Nerve Infiltration Research Articles

Sciatic and median nerve neurolymphomatosis as initial presentation of B-cell lymphoma

Neurolymphomatosis (NL) is the infiltration of cranial nerves or nerves and roots from the peripheral nervous system by lymphoma, usually by B-cell non-Hodgkin’s lymphoma. It is uncommon as initial presentation of the disease and can lead to extremely heterogeneous clinical manifestations. We report the case of a 72-year old male who presented with numbness of the right hand, progressive weakness in both lower limbs and weight loss. 18F-FDG PET/CT showed bilateral hypermetabolic adrenal masses, gastric ulcer, small hypermetabolic adenopathies, multiple focal bone marrow uptake and intense uptake in both sciatic nerves and right median nerve. A node and gastric biopsy confirmed diffuse large-B-cell lymphoma, activated B cell type, with posterior resolution of peripheral nerves uptake after beginning chemotherapy.

Optic nerve infiltration by large B-cell lymphoma

Optic nerve infiltration by large B-cell lymphoma

Interaction of Neurovascular Signals in the Degraded Condylar Cartilage.

Introduction: Degradation of the condylar cartilage during temporomandibular joint osteoarthritis (TMJ-OA) results in the infiltration of nerves, blood vessels and inflammatory cells from the subchondral bone into the cartilage. The interaction among innervation, angiogenesis and inflammation in the condylar cartilage of TMJ-OA remains largely unknown. Method: In the present study, microarray-based transcriptome analysis was used to detect, and quantitative real-time polymerase chain reaction was used to validate transcriptome changes in the condylar cartilage from a well-established rat TMJ-OA model. Gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) pathway and protein-protein interaction (PPI) analyses were conducted. Result: There were 1817 differentially expressed genes (DEGs, fold change ≥2, p < 0.05) between TMJ-OA and control cartilages, with 553 up-regulated and 1,264 down-regulated genes. Among those genes, representative DEGs with known/suspected roles in innervation, angiogenesis and inflammation were further validated by enriched GO terms and KEGG pathways. The DEGs related to innervation were predominately enriched in the GO terms of neurogenesis, generation of neurons, and KEGG pathways of cholinergic synapse and neurotrophin signaling. Genes related to angiogenesis were enriched in GO terms of vasculature and blood vessel development, and KEGG pathways of hypoxia-inducible factor 1 (HIF-1) pathway and calcium signaling pathway. For inflammation, the DEGs were enriched in the GO terms of immune system process and immune response, and KEGG pathways of Toll-like receptor and transforming growth factor β (TGFβ) signaling. Analysis with PPI indicated that the aforementioned DEGs were highly-interacted. Several hub genes such as v-akt murine thymoma viral oncogene homolog 1 (Akt1), glycogen synthase kinase 3β (Gsk3b), fibroblast growth factor 2 (Fgf2) and nerve growth factor receptor (Ngfr) were validated. Conclusion: The present study demonstrated, for the first time, that intimate interactions exist among innervation, angiogenesis and inflammation in the condylar cartilage of TMJ-OA.

Case report: atypical, unilateral optic nerve infiltration as the first sign of acute lymphoblastic leukemia (ALL) relapse

BackgroundWe describe a case of an atypical presentation of leukemic optic nerve infiltration.Case presentationA patient with acute lymphoblastic leukemia (ALL) in remission suffered from sudden right eye vision loss. At the time of presentation, the affected eye presented with an afferent pupillary defect, while the fundus examination was normal. A complete work up of the patient revealed no signs of ALL relapse, but MR imaging of the optic nerve showed contrast agent uptake consistent with optic nerve infiltration. The patient developed a fulminant ALL relapse and died shortly after. Histology of the optic nerve showed a leukemic infiltration with CD10 positive cells.ConclusionsThis is the first report of an ALL relapse in the optic nerve without intraocular signs. Patients’ medical history should therefore be taken into consideration in patients with unclear vision loss.

Sex-Specific B Cell and Anti-Myelin Autoantibody Response After Peripheral Nerve Injury.

