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Aplasia of salivary glands is rare and usually involves several major salivary glands. Isolated unilateral submandibular gland aplasia or aplasia accompanied by hypertrophy of contralateral submandibular gland or sublingual glands is a rare entity. The majority of cases are incidentally detected findings in asymptomatic patients; however, imaging findings may mimic mass-like lesions, posing diagnostic challenges in cancer patients. We presented 2 cases, a case with melanoma and an asymptomatic case, who had asymmetric lesion at left submandibular space, demonstrated to represent left submandibular gland accompanied by right submandibular gland aplasia. We aimed to highlight the imaging features for correct identification of these mass-like lesions as normal contralateral salivary gland accompanied by unilateral submandibular gland aplasia.

Chronic sclerosing sialadenitis may represent one of many manifestations of an immunoglobulin G4-related disease. However, existing studies typically consist of small patient cohorts rarely conducted in Western populations. The clinical behavior of chronic sclerosing sialadenitis, including follow-up data, warrants further study. Thus, we aimed to determine whether chronic sclerosing sialadenitis always presents as IgG4-related disease or associates with autoimmune diseases and to determine which additional examinations patients may require. Between 2000 and 2017, 51 patients undergoing submandibular gland resection within the Helsinki University Hospital area were diagnosed with chronic sclerosing sialadenitis. We re-evaluated all specimens and performed immunostaining for IgG4. IgG and CD31 stainings were performed for IgG4-positive specimens. IgG4-related disease diagnosis was defined by the Boston consensus statement criteria. We revised clinical data, distributing a follow-up questionnaire to patients to register symptoms of IgG4-related disease or autoimmune disease during follow-up. The chronic sclerosing sialadenitis criteria were fulfilled in 34 patients, whereby 17 were diagnosed as non-sclerosing chronic sialadenitis. In 19 cases, a sialolith associated with a salivary gland lesion. In total, 12 of 51 cases were recognized as IgG4-positive, while two met the criteria for IgG4-related disease. These two cases belonged to the non-sclerosing chronic sialadenitis group, and both involved other organs. The histopathological features between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis overlapped regarding the degree of fibrosis and inflammatory infiltrates. In the Finnish population, chronic sclerosing sialadenitis of the submandibular gland does not appear to present as IgG4-related disease. Non-sclerosing chronic sialadenitis can associate with IgG4-related disease. A histopathological distinction between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis is not always unequivocal and the presence of a sialolith does not exclude IgG4-positivity. Therefore, immunostaining for IgG4 should be performed when dense plasma cell infiltration is present in either non-sclerosing chronic sialadenitis or chronic sclerosing sialadenitis.

Objectives: The majority of cases of salivary gland involvement are diagnosed in its late stages as may be missed in the evaluation, the low detection rate of involvement of salivary gland by OSCC may have significant impact on spread and recurrence of the OSCC. The study aimed to evaluate involvement of parotid and submandibular salivary glands by tongue oral squamous cell carcinoma., Material and Method: The 144 histo-pathologically proven cases of tongue squamous cell carcinoma were evaluated for clinical staging, margins and extent of tumor and involvement of salivary gland on T1 - T2 Weighted, STIR, diffusion-weighted and contrast-enhanced MRI sequences and data was subjected to analysis., Results: In tongue OSCC, total 9 (6.25%) patients showed salivary gland involvement, 2 of them involved parotid glands and 7 of them involved submandibular gland. The OSCC involving the salivary glands were in Stage 4 except for 2 cases with predilection for antero-lateral border and tendency towards midline crossing. Out of 9 cases that showed salivary gland involvement, the 5 cases showed direct involvement from the spreading lesion, the 3 cases showed the infiltration from adjacent lymph nodes and 2 cases showed infiltration from sublingual gland and medial pterygoid muscle., Conclusion: The present study revealed the greater percentage of OSCC with salivary gland involvement as compared to previous studies; in contradiction present study demonstrated higher involvement of submandibular gland compared to parotid gland with additional imaging features in salivary glands (15.97%) suggesting the likely possibility of their involvement by OSCC in near future., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background/aim: To define the cytomorphologic findings leading to difficulties in diagnosis of Warthin tumors (WTs)., Materials and Methods: Forty-eight histopathologically diagnosed WT patients who had fine needle aspiration cytology preoperatively were reevaluated for defining the presence or absence of lymphocytes, oncocytic cell layer, oncocytic cell papillae, granular debris background, mucoid background, macrophages, polymorphonuclear cells, mast cells, squamous-like cells, atypical vacuolated cytoplasmic cells, and giant cells., Results: Forty-seven tumors were in the parotid gland and one in the submandibular gland. There were 37 (77%) male and 11 (23%) female patients. Cytopathologically in 36 patients the diagnosis was benign neoplasm (WT); in 6, other benign entities; and in 6, suspicious for malignancy. The main characteristic cytomorphologic features of WTs were as follows: 92% lymphoid cells, 83% oncocytic cell layers, and 67% granular debris background. These percentages were 67%, 17%, and 17% in the benign cytology group and 67%, 50%, and 17% in the suspicious for malignancy group, respectively., Conclusion: Absence or lack of main features of WTs with or without presence of squamous-like cells, vacuolated cytoplasmic cells, and inflammatory reaction may cause diagnostic dilemma. The presence of the mast cells accompanied by epithelial tissue was striking for WT diagnosis., Competing Interests: None declared., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Background: Identification of a peripheral biomarker is a major roadblock in the diagnosis of PD. Immunohistological identification of p-serine 129 α-synuclein in the submandibular gland tissues of PD patients has been recently reported., Objective: We report on a proof-of-principle study for using an ultra-sensitive and specific, real-time quaking-induced conversion assay to detect pathological α-synuclein in the submandibular gland tissues of PD patients., Methods: The α-synuclein real-time quaking-induced conversion assay was used to detect and quantify pathological α-synuclein levels in PD, incidental Lewy body disease, and control submandibular gland tissues as well as in formalin-fixed paraffin-embedded sections., Results: We determined the quantitative seeding kinetics of pathological α-synuclein present in submandibular gland tissues from autopsied subjects using the α-synuclein real-time quaking-induced conversion assay. A total of 32 cases comprising 13 PD, 3 incidental Lewy body disease, and 16 controls showed 100% sensitivity and 94% specificity. Interestingly, both PD and incidental Lewy body disease tissues showed 100% concordance for elevated levels of pathological α-synuclein seeding activity compared to control tissues. End-point dilution kinetic analyses revealed that the submandibular gland had a wide dynamic range of pathological α-synuclein seeding activity., Conclusions: Our results are the first to demonstrate the utility of using the real-time quaking-induced conversion assay on peripherally accessible submandibular gland tissues and formalin-fixed paraffin-embedded tissue sections to detect PD-related pathological changes with high sensitivity and specificity. Additionally, the detection of seeding activity from incidental Lewy body disease cases containing immunohistochemically undetected pathological α-synuclein demonstrates the α-synuclein real-time quaking-induced conversion assay's potential utility for identifying prodromal PD in submandibular gland tissues. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

