Cervical Lymphatics Research Articles

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Treatment of Mantle and Inverted Y Fields in Modern Era: A VMAT Approach.

Hodgkin's lymphoma has been treated with combined modality therapy (chemotherapy and radiation) with a very high degree of success. Total Nodal Irradiation (TNI) performed with large AP/PA mantle fields for treatment of axillary, cervical, and mediastinal lymphatics, provide adequate coverage to the mediastinum and bilateral axillae and hila, while blocking lungs. The para-aortic and pelvic lymph nodes are treated with the so called inverted-Y AP/PA fields, which often includes the spleen in cases of TNI. Multileaf Collimators (MLC) have been tried, but due to the irregular shape of the fields and necessity of island blocking in 3D treatment, they have not been successful in full elimination of Cerrobend blocks. We hypothesize that using two or three matched Volumetric Modulated Arc Therapy (VMAT) fields will not only eliminate a need for Cerrobend blocks or island blocks, but will also provide better target coverage and better organs at risk (OAR) sparing. Under IRB study, 10 patients were retrospectively planned using two or three matched VMAT technique for mantle and inverted-Y treatments of TNI that had been previously treated using MLC and Cerrobend block combination. Pinnacle treatment planning system version 16.2.1 was used to generate plans using mantle/inverted-Y technique and corresponding VMAT plans using 2-3 arcs per isocenter (2 isocenters per plan). Optimization was performed to cover targets with the prescribed dose of 1500 cGy in 10 fractions per institutional protocol. The VMAT plans were compared with traditional 3D plans. VMAT consistently provided better or similar results to traditional field arrangements. Target coverage: V15Gy - 95.45% vs 77.99% (p = 0.00017), OAR coverage: total lung V5Gy 63.7% vs 68.8% (p = 0.016), bone marrow mean dose 539.1 cGy vs 727.8 cGy (p = 0.00047), Integral Dose 464.1 mJ vs 573.9 mJ (p = 0.0026). Low isodose lines- mean volume of 5 Gy isodose line was not significantly different - 24036 cc vs 25091 cc (p = 0.271). Cord maximum dose was 40% lower for VMAT plans (p = 0.00006). Mean bladder dose was similar in VMAT plans compared to 3D plan - 821.7 cGy vs 804.9 cGy (p = 0.454). One counter-intuitive result is that the mean integral dose for 10 patients was 24% lower for VMAT plans. VMAT based mantle fields for TNI eliminates Cerrobend blocks and improve dosimetry significantly for target volumes and all OARs; including bone marrow, which plays important role in patient's recovery after chemotherapy, radiation and often stem cell transplantation in recurrent disease. Lower integral dose for VMAT plans is explained by the large irradiated in-fields and small out-of-field volumes. The VMAT process requires minimal effort for optimization and is economical compared to the traditional planning, while improving the target coverage and decreasing dose to OARs.

Lymph Node Metastases from Non-Melanoma Skin Cancer of the Head and Neck.

Non-melanoma skin cancer (NMSC) represents the most common malignancy in the world, comprising exceedingly common lesions such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) and rare lesions such as Merkel cell carcinoma. Risk factors are widely recognized and include ultraviolet (UV) light exposure, radiation exposure, immunosuppression, and many others. As a whole, survival and functional outcomes are favorable, but each histopathological subtype of NMSC behaves differently. Treatment regimens for the primary site usually include wide surgical excision and neck dissection in cases of clinically involved metastatic lymph nodes. The elective management of draining nodal basins, however, is a contested topic. Nearly all subtypes, excluding BCC, have a significant risk of lymphatic metastases, and have been studied with regard to sentinel lymph node biopsy (SLNB) and elective neck dissection. To date, no studies have definitively established a true single standard of care, as exists for melanoma, for any of the NMSCs. As a result, the authors have sought to summarize the current literature and identify indications and management options for the management of the cervical lymphatics for each major subtype of NMSC. Further research remains critically necessary in order to develop complete treatment algorithms.

