of mycotic lesions of the removed lymphoid masses.Conclusion. The relationship between the pathology of lymphoid structures of the pharynx in three nosological forms (CDT, HPT, HLT) and the age of patients was revealed. The role of mycobiota in the overall study group in the structure of pharyngeal morbidity at the present stage was evaluated.

Chronic Compensated Tonsillopharingitis: Clinical and Microbiological Features

The article presents the results of a complex clinical and bacteriological study aimed at determining the quantitative and qualitative composition of the microflora of the pharyngeal lymphatic ring in patients with chronic compensated tonsillopharyngitis, including identification of microorganisms followed by determination of their sensitivity toward antibacterial and antimycotic drugs. β-hemolytic streptococcus was revealed to be the most etiologically significant microorganism in the development of chronic compensated tonsillopharyngitis. In addition, populations of microorganisms growing in the throat of such patients were found to exhibit high resistance toward antibacterial and antifungal drugs.

Comparison of Biochemistry Values from Plasma and Lymph in Krefft's River Turtles (Emydura macquarii krefftii)

Lymph contamination of peripheral blood samples is common in reptile species due to a close association of the lymphatic and vascular systems. Grossly lymph-diluted samples are generally discarded due to potential effects on hematologic and biochemical parameters. Differences in biochemistry values from different sample sites in chelonians are often attributed to lymph contamination. Previous studies have evaluated blood-lymph mixtures but provide limited information since the proportion of lymph is unknown. Differences in biochemistry values of pure lymph compared to plasma are unknown in chelonian species. Paired plasma samples collected from the jugular vein and lymph samples collected from the dorsal lymphatic ring adjacent to the subcarapacial plexus were collected from 11 (6 females, 5 males) Krefft’s river turtles ( Emydura macquarii krefftii ) for comparison of biochemical analytes. No statistically significant differences were found between lymph and plasma samples for chloride, glucose, alanine aminotransferase, aspartate aminotransferase, creatinine kinase, urea nitrogen, and total bilirubin. Statistically significant (P ≤ 0.05) differences were found between lymph and plasma samples for gamma-glutamyltransferase (GGT), total protein, globulin, and uric acid. Sex and sample differences were statistically significant for sodium, potassium, calcium, phosphorous, magnesium, lactate dehydrogenase (LDH), albumin, and triglycerides, while significant sex differences only were found for alkaline phosphatase, cholesterol, and iron. Severe lymph dilution (1:1 with plasma) may cause clinically significant decreases of potassium, total protein, globulin, and LDH, and increases of GGT and uric acid in both sexes, as well as clinically significant decreases of calcium and triglycerides in female Krefft’s river turtles.

Correlation between Reference Tissue Normalized 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Standardized Uptake Value Max of Nodal and Extranodal Sites in Lymphomas: An Empirical Study.

Context:Extranodal (EN) lymphomas involve sites other than lymph nodes (LNs), spleen, thymus, and the pharyngeal lymphatic ring. The highest standardized uptake value (SUV) max of the LN can aid in the diagnosis of EN site lymphomatous infiltrations over inflammation or infection especially when there are no contrast-enhanced computed tomography (CT) changes.Aims:The purpose of this study was to find the significance of correlation between absolute SUVmax and mediastinal blood pool (mbSUVmax) and liver (lvSUVmax) normalized SUVmax of EN sites and the most fluorodeoxyglucose (FDG) avid LN in patients with primary and secondary EN involvement in Non-Hodgkin's and Hodgkin's Lymphoma.Settings and Design:This was a retrospective study of 70 patients with histopathologically proven lymphoma in whom 18F-FDG positron emission tomography CT was performed for pretherapy staging.Materials and Methods:Images were used to detect EN sites of disease and SUVmax of mediastinal blood pool, liver, highest SUVmax LN, and highest SUVmax EN site were calculated.Statistical Analysis Used:Karl Pearson's coefficient of correlation (r) was used to correlate the highest SUV max of LN and EN site and corresponding highest blood pool corrected and liver corrected SUV max. In view of small sample size, t-test for paired samples at 5% and 10% significance was conducted to validate the findings. Two-tailed t-test for independent samples was also used to compare means of SUVmax values between data grouped according to gender and lymphoma subtype (Non-Hodgkin lymphoma and Hodgkin lymphoma).Results:r = 0.54 for the highest LN SUVmax-highest EN SUVmax values and on further validation by one- and two-tailed paired t-test at significance levels of 5% and 10%, P = 0.00052 and 0.00103 respectively which denoted significant positive and moderate correlation. r = 0.59 for highest LN lvSUVmax-highest EN vSUVmax and P = 0.00032 and 0.00065 showing positive and moderate correlation. r = 0 0.82 for highest LN mbSUVmax-highest EN mbSUVmax values and P = 0.00034 and 0.00068 revealing positive and strong correlation.Conclusion:Significant positive and strong correlation exists between nodal and EN mbsUVmax. This is stronger than the correlation between nodal and EN absolute SUVmax and lvSUVmax. Since normalization of lesion SUVmax to reference tissues reduces the variability of SUV, this can be a useful adjunct to determine whether high SUVmax of the EN site is due to lymphomatous infiltration.