The natriuretic peptide (NP) system comprises of three ligands, the Atrial Natriuretic Peptide (ANP), Brain Natriuretic peptide (BNP) and C-type Natriuretic peptide (CNP), and three natriuretic peptide receptors, NPRA, NPRB and NPRC. Here we present a comprehensive study of the natriuretic peptide system in healthy murine and human submandibular salivary glands (SMGs). We show CNP is the dominant NP in mouse and human SMG and is expressed together with NP receptors in ducts, autonomic nerves and the microvasculature of the gland, suggesting CNP autocrine signalling may take place in some of these glandular structures. These data suggest the NP system may control salivary gland function during homeostasis through the regulation of electrolyte re-absorption, neural stimulation and/or blood vessel wall contraction/relaxation. We also show abnormal expression of NPRA in the stroma of a subset of human SMGs resected from patients diagnosed with oral squamous cell carcinoma (OSCC) of non-salivary gland origin. This finding warrants further research to investigate a possible correlation between early OSCC invasion and NPRA overexpression.

Purpose: To explore the role of salivary fat fraction (FF) values in evaluating patients with primary Sjögren's syndrome (pSS)., Material and Method: A total of 28 patients with pSS, ten patients with suspected pSS, and 28 volunteers were enrolled. The FF values of the parotid and submandibular glands were generated from mDIXON Quant. A one-way analysis of variance was used to compare the FF values among the groups. A receiver-operating characteristic analysis was applied to assess the diagnostic performance of the parotid and submandibular FF values in distinguishing patients with pSS from non-pSS subjects. In particular, we focused on distinguishing patients with grade 0 pSS from those with suspected pSS., Results: The parotid and submandibular mean FF value of patients with pSS was significantly higher than that of healthy volunteers. The submandibular mean FF value of patients with pSS was higher than those suspected ones. Submandibular FF value performed better than parotid FF value in differentiating patients with pSS from those non-pSS subjects (area under the curve [AUC] = 0.927 vs. 0.734), patients with pSS from patients with suspected pSS (AUC = 0.907 vs. 0.725). This value also performed better at distinguishing patients with grade 0 pSS from those patients with suspected pSS (AUC = 0.925 vs. 0.783)., Conclusions: The salivary gland FF value, especially the submandibular gland FF value, distinguished patients with pSS from those patients with suspected pSS and healthy volunteers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Surgical scars are a significant cosmetic problem, especially when in exposed areas such as the anterior neck. To avoid or reduce visible scarring, diverse innovative surgical approaches to the neck have been introduced. The purpose of this study was to evaluate the feasibility and safety of the endoscopic resection using the retroauricular approach for submandibular gland excision., Methods: The present study enrolled 48 patients who underwent conventional transcervical submandibular gland excision and 23 patients who underwent endoscope-assisted retroauricular approach submandibular gland excision, from February 2014 through February 2018 at the Department of Head and Neck Surgery and Otorhinolaryngology of the AC Camargo Cancer Center, in Sao Paulo, Brazil. The surgical outcomes were retrospectively reviewed., Results: In the conventional group, 26 (54%) patients were male. The mean age was 49.3 years (range 22-81). Twenty-two patients (46%) had sialoadenitis; twenty-one (44%) had benign and five (10%) had malignant tumors. The mean total surgical time was 86.4 min (range 40-180), and the mean total length of hospital stay was 1.3 days. Twenty-seven (56%) patients suffered from local postoperative complications in the neck. In the retroauricular group, 14 (61%) patients were male. The mean age was 44.1 years (range 24-71 years). Seven patients (31%) had sialoadenitis, twelve (53%) had benign tumors and four (16%) had malignant tumors. The mean total surgical time was 86.4 min (range 75-300 min), and the mean total length of hospital stay was 1.2 days. Twelve (53%) patients suffered from local postoperative complications in the neck. No surgical site infections or systemic complications were described., Conclusions: The retroauricular endoscopic-assisted submandibular gland resection is feasible, with excellent cosmetic results and no significant complication rate increase, and can be a safe potential surgical alternative for patients who are motivated to avoid a visible neck scar.