ABNORMAL LYMPHATIC PHENOTYPE IN A CRISPR MOUSE MODEL OF THE HUMAN LYMPHEDEMA-CAUSING CONNEXIN47 R260C POINT MUTATION

Connexin proteins form gap junctions controlling exchange of ions and small molecules between cells and play an important role in movement of lymph within lymphatic vessels. Connexin47 (CX47) is highly expressed in lymphatic endothelial cells and CX47 missense mutations, i.e., R260C, cosegregate with primary lymphedema in humans. However, studies utilizing CX47 knockout mice have failed to demonstrate any lymphatic anomalies. To unravel the lymphatic consequences of expressing a mutant CX47 protein, we used CRISPR technology to create a mouse carrying a Cx47 missense mutation (Cx47R259C) equivalent to the human CX47R260C missense mutation associated with human primary lymphedema. Intradermal Evans Blue dye injection identified a 2-fold increase in regional lymph nodes in homozygous Cx47R259C mice compared to wildtype, particularly in the jugular region (4.8 ± 0.4 and 2.0 ± 0.0, respectively, p<0.01). Associated lymphatic channels were increased in Cx47R259C mice and mesenteric lymph reflux occurred in homozygous Cx47R259C mice but not in wildtype. Contractility of superficial cervical lymphatics, assessed by pressure myography, was reduced in homozygous Cx47R259C mice compared to wildtype. In conclusion, our data are the first to demonstrate a role for the Cx47 protein in lymphatic anatomy and function. This phenotype is similar to that found with other valve deficient mouse mutants, e.g., in Foxc2. Of significance, this study is the first to use CRISPR technology to develop a pre-clinical model of primary lymphedema and demonstrates the importance of distinguishing between lack of and presence of mutant protein when developing clinically relevant animal models for translation of pre-clinical findings.

Sparing the Larynx and Hypopharynx With Radiotherapy for Squamous Cell Carcinoma of Unknown Primary Site and Predominant Adenopathy in Level IIA

There is controversy about the need to target the mucosa of the larynx and hypopharynx during radiotherapy (RT) for squamous cell carcinoma of unknown primary site (SCCA-UP). By 1997, the policy in our department was to target only the oropharynx and nasopharynx in patients with SCCA-UP metastatic to the level II cervical nodes. The purpose of this study is to report the rate of cancer recurrence in the larynx or hypopharynx using an approach that excluded these areas from the RT target volumes.We reviewed the medical records of patients who met the following inclusion criteria: received RT in our department for SCCA-UP between January 1, 1997, and December 31, 2019; no history of surgery that could disrupt the cervical lymphatics; predominant adenopathy in level IIA; and neck stage N1-2c. We excluded N3 because the incidental dose to the larynx and hypopharynx is usually high in patients with a > 6-cm nodal conglomerate. We calculated the following from the date of the last RT fraction: mucosal control to the date of first recurrence in a mucosal site in the head and neck; regional control with or without distant control to the date of first recurrence in ipsilateral or contralateral neck nodes with or without distant disease; distant control to the date of first documented metastatic lesion most likely originating from SCCA-UP; relapse-free survival to the date of recurrent disease at any site or death; cause-specific survival to the date of death due to SCCA-UP; and overall survival to the date of death from any cause.The study population included 50 patients with a median follow-up after RT of 7.1 years. No patient developed recurrent cancer in a mucosal site (0/50), 2% (1/50) developed a neck recurrence in a high-dose area with synchronous distant metastases, and 2% (1/50) developed distant metastases with no evidence of local or regional recurrence. At most recent follow-up, 70% (35/50) of patients were alive without evidence of recurrent SCCA-UP (NED), 4% (2/50) died of recurrent cancer, 22% (11/50) died of intercurrent disease (DID), and 4% (2/50) died of unknown causes (unknown).When delivering RT for SCCA-UP metastatic predominantly to level IIA, it is not necessary to target the mucosa of the larynx or hypopharynx. The extent to which the incidental RT dose to these areas contributes to cancer control is not evaluated in this study.

Altered Cerebrospinal Fluid Clearance and Increased Intracranial Pressure in Rats 18 h After Experimental Cortical Ischaemia.

Oedema-independent intracranial pressure (ICP) rise peaks 20–22-h post-stroke in rats and may explain early neurological deterioration. Cerebrospinal fluid (CSF) volume changes may be involved. Cranial CSF clearance primarily occurs via the cervical lymphatics and movement into the spinal portion of the cranio-spinal compartment. We explored whether impaired CSF clearance at these sites could explain ICP rise after stroke. We recorded ICP at baseline and 18-h post-stroke, when we expect changes contributing to peak ICP to be present. CSF clearance was assessed in rats receiving photothrombotic stroke or sham surgery by intraventricular tracer infusion. Tracer concentration was quantified in the deep cervical lymph nodes ex vivo and tracer transit to the spinal subarachnoid space was imaged in vivo. ICP rose significantly from baseline to 18-h post-stroke in stroke vs. sham rats [median = 5 mmHg, interquartile range (IQR) = 0.1–9.43, n = 12, vs. −0.3 mmHg, IQR = −1.9–1.7, n = 10], p = 0.03. There was a bimodal distribution of rats with and without ICP rise. Tracer in the deep cervical lymph nodes was significantly lower in stroke with ICP rise (0 μg/mL, IQR = 0–0.11) and without ICP rise (0 μg/mL, IQR = 0–4.47) compared with sham rats (4.17 μg/mL, IQR = 0.74–8.51), p = 0.02. ICP rise was inversely correlated with faster CSF transit to the spinal subarachnoid space (R = −0.59, p = 0.006, Spearman’s correlation). These data suggest that reduced cranial clearance of CSF via cervical lymphatics may contribute to post-stroke ICP rise, partially compensated via increased spinal CSF outflow.

Sparing the Larynx and Hypopharynx With Radiation Therapy for Squamous Cell Carcinoma of Unknown Primary Site and Predominant Adenopathy in Level IIA

PurposeThere is controversy about the need to target the mucosa of the larynx and hypopharynx during radiation therapy (RT) for squamous cell carcinoma of an unknown primary site (SCCA-UP). By 1997, the policy in our department was to target only the oropharynx and nasopharynx in patients with SCCA-UP metastatic to the level II cervical nodes. The purpose of this study was to report the rate of cancer recurrence in the larynx or hypopharynx using an approach that excluded these areas from the RT target volumes. Methods and MaterialsThe inclusion criteria for this study were RT in our department for SCCA-UP between January 1, 1997, and December 31, 2019; no history of surgery that could disrupt the cervical lymphatics; predominant adenopathy in level IIA; and neck stage N1-2c. We excluded N3 because the incidental dose to the larynx and hypopharynx is usually high in patients with a >6-cm nodal conglomerate. ResultsThe study population was comprised of 50 patients with a median follow-up after RT of 7.1 years. No patient developed recurrent cancer in a mucosal site (0/50), 2% (1/50) developed a neck recurrence in a high-dose area with synchronous distant metastases, and 2% (1/50) developed distant metastases with no evidence of local or regional recurrence. ConclusionsWhen delivering RT for SCCA-UP metastatic predominantly to level IIA, it is not necessary to target the mucosa of the larynx or hypopharynx. The extent to which the incidental RT dose to these areas contributes to cancer control is not evaluated in this study.