Complex Analysis of the Microflora of the Pharyngeal Lymphatic Ring in Patients with Compensated Chronic Tonzillopharyngitis

The article presents the results of a complex clinical and bacteriological study aimed at determining the quantitative and qualitative composition of microflora in the pharyngeal lymphatic ring. The microflora composition was determined in terms of microorganism identification and their sensitivity to antibacterial and antimycotic drugs in patients with the compensated form of chronic tonsillopharyngitis (CCTP). It was revealed that β-hemolytic streptococcus is the most etiologically significant microorganism in the development of CCTP. In addition, populations of microorganisms growing in the throat of people with CCTP exhibit a high resistance to antibacterial and antifungal drugs. Thus, 57.14% of the detected microorganisms showed resistance to several antibacterial drugs, and the identified Candida cultures demonstrated resistance to 3–4 antimycotic drugs in 52.3% of cases.

A role of oropharyngeal microbiota in developing acute and chronic diseases of the upper respiratory tract

Currently, a rise in incidence of polyethological inflammation of the upper respiratory tract mucosa paralleled by altered resident and transient microbiota displaying in many cases increased antibiotic resistance has been noted. Opportunistic microbes play a major role in developing inflammatory process in Pirogov–Waldeyer’s ring. An inflammatory process occurring in the tonsillar lymphatic tissue results in host systemic complications. Fighting against acute and chronic infections of the upper respiratory tract holds the main task in pediatric otorhinolaryngology, as they can consequently elicit the cardiovascular, genitourinary and musculoskeletal complications. The results of studies examining this issue remain very contradictory, which accounted for a need to conduct our study on the territory of Moldova featured with mixed climatic conditions. Here, we wanted to study a role of microbial factor in etiopathogenesis of chronic tonsillitis in children. Bacteriological microbiota data for superficial palatine tonsils were obtained form 608 children subdivided into 5 groups: group I — 333 children with compensated chronic tonsillitis; group II — 87 children with decompensated chronic tonsillitis; group III — 91 children with acute upper respiratory tract infections (comparison group); group IV — 48 children with acute upper respiratory tract infections treated with antibiotic therapy; group V — 49 apparently healthy children (control group). It was found that β-hemolytic streptococcus exerting high sensitivity to virtually all antibiotics groups was detected in 17.4% of children with acute tonsilar inflammatory processes and decompensated defense in the lymphatic pharyngeal ring compared to 3.5% in control group. Streptococcus pneumoniae was isolated in all study groups ranging within 4.8–21.7%, including 14% in apparently healthy children characterized by reduced antibiotics sensitivity. The data obtained suggest that sickly children with acute and chronic upper respiratory tract infections constitute a risk group for developing somatic diseases. The high incidence of Streptococcus pneumoniae indicates a need for performing immunoprophylaxis, use of therapeutic vaccination as a up-to-date, combined approach in treatment of such pediatric cohort.

