Periocular Mass Due to Persistent Secretion Within a Transplanted Parotid Duct.

A male patient underwent microvascular transplantation of an autologous submandibular gland and its associated (Wharton's) duct for management of very severe right keratoconjunctivitis sicca due to Stevens-Johnson syndrome; due to hypersecretion, the gland was later removed in toto. Twenty-two years later, he presented with a nontender, sausage-like mass lying subcutaneously in the right temple. Intraoperatively a fluctuant tubular mass passing from the temporalis fossa to the superotemporal conjunctiva was identified and excised intact. Histology showed a slightly proteinaceous fluid within a duct lined with cuboidal epithelium, this being compatible with Wharton's duct. This case highlights that iatrogenic causes should be considered with any history of periocular injury or surgery.

Microvascular Submandibular Gland Transplantation for Severe Keratoconjunctivitis Sicca: A Single-Institution Experience of 61 Grafts.

PURPOSE: Keratoconjunctivitis sicca (KCS) is a relatively common disease that results in discomfort, tear film instability, visual impairment, and ocular surface damage. Artificial tear substitutes may be suitable for the treatment of mild KCS, but no effective treatment currently exists for severe KCS. Therefore, this study evaluated the effectiveness of autologous microvascular submandibular gland transplantation in the treatment of severe KCS. PATIENTS AND METHODS: A total of 61 eyes (56 patients) with severe KCS were treated with autologous submandibular gland transplantation from June 2002 to June 2017. The cephalic vein or the great saphenous vein was applied to solve the problem of unmatched veins. RESULTS: In 53 cases (53 of 56, 94.6%), 58 glands (58 of 61, 95.1%) were transplanted successfully. The mean Schirmer I test value improved from 0.78 ± 0.84 mm preoperatively to 18.83 ± 5.72 mm in the stable period after transplantation. Epiphora (14 of 58, 24.14%) was the most common complication of this procedure. Other postoperative complications included venous thrombosis (6 of 61, 9.84%), local infection (2 of 58, 3.45%), xerostomia (2 of 53, 3.77%), duct fistula (1 of 58, 1.72%), sialolithiasis (1 of 58, 1.72%), and ranula (1 of 58, 1.72%). CONCLUSIONS: Autologous microvascular submandibular gland transplantation is a credible and effective solution for severe KCS.

[A 20-year study on microvascular autologous transplantation of submandibular gland for treatment of severe dry eye].

Severe dry eye is a refractory ophthalmologic disease. Our multidisciplinary research group treated severe dry eye by microvascular autologous transplantation of submandibular gland (SMG) during the past 20 years. The SMG, with its blood vessels and Wharton's duct, was harvested from the submandibular triangle and transferred to the temporal area. The blood vessels in the SMG were anastomosed with the temporal blood vessels using a microsurgical technique. Then, the distal end of Wharton's duct was sutured to form an opening in the upper lateral conjunctival fold. The tear was replaced by the secretion of the transplanted SMG to lubricate the ocular surface. In our study, the surgical techniques of blood vessel management were continuously modified to increase the survival rate of the transplanted SMG. A novel surgical modality of partial transplantation of SMG was established to prevent postoperative epiphora. A clinical study with the largest case number in the world was conducted and the effectiveness of transplantation of SMG for severe dry eye was fully confirmed. In order to resolve two main clinical problems including ductal obstruction resulted from low secretion rate during the latent period, and epiphora due to over secretion of the transplanted SMG in the later term of transplantation, the regulation of the secretion mechanism of the normal and transplanted SMG were investigated. New opinions on mechanisms of saliva secretion were provided. Based on the priniciple of translational medicine, the results of related basic research were applied in the clinic. The clinical guidelines for secretion regulation of transplanted SMG were established. A concept of chronic obstructive sialadenitis of transplanted SMG was provided and its diagnostic criteria, diagnostic technique of sialography, and therapeutic regimen were established. As a result, the surgical success rate was obviously elevated, the surgical complications were decreased, and life quality of the patients was greatly improved.