Papillary Thyroid Carcinoma With Axillary Lymph Node Metastasis

Papillary thyroid carcinoma (PTC) is typically known to be a non-aggressive form of thyroid follicular epithelial-derived cancer. It is characterized histologically by classic and variant forms. Metastases are uncommon and spread mainly via lymphatic channels to cervical lymph nodes and less commonly via hematogenous spread to lungs and bone. Axillary lymph node (ALN) metastasis is a rare sequela of disease presentation. A 59-year-old female presented for evaluation of shortness of breath and chest pain for one week. She had a longstanding history of hypothyroidism due to chronic lymphocytic thyroiditis which was stable on levothyroxine. Her physical exam revealed a firm mass on the inferior aspect of the left neck. Computed tomography (CT) angiogram ruled out pulmonary embolism but noted a superior mediastinal mass and significant left axillary and subpectoral adenopathy. Mammogram was negative for breast malignancy. Left axillary ultrasound showed a 1.1 x 1.8 x 1.9 cm enlarged lymph node. Thyroid ultrasound showed a 3 mm nodule on the left lower pole and a 3.7 x 2.9 x 2.1 cm heterogeneous and irregular mass in the left neck. Positron emission tomography/CT showed increased uptake in left lower paratracheal, left supraclavicular and axillary lymph nodes. Fine needle aspiration of the left neck mass and left ALN confirmed metastatic papillary carcinoma. She underwent total thyroidectomy, left modified neck, central neck, and left ALN dissection along with partial esophageal wall excision. Intraoperatively, she was found to have a multifocal tumor in the left thyroid lobe with the largest dimension of 1 cm. Surgical pathology noted that the primary tumor in the left thyroid was classic type of papillary carcinoma, and the metastatic tumor in the lymph nodes was of tall cell variant. I-123 thyroid uptake and scan after surgery showed low residual thyroid uptake of 0.6%. She underwent adjuvant ablation with 155 millicuries (mCi) of radioiodine (RAI or I-131) following levothyroxine withdrawal protocol. Post ablation therapy thyroid uptake and scan showed no radiotracer uptake within the thyroidectomy bed. According to the American thyroid association (ATA) risk stratification system, she was categorized as high risk. This case illustrates that PTC may exceptionally spread to axillary lymph nodes. Physiologic flow is centripetal to the jugulosubclavian junction and there is no communication between cervical and axillary lymphatics. However malignant tumors can alter and partially block lymphatic pathways, resulting in ALN metastasis in a retrograde direction. This case also demonstrates that PTC can be transformed into aggressive forms associated with worse prognosis such as tall cell variant. Further comprehensive monitoring and management approaches are needed to plan treatment and gauge prognosis of patients with PTC who present with ALN metastasis.

An immunohistochemical study of lymphatic elements in the human brain

Almost 150 papers about brain lymphatics have been published in the last 150 years. Recently, the information in these papers has been synthesized into a picture of central nervous system (CNS) "glymphatics," but the fine structure of lymphatic elements in the human brain based on imaging specific markers of lymphatic endothelium has not been described. We used LYVE1 and PDPN antibodies to visualize lymphatic marker-positive cells (LMPCs) in postmortem human brain samples, meninges, cavernous sinus (cavum trigeminale), and cranial nerves and bolstered our findings with a VEGFR3 antibody. LMPCs were present in the perivascular space, the walls of small and large arteries and veins, the media of large vessels along smooth muscle cell membranes, and the vascular adventitia. Lymphatic marker staining was detected in the pia mater, in the arachnoid, in venous sinuses, and among the layers of the dura mater. There were many LMPCs in the perineurium and endoneurium of cranial nerves. Soluble waste may move from the brain parenchyma via perivascular and paravascular routes to the closest subarachnoid space and then travel along the dura mater and/or cranial nerves. Particulate waste products travel along the laminae of the dura mater toward the jugular fossa, lamina cribrosa, and perineurium of the cranial nerves to enter the cervical lymphatics. CD3-positive T cells appear to be in close proximity to LMPCs in perivascular/perineural spaces throughout the brain. Both immunostaining and qPCR confirmed the presence of adhesion molecules in the CNS known to be involved in T cell migration.

Controversies in the Workup and Surgical Management of Parotid Neoplasms.

Parotid neoplasms are a rare heterogeneous group of tumors with varied clinical presentation and behavior. Here we provide an evidence-based review of the contemporary approach to evaluation and surgical management of parotid tumors. PubMed and Web of Science Databases. Searches of the PubMed and Web of Science databases were performed on subjects related to the diagnosis and surgical management of parotid neoplasms. Particular emphasis was placed on the following areas: evaluation of parotid tumors, including imaging workup and the utility of fine-needle aspiration; extent of surgery of the primary lesion, including the extent of parotidectomy as well as oncologic management of the facial nerve; the extent of surgery of involved and at-risk cervical lymphatics; and parotid bed reconstruction. Articles published from 2014 to the present were prioritized, supplementing with information from prior studies in areas where data are lacking. A summary of the literature in these areas is outlined to provide an evidence-based approach to evaluation and management of parotid neoplasms. While data are available to help guide many aspects of workup and management of parotid neoplasms, further research is needed to refine protocols for this heterogeneous group of diseases.

Intracranial pressure elevation alters CSF clearance pathways

BackgroundInfusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models.MethodsWe used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters.ResultsAt baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route.ConclusionsThe relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.

Assessing lymphatic route of CSF outflow and peripheral lymphatic contractile activity during head-down tilt using near-infrared fluorescence imaging.