The metastases of bronchopulmonary cancer in the submandibular gland are infrequent. We report a case of metastasis in the submandibular gland in a patient with small cell lung cancer who had chemotherapy with disease stability.

Chronic sclerosing sialadenitis, also known as Küttner's tumour, is a chronic inflammatory condition affecting the salivary glands. We present the case of an arteriovenous vascular malformation (AVM) of the right submandibular gland mimicking a Küttner's tumour on ultrasound scan in a 63-year-old woman. Examination revealed a 2 cm firm, mobile, non-pulsatile, right-sided submandibular mass with no overlying skin changes but with mild tenderness to palpation. Histological appearances revealed an AVM associated with localised fatty metaplasia and glandular atrophy. Although rare, AVMs should be considered a differential diagnosis for a submandibular gland mass that gives unclear or unusual radiological appearances., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: ChondroT, a new herbal medication, consists of Angelica grosseserrata Maxim., Lonicera japonica Thunb., Angelica gigas Nakai, Clematis terniflora var. manshurica (Rupr.) Ohwi, and Phellodendron amurense Rupr. (6:4:4:4:3). Our previous studies have shown that ChondroT exhibits significant anti-arthritic and anti-inflammatory effects. In this study, we aimed to assess the toxicological safety assessment of ChondroT., Methods: This study was designed to assess the safety of ChondroT after repeated oral administration. Male and female Sprague-Dawley rats were treated with ChondroT at oral doses of 0, 500, 1000, and 2000 mg/kg for 13 weeks. Mortality, clinical signs, body weight changes, food consumption, ophthalmological findings, urinalysis, hematological and blood-chemical parameters, necropsy findings, organ weights, and histological markers were recorded throughout the study period. Rats were also monitored for an additional 4 weeks to determine the recovery time., Results: No death occurred and no significant changes in food consumption, ophthalmologic findings, and urinalysis were found. Although there were alterations in clinical signs, body weights, hematological parameters, blood-chemical parameters, necropsy findings, organ weights, and histological markers, they were not considered to be toxicologically significant., Conclusions: The results suggest that the no-observed adverse effects level (NOAEL) was 2000 mg/kg/day for the test substance. ChondroT, a new complex herbal medication composed of five plants, can therefore be used safely at the NOAEL.

This prospective study aimed to investigate metastases of oral squamous cell carcinoma (OSCC) to cervical lymph nodes and submandibular glands and to analyze the safety and feasibility of preserving and using submandibular glandular flaps to repair postoperative OSCC defects.Overall, 330 patients with OSCC who met the inclusion criteria were enrolled in the study from January 2014 to July 2018. OSCC metastasis to cervical lymph nodes and submandibular glands was investigated using intraoperative frozen section and postoperative pathological observation. Fifteen patients who underwent repair of postoperative OSCC defects with submandibular glandular flaps were monitored for postoperative wound healing, complications, pathology, and appearance satisfaction and were followed up long term.Among the 330 patients with OSCC, the most common type was tongue cancer (138/330); 204 patients were node negative and 126 were node positive. Of 363 samples of the submandibular gland, 7 were metastatic with stage IV lesion, 5 were directly invaded by the primary tumor, and 2 were metastatic with extranodal extension in level Ib. None of the submandibular gland samples showed intraglandular hematogenous and nodal metastases. The repair of OSCC defects with submandibular glandular flaps was successful in all 15 patients, including 11 males and 4 females, with an age range of 19-74 years and a mean of 51 years. Of 15 patients, some had complications with heart and cerebrovascular diseases, diabetes, or chronic respiratory disease. All the submandibular glandular flaps survived postoperatively without any complications, and the mucosification on the surface was adequate. Follow-ups (median duration: 14 months) revealed the satisfactory recovery of shape and function without any local recurrences or distant metastases.Direct invasion is the main form of OSCC metastasis to the submandibular gland, while hematogenous and nodal metastases are uncommon. Preservation of the submandibular gland is oncologically safe. Thus, repair of postoperative OSCC defects with submandibular gland flaps is a feasible and promising procedure.