Immunotherapy holds promise as a non-addictive treatment of refractory chronic pain states. Increasingly, sex is recognized to impact immune regulation of pain states, including mechanical allodynia (pain from non-painful stimulation) that follows peripheral nerve trauma. This study aims to assess the role of B cells in sex-specific responses to peripheral nerve trauma. Using a rat model of sciatic nerve chronic constriction injury (CCI), we analyzed sex differences in (i) the release of the immunodominant neural epitopes of myelin basic protein (MBP); (ii) the levels of serum immunoglobulin M (IgM)/immunoglobulin G (IgG) autoantibodies against the MBP epitopes; (iii) endoneurial B cell/CD20 levels; and (iv) mechanical sensitivity behavior after B cell/CD20 targeting with intravenous (IV) Rituximab (RTX) and control, IV immunoglobulin (IVIG), therapy. The persistent MBP epitope release in CCI nerves of both sexes was accompanied by the serum anti-MBP IgM autoantibody in female CCI rats alone. IV RTX therapy during CD20-reactive cell infiltration of nerves of both sexes reduced mechanical allodynia in females but not in males. IVIG and vehicle treatments had no effect in either sex. These findings provide strong evidence for sexual dimorphism in B-cell function after peripheral nervous system (PNS) trauma and autoimmune pathogenesis of neuropathic pain, potentially amenable to immunotherapeutic intervention, particularly in females. A myelin-targeted serum autoantibody may serve as a biomarker of such painful states. This insight into the biological basis of sex-specific response to neuraxial injury will help personalize regenerative and analgesic therapies.

Analysis of the related risk factors of inguinal lymph node metastasis in patients with penile cancer: A cross-sectional study.

ABSTRACTPurpose:To determine independent predictors of inguinal lymph node (ILN) metastasis in patients with penile cancer.Patients and methods:We retrospectively analyzed all patients with penile cancer who underwent surgery at our medical center in the last ten years (n=157). Using univariate and multivariate logistic-regression models, we assessed associations with age, medical-history, phimosis, onset-time, number and maximum diameter of involved ILNs measured by imaging, pathological T stage, degree of tumor differentiation and/or cornification, lymphatic vascular infiltration (LVI), nerve infiltration, and ILN metastases. Interaction and stratified analyses were used to assess age, phimosis, onset time, number of ILNs, cornification, and nerve infiltration.Results:A total of 110 patients were included in the study. Multiple logistic regression analysis showed that the following factors were significantly correlated with ILN metastasis: maximum diameter of enlarged ILNs, T stage, pathological differentiation, and LVI. Among patients with a maximum ILN diameter ≥1.5cm, 50% had lymph node metastasis whereas 30.6% patients with a maximum ILN diameter <1.5cm showed LNM. Among 44 patients with stage Ta/T1, 10 showed ILN metastases, while 47.0% patients with stage T2 showed ILN metastases. Among 40 patients with highly differentiated penile-cancer, eight showed ILN metastasis, while 47.1% patients with low-to-middle differentiation showed ILN metastases. The rate of LNM was 33.3% in the LVI-free group and 64.3% in the LVI group.Conclusion:Our single-center results suggested that maximum ILN diameter, pathological T stage, pathological differentiation, and LVI were independent risk factors for ILN metastases.

Unilateral Sciatic Nerve Crush Induces White Blood Cell Infiltration of the Contralateral Nerve.

Nerve injury leads to the accumulation of white blood cells derived from the bone marrow in the lesioned nerve, but it is still unknown whether there are similar responses in unlesioned nerves. To address this question, sciatic nerves of mice expressing enhanced green fluorescent protein (EGFP) in their bone marrow were crushed unilaterally to observe the invasion of bone marrow-derived cells into the contralateral unlesioned nerve. Two days after surgery, EGFP+ cells began to infiltrate both the damaged and undamaged nerves. These cells gradually amplified to the highest point within 14 days and slowly lowered. In ipsilateral (lesioned) and contralateral (unlesioned) nerves, the time course of infiltration of EGFP+ cells was similar, but the magnitude was much less for the unlesioned one. Through CD68 staining, some cells were identified as macrophages. Transmission electron microscopy revealed slight demyelination and phagocytosing macrophages in the contralateral nerve. The data showed that infiltration by white blood cells is a response to nerve injury, even in uninjured nerves.