Two-stage autotransplantation of human submandibular gland: a novel approach to treat postradiogenic xerostomia.

Xerostomia is a persistent side effect of radiotherapy (RT), which severely reduces the quality of life of the patients affected. Besides drug treatment and new irradiation strategies, surgical procedures aim for tissue protection of the submandibular gland. Using a new surgical approach, the submandibular gland was autotransplanted in 6 patients to the patient's forearm for the period of RT and reimplanted into the floor of the mouth 2-3 months after completion of RT. Saxon's test was performed during different time points to evaluate patient's saliva production. Furthermore patients had to answer EORTC QLQ-HN35 questionnaire and visual analog scale. Following this two-stage autotransplantation, xerostomia in the patients was markedly reduced due to improved saliva production of the reimplanted gland. Whether this promising novel approach is a reliable treatment option for RT patients in general should be evaluated in further studies.

Submandibular gland transfer for the prevention of postradiation xerostomia in patients with head and neck cancer: a systematic review and meta-analysis.

BACKGROUND: Submandibular gland transfer has been widely used to prevent postradiation xerostomia in head-and-neck cancers. However, there are still some controversies. METHODS: Six databases were searched, data extraction was performed and the risk of bias was assessed by 2 reviewers independently. The meta-analysis was performed using Review Manager, version 5.2. RESULTS: A total of 7 trials (12 articles) and 369 participants were included. CONCLUSIONS: The present clinical evidence suggests that submandibular gland transfer might be highly effective to prevent postradiation xerostomia in head-and-neck cancers without serious adverse events. However, more randomized controlled trials are still needed to confirm this conclusion.

Proteomic analysis of secretion from human transplanted submandibular gland replacing lacrimal gland with severe keratoconjunctivitis sicca.

PURPOSE: Proteomic analysis of secretions from transplanted or non-transplanted submandibular glands in patients with severe keratoconjunctivitis sicca and tears from normal eyes. EXPERIMENTAL DESIGN: Secretions from submandibular glands transplanted to replace lacrimal glands and non-transplanted submandibular glands were collected at 1year from 5 patients with severe keratoconjunctivitis sicca undergoing transplantation, and tears were collected from 3 normal subjects. 2-D electrophoresis (2-DE), then mass spectrometry was used to identify proteins. Western blot analysis was used to confirm protein expression. RESULTS: We identified 34 and 11 distinct proteins in the saliva from transplanted submandibular glands and tears, respectively. The saliva from transplanted submandibular glands contained almost all the proteins abundant in tear fluid. The functions of identified proteins in the saliva from transplanted submandibular gland were mainly immune response and anti-bacterial. In total, 7 proteins showed differential expression between the saliva of transplanted and non-transplanted submandibular glands. The upregulation of short palate, lung and nasal epithelium carcinoma-associated protein 2 and carbonic anhydrase VI was confirmed by Western blot analysis. CONCLUSIONS: Identified proteins in saliva from transplanted submandibular glands may protect ocular structures. These findings can help in understanding the functional status of transplanted submandibular glands.

Ischemic preconditioning reduces transplanted submandibular gland injury.

BACKGROUND: Ischemic preconditioning (IPC) can reduce ischemia/reperfusion (I/R) injury in multiple organs and species. However, the effect of IPC on transplanted submandibular glands remains unknown. We explored the protection of IPC in transplanted submandibular glands in the rabbit and the underlying mechanism. METHODS: IPC was performed by clamping the lingual artery for 10 min, with 10 min of reperfusion before transplantation. Male rabbits were randomly divided into control, transplantation, and IPC groups (n = 6 each). Saliva secretion, oxidative stress, pro-inflammatory cytokine levels, and apoptosis-related protein levels were determined at 1, 12, and 24 h after reperfusion. RESULTS: Salivary flow was significantly increased at 12 h and decreased at 24 h in the transplanted glands. IPC treatment prevented the reduced saliva secretion at 24 h after reperfusion (P < 0.01). The mRNA levels of tumor necrosis factor-α, interleukin-1ß, and reactive oxygen species, as well as malondialodehyde (MDA) and myeloperoxidase activity, were significantly increased and superoxide dismutase activity was decreased in the transplanted glands. However, these changes were all attenuated with IPC treatment (all P < 0.05). Also, acinar cell apoptosis and Bax protein expression were decreased and Bcl-2 protein expression was increased in the IPC-treated glands at 1 and 12 h after reperfusion (all P < 0.05). CONCLUSIONS: IPC protects the secretory function of transplanted submandibular gland in the rabbit by reducing the inflammatory response, attenuating oxidative stress, and an anti-apoptosis process.