Competing Interests: Competing interests The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none. Further details of The BMJ policy on financial interests are here: https://www.bmj.com/about-bmj/resources-authors/forms-policies-and-checklists/declaration-competing-interests

IgG4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic fibroinflammatory disease that affects salivary glands and leads to hyposalivation. Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine involved in several salivary gland disorders, but its role and mechanism regarding acinar cell injury in IgG4-RS are unknown. Here, we found that TNF-α level was significantly increased in serum and submandibular gland (SMG) of patients and that serum TNF-α level was negatively correlated with saliva flow rate. Ultrastructural observations of IgG4-RS SMGs revealed accumulation of large autophagic vacuoles, as well as dense fibrous bundles, decreased secretory granules, widened intercellular spaces, swollen mitochondria, and expanded endoplasmic reticulum. Expression levels of LC3 and p62 were both increased in patients' SMGs. TNF-α treatment led to elevated levels of LC3II and p62 in both SMG-C6 cells and cultured human SMG tissues but did not further increase their levels when combined with bafilomycin A1 treatment. Moreover, transfection of Ad-mCherry-GFP-LC3B in SMG-C6 cells confirmed the suppression of autophagic flux after TNF-α treatment. Immunofluorescence imaging revealed that costaining of LC3 and the lysosomal marker LAMP2 was significantly decreased in patients, TNF-α-treated SMG-C6 cells, and cultured human SMGs, indicating a reduction in autophagosome-lysosome fusion. Furthermore, the ratio of pro/mature cathepsin D was elevated in vivo, ex vivo, and in vitro. TNF-α also appeared to induce abnormal acidification of lysosomes in acinar cells, as assessed by lysosomal pH and LysoTracker DND-26 fluorescence intensity. In addition, TNF-α treatment induced transcription factor EB (TFEB) redistribution in SMG-C6 cells, which was consistent with the changes observed in IgG4-RS patients. TNF-α increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, and inhibition of ERK1/2 by U0126 reversed TNF-α-induced TFEB redistribution, lysosomal dysfunction, and autophagic flux suppression. These findings suggest that TNF-α is a key cytokine related to acinar cell injury in IgG4-RS through ERK1/2-mediated autophagic flux suppression.

Treatment for ranula is classified into three categories depending on how the leaking saliva is managed: removal of the leaking site by intraoral or transcervical resection of the sublingual gland; formation of a drainage tract through the wall of the pseudocyst by micromarsupialisation or marsupialisation; or sealing of the site of the leak by inducing fibrosis with a sclerosing agent. Resection of the sublingual gland is probably the option most likely to be curative for both oral and plunging ranula considering their pathophysiology. Although alternative treatments have been introduced to avoid the invasiveness of resection of the gland, their outcomes have been inconsistent. The objective of this study therefore was to help decision-making by providing more integrated rates of cure, consistency of treatment, and morbidity, depending on types of treatment used in previous series of cases. We used proportion meta-analysis of 39 such published series, and the most curative treatment for oral ranula was intraoral resection of the sublingual gland. Micromarsupialisation and its modification showed cure rates comparable with those of resection of the gland, but these were moderately inconsistent. In the treatment of plunging ranula, there was no significant difference in cure rate between the intraoral and transcervical approaches, although they both showed higher cure rates than injection of OK-432. Comparisons of morbidity were available for patients who had developed nerve dysfunction and haematoma after the intraoral and transcervical approaches and there was no significant difference between the two, though the morbidity was higher after the transcervical than that after the intraoral approach. In conclusion, intraoral resection of the sublingual gland is sufficient treatment with a tendency to have fewer complications than that in the transcervical approach., (Copyright © 2019 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Aging has pronounced effects on mammalian tissues and cells, but the impacts of aging on salivary gland function are relatively unknown. This study aims to evaluate the effects of aging on submandibular gland (SMG) and parotid gland (PG) functions in the male senescence-accelerated mouse. In vivo analysis at the systemic level revealed that salivary secretion induced by pilocarpine, a muscarinic agonist, from the SMG was significantly decreased in aged mice, whereas salivary secretion from the PG was not affected. To evaluate organ-level function, the SMG was perfused with the muscarinic agonists carbachol and calcium ionophore A23187 ex vivo to induce salivary secretion, and decreased saliva production was also observed in the aged SMG. Histological analysis revealed the presence of CD4-positive lymphocytes infiltrating the aged SMG. Furthermore, real-time PCR revealed that the aged SMG exhibited accelerated cell aging, increased levels of the inflammatory cytokine interleukin-6, and decreased mRNA levels of the water channel protein aquaporin-5 (AQP5). In summary, these results demonstrate that SMG function in aged mice was diminished, and that cell senescence, chronic inflammation, and the decreased gene expression of AQP5 are the likely causes of hyposalivation in the SMG of aged mice.