COVID-19 in children; is there an impact of Waldeyers Lymphatic Ring?

COVID-19 in children; is there an impact of Waldeyers Lymphatic Ring?

Clinicoepidemiological profile of extranodal lymphoma: The experience of a tertiary care center in India

Introduction: Lymphoma is a neoplastic proliferation of lymphoid cells at various stages of differentiation and affects lymph nodes, with infiltration into the bone marrow, spleen, and thymus, which form the primary lymphatic organs. Extranodal lymphoma, by definition, involves sites other than lymph nodes, spleen, thymus, and the pharyngeal lymphatic ring. Extranodal involvement is less common with Hodgkin lymphoma (HL) than with non-Hodgkin lymphoma (NHL). Materials and Methods: A single-center retrospective observational study was conducted over the period of 2017–2019. Age, gender, histologic type, location, type of clinical presentation, histologic diagnosis, and presence of specific symptoms were recorded, as were the specialty of the physician initially consulted and of the physician taking the diagnostic sample. Results: Twenty-seven cases of extranodal lymphoma were diagnosed: 12 (44.4%) were male and 15 (56.6%) were female patients. The median age for males was 49.6 years and for females was 45.7 years. In this study, we had varied presentations of the lymphoma with involvement of various structures. We had few patients with very rare site of involvement like an elderly female patient presented with firm swelling over the right forearm which on excision turned out to myeloid sarcoma. Similarly, an elderly woman had presented with pyrexia of unknown origin that was later diagnosed as having primary bone Hodgkin lymphoma (HL) which is a very rare diagnosis and rarely has been described in world literature. The most common site of extranodal lymphoma was gastrointestinal tract (7 out of 27 patients; 25.9%); the other sites reported were testis (14.8%), breast (7.4%) thyroid, and ovary. Few rare sites reported were bone, central nervous system, and mediastinum. We report an extremely rare patient who had presented with anterior chest wall swelling, and on evaluation was detected to have primary mediastinal B cell lymphoma. Conclusion: Extranodal lymphoma is the rare presentation of NHL and extremely rare for HL. As it is a very rare disease, there are very limited studies available for its staging and management. We have presented a case series of extranodal lymphoma with few very rare presentations.

Quantification of Angiogenesis and Lymphangiogenesis in the Dual ex vivo Aortic and Thoracic Duct Assay.

: BackgroundLymphatic vessel formation (lymphangiogenesis) plays important roles in cancer metastasis, organ rejection, and lymphedema, but the underlying molecular events remain unclear. Furthermore, despite significant overlap in the molecular families involved in angiogenesis and lymphangiogenesis, little is known about the crosstalk between these processes. The ex vivo aortic ring assay and lymphatic ring assay have enabled detailed studies of vessel sprouting, but harvesting and imaging clear thoracic duct samples remain challenging. Here we present a modified ex vivo dual aortic ring and thoracic duct assay using tissues from dual fluorescence reporter Prox1-GFP/Flt1-DsRed (PGFD) mice, which permit simultaneous visualization of blood and lymphatic endothelial cells.ObjectiveTo characterize the concurrent sprouting of intrinsically fluorescent blood and lymphatic vessels from harvested aorta and thoracic duct samples.MethodsDual aorta and thoracic duct specimens were harvested from PGFD mice, grown in six types of endothelial cell growth media (one control, five that each lack a specific growth factor), and visualized by confocal fluorescence microscopy. Linear mixed models were used to compare the extent of vessel growth and sprouting over a 28-day period.ResultsAngiogenesis occurred prior to lymphangiogenesis in our assay. The control medium generally induced superior growth of both vessel types compared with the different modified media formulations. The greatest decrease in lymphangiogenesis was observed in vascular endothelial growth factor-C (VEGF-C)-devoid medium, suggesting the importance of VEGF-C in lymphangiogenesis.ConclusionThe modified ex vivo dual aortic ring and thoracic duct assay represents a powerful tool for studying angiogenesis and lymphangiogenesis in concert.