Evidence overwhelmingly suggests that the lymphatics play a critical role in the clearance of cerebrospinal fluid (CSF) from the cranial space. Impairment of CSF outflow into the lymphatics is associated with a number of pathological conditions including spaceflight‐associated neuro‐ocular syndrome (SANS), a problem that limits long‐duration spaceflight. We used near‐infrared fluorescence lymphatic imaging (NIRFLI) to dynamically visualize the deep lymphatic drainage pathways shared by CSF outflow and disrupted during head‐down tilt (HDT), a method used to mimic the cephalad fluid shift that occurs in microgravity. After validating CSF clearance into the lymph nodes of the neck in swine, a pilot study was conducted in human volunteers to evaluate the effect of gravity on the flow of lymph through these deep cervical lymphatics. Injected into the palatine tonsils, ICG was imaged draining into deep jugular lymphatic vessels and subsequent cervical lymph nodes. NIRFLI was performed under HDT, sitting, and supine positions. NIRFLI shows that lymphatic drainage through pathways shared by CSF outflow are dependent upon gravity and are impaired under short‐term HDT. In addition, lymphatic contractile rates were evaluated from NIRFLI following intradermal ICG injections of the lower extremities. Lymphatic contractile activity in the legs was slowed in the gravity neutral, supine position, but increased under the influence of gravity regardless of whether its force direction opposed (sitting) or favored (HDT) lymphatic flow toward the heart. These studies evidence the role of a lymphatic contribution in SANS.

Management of Persistent or Recurrent Structural Neck Disease in Differentiated Thyroid Carcinoma: Point and Counterpoint.

The optimal management of structurally identified neck disease after initial surgery for thyroid carcinoma is nuanced and must be individually tailored to thepatient andhis or her disease. As such, it is ideally evaluated and managed with the patient from an experienced interdisciplinary program perspective. Proficiency and focused expertise in diagnostic imaging (ultrasound, cross-sectional, and nuclear), pathology, surgery, endocrinology, radiation oncology, and systemic therapy are integral components of such a program.Athoroughunderstandingof the risksof thediseaseandtreatmentoptions, includingmanagementof complications, is required. While no single algorithm is available, several large series, systematic reviews, andguidelineshavebeenpublished, fromwhich some generalities can be gleaned.1-8 The likelihood of persistent or recurrent structural disease can be predicted by tumor type, TNM stage, and American Thyroid Association (ATA) risk of recurrence. A structurally incomplete response to initial therapy implies disease that can be identified with imaging and is biopsy proven or highly likely to be malignant. For well-differentiated papillary and follicular thyroid carcinoma, this occurrence is observed in approximately 5% of ATA low-risk patients, 25% of ATA intermediate-risk patients, and 70% of ATA high-risk patients. The disease-specific mortality rate of patients with biochemically incomplete response but without structurally identifiable disease is essentially zero but increases to approximately 10% in patients with locoregional structural disease and approximately 60% in patients with distant disease. The histologic type of thyroid carcinoma significantly affects both prognosis and local, regional, or distant disease. Classic papillary thyroid carcinomahas a highpredilection for nodalmetastasis, whereas follicular carcinomas, including Hurthle and insular variants, have a higher likelihood of hematogenous and lymphatic spread, especially when vascular invasion is present, which in the neck often manifests as soft-tissue and local recurrence. Local invasion ismuchmorecommon insoft-tissue recurrence, althoughextranodal extension of regional metastatic disease can also be invasive. The morbidity of untreated invasive disease is inherently greater, arguing formore aggressivemanagement, but the surgical morbidity is also greater. The likelihood of surgical cure of persistent structural disease isolated to the neck is greatest for initially understaged and undertreated nodal disease, for which a compartment-oriented neck dissection has a 70% to 90% chance of complete eradication of structurally detectable disease.3 Biochemical resolution of disease is less likely, approximately 25% to 50% based on stimulated thyroglobulin levels.3 The structural burden of disease inversely correlates with the likelihood of surgical cure, with patients having multiple detectable lesions in multiple levels less likely curable than those with one or a few isolated lesions. The biochemical burden of disease also inversely correlates, such that patients with higher biochemical markers are much less likely to be cured surgically. The small subset of patients with radioiodine-avid, low-volume structural disease have the highest likelihood of biochemical cure (80%) with revision surgery and repeat radioiodine therapy.3 The goal of revision neck surgery is generally resolution of all structurally detectable disease, as well as associated occult microscopic disease, while minimizing the surgical morbidity. However, patients with known distant metastasis may occasionally benefit from revision neck surgery to prevent complications of locally invasive disease, especially involving the aerodigestive tract. A lateral neck dissection for differentiated thyroid cancer is a frequently performed surgery; however, the dissection is not the same as that for aerodigestive tract cancers, and nuances are worth elucidating. Surgery for lateral neck disease should include levels IIa to Vb to minimize risk to the marginal and spinal accessory nerves unless there is disease beyond these levels or bulky disease at the borders. The spinal accessory nerve should be identified and preserved in all lateral neck dissections for thyroid malignancies. The transverse cervical lymphatics, including the infraclavicular nodes, extending into level Vb and lymphatic contents posterior to the carotid artery in levels III and IV are the primary echelon of lateral neck nodal metastases due to the thyroid vasculature originating from the thyrocervical trunk inferiorly and external carotid superiorly. Meticulous dissection in the carotid and vertebral area is required, and control of chylous and lymphatic vessels is a necessary component of the dissection. Last, the lateral neck dissection must fully dissect level IIa anterior to the internal jugular vein in the subdigastric area, identify the hypoglossal nerve, and remove the nodal basins through to the transition to level VI superiorly. In the event of prior lateral neck surgery, more selective revision compartmental surgery may be appropriate to minimize the surgical morbidity.

Malignant Melanoma of Oral Cavity, A Case-Based Review of the Literature

Introduction : Primary Mucosal Malignant Melanoma is an aggressive cancer, especially when there is a late diagnosis. The mortality is low in early stages but in advanced stages is less than a 30% on a 5-years following. Only a 0.5% to 3% of Melanomas are Mucosal Melanomas. Among them, the Mucosal Malignant Melanoma of oral cavity is a rare tumor, with an extremely aggressive behavior at diagnosis. Case Report : 51 years old male, consult on April 2015, at Centro de Salud Familiar Flor Pedreros Parra, Trehuaco city, Chile, for dark blue round tumor, 1.5 cm wide, placed near the tooth 1.3, compromising the gum. The patient refers previous consultations with a smaller and flat lesion. He reveals important everyday sun exposure, without proper UV protection. One month later, the tumor grows and becomes indurate, consequently the patient was transferred to Herminda Martin Hospital of Chillan City, where incisional biopsy concludes “Mucosal Malignant Melanoma with infiltration of surroundings tissues”. Chemotherapy is realized with poor results. Last control with Odontology in August 2015, the tumor evolves to a black nodule, 4 cm wide, compromising the upper maxilla, right eye and mouth opening, concomitant to multiple black satellite papula. Computed Tomography showed skull base infiltration, cervical lymphatics and other zones of head and neck. The patient was transferred to palliative care and died before a year from diagnosis. Discussion : The primary Mucosal Malignant Melanoma of oral cavity it’s a very strange condition. It has variable presentations, sometimes like a little maculae with different colors or like a highly pigmented tumor with ulcers or hemorrhage, with a high growing rate. It has an important metastatic potential and a poor prognostic. This is the reason why early clinical suspect and diagnosis is extremely valuable.

Elective neck management for squamous cell carcinoma metastatic to the parotid area lymph nodes.

The objective of this study is to determine if radiotherapy (RT) alone to the cervical lymphatics is a suitable alternative to elective neck dissection (END) in patients who undergo parotidectomy and postoperative RT for squamous cell carcinoma metastatic to the parotid area lymph nodes (PALN). We retrospectively reviewed the medical records of 107 patients consecutively treated from November 1969 to March 2012 for cutaneous squamous cell carcinoma metastatic to the PALN with a clinically node-negative neck. Primary therapy consisted of parotidectomy in all cases. We compared regional (cervical) control in two subgroups: 42 patients treated with END and RT and 65 patients treated with elective neck irradiation (ENI) alone. The median time of follow-up was 5.5years (range 0.3-30years) for all patients and 11years for living patients (range 1.8-26years). There was 1 neck recurrence in each subgroup: END and RT, 1/42 (2%); and ENI alone, 1/65 (1.5%). No patient experienced a complication related to neck RT. ENI to a dose of approximately 50-60Gy is a suitable alternative to END and postoperative RT in patients with squamous cell carcinoma metastatic to the PALN.

Elective Neck Management for Squamous Cell Carcinoma Metastatic to the Parotid-area Lymph Nodes

The objective of this study is to determine if radiotherapy (RT) alone to the cervical lymphatics is a suitable alternative to elective neck dissection (END) in patients who undergo parotidectomy and postoperative RT for squamous cell carcinoma metastatic to the parotid area lymph nodes (PALN). We retrospectively reviewed the medical records of 107 patients consecutively treated from November 1969 to March 2012 for cutaneous squamous cell carcinoma metastatic to the PALN with a clinically node-negative neck. Primary therapy consisted of parotidectomy in all cases. We compared regional (cervical) control in two subgroups: 42 patients treated with END and RT and 65 patients treated with elective neck irradiation (ENI) alone. The median time of follow-up was 5.5 years (range 0.3-30 years) for all patients and 11 years for living patients (range 1.8-26 years). There was 1 neck recurrence in each subgroup: END and RT, 1/42 (2 %); and ENI alone, 1/65 (1.5 %). No patient experienced a complication related to neck RT. ENI to a dose of approximately 50-60 Gy is a suitable alternative to END and postoperative RT in patients with squamous cell carcinoma metastatic to the PALN.

Çocukluk çağında nadir görülen bir lenfadenopati nedeni: masif lenfadenopatili sinüs histiositozu (Rosai-Dorfman hastalığı)

The sinus histiocytosis (Rosai-Dorfman Disease) is a rarely seen histiocytic disease and its etiology is not clearly known. Massive lymphadenopathies that are formed by accumulation of lymphocytes and histiocytes in lymph node sinuses are the main characteristics of the disease. Although cervical lymphatics are the most frequently affected region , the other lymph nodes can also be involved. The diagnosis is histopathologically established. In addition to asymptomatic cases followed up without any treatment, there are also cases requiring immunosuppressive therapy, surgical treatment or radiotherapy due to life-threatening organ involvement. Hereby, we present two cases diagnosed with Rosai-Dorfman Disease on histopathological examination. In these cases, the malignancies were considered in differential diagnosis because of massive lymphadenopathies in cervical area.&nbsp;

Inspiration is the major regulator of human CSF flow.

The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans. Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to design therapeutic strategies in relation to CSF flow alterations.

Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system.

The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity.

Clinicopathological Characteristics and Outcome Predictors in Squamous Cell Carcinoma of the Maxillary Gingiva and Hard Palate

Squamous cell carcinoma (SCC) located in the maxillary gingiva and hard palate is relatively rare. There are few published guidelines for the treatment of SCC of the maxilla. The aim of the present study was to characterize the clinicopathologic features of SCC of the maxillary gingiva and hard palate and determine factors that predict outcome and lead to a strategic treatment plan. A retrospective cohort study of patients with SCC of the maxillary gingiva and hard palate was conducted from 2003 to 2012 at the Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University. Clinicopathologic characteristics, treatments, outcome predictors, and 3- and 5-year overall survival rates were analyzed. The Kaplan-Meier method was used to evaluate 3- and 5-year overall survival rates. Univariate and multivariate Cox regression analyses were used to identify predictors of survival. A P value less than .05 was considered statistically significant. The 3- and 5-year survival rates of the 62 participants were 66.6 and 57.3%, respectively. Univariate analyses showed statistically significant (P < .05) associations between patient survival rate and tumor differentiation grade, T classification, marginal status, cervical lymphatics, and local recurrence. Occult lymph node metastases of maxillary SCC in tumor stages T2 to T4 occurred in 20 to 40% of patients. Patients who presented with lesions located after the first premolar plane area and received postoperative radiotherapy had a better prognosis. Elective neck dissection is recommended for management of T2 to T4 SCCs in the maxillary gingiva and hard palate. Postoperative radiotherapy can improve the prognosis and decrease the recurrence of SCC after the first premolar plane area.