Interleukin (IL)‑12 modulates the generation and function of various immune cells and plays a vital role in the pathogenesis of Sjögren's syndrome (SS). Myeloid‑derived suppressor cells (MDSCs) are involved in autoimmune diseases by regulating various immune responses. However, it has not been confirmed whether inflammatory IL‑12 participates in the progression of SS via regulating MSDCs. In the present study, the plasma levels of IL‑12 were detected by ELISA in SS‑like non‑obese diabetic (NOD) mice. The mice were treated by intraperitoneal injection of IL‑12 and anti‑IL‑12 antibody, respectively, and then the salivary flow rate was detected. The pathology of submandibular glands was evaluated in tissue sections stained with hematoxylin and eosin. The proportion of MDSCs was assessed by flow cytometry. The results showed that plasma IL‑12 was significantly increased in the SS‑like NOD mice comparing with that noted in the control mice. The exogenous IL‑12 exacerbated SS‑like symptoms of NOD mice and promoted the generation of both bone marrow (BM) and splenic MDSCs in the SS‑like NOD mice. Of note, anti‑IL‑12 alleviated SS‑like symptoms of NOD mice and inhibited the generation of BM and splenic MDSCs. Moreover, the generation of MDSCs was crippled in the IL‑12‑deficient C57BL/6 (Il‑12‑/‑ B6) mice. Our findings suggest that aggravation of SS‑like symptoms by IL‑12 in NOD mice may be attributed to its promotion of MDSC development.

We report a 54-year-old man, who presented with an acute onset of diplopia and ptosis on the left side. On admission, neurological examination showed left oculomotor and abducens nerve palsy. Brain MRI showed thickening of the left parieto-temporal dura mater with gadolinium enhancement. Whole-body CT revealed a mass lesion in the right submandibular gland, diffuse goiter, and bilateral hilar lymph node enlargement. Initially, IgG4-related disease was considered because of an elevated serum IgG4 level (240 mg/dl); however, biopsy of the submandibular gland showed non-caseating epithelioid cell granulomas that suggested sarcoidosis, which could be associated with the intracranial lesions causing his neurological manifestation. In cases of hypertrophic pachymeningitis, especially with increased serum IgG4 including our case, a careful assessment with pathological examination is critical for identifying various underlying conditions.

Purpose: To analyze baseline CT/MR-based image features of salivary glands to predict radiation-induced xerostomia 3-months after head-and-neck cancer (HNC) radiotherapy., Methods: A retrospective analysis was performed on 266 HNC patients who were treated using radiotherapy at our institution between 2009 and 2018. CT and T1 post-contrast MR images along with NCI-CTCAE xerostomia grade (3-month follow-up) were prospectively collected at our institution. CT and MR images were registered on which parotid/submandibular glands were contoured. Image features were extracted for ipsilateral/contralateral parotid and submandibular glands relative to the location of the primary tumor. Dose-volume-histogram (DVH) parameters were also acquired. Features were pre-selected based on Spearman correlation before modelling by examining the correlation with xerostomia (p < 0.05). A shrinkage regression analysis of the pre-selected features was performed using LASSO. The internal validity of the variable selection was estimated by repeating the entire variable selection procedure using a leave-one-out-cross-validation. The most frequently selected variables were considered in the final model. A generalized linear regression with repeated ten-fold cross-validation was developed to predict radiation-induced xerostomia at 3-months after radiotherapy. This model was tested in an independent dataset (n = 50) of patients who were treated at the same institution in 2017-2018. We compared the prediction performances under eight conditions (DVH-only, CT-only, MR-only, CT + MR, DVH + CT, DVH + CT + MR, Clinical+CT + MR, and Clinical+DVH + CT + MR) using the area under the receiver operating characteristic curve (ROC-AUC)., Results: Among extracted features, 7 CT, 5 MR, and 2 DVH features were selected. The internal cohort (n = 216) ROC-AUC values for DVH, CT, MR, and Clinical+DVH + CT + MR features were 0.73 ± 0.01, 0.69 ± 0.01, 0.70 ± 0.01, and 0.79 ± 0.01, respectively. The validation cohort (n = 50) ROC-AUC values for DVH, CT, MR, and Clinical+DVH + CT + MR features were 0.63, 0.57, 0.66, and 0.68, respectively. The DVH-ROC was not significantly different than the CT-ROC (p = 0.8) or MR-ROC (p = 0.4). However, the CT + MR-ROC was significantly different than the CT-ROC (p = 0.03), but not the Clinical+DVH + CT + MR model (p = 0.5)., Conclusion: Our results suggest that baseline CT and MR image features may reflect baseline salivary gland function and potential risk for radiation injury. The integration of baseline image features into prediction models has the potential to improve xerostomia risk stratification with the ultimate goal of truly personalized HNC radiotherapy.