Adenoidal Hypertrophy and Physiotherapy

Adenoid hypertrophy (AH) refers to the most common pathology of pediatric otorhinolaryngology. The lymphatic pharyngeal ring plays a leading role in creating the immune barrier of the upper respiratory tract. In this regard, the conservative methods of therapy that do not require surgical intervention and ensure the preservation of the immune protection are more relevant.

Impact of Single-Energy Metal Artifact Reduction on CT image quality in patients with dental hardware

BackgroundTo evaluate whether Canon's Single-Energy Metal Artifact Reduction (SEMAR) algorithm can significantly improve subjective and objective image quality of patients with nonremovable dental hardware undergoing CT imaging of the oral cavity and oropharynx. Materials and methodsSEMAR was reconstructed from routine Adaptive Iterative Dose Reduction (AIDR) images in 154 patients (46 females and 108 males; mean age 66.3 ± 10.5 years). Subjective SEMAR and AIDR image quality of the mouth floor, sublingual glands, lymphatic ring and overall impression were evaluated by two independent radiologists on a 6-point scale (1 = very good image quality, 6 = poor image quality) and compared to ratings of an oral and maxillofacial surgeon. Interrater agreement was assessed using the intraclass correlation coefficient (ICC). Objective image analysis was performed by placing regions of interest (ROIs) on the mouth floor and measuring CT attenuation in Hounsfield units (HU) and standard deviation (SD). ResultsSEMAR significantly improved subjective image quality in all evaluated structures for all raters (p < 0.001). Furthermore, SEMAR significantly reduced objective metal artifacts and image noise (p < 0.001). ConclusionSEMAR significantly improved diagnostic quality of CT images of the oral cavity and oropharynx by reducing artifacts caused by dental hardware.

Study of adenotonsillectomy specimens: An institutional experience.

Objective:Waldeyer's lymphatic ring consists of group of tonsils located over the posterior oropharyngeal wall. The palatine tonsils are largest tonsil. The present study was aimed to evaluate the significance of lymphoid hyperplasia, lymphocyte infiltration with and without defect in the surface epithelium in chronic tonsillitis (CT) and chronic adenotonsillar hypertrophy (CAH) in resected tonsillectomy and adenotonsillectomy specimens.Materials and Methods:A total of 85 patients were included in the study. Fifty-one cases underwent bilateral tonsillectomy and 34 cases underwent adenotonsillectomy.Results:The lymphoid hyperplasia was higher in CAH (30/34; 88.24%) as compared to CT (26/50; 52%). Lymphocyte infiltration with or without defect in the surface epithelium was common in CT. The histopathologic criteria of lymphoid hyperplasia and lymphocyte infiltration with or without defect in the surface epithelium showed a statistically significant difference between CT and CAH.Conclusion:CT and CAH may be differentiated on the basis of reliable histopathological criteria. Punch biopsy can be performed to avoid CT complication if the clinical diagnosis is true. Choristomas can be clinically confused with true neoplasms, if large in size.

Evaluation of Coincidence of Geographic or Fissured Tongue with Inflammation of Lymphoid Tissue

Introduction: Geographic tongue and fissured tongue are the most common developmental tongue disorders. One of their causes is allergy. Allergy usually is accompanied by different abnormalities such as lymphoid hyperplasia and post nasal discharge (PND). The purpose of this study was assessing coincidence of oral lymphatic condition and PND in patients with geographic or fissured tongue. Materials & methods: This case control study was done on 190 patients referring to oral medicine department of Yazd dental school with convenience sampling method. All patients were divided into two groups, the first group with geographic or fissured tongue and the other one without it. After taking informed consent, all of them were examined for PND and involvement of Waldeyer's lymphatic ring. Finally the results of both groups were compared with Chi-Square test and SPSS 17 software. Findings: 19 persons of examined patients (10%) in this study had tongue tonsils. Involvement of pharyngeal tonsils were seen in 30 and 21 persons in case and control group respectively.According to the results, it was found that, there was a significant relationship between the involvement of Waldeyer's lymphatic ring and the presence of geographic or fissured tongue (Pvalue=.015). 20 persons in case group (21.1%) had PND, and there was no significant relationship between PND and geographic or fissured tongue (Pvalue=.562). Discussion & conclusions: According to significant difference in Waldeyer's lymphatic ring involvement in groups, the probable signs and symptoms of allergy should be considered in these patients. Also, with regular follow up in these susceptible persons well-timed diagnosis and treatment could be achieved.

Targeting VEGFR-3/-2 signaling pathways with AD0157: a potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases

BackgroundLymphatic metastasis is one of the leading causes of death in patients with different types of cancer and is the main prognostic factor for the disease survival. The formation of new lymphatic vessels (lymphangiogenesis) in primary tumors facilitates tumor cell dissemination to regional lymph nodes and correlates with distant metastases. Lymphangiogenesis has thus emerged as a suitable therapeutic target to block metastases, but no anti-lymphangiogenic compounds have been approved for clinical use to date. Therefore, new or improved therapies blocking lymphatic metastases are urgently required.MethodsWe established murine breast tumors to assess the effect of AD0157 on tumor growth, lymphangiogenesis, and lymphatic dissemination. Then, a battery of in vivo (mouse corneal neovascularization and ear sponges), ex vivo (mouse lymphatic rings and rat mesentery explants), and in vitro (proliferation, tubulogenesis, wound-healing, Boyden chambers, and spheroids) assays was used to give insight into the lymphangiogenic steps affected by AD0157. Finally, we investigated the molecular pathways controlled by this drug.ResultsAD0157 was found to inhibit the growth of human breast cancer xenografts in mice, to strongly reduce tumor-associated lymphangiogenesis and to block metastatic dissemination to both lymph nodes and distant organs. The high anti-lymphangiogenic potency of AD0157 was further supported by its inhibitory activity at low micromolar range in two in vivo pathological models and in two ex vivo assays. In addition, AD0157 inhibited lymphatic endothelial cell proliferation, migration and invasion, cellular sprouting, and tube formation. Mechanistically, this compound induced apoptosis in lymphatic endothelial cells and decreased VEGFR-3/-2, ERK1/2, and Akt phosphorylations.ConclusionsThese findings demonstrate the suitability of AD0157 to suppress tumor-associated lymphangiogenesis. Beyond discovering a new potent anti-lymphangiogenic drug that is worth considering in future clinical settings, our study supports the interest of designing anti-lymphangiogenic therapies to avoid distant metastatic processes.

Novel application assigned to toluquinol: inhibition of lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signalling pathway.

Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphoedema and other inflammatory disorders. The development of new drugs that block lymphangiogenesis has become a promising therapeutic strategy. In this study, we investigated the ability of toluquinol, a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004, to inhibit lymphangiogenesis in vitro, ex vivo and in vivo. We used human lymphatic endothelial cells (LECs) to analyse the effect of toluquinol in 2D and 3D in vitro cultures and in the ex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, mouse ear sponges and cornea models were used. Western blotting and apoptosis analyses were carried out to search for drug targets. Toluquinol inhibited LEC proliferation, migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol induced apoptosis of LECs after 14 h of treatment in vitro, blocked the development of the thoracic duct in zebrafish and reduced the VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we demonstrated that this drug attenuates VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependent manner and suppresses the phosphorylation of Akt and ERK1/2. Based on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment of lymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications in vascular ocular pathologies.

Clinical features and prognostic analysis of 66 patients with pharyngeal lymphatic ring diffuse large B-cell lymphoma