The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

Collaborative studies of U.S.-China neurologists on acute motor axonal neuropathy.

Collaborative studies of U.S.-China neurologists on acute motor axonal neuropathy.

Neoplastic nerve lesions.

Though metastasis and malignant infiltration of the peripheral nervous system is relatively rare, physicians should have a familiarity with their presentations to allow for prompt diagnosis and initiation of treatment. This article will review the clinical presentations, diagnostic evaluation, and treatment of neoplastic involvement of the cranial nerves, nerve roots, peripheral nerves, and muscle. Due to the proximity of the neural structure traversing the skull base, metastasis to this region results in distinctive syndromes, most often associated with breast, lung, and prostate cancer. Metastatic involvement of the nerve roots is uncommon, apart from leptomeningeal carcinomatosis and bony metastasis with resultant nerve root damage, and is characterized by significant pain, weakness, and numbness of an extremity. Neoplasms may metastasize or infiltrate the brachial and lumbosacral plexuses resulting in progressive and painful sensory and motor deficits. Differentiating neoplastic involvement from radiation-induced injury is of paramount importance as it dictates treatment and prognosis. Neurolymphomatosis, due to malignant lymphocytic infiltration of the cranial nerves, nerve roots, plexuses, and peripheral nerves, deserves special attention given its myriad presentations, often mimicking acquired demyelinating neuropathies.

Autophagic Schwann cells promote perineural invasion mediated by the NGF/ATG7 paracrine pathway in pancreatic cancer

BackgroundPerineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated.MethodsTo investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion (DRG) coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08–2750(RO) and the autophagy inhibitor Chloroquine (CQ) were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.ResultsSC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.ConclusionsPanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a “nerve-repair like effect”, induce a high level of autophagy of cancer cells, provide a “beacon” for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.

Progressive Retinal and Optic Nerve Damage in a Mouse Model of Spontaneous Opticospinal Encephalomyelitis.

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) are antibody mediated CNS disorders mostly affecting the optic nerve and spinal cord with potential severe impact on the visual pathway. Here, we investigated inflammation and degeneration of the visual system in a spontaneous encephalomyelitis animal model. We used double-transgenic (2D2/Th) mice which develop a spontaneous opticospinal encephalomyelitis (OSE). Retinal morphology and its function were evaluated via spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG) in 6- and 8-week-old mice. Immunohistochemistry of retina and optic nerve and examination of the retina via RT-qPCR were performed using markers for inflammation, immune cells and the complement pathway. OSE mice showed clinical signs of encephalomyelitis with an incidence of 75% at day 38. A progressive retinal thinning was detected in OSE mice via SD-OCT. An impairment in photoreceptor signal transmission occurred. This was accompanied by cellular infiltration and demyelination of optic nerves. The number of microglia/macrophages was increased in OSE optic nerves and retinas. Analysis of the retina revealed a reduced retinal ganglion cell number and downregulated Pou4f1 mRNA expression in OSE retinas. RT-qPCR revealed an elevation of microglia markers and the cytokines Tnfa and Tgfb. We also documented an upregulation of the complement system via the classical pathway. In summary, we describe characteristics of inflammation and degeneration of the visual system in a spontaneous encephalomyelitis model, characterized by coinciding inflammatory and degenerative mechanisms in both retina and optic nerve with involvement of the complement system.

The Offprint of an Abnormal Pre-Parotidectomy Electrodiagnostic Finding in a Normally Functioning Facial Nerve: Correlation with Intraoperative Findings, Histology and Postoperative Facial Nerve Function.

The aim of this study was to search for associations between an electrodiagnostically abnormal but clinically normal facial nerve before parotidectomy and the intraoperative findings, as well as the postoperative facial nerve function. The records of all patients treated for parotid tumors between 2002 and 2021 with a preoperative House–Brackmann score of grade I but an abnormal electrophysiologic finding were studied retrospectively. A total of 285 patients were included in this study, and 222 patients had a benign lesion (77.9%), whereas 63 cases had a malignant tumor (22.1%). Electroneurographic facial nerve involvement was associated with nerve displacement in 185 cases (64.9%) and infiltration in 17 cases (6%). In 83 cases (29.1%), no tumor–nerve interface could be detected intraoperatively. An electroneurographic signal was absent despite supramaximal stimulation in 6/17 cases with nerve infiltration and in 17/268 cases without nerve infiltration (p < 0.001). The electrophysiologic involvement of a normal facial nerve is not pathognomonic for a malignancy (22%), but it presents a rather rare (~6%) sign of a “true” nerve infiltration and could also appear in tumors without any contact with the facial nerve (~29%). Of our cases, two thirds of those with an anatomic nerve preservation and facial palsy had already directly and postoperatively recovered to a major extent in the midterm.

Infiltrative optic neuropathy: A neuro-oncological emergency

Acute lymphoblastic leukemia (ALL) is a disorder caused by the abnormal proliferation of immature lymphocytes. Of the varied ocular manifestations seen in ALL, infiltration of the optic nerve is a rare and serious complication that heralds a relapse of the disease. It requires a high index of suspicion for diagnosis. Urgent intervention may prove to be lifesaving. We describe a case of optic neuropathy in a 12-year-old boy with ALL and wish to emphasize the need to maintain a low threshold for diagnosing optic nerve infiltration in patients with a prior history of leukemia.

Recurrence of Lymphoblastic Leukemia Manifesting as Bilateral Optic Disk Neovascularization During Complete Clinical Remission--Case Report

<i>Background</i>: The intraocular manifestations of leukemia are diverse. The retina is the most common ophthalmic involvement site. The most common retinal manifestations of acute lymphoblastic leukemia (ALL) include dilated and tortuous vessels, serous retinal detachment (SRD), intraretinal hemorrhages as well as roth spots. Optic nerve infiltration and retinal neovascularization are unusual, especially in complete clinical remission of ALL. However, neovascularization in optic disk has not been observed in ALL during complete clinical remission. <i>Objective</i>: To report clinical characteristics of a bilateral optic disk neovascularization associated with relapse of ALL. <i>Method</i>: A 31-year-old male with ALL after having reached complete remission from chemotherapy complained about a vision loss in both eyes. First examination showed that best corrected visual acuity (BCVA) was 20/200 for his right eye and 20/160 for his left eye, respectively. Fundus examination revealed bilateral profound optic disk edema with multiple yellow-white exudates and retinal hemorrhages. Optical coherence tomography (OCT) showed bilateral optic disk edema and SRD in both maculas. Fundus fluorescein angiography (FFA) showed bilateral optic disk neovascularization. All these changes were present in remission. The patient received intravitreal Conbercept injection 0.5 mg (10 mg/ml) in both eyes for once on June 29, 2019. Optic disk neovascularization resolved three weeks after treatment. BCVA improved to 20/200 in his right eye, but still light perception in his right eye. No optic disk neovascularization recurrence was observed in 3-month follow-up. BCVA of the right eye maintained 20/200 at the latest follow-up. After intravitreal injection for 4 months the patient suffered from cerebral hemorrhage. He received bone marrow biopsy and cerebrospinal fluid sampling. The results showed relapse in hemogram and lymphocytes in central nervous system (CNS). Therefore, the chemotherapy treatment did not cause a new remission of the disease and the patient failed to recover. <i>Conclusion</i>: Optic disk neovascularization may appear as a sign of extramedullary relapse of ALL months in advance of the hematologic relapse. Intravitreal injection of conbercept could be beneficial and safe in treating this neovascularization.

The clinical diagnostic value of plasma miR-592 and miR-217-3p levels in retinoblastoma.

This study was designed to investigate the abnormal expression of plasma miR-592 and miR-217-3p in retinoblastoma (Rb) and explore the clinical diagnostic value of their expression levels for Rb. The 100 Rb patients who came to Nanchang Hongdu Hospital of Traditional Chinese Medicine from January 2018 to January 2019 were selected as the Rb group, and 100 healthy patients who came to the physical examination centre during the same period were selected as the control group. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression levels of plasma miR-592 and miR-217-3p in all subjects; analyse the relationship between plasma miR-592 and miR-217-3p levels and the clinicopathological characteristics of Rb. Pearson correlation analysis evaluated the relationship between plasma miR-592 and miR-217-3p levels and overall survival. Plasma levels of miR-592 and miR-217-3p in the Rb group were significantly higher than those in the control group (p<0.0001), and the expression of miR-592 was significantly correlated with family genetic history (p 0.0001), tumour bias (p=0.0081), lymph node metastasis (p=0.0048) and pathological grade (p=0.0025), and the expression of miR-217-3p was significantly related to family genetic history (p 0.0001), optic nerve infiltration (p 0.0001), lymph node metastasis (p=0.0090), and pathological grade (p 0.0001). The high expression of miR-592 and miR-217-3p presents a more serious pathological manifestation of Rb, and the overall survival of patients is significantly shortened with the increase of miR-592 (r=-0.2276, p=0.0052) and miR-217-3p levels (r=-0.6461, p 0.0001). and miR-217-3p are highly expressed in the plasma of Rb patients, and their elevated levels present severe pathological manifestations of Rb and shortened overall survival, which is expected to become biomarkers for clinical diagnosis of Rb.

The role of optical coherence tomography in the diagnosis of the leukemic infiltration of the optic nerve and retina

Even though there are multiple diseases of the optic nerve and the retina in patients with hemoblastosis, their ophthalmoscopic picture is similar in many respects. The purpose of this study is to determine the role of optical coherence tomography (OCT) in the differential diagnosis of various manifestations of hemoblastosis in the fundus. Material and methods. From Jan. 2015 to Jan. 2019, 9 patients (5 men and 4 women aged 29 to 72) with hemoblastosis and lesions of the optic nerve and retina were examined. Results. 5 patients were diagnosed with leukemic infiltration of the optic nerve. The remaining 4 patients had, congestive optic discs (1), occlusion of the central retinal vein (1), anterior ischemic optic neuropathy (1), and bilateral occlusion of the central retinal artery with leukemic infiltration of eye membranes (1). The article describes the ophthalmoscopic pictures and OCT data for the specific diseases. Unlike other diseases of the optic nerve and retina, leukemic infiltration is characterized by a pronounced dense edema in the inner layers of the retina with shielding of the underlying outer layers of the retina. Conclusion. OCT is an important additional method for differential diagnosis of leukemic infiltration and other diseases of the optic nerve and retina in patients with hemoblastosis.

LPA1 signaling drives Schwann cell dedifferentiation in experimental autoimmune neuritis

BackgroundLysophosphatidic acid (LPA) is a pleiotropic lipid messenger that addresses at least six specific G-protein coupled receptors. Accumulating evidence indicates a significant involvement of LPA in immune cell regulation as well as Schwann cell physiology, with potential relevance for the pathophysiology of peripheral neuroinflammation. However, the role of LPA signaling in inflammatory neuropathies has remained completely undefined. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN).MethodsWe induced active EAN by inoculation of myelin protein 2 peptide (P255–78) in female Lewis rats. Animals received the orally available LPA receptor antagonist AM095, specifically targeting the LPA1 receptor subtype. AM095 was administered daily via oral gavage in a therapeutic regimen from 10 until 28 days post-immunization (dpi). Analyses were based on clinical testing, hemogram profiles, immunohistochemistry and morphometric assessment of myelination.ResultsLewis rats treated with AM095 displayed a significant improvement in clinical scores, most notably during the remission phase. Cellular infiltration of sciatic nerve was only discretely affected by AM095. Hemogram profiles indicated no impact on circulating leukocytes. However, sciatic nerve immunohistochemistry revealed a reduction in the number of Schwann cells expressing the dedifferentiation marker Sox2 paralleled by a corresponding increase in differentiating Sox10-positive Schwann cells. In line with this, morphometric analysis of sciatic nerve semi-thin sections identified a significant increase in large-caliber myelinated axons at 28 dpi. Myelin thickness was unaffected by AM095.ConclusionThus, LPA1 signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation.

Laparoscopic morphological aspects and tentative explanation of the aetiopathogenesis of isolated endometriosis of the sciatic nerve: a review based on 267 patients.

Endometriosis of the sciatic nerve (ESN) is considered a rare disease. How can endometriosis develop within the sciatic nerve; a structure which has nothing in common with the uterus either anatomically or functionally, and why it occurs in the absence of any retroperitoneal/parametric endometriosis, is unknown. A better understanding of the pathophysiology of this enigmatic disease may improve its diagnosis and therapy. From a pool of 452 patients operated for ESN, only patients with "isolated" endometriosis of the sciatic nerve" confirmed at laparoscopy were included in this study. Patients with suspicion of ESN by extension from a parametric, ovarian or other intraperitoneal deeply infiltrating endometriosis were excluded from this study. All information acquired during the preoperative patient's medical history and clinical examination were collected and compared with the morphological aspects of the disease observed by the laparoscopic treatment. Patients were classified into three groups according to the time interval between the onset of sciatic pain and the time of surgery: less than 1 year (Group 1), between 1 and 3 years (Group 2), and more than 3 years (Group 3). Two hundred sixty-seven consecutive patients were included in this study. In Group 1 (n=67), 76% of the patients presented with cyclical sciatica, without sensory or motor disorders of the lower limbs. Laparoscopic exploration found in the great majority of these patients only the presence of an isolated endometrioma in the nerve itself, the size of which was proportional to the time elapsed since the onset of pain. In Group 2 (n=83), pain had become constant in 91% of the patients with neurological disorders of the lower limb (foot drop, Trendelenburg gait, atrophied muscles) in about 30% of patients. Laparoscopic examination revealed, in addition to intraneural cystic lesions, a retroperitoneal fibrosis in more than 80% of the patients. In the third group (N=117), more than 80% of the patients presented with neurological disorders of the lower limb, with, on laparoscopic examination, massive retroperitoneal fibrosis with endometriomas in the nerve and adjacent pelvic wall muscles in all patients and an infiltration of the obturator nerve in 41% of patients. The different morphologic aspects of ESN do not correspond to different forms of the disease, but obviously to one single disease at different stages of its evolution. ENS starts first with the development of an endometrioma within the sciatic nerve, then develops in a second step a perineural fibrosis that expands into the whole retroperitoneal space and finally involves surrounding anatomical structures. The ESN is a very particular pathology because it induces a completely new aspect on the pathogenesis of endometriosis: all hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread or the metaplasia theory cannot explain the pathogenesis of this disease. ESN obviously does not develop from "genital metastatic cells". A possible hypothesis for explanation the pathogenesis of ESN, could consist in the development of endometriosis of the nerve from progenitor stem cells present within the nerve, pluripotent cells which, for an as yet unknown reason (possibly in connection with iterative inflammations and micro-damages of the nerve itself), mutate and proliferate to form endometriosis.

Tumor innervation is triggered by endoplasmic reticulum stress.

Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation. Anti-proBDNF antibody inhibited both tumor innervation and cancer progression induced by ER stress. Interestingly, the chemotherapeutic drug 5-Fluorouracil (5-FU) was found to induce ER stress and tumor innervation, and this effect was inhibited by anti-proBDNF antibody. Finally, in human tumors, cancer tissues with nerve infiltration expressed high XBP1 and proBDNF while EGLN3 was upregulated in infiltrated nerves. This study reveals that ER stress participates in tumor innervation through the release of proBDNF and that targeting this pathway could be used in future therapies.