Botulinum toxin type A (BTXA) is a neurotoxic protein produced by Clostridium botulinum Our previous studies demonstrated that BTXA inhibits the secretory function of submandibular gland (SMG) and changes its structure. Several studies reported that SMG damage and repair often occur with autophagy in the rat. However, no studies reported whether secretory inhibition and structural changes of SMG after BTXA injection is related with autophagy. The present study was carried out to explore the association between BTXA injection and autophagy in rat SMG. Western blotting and immunofluorescence were used to detect the expression and distribution of light chain 3 (LC3) in rat SMG. MTS was used to detect the toxicity of BTXA on rat SMG-C6 cell line. GFP-LC3 and Lyso-Tracker Red fluorescence probe were used to assess the levels of autophagosomes and lysosome fusion and the effect of BTXA on autophagic flux in SMG-C6. Western blotting and immunofluorescence results showed that BTXA temporarily increased autophagosomes in rat SMG. MTS results showed that BTXA exerted its toxicity on SMG-C6 in a dose-dependent manner. BTXA increased the number of autophagosomes in SMG-C6; however, most autophagosomes did not colocalize with lysosome. Therefore, we presume that BTXA can change autophagic flux of SMG cells, the mechanism of which might relate with BTXA's disturbing autophagosome-lysosome fusion., (© 2019 The Author(s).)

Objective: This study aimed to analyze the effects of comprehensive protection of bilateral parotid glands (PG-T), contralateral submandibular gland (cSMG), and accessory salivary glands in the oral cavity (OC) by helical tomotherapy for head-and-neck cancer patients., Methods: Totally 175 patients with histologically confirmed head-and-neck cancer treated with helical tomotherapy were recruited. The doses delivered to PG-T, cSMG, and OC were constrained to be as low as possible in treatment planning. The saliva flow rates and xerostomia questionnaire were evaluated. Correlation between xerostomia and other clinical factors were assessed using univariate and multivariate models. The impact of salivary gland dose on locoregional (LR) recurrence was assessed by Cox analysis. ROC curve was used to determine the threshold of mean dose for each gland., Results: The median follow-up was 25 (19-36) months. The OC mean dose, PG-T mean dose, cSMG mean dose, age, clinical stage (II and III versus IV), and both unstimulated and stimulated saliva flow rates were significantly correlated with xerostomia. The OC mean dose, cSMG mean dose, age, and clinical stage were predictors of xerostomia after adjusting PG-T mean dose, and unstimulated and stimulated saliva flow rates. Xerostomia was significantly decreased when the mean doses of PG-T, cSMG, and OC were kept below 29.12Gy, 29.29Gy, and 31.44Gy, respectively. At 18 months after radiation therapy, early LR recurrence rate was only 4%., Conclusion: Comprehensive protection of salivary glands minimized xerostomia in head-and-neck cancer patients treated by helical tomotherapy, without increasing early LR recurrence risk., Competing Interests: The authors declare that they have no conflicts of interest.

Objective: To compare two different Ho:YAG laser systems in relation to the preset parameters and their effectiveness for intraductal fragmentation of the salivary stones., Patients and Methods: We made a retrospective study in two tertiary referral centers (Department of ENT, Head and Neck Surgery, University of Erlangen-Nuremberg, Germany and the MacKay Memorial Hospital, Taipei, Taiwan). Patients with a diagnosis of sialolithiasis were treated in Erlangen and Taipei. The Erlangen patients were treated using the Calculase II™ Ho:YAG laser (Karl Storz, Tuttlingen, Germany) at 4 Hz, 1.2 J (4.8 W) and the MacKay patients were treated using the VersaPulse® PowerSuite™ Ho:YAG laser (Lumenis Ltd., Yokneam, Israel) at 6 Hz, 0.5 J (3 W)., Results: A total of 12 patients with 12 stones were treated in Erlangen and 54 with 75 stones in Taipei. The submandibular stones were present in 50% and 86.7% of cases, respectively. The complete fragmentation was achieved in all of the treated stones in both groups; 100% and 92.6% of the patients were stone-free, 100% and 94.4% of the patients became symptom-free, respectively. 33% of the Erlangen patients had multimodal treatments. The glands were preserved in all cases in both centers., Conclusions: The Ho:YAG laser proved to be effective in the treatment of sialolithiasis. Stone size, location, and involved gland were important additional parameters. Our experience and the literature results show that the laser presetting with a frequency of 3-6 Hz, an energy level of 0.5-1.2 J, and effective power of between 3 and 4.8 W is sufficient to achieve maximum success without any increased risk for complications.

Neuroendocrine tumors (NET) are a heterogeneous group of malignancies with a broad spectrum of histomorphologies, tissue origins, and clinical outcomes, which arise from neural crest cells with neuroendocrine differentiation. Salivary gland tumors account for 3-6% of all head and neck neoplasms, while large cell neuroendocrine carcinomas (LCNEC) of the salivary gland are extremely rare, with few cases reported in literature, and only 5 cases involving submandibular gland. The rarity of these tumors in salivary glands is probably related to the scarcity of neuroendocrine cells in this tissue, whose presence is still a matter of debate. Regardless of their low frequency, it is imperative to differentiate these tumors from the much more common squamous cell carcinomas and metastatic NETs, due to different therapeutic approach and prognosis. In this paper, we report the case of a 21-year-old man, with a LCNEC involving a submandibular gland followed by several recurrences over the years. In addition, we include a comprehensive review of the available literature on this topic., (Copyright © 2019 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: Allotransplantation of submandibular salivary glands (SMGs) could be an alternative treatment option for severe keratoconjunctivitis sicca in noncandidates for autologous SMG transplantation. This study was conducted to evaluate the effect of allogeneic mesenchymal stem cell (MSC) therapy on the survival of allotransplanted SMGs., Methods: Thirty-six SMG allotransplantations (n = 6 per group) were performed in New Zealand white rabbits and randomly divided into the following groups: allograft control (Allo-Ctrl), low-dose FK506 (FK506-L), high-dose FK506 (FK506-H), allogeneic MSCs, MSCs+FK506-L, and MSCs+FK506-H. Rabbits were closely observed for 2 weeks. Gland viability and rejection were assessed by monitoring interleukin-2 levels by ELISA, sialoscintigraphy, M3-muscarinic acetylcholine receptor expression, histological evaluation, and apoptosis assay., Results: Intraoperatively, all glands showed patency and saliva flow except 1 gland. Sialoscintigraphy revealed significantly higher saliva production within the MSC-treated glands. Histologically, MSC-treated glands showed higher glandular tissue preservation and less acini atrophy. The MSCs+FK506-H group revealed significantly lower apoptosis percentage. The highest survival was observed in the MSCs+FK506-H group, followed by the FK506-H and MSCs+FK506-L groups, and lastly less in the FK506-L and MSCs groups., Conclusions: Concurrent administration of MSCs with FK506-H (0.16 mg/kg) resulted in higher survival rate with greater glandular tissue preservation and salivary secretion. MSCs with FK506-L (0.08 mg/kg) could be an alternative to FK506-H (0.16 mg/kg) in salivary gland allotransplantation.

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a 6-tier diagnostic category system with associated risks of malignancy (ROMs) and management recommendations. Submandibular gland fine-needle aspiration (FNA) is uncommon with a higher frequency of inflammatory lesions and a higher relative proportion of malignancy, and this may affect the ROM and subsequent management. This study evaluated the application of the MSRSGC and the ROM for each diagnostic category for 734 submandibular gland FNAs., Methods: Submandibular gland FNA cytology specimens from 15 international institutions (2013-2017) were retrospectively assigned to an MSRSGC diagnostic category as follows: nondiagnostic, nonneoplastic, atypia of undetermined significance (AUS), benign neoplasm, salivary gland neoplasm of uncertain malignant potential (SUMP), suspicious for malignancy (SM), or malignant. A correlation with the available histopathologic follow-up was performed, and the ROM was calculated for each MSRSGC diagnostic category., Results: The case cohort of 734 aspirates was reclassified according to the MSRSGC as follows: nondiagnostic, 21.4% (0%-50%); nonneoplastic, 24.2% (9.1%-53.6%); AUS, 6.7% (0%-14.3%); benign neoplasm, 18.3% (0%-52.5%); SUMP, 12% (0%-37.7%); SM, 3.5% (0%-12.5%); and malignant, 13.9% (2%-31.3%). The histopathologic follow-up was available for 333 cases (45.4%). The ROMs were as follows: nondiagnostic, 10.6%; nonneoplastic, 7.5%; AUS, 27.6%; benign neoplasm, 3.2%; SUMP, 41.9%; SM, 82.3%; and malignant, 93.6%., Conclusions: This multi-institutional study shows that the ROM of each MSRSGC category for submandibular gland FNA is similar to that reported for parotid gland FNA, although the reported rates for the different MSRSGC categories were variable across institutions. Thus, the MSRSGC can be reliably applied to submandibular gland FNA., (© 2019 American Cancer Society.)

Adenoid cystic carcinoma is one of the most common salivary gland malignancies with poor long-term prognosis, but the coexistence of sialoliths is extraordinarily rare. In this article, we report a case of 30-year-old woman with a history of submandibular area swelling with intermittent pain increasing during mealtimes that had led her attending physician to diagnose a sialolith in the left submandibular gland on a radiograph 10 years before. However, the surgical specimen proved to be an adenoid cystic carcinoma accompanied with a sialolith. Histopathologically, the submandibular gland was displaced with a fibrous granulation tissue containing a small cribriform carcinoma invading the extracapsular region of the gland. We performed fluorescence in situ hybridization examination with an MYB-NFIB fusion probe of the lesion, with positive results. The patient underwent a supraomohyoid neck dissection as additional procedure because of the possibility of the extracapsular cancer nest remaining around the submandibular gland, but she remains well and disease free 11 years after the first operation.

Family with sequence similarity 20‑member C (FAM20C), a recently characterized Golgi kinase, performs numerous biological functions by phosphorylating more than 100 secreted proteins. However, the role of FAM20C in the salivary glands remains undefined. The present study demonstrated that FAM20C is mainly located in the cytoplasm of duct epithelial cells in the salivary glands. Fam20cf/f; Mmtv‑Cre mice were created in which Fam20c was inactivated in the salivary gland cells and observed that the number of ducts and the ductal cross‑sectional area increased significantly, while the number of acinar cells was reduced. The granular convoluted tubules (GCTs) exhibited an accumulation of aberrant secretory granules, along with a reduced expression and altered distribution patterns of β nerve growth factor, α‑amylase and bone morphogenetic protein (BMP) 4. This abnormality suggested that the GCT cells were immature and exhibited defects in developmental and secretory functions. In accordance with the morphological alterations and the reduced number of acinar cells, FAM20C deficiency in the salivary glands significantly decreased the salivary flow rate. The Na+, Cl- and K+ concentrations in the saliva were all significantly increased due to dysfunction of the ducts. Furthermore, Fam20c deficiency significantly increased BMP2 and BMP7 expression, decreased BMP4 expression, and attenuated the canonical and noncanonical BMP signaling pathways in the salivary glands. Collectively, the results of the present study demonstrate that FAM20C is a key regulator of acinar and duct structure and duct maturation and provide a novel avenue for investigating novel therapeutic targets for oral diseases including xerostomia.

Perineural invasion (PNI), the neoplastic invasion of nerves, is a common pathologic finding in head and neck cancer that is associated with poor clinical outcomes. PNI is a histologic finding of tumor cell infiltration and is distinct from perineural tumor spread (PNTS), which is macroscopic tumor involvement along a nerve extending from the primary tumor that is by definition more advanced, being radiologically or clinically apparent. Despite widespread acknowledgment of the prognostic significance of PNI and PNTS, the mechanisms underlying its pathogenesis remain largely unknown, and specific therapies targeting nerve invasion are lacking. The use of radiation therapy for PNI and PNTS can improve local control and reduce devastating failures at the skull base. However, the optimal volumes to be delineated with respect to targeting cranial nerve pathways are not well defined, and radiation can carry risks of major toxicity secondary to the location of adjacent critical structures. Here we examine the pathogenesis of these phenomena, analyze the role of radiation in PNI and PNTS, and propose guidelines for radiation treatment design based on the best available evidence and the authors' collective experience to advance understanding and therapy of this ominous cancer phenotype., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction:: Recurrent salivary gland swelling of the parotid and submandibular glands results in painful swelling in the pediatric population. There is no defined algorithm for workup and treatment of these disorders, resulting in wide heterogeneity and in some cases overuse of computed tomography (CT) imaging. Sialendoscopy (SE) is an interventional option for recurrent swelling of both glands; however, its effectiveness in the pediatric population is still being determined., Objectives:: To assess preoperative imaging utilization and benefit in the workup of recurrent pediatric sialadenitis, intraoperative SE findings, and postoperative outcomes after intervention with SE., Methods:: Case-series with a 5-year retrospective chart review on children undergoing SE for recurrent sialadenitis., Results:: Forty-nine SE procedures were performed on 38 parotid glands (PG) and 11 submandibular glands (SMGs) in 29 children. CT imaging findings were useful for identifying a stone or stricture and guiding surgical management in 45.5% of SMGs versus 2.6% of PGs ( P < .001). A stone was found in 45.5% of SMGs and none in PG ( P < .001). SE intervention such as balloon dilation or stone removal was performed in 54.6% of SMGs and 5.3% of PGs ( P < .001). 74% of parotid patients undergoing SE responded to 1 intervention with a cessation of recurrent gland swelling, while 26% required additional interventions. One hundred percent of SMG patients responded to first intervention. There was no improvement in the beneficial effect of SE with steroid injection ( P = .897) regardless of steroid used ( P = .082)., Conclusion:: CT findings were found to be low yield for recurrent parotid swelling, and ultrasound is a recommended first-line step for PG pathology. SE is a recommended first-line intervention for SMG and parotid sialadenitis as demonstrated by 100% and 74% response rate to initial SE, respectively.

Xerostomia is a common consequence of radiotherapy in head and neck cancer. The objective was to compare the regional radiation dose distribution in patients that developed xerostomia within 6 months of radiotherapy and those recovered from xerostomia within 18 months post-radiotherapy. We developed a feature generation pipeline to extract dose volume histogram features from geometrically defined ipsilateral/contralateral parotid glands, submandibular glands, and oral cavity surrogates for each patient. Permutation tests with multiple comparisons were performed to assess the dose difference between injury vs. non-injury and recovery vs. non-recovery. Ridge logistic regression models were applied to predict injury and recovery using clinical features along with dose features (D10-D90) of the subvolumes extracted from oral cavity and salivary gland contours + 3 mm peripheral shell. Model performances were assessed by the area under the receiver operating characteristic curve (AUC) using nested cross-validation. We found that different regional dose/volume metrics patterns exist for injury vs. recovery. Compared to injury, recovery has increased importance to the subvolumes receiving lower dose. Within the subvolumes, injury tends to have increased importance towards D10 from D90. This suggests that different threshold for xerostomia injury and recovery. Injury is induced by the subvolumes receiving higