Crohn’s disease as the intestinal manifestation of pan-lymphatic dysfunction:An exploratory proposal based on basic and clinical data

Crohn’s disease(CD)is caused by immune,environmental,and genetic factors.It can involve the entire gastrointestinal tract,and although its prevalence is rapidly increasing its etiology remains unclear.Emerging biological and small-molecule drugs have advanced the treatment of CD;however,a considerable proportion of patients are non-responsive to all known drugs.To achieve a breakthrough in this field,innovations that could guide the further development of effective therapies are of utmost urgency.In this review,we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases,and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data.The supporting evidence is fully summarized,including the existence of lymphatic system dysfunction,recognition of the inside-out model,disorders of immune cells,changes in cell plasticity,partial overlap of the underlying mechanisms,and common gut-derived fatty and bile acid metabolism.Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases,especially CD,as this model is good at presenting and mimicking lymphatic dysfunction.More importantly,the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

Lymphatic plastic bronchitis and primary chylothorax: A study based on computed tomography lymphangiography

BACKGROUND This study presents an evaluation of the computed tomography lymphangio-graphy(CTL)features of lymphatic plastic bronchitis(PB)and primary chylotho-rax to improve the diagnostic accuracy for these two diseases.AIM To improve the diagnosis of lymphatic PB or primary chylothorax,a retrospective analysis of the clinical features and CTL characteristics of 71 patients diagnosed with lymphatic PB or primary chylothorax was performed.METHODS The clinical and CTL data of 71 patients(20 with lymphatic PB,41 with primary chylothorax,and 10 with lymphatic PB with primary chylothorax)were collected retrospectively.CTL was performed in all patients.The clinical manifestations,CTL findings,and conventional chest CT findings of the three groups of patients were compared.The chi-square test or Fisher's exact test was used to compare the differences among the three groups.A difference was considered to be statistically significant when P<0.05.RESULTS(1)The percentages of abnormal contrast medium deposits on CTL in the three groups were as follows:Thoracic duct outlet in 14(70.0%),33(80.5%)and 8(80.0%)patients;peritracheal region in 18(90.0%),15(36.6%)and 8(80.0%)patients;pleura in 6(30.0%),33(80.5%)and 9(90.0%)patients;pericardium in 6(30.0%),6(14.6%)and 4(40.0%)patients;and hilum in 16(80.0%),11(26.8%)and 7(70.0%)patients;and(2)the abnormalities on conven-tional chest CT in the three groups were as follows:Ground-glass opacity in 19(95.0%),18(43.9%)and 8(80.0%)patients;atelectasis in 4(20.0%),26(63.4%)and 7(70.0%)patients;interlobular septal thickening in 12(60.0%),11(26.8%)and 3(30.0%)patients;bronchovascular bundle thickening in 14(70.0%),6(14.6%)and 4(40.0%)patients;localized mediastinal changes in 14(70.0%),14(34.1%),and 7(70.0%)patients;diffuse mediastinal changes in 6(30.0%),5(12.2%),and 3(30.0%)patients;cystic lesions in the axilla in 2(10.0%),6(14.6%),and 2(20.0%)patients;and cystic lesions in the chest wall in 0(0%),2(4.9%),and 2(4.9%)patients.CONCLUSION CTL is well suited to clarify the characteristics of lymphatic PB and primary chylothorax.This method is an excellent tool for diagnosing these two diseases.

Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases

Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.

Roles of cancer-associated fibroblast functional heterogeneity in shaping the lymphatic metastatic landscape:new insights and therapeutic strategies

Lymph node (LN) metastasis is a process in which cancer cells travel from primary tumors to LNs via the lymphatic system,then proliferate and spread within the LNs. In most cancers,LN metastasis is a major mode of cancer dissemination,and a critical indicator of cancer progression and worsening prognosis1. The occurrence of LN metastasis indicates that the tumor has invaded the lymphatic system.

Promising outcomes 5 weeks after a surgical cervical shunting procedure to unclog cerebral lymphatic systems in a patient with Alzheimer’s disease

Recently,the glymphatic system has been recognised as an important‘waste solutes transport channel’within the brain.1 Studies have shown that blockage of the glymphatic system leads to increased beta-amyloid deposits,accelerating the onset and progression of Alzheimer’s disease(AD).12 Given that cervical lymph nodes receive cerebrospinal fluid from the brain’s glymphatic system,34 we speculated that decompression of the lymphatic trunk and cervical lymphatic-venous anastomosis(LVA)could facilitate the flow of cerebrospinal fluid in the cranial glymphatic system,potentially accelerating the clearance of harmful beta-amyloid and tau proteins.We collaborated with surgeons who specialise in LVA supermicrosurgery for maxillofacial tumours and lymphoedema to develop a procedure to relieve the blockage of the glymphatic system.This surgery employs supermicrosurgery techniques to create LVA connecting the bilateral cervical,deep lymphatic vessels to the veins,resulting in lymphatic trunk decompression,which allows the lymph fluid in the high-pressure lymphatic vessels to flow into the low-pressure venous system.The goal of the minimally invasive surgery is to enhance the removal of proteins,such as beta-amyloid and tau,from the brain’s lymphatic systems to the maxillofacial lymphatic vessels,unclogging protein blockages within the brain.This extracranial procedure is safer than intracranial approaches.

Clinical approach for pulmonary lymphatic disorders

In this editorial,we discuss the clinical implications of the article“Lymphatic plastic bronchitis and primary chylothorax:A study based on computed tomography lymphangiography”published by Li et al.Pulmonary lymphatic disorders involve abnormalities in the lymphatic tissues within the thoracic cavity.Specifically,pulmonary lymphatic perfusion syndrome describes a condition where the flow of lymphatic fluid in the lungs is redirected towards abnormally widened lymphatic vessels.Clinically,individuals with this syn-drome may experience symptoms such as chyloptysis,plastic bronchitis(PB),chylothorax,chylopericardium,and interstitial lung disease.These disorders can be caused by various factors,including PB,chylothorax,and complex lymphatic malformations.Advancements in lymphatic imaging techniques,such as in-tranodal lymphangiography,computed tomography lymphangiography,and dynamic contrast-enhanced magnetic resonance lymphangiography,have enabled the detection of abnormal lymphatic flow.This has enhanced our understanding of the pathophysiology of these conditions.Additionally,innovative minimally invasive treatments,such as thoracic duct embolization,selective embolization of lymphatic channels,and surgical procedures aim to improve clinical condition of patients and address their dietary needs.

Functional aspects of the brain lymphatic drainage system in aging and neurodegenerative diseases

The phenomenon of an aging population is advancing at a precipitous rate.Alzheimer's disease(AD)and Parkinson's disease(PD)are two of the most common age-associated neurodegenerative diseases,both of which are primarily characterized by the accumulation of toxic proteins and the progressive demise of neuronal structures.Recent discoveries about the brain lymphatic drainage system have precipitated a growing body of investigations substantiating its novel roles,including the clearance of macromolecular waste and the trafficking of immune cells.Notably,aquaporin 4-mediated glymphatic transport,crucial for maintaining neural homeostasis,becomes disrupted during the aging process and is further compromised in the pathogenesis of AD and PD.Functional meningeal lymphatic vessels,which facilitate the drainage of cerebrospinal fluid into the deep cervical lymph nodes,are integral in bridging the central nervous system with peripheral immune responses.Dysfunction in these meningeal lymphatic vessels exacerbates pathological trajectory of the age-related neurodegenerative disease.This review explores modulatory influence of the glymphatic system and meningeal lymphatic vessels on the aging brain and its associated neurodegenerative disorders.It also encapsulates the insights of potential mechanisms and prospects of the targeted non-pharmacological interventions.

Combination of manual lymphatic drainage and Kinesio taping for treating pigmented villonodular synovitis:A case report

BACKGROUND Pigmented villonodular synovitis(PVNS)is a benign proliferative disorder that affects the synovial joints,bursae,and tendon sheaths.To date,few studies have reported on the treatment of postoperative pain and edema in patients with PVNS.Herein,we present the case of a woman who developed pain and edema in the left lower limb 1 wk after synovectomy and arthroscopic partial meniscectomy and was unable to walk due to limited flexion and extension of the left knee.CASE SUMMARY A 32-year-old woman underwent synovectomy and arthroscopic partial meniscectomy successively and was treated with a combination of manual lymphatic drainage(MLD)and kinesio taping(KT)in our hospital to alleviate postoperative pain and edema.The following parameters were assessed at 2 wk post-treatment and 1 wk post-discharge follow up:suprapatellar circumference,infrapatellar circumference,visual analog scale score,knee range of motion,pittsburgh sleep quality index score,hamilton anxiety rating scale(HAMA)score,and hamilton depression rating scale(HAMD)score.After treatment,the postoperative pain and edema in the patient’s left knee were effectively relieved,resulting in improved sleep quality and remarkably attenuated HAMA and HAMD scores.CONCLUSION Combined MLD and KT may be an effective approach for relieving postoperative pain and edema in patients with PVNS.

Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma:A comprehensive review

The tumor microenvironment is a complex network of cells,extracellular matrix,and signaling molecules that plays a critical role in tumor progression and metastasis.Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits.However,recent studies have shown that lymphatic endothelial cells(LECs)and blood endothelial cells(BECs)also play multifaceted roles in the tumor microenvironment beyond their structural functions,particularly in hepatocellular carcinoma(HCC).This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC,including their involvement in angiogenesis,immune modulation,lymphangiogenesis,and metastasis.By providing a detailed account of the complex interplay between LECs,BECs,and tumor cells,this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.

The lymphatic drainage systems in the brain:a novel target for ischemic stroke?

Recent studies have proposed three lymphatic drainage systems in the brain,that is,the glymphatic system,the intramural periarterial drainage pathway,and meningeal lymphatic vessels,whose roles in various neurological diseases have been widely explored.The glymphatic system is a fluid drainage and waste clearance pathway that utilizes perivascular space and aquaporin-4 protein located in the astrocyte endfeet to provide a space for exchange of cerebrospinal fluid and interstitial fluid.The intramural periarterial drainage pathway drives the flow of interstitial fluid through the capillary basement membrane and the arterial tunica media.Meningeal lymphatic vessels within the dura mater are involved in the removal of cerebral macromolecules and immune responses.After ischemic stroke,impairment of these systems could lead to cerebral edema,accumulation of toxic factors,and activation of neuroinflammation,while restoration of their normal functions can improve neurological outcomes.In this review,we summarize the basic concepts of these drainage systems,including drainage routes,physiological functions,regulatory mechanisms,and detection technologies.We also focus on the roles of lymphatic drainage systems in brain injury after ischemic stroke,as well as recent advances in therapeutic strategies targeting these drainage systems.These findings provide information for potential novel strategies for treatment of stroke.

Elimination of lymphatic filariasis:Where do we stand so far?

Lymphatic filariasis(LF),an asymptomatic,acute,and chronic condition in human beings,is the second most common vector-borne disease after malaria.According to the World Health Organization,there are 120 million LF cases detected in 81 tropical and subtropical countries,and one billion people are at risk.Therefore,the Global Program to Eliminate Lymphatic Filariasis was launched in 2000,with the primary objective of stopping LF transmission among all at-risk groups using mass drug administration(MDA),managing morbidities,and preventing LF-related impairments using a minimum treatment package.Additionally,other programs such as epidemiological assessment including National Filaria Control Program and World Health Organization recommended routine and pre-MDA microfilaremia surveys also implemented to stop the LF transmission.The routine filaria surveys were also carried out in around 2000-4000 individuals/month throughout the year whereas pre-MDA surveys were also conducted every year in approximately 4000 individuals in four fixed and four random sites.Furthermore,the Transmission Assessment Survey was also conducted to check the risk of LF among primary school children.Moreover,potential diagnostic methods,systematic surveillance regimes,the Direct Network Report system,and regular trainings and awareness may be also effective in preventing the recurrence of LF.Hence,this review emphasizes the potential advocacy tools and various strategies as well as procedures for monitoring,which could be impactful in eliminating LF.

The lymphatic system:a therapeutic target for central nervous system disorders

The lymphatic vasculature forms an organized network that covers the whole body and is involved in fluid homeostasis,metabolite clearance,and immune surveillance.The recent identification of functional lymphatic vessels in the meninges of the brain and the spinal cord has provided novel insights into neurophysiology.They emerge as major pathways for fluid exchange.The abundance of immune cells in lymphatic vessels and meninges also suggests that lymphatic vessels are actively involved in neuroimmunity.The lymphatic system,through its role in the clearance of neurotoxic proteins,autoimmune cell infiltration,and the transmission of pro-inflammatory signals,participates in the pathogenesis of a variety of neurological disorders,including neurodegenerative and neuroinflammatory diseases and traumatic injury.Vascular endothelial growth factor C is the master regulator of lymphangiogenesis,a process that is critical for the maintenance of central nervous system homeostasis.In this review,we summarize current knowledge and recent advances relating to the anatomical features and immunological functions of the lymphatic system of the central nervous system and highlight its potential as a therapeutic target for neurological disorders and central nervous system repair.

HSP90AA1 promotes lymphatic metastasis of hypopharyngeal squamous cell carcinoma by regulating epithelial-mesenchymal transition

Lymphatic metastasis(LM)emerges as an independent prognostic marker for hypopharyngeal squamous cell carcinoma(HSPSCC),chiefly contributing to treatment inefficacy.This study aimed to scrutinize the prognostic relevance of HSP90AA1 and its potential regulatory mechanism of concerning LM in HPSCC.Methods:In a preceding investigation,HSP90AA1,a differential gene,was discovered through transcriptome sequencing of HPSCC tissues,considering both the presence and absence of LM.Validation of HSP90AA1 expression was accomplished via qRT-PCR,western-blotting(WB),and immunohistochemistry(IHC),while its prognostic significance was assessed employing Kaplan–Meier survival analysis(KMSA),log-rank test(LR),and Cox’s regression analysis(CRA).Bioinformatics techniques facilitated the prediction and analysis of its plausible mechanisms in LM,further substantiated by in vitro and in vivo experiments utilizing FaDu cell lines.Results:HSP90AA1 is substantially upregulated in HPSCC with LM and is identified as an independent prognostic risk determinant.The down-regulation of HSP90AA1 can achieve inhibition of tumor cell proliferation,migration and invasion.Both in vivo experiments and Bioinformatics exploration hint at promoting LM by Epithelial-mesenchymal transition(EMT),regulated by HSP90AA1.Conclusions:HSP90AA1,by controlling EMT,can foster LM in HPSCC.This finding sets the foundation for delving into new therapeutic targets for HPSCC.

Expression and Evaluation of Wb-SXP-1 and Wb-123 Recombinant Antigens as Potential Diagnostic Biomarkers for Lymphatic Filariasis

Lymphatic filariasis (LF) remains a public health concern as it can cause permanent morbidity and disability to those infected. While the global elimination of LF in these endemic areas is ongoing through mass drug administration, there is the need to develop diagnostic tools that would be utilized to track the progress of total global eradication as well as perform surveillance for the recurrence of lymphatic filariasis transmission. Currently, approved LF diagnosis tools are faced with lack of specificity, low sensitivity, and periodicity dependence. Recombinant filarial antigen-based assays can address these drawbacks and offer practical instruments for LF diagnosis and surveillance. This present study, evaluated rWb-SXP-1 and rWb-123 antigens as potential diagnostic biomarker tools for Wuchereria banchrofti in human sera using microspheres-based multiplex serological assay. Based on statistical analysis using XLSTAT 2019 (Addinsoft) on data generated from multiplex technology assay, generated ROC curves for both rWb-SXP-1 and rWb-123 demonstrated 87.1% sensitivity to Wuchereria banchrofti human sera with rWb-SXP-1 antigens having the highest specificity of 96%. Indication that rWb-SXP-1 and rWb-123 antigens are capable of detecting immunoglobulin G4 (IgG4) antibodies in human sera synthesized specifically against W. banchrofti infections. Therefore, rWb-SXP-1 and rWb-123 antigens can be utilized to detect W. banchrofti infections by antibody profiling with excellent diagnostic sensitivity and specificity using microsphere-based multiplex serological tests. This method can be particularly practical for screening a large number of sera samples and/or for quick, extensive field-testing due to the high-throughput and quick formats applied.

Extracellular vesicle-mediated heterogeneous communication between cancer and the lymphatic system facilitates lymphatic metastasis

Introduction The dissemination of cancer cells to organs initiates the formation of an aggressive cancer phenotype and is a predominant cause of cancer-associated death.For most epithelial cancers,lymphatic system metastasis has been characterized as the most common and earliest metastatic pathway,and the detection of metastasis in lymph nodes(LNs)often predicts poor survival among patients'.Although increasing attention is being paid to the clinical importance of LN metastasis,the underlying mechanisms have remained unclear in the past decade.Accumulating evidence suggests that the occurrence of LN metastasis is not stochastic but is a programming biological event regulated by the bidirectional crosstalk between metastasis-initiating cancer cells and the tumor microenvironment(TME)2.However,the regulators and patterns of cancer-TME communication in LN metastasis remain to be furtherexplored.

Elimination of lymphatic filariasis-Challenging but not impossible

We recently went through your article titled“Elimination of lymphatic filariasis:Where do we stand so far?”by Aashna Sinha et al[1].The authors have brought about relevant information regarding lymphatic filariasis focussing on history,diagnostic aspects,treatment strategies and various control measures.Lymphatic filariasis is a neglected parasitic infection affecting millions of people worldwide.

Is lymphatic invasion of microrectal neuroendocrine tumors an incidental event?:A case report

BACKGROUND A rectal neuroendocrine tumor(rNET)is a malignant tumor originating from neuroendocrine cells.Currently,tumor size is the primary basis for assessing tumor risk.CASE SUMMARY This article reports the case of a 46-year-old male patient who underwent a colonoscopy that found a 3 mm rectal polypoid bulge.The pathological examination of a sample collected with biopsy forceps revealed a neuroendocrine tumor.Further endoscopic submucosal dissection rescue therapy was used.The presence of lymphatic vessels indicated that the tumor had infiltrated the negative resection margin.The lesion was located in the distal rectum near the anal canal.Therefore,to ensure the patient’s quality of life,follow-up observation was conducted after full communication with the patient.No tumor recurrence or distant metastasis has been found during the 13-mo follow-up after surgery.CONCLUSION Despite the presence of lymphatic invasion and extremely small diameter rNETs in our case,this phenomenon may not imply a higher risk of distant lymph node and organ metastasis.

Prediction of the lymphatic,microvascular,and perineural invasion of pancreatic neuroendocrine tumors using preoperative magnetic resonance imaging

BACKGROUND Significant correlation between lymphatic,microvascular,and perineural invasion(LMPI)and the prognosis of pancreatic neuroendocrine tumors(PENTs)was confirmed by previous studies.There was no previous study reported the relationship between magnetic resonance imaging(MRI)parameters and LMPI.AIM To determine the feasibility of using preoperative MRI of the pancreas to predict LMPI in patients with non-functioning PENTs(NFPNETs).METHODS A total of 61 patients with NFPNETs who underwent MRI scans and lymphadenectomy from May 2011 to June 2018 were included in this retrospective study.The patients were divided into group 1(n=34,LMPI negative)and group 2(n=27,LMPI positive).The clinical characteristics and qualitative MRI features were collected.In order to predict LMPI status in NF-PNETs,a multivariate logistic regression model was constructed.Diagnostic performance was evaluated by calculating the receiver operator characteristic(ROC)curve with area under ROC,sensitivity,specificity,positive predictive value(PPV),negative predictive value(NPV)and accuracy.RESULTS There were significant differences in the lymph node metastasis stage,tumor grade,neuron-specific enolase levels,tumor margin,main pancreatic ductal dilatation,common bile duct dilatation,enhancement pattern,vascular and adjacent tissue involvement,synchronous liver metastases,the long axis of the largest lymph node,the short axis of the largest lymph node,number of the lymph nodes with short axis>5 or 10 mm,and tumor volume between two groups(P<0.05).Multivariate analysis showed that tumor margin(odds ratio=11.523,P<0.001)was a predictive factor for LMPI of NF-PNETs.The area under the receiver value for the predictive performance of combined predictive factors was 0.855.The sensitivity,specificity,PPV,NPV and accuracy of the model were 48.1%(14/27),97.1%(33/34),97.1%(13/14),70.2%(33/47)and 0.754,respectively.CONCLUSION Using preoperative MRI,ill-defined tumor margins can effectively predict LMPI in patients with NF-PNETs.

Lymphatic spreading and lymphadenectomy for esophageal carcinoma

Esophageal carcinoma(EC) is a highly lethal malignancywith a poor prognosis. One of the most important prognostic factors in EC is lymph node status. Therefore, lymphadenectomy has been recognized as a key that influences the outcome of surgical treatment for EC. However, the lymphatic drainage system of the esophagus, including an abundant lymph-capillary network in the lamina propria and muscularis mucosa, is very complex with cervical, mediastinal and celiac node spreading. The extent of lymphadenectomy for EC has always been controversial because of the very complex pattern of lymph node spreading. In this article, published literature regarding lymphatic spreading was reviewed and the current lymphadenectomy trends for EC are discussed.

Lymphangiogenesis, Lymphatic Endothelial Cells and Lymphatic Metastasis in Head and Neck Cancer—A Review of Mechanisms

Lymphatic metastasis is a continuous and complicated process. The detailed mechanisms of lymphatic metastasis are still not very clear, despite considerable research efforts in recent years. Previously, it was commonly accepted that there were no lymphatic vessels in the primary tumor. However, recent studies have demonstrated that lymphatic vessels are detectable in certain types of cancer, and more and more evidence has shown that cancer cells invade into local lymph nodes mainly via peritumoral lymphatic vessels, Moreover, activated endothelial cells may also be important, having an influence on lymphatic metastasis of cancer cells. This article, based on recent research findings, provides an in-depth discussion of the relationship between lymphangiogenesis, tumor-derived lymphatic endothelial cells and lymphatic metastasis in head and neck cancer.