Characteristics and management of vascular compromise after an organ transplantation surgery of the head and neck region: Analysis of 220 submandibular glands with autologous transplantation.

BACKGROUND: Microvascular submandibular gland transplantation (SMGT) for severe dry eye disease (DED) has rarely been reported in the literature. The aim of this study was to report a case series of SMGT with the special focus on monitoring and management of postoperative vascular compromise. METHODS: Using a retrospective single-cohort study design, the investigators enrolled a sample of DED patients undergoing SMGT in a Chinese university hospital during 1999 and 2021. The main outcomes were baseline and surgical data, post-operative manifestations, and surgical results. Descriptive, uni- and bivariate statistics were computed with the significant P < 0.05. RESULTS: During the study period, 220 DED patients (55.9% female) with a mean age of 32.66±14.47 years underwent SMGT. Vascular compromises occurred in 27 grafted glands (12.3%; 22 venous compromises and 5 arterial compromises) at a median of 27 h(range, 3.3 to 288 h) after surgery. Harden texture and swelling of the covering skin flap of the donor indicated venous compromises, while some specific sign was absent for arterial compromise. The accompanying vein of the facial artery (FAV) as a donor's vein was associated with less vascular compromise compared to the anterior facial vein (AFV). Timely reexploration was performed in 25 glands (92.6%), with a salvaged rate of 48%, and more venous compromises were salvaged compared to artery compromises (54.6% vs. 0%, P = 0.047). Temporary hypersecretion on postoperative 2-5 days was noticed in the grafted glands with no or salvaged vascular compromise (Schirmer's test, 35 mm/5 min and 37 mm/5 min, respectively, P = 0.749), while they were absent for the 15 surgically failed grands (Schirmer's test 0 mm/5 min, P<0.001). CONCLUSIONS: Vascular compromise appears to be a common complication of SMGT. Postoperative hypersecretion of the grafted glands may indicate good circulation, and the use of FAV as the donor's vein could help to decrease the risk of vascular compromise.

Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland.

Tight junction (TJ) is an important structure that regulates material transport through the paracellular pathway across the epithelium, but its significance in salivary physiology and pathogenesis of salivary dysfunctional diseases is not fully understood. We previously demonstrated that a functional transient receptor potential vanilloid subtype 1 (TRPV1) expresses in submandibular gland (SMG). However, association of TRPV1-induced saliva secretion with TJ remains unknown. Here we explored the effect of TRPV1 activation on expression and function of TJ of rabbit SMG in vitro and in vivo. RT-PCR and western blot analysis revealed that capsaicin upregulated expression of zonula occludin-1 (ZO-1), claudin (Cldn)-3, and -11, but not Cldn-1, -2, -4, -5, and -7 in cultured SMG cells. Capsaicin also increased the entering of 4 kDa FITC-dextran into the acinar lumen, induced redistribution of cytoskeleton F-actin under confocal microscope, and these effects were abolished by preincubation of capsazepine, a TRPV1 antagonist, indicating that activation of TRPV1 increases expression and permeability of TJ in SMG. Additionally, in a hyposecretory model induced by rabbit SMG transplantation, the expression of ZO-1, Cldn-3, and -11 was decreased, whereas other TJs remained unaltered. The structure of TJ was impaired and the width of apical TJs was reduced under transmission electron microscope, concomitant with diminished immunofluorescence of F-actin in peri-apicolateral region, indicating impaired TJ expression and decreased paracellular permeability in the transplanted SMG. Moreover, topical capsaicin cream increased secretion, decreased TJ structural injury, reversed TJ expression levels, and protected F-actin morphology from disarrangement in transplanted SMGs. These data provide the first evidence to demonstrate that TJ components, particularly ZO-1, Cldn-3, and -11 have important roles in secretion of SMG under both physiological and pathophysiological conditions. The injury in TJ integrity was involved in the hypofunctional SMGs, and TRPV1 might be a potential target to improve saliva secretion through modulating expression and function of TJs.

Compensatory function of submandibular gland in mice with streptozotocin diabetes under conditions of transplantation.

Transplantation of the submandibular gland under the renal capsule of mice with streptozotocin-induced diabetes mellitus stimulated the compensatory function of the recipient submandibular gland. An increase in insulin I and insulin II gene expression in the submandibular gland after transplantation was demonstrated by PCR. More intensive production and extrusion of these proteins in the apical and basal directions in granular compartment cells of the submandibular gland was confirmed by electron microscopy. All these changes led to a reduction of blood glucose levels in diabetic animals as soon as 2-2.5 weeks after transplantation.

Salivary gland transplantation for dry eye disease: Indications, techniques, and outcomes.

The transplantation of salivary glands to the eye serves as a substitute for restoring tear volume in patients with severe dry eye disease. The lacrimal gland and salivary glands share similar acinar-ductal organization with some differences in the nature of secretions. This review summarizes the comparative anatomy of salivary and lacrimal glands, various salivary gland transplantation techniques, their indications, outcomes and complications along with future perspectives. Autologous microvascular submandibular gland transplantation (SMGT) into the temporal fossa with duct placement into the conjunctival fornix improves tear volume considerably but provides a hyposmolar tear film, which can induce corneal edema (in 3.5-40% of eyes). The transplanted submandibular graft improves tear volume and stability but visual acuity and conjunctival inflammation remain unchanged. The transplanted submandibular gland maintains stable function in the long-term and can have hypersecretion in 24-60% secondary to persistent autonomic innervation. Partial SMGT, gland reduction surgery, topical atropine gel or Botulinum Toxin A injection are options for treatment of postoperative epiphora. Minor salivary gland transplantation (MSGT) into the upper and/or lower conjunctival fornix results in an average improvement of 2-4 mm in Schirmer values compared to 16 to > 30 mm observed in eyes after SMGT. Reflex epiphora is rarely a problem in MSGT. Both MSGT or SMGT can improve the ocular surface and quality of life of patients with severe, debilitating dry eye disease. However, postoperative visual acuity and outcomes of corneal transplantation are still inconsistent. More studies and additional technical improvements are needed to further improve the results of these procedures.

Proteomic analysis of human transplanted submandibular gland in patients with epiphora after transplantation.

Submandibular gland autotransplantation is effective for treating severe dry eye syndrome. However, more than 40% of patients show epiphora within 3-6 months after treatment. The mechanism underlying the hypersecretion in epiphora remains to be elucidated for developing novel interventions. Since salivary gland secretion is dependent on a variety of proteins, we analyzed the changes in protein expression in transplanted glands of epiphora patients with 2-D gel electrophoresis and electrospray ionization quadrupole/time-of-flight mass spectrometry and evaluated their possible roles in epiphora. There were 23 proteins that showed altered expression in the glands of epiphora patients, 15 being up-expressed and 8 being down-expressed. The expression of secretory proteins was decreased in these glands, including alpha-amylase, cystatin S, SA, and SN. In contrast, cytoskeletal proteins were all up-regulated, including actin and vimentin. Immunofluorescence revealed that the intensity ratio of F-actin in apical and lateral cytoplasm to total F-actin in acini was decreased in the glands of epiphora patients. Carbachol stimulation induced a similar redistribution of F-actin in the control glands. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) was increased in both carbachol-stimulated and epiphora glands. Preincubation of submandibular glands with ERK1/2 inhibitors PD98059 or U0126 inhibited carbachol-induced F-actin redistribution. These results indicated that differentially expressed proteins participated in the hypersecretion of transplanted submandibular glands and the redistribution of F-actin might be involved in this hypersecretion in an ERK1/2-dependent manner.