Objective To analyze the clinical features, prognosis and its influence factors of pharyngeal lymphatic ring diffuse large B-cell lymphoma. Methods 66 cases diagnosed with pharyngeal lymphatic ring diffuse large B-cell lymphoma were analyzed retrospectively, including 13 nasopharynx cases, 49 tonsil cases and 4 tongue root cases. The patients in Ⅰ-Ⅱ phases were mainly treated with chemotherapy plus involvement wild illuminate, and the patients in Ⅲ-Ⅳ phases were mainly treated with chemotherapy. Results Most patients with pharyngeal lymphatic ring diffuse large B-cell lymphoma were in phase Ⅱ, showing that neighboring organs were infiltrated, but rare systemic symptom, spleen were invaded and lactic acid dehydrogenase was increased. The overall survival rates of 3 and 5 years in patients with pharyngeal lymphatic ring diffuse large B-cell lymphoma were 77.9 % and 66.9 % respectively. The single-factor analysis indicated that the lactic acid dehydrogenase ≥ 248 U/L, the international prognostic index (IPI) score ≥1, and ECOG score ≥2 were the adverse prognosis influence factors. The multiple-factor analysis showed that the IPI score ≥ 1 was related to poor prognosis of pharyngeal lymphatic ring diffuse large B-cell lymphoma. Conclusion Pharyngeal lymphatic ring diffuse large B-cell lymphoma has unique clinical characteristics, and IPI score can influence the prognosis. Key words: Pharyngeal lymphatic ring; Lymphoma, large B-cell, diffuse

Inhibition of TGFBIp expression reduces lymphangiogenesis and tumor metastasis.

Transforming growth factor-β-induced protein (TGFBIp) is an extracellular matrix protein that has a role in a wide range of pathological conditions. However, the role of TGFBIp signaling in lymphangiogenesis is poorly understood. The purpose of this study was therefore to analyze the effects of TGFBIp on lymphangiogenesis and determine whether TGFBIp-related lymphangiogenesis is important for the metastasis of tumor cells. TGFBIp increased adhesion, migration, and morphologic differentiation of human lymphatic endothelial cells (LECs), consistent with an increase in lymphatic vessel sprouting in a three-dimensional lymphatic ring assay. TGFBIp also induced phosphorylation of intracellular signaling molecules SRC, FAK, AKT, JNK and ERK. TGFBIp-induced lymphatic vessel sprouting was inhibited by addition of anti-integrin β3 antibody and pharmacologic inhibitors of FAK, AKT, JNK or ERK. TGFBIp increased both CCL21 expression in LECs, a chemokine that actively recruits tumor cells expressing the cognate chemokine receptors to lymphatic vessels and LEC permeability by inducing the dissociation of VE-cadherin junctions between LECs via the activation of SRC signaling. In vivo, inhibition of TGFBIp expression in SW620 cancer cells dramatically reduced tumor lymphangiogenesis and metastasis. Collectively, our findings demonstrate that TGFBIp is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis.

Bone marrow-derived mesenchymal stem cells drive lymphangiogenesis.

It is now well accepted that multipotent Bone-Marrow Mesenchymal Stem Cells (BM-MSC) contribute to cancer progression through several mechanisms including angiogenesis. However, their involvement during the lymphangiogenic process is poorly described. Using BM-MSC isolated from mice of two different backgrounds, we demonstrate a paracrine lymphangiogenic action of BM-MSC both in vivo and in vitro. Co-injection of BM-MSC and tumor cells in mice increased the in vivo tumor growth and intratumoral lymphatic vessel density. In addition, BM-MSC or their conditioned medium stimulated the recruitment of lymphatic vessels in vivo in an ear sponge assay, and ex vivo in the lymphatic ring assay (LRA). In vitro, MSC conditioned medium also increased the proliferation rate and the migration of both primary lymphatic endothelial cells (LEC) and an immortalized lymphatic endothelial cell line. Mechanistically, these pro-lymphangiogenic effects relied on the secretion of Vascular Endothelial Growth Factor (VEGF)-A by BM-MSC that activates VEGF Receptor (VEGFR)-2 pathway on LEC. Indeed, the trapping of VEGF-A in MSC conditioned medium by soluble VEGF Receptors (sVEGFR)-1, -2 or the inhibition of VEGFR-2 activity by a specific inhibitor (ZM 323881) both decreased LEC proliferation, migration and the phosphorylation of their main downstream target ERK1/2. This study provides direct unprecedented evidence for a paracrine lymphangiogenic action of BM-MSC via the production of VEGF-A which acts on LEC VEGFR-2.