Microanatomic study of the vascular and duct system of the submandibular gland.

PURPOSE: Autologous microvascular submandibular gland (SMG) transfer is an effective treatment for severe keratoconjunctivitis sicca (KCS). However, epiphora (excessive tear secretion) may occur after the successful transfer of whole submandibular gland because tear secretion level is closely related to the size of the transferred gland. The aim of this study was to investigate the microanatomy of SMG to explore the possibility of partial SMG transfer to prevent postoperative epiphora. MATERIALS AND METHODS: Sixty intact and histologically normal human SMGs from patients with benign tumor of the mandible who underwent vascularized mandibular reconstruction and removal of the SMG for anastomosis of the blood vessels were included in the study. SMGs were perfused with methacrylate to form resin casts of blood vessels and ducts. The length and diameter of the blood vessels and ducts in the casts were measured using a sliding caliper. The numbers of lobules, distribution of arteries, veins, and ducts, as well as the relationship among them, were analyzed. RESULTS: The resin cast of the gland showed a treelike structure, with the vessels gradually dividing into multiple branches. The arteries, veins, and ducts run in parallel and were roughly divided into 3 levels: from the stem extending into the main branches (level I), into the narrower secondary branches (level II), and then the secondary branches subsequently divided into terminal branches (level III). The structures of the blood vessels and ducts were similar at each level in the lobules. In the vein casts, communicating vessels were found between the anterior facial vein and the concomitant vein of the facial artery. CONCLUSION: The characteristic treelike structure of the SMG vascular and ductal system may provide useful information for partial gland transfers.

Activation of transient receptor potential vanilloid subtype 1 increases secretion of the hypofunctional, transplanted submandibular gland.

Hyposecretion occurs in most patients early after submandibular gland autotransplantation for severe keratoconjunctivitis sicca. Endogenous transient receptor potential vanilloid subtype 1 (TRPV1) has been recently demonstrated in rabbit submandibular glands, and activation of TRPV1 by capsaicin increases secretion in isolated glands, but the TRPV1-mediated secretory mechanism remains to be elucidated. The purpose of this study was to verify whether activation of TRPV1 by capsaicin could improve the secretion of transplanted gland and its underlying mechanism. The salivary flow of the transplanted glands was significantly decreased, and the mRNA and protein levels of TRPV1 and aquaporin 5 (AQP5) were downregulated in the transplanted glands. Topical capsaicin cream increased secretion and upregulated levels of TRPV1 and AQP5 in transplanted glands. Moreover, in cultured submandibular gland cells, capsaicin increased the mRNA expression of AQP5 and led to redistribution of AQP5 from the cytoplasm to the plasma membrane via TRPV1 activation. Capsaicin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK). Preincubation of cells with PD98059, an inhibitor of ERK kinase, suppressed the capsaicin-induced mRNA expression of AQP5. In summary, the capsaicin-induced secretory mechanism involved activation of TRPV1 and upregulation of AQP5 in an ERK-dependent manner and promoted the redistribution of AQP5 in submandibular gland cells. Activation of TRPV1 may provide a new therapeutic strategy to improve submandibular gland hypofunction.

Carbachol improves secretion in the early phase after rabbit submandibular gland transplantation.

OBJECTIVES: To investigate the changes in the muscarinic receptor signaling pathway with submandibular gland (SMG) transplantation and whether carbachol improves secretion in transplanted SMGs. MATERIALS AND METHODS: SMG autotransplantation was performed in a rabbit model. Carbachol (1 microM) was infused into the transplanted glands from postoperative day 1-7. The expression of the M1 and M3 muscarinic receptors, aquaporin-5 (AQP5), and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) was measured by RT-PCR, immunoblotting or immunofluorescence. The content of inositol 1, 4, 5-trisphosphate (IP(3)) was measured by radioimmunoassay. RESULTS: Salivary flow of the transplanted SMGs was decreased after transplantation. As well, the expressions of M1 and M3 receptors and their downstream signaling molecules, IP(3), p-ERK1/2 and AQP5, were all reduced. Atrophy of acinar cells was shown in transplanted glands. However, all these alterations were reversed after carbachol treatment for 7 days. Furthermore, carbachol directly increased the mRNA expression of AQP5 and phosphorylation of ERK1/2 in cultured neonatal rabbit SMG cells. CONCLUSION: A lack of acetylcholine and downregulation of the muscarinic receptor signaling pathway is involved in the early hypofunction of transplanted SMGs. Carbachol treatment could be a new therapeutic strategy to improve secretion and prevent the obstruction of Wharton's duct in the early phase after SMG transplantation.

Clinical and anatomic study on the ducts of the submandibular and sublingual glands.

PURPOSE: To investigate the relationship between the ducts of the submandibular gland (SMG) and sublingual gland (SLG) and discuss its clinical application relating to SMG radiologic examinations and transfer. MATERIALS AND METHODS: The microanatomy of the SMG and SLG was investigated by use of 30 adult cadavers through anatomic dissection by use of a microscope. The relationship between the SMG and SLG ducts was observed and recorded during operations of microvascular autologous SMG transfer in 63 cases of severe keratoconjunctivitis sicca. RESULTS: There were 3 patterns of SLG and SMG duct anatomic variation: 1) The SMG and SLG have their own respective ducts that secrete separately at the orifices of the ducts in the floor of the mouth. 2) The SLG has a major duct that joins the duct of the SMG. 3) The SLG only has many fine ducts (7-15) that secrete in the floor of the mouth. CONCLUSIONS: The anatomy of the ducts of the SMG and SLG is quite complicated. More attention should be paid to the anatomy of the ducts during surgery or imaging procedures related to the SMG.

[Post-operation nursing for patients with autologous transplantation of the microvascular submandibular gland].

OBJECTIVE: To summarize the complications' prevention and nursing experience for patients after autologous transplantation of the microvascular submandibular gland for severe keratoconjunctivis sicca. METHODS: Retrospective analysis of 141 patients(151 sides) after autologous microvascular submandibular gland transfer operation was undertaken to record the timing and incidence of major complications and to summarize the nursing experience. RESULTS: The main complications after the transplantation were: vascular crisis, catheter obstruction, salivary fistula and temporary paralysis of hypoglossal nerve. Related nursing measures in response to these complications were discussed. CONCLUSION: Targeted nursing interventions for patients with autologous transplantation the submandibular gland have a positive effect on the prevention of the surgical complications.

Use of a submandibular gland flap for closure of oral cutaneous fistula.

We reported a rare case of submandibular oral cutaneous fistula (OCF) in a 27-year-old female. A submandibular gland flap (SMGF) was prepared after fistula resection to fill the dead space under the mouth floor. Based on this case report and a literature review, we discussed the pathogenesis and treatment of OCF, and compared the differences between the SMGF and other types of flaps.

Preliminary application and evaluation of autograft reconstruction of parotid duct defect with submandibular gland duct for buccal cancer.

Background: We aimed to preserve parotid function in patients with buccal carcinoma by applying a new surgical protocol based on reconstruction of parotid ductal defect with submandibular gland ductal.Aims/Objectives: The aim of this study is to introduce the method of autologous submandibular gland duct reconstruction for the treatment of parotid duct defect in buccal carcinoma, and to evaluate its clinical application in follow-up.Material and methods: A total of 28 patients with buccal carcinoma who underwent buccal and neck combined with radical surgery and vascularized flap transplantation were enrolled. Function of the reconstructed duct was reviewed in 6 months after surgery.Results: Both groups achieved good short-term results within 1 month after surgery. The 6-month postoperative angiography examination of the submandibular gland duct showed that 6% of patients in the submandibular gland duct graft group had a blockage or was not smooth. At the same time, 45% of the patients in the vein graft group had failure or obstruction, and the VAS score of pain was higher than that of the submandibular gland ductal graft group (p < .05).Conclusion and significance: Compared with vein grafting, the reconstruction of parotid ductal defect with submandibular gland ductal graft has better long-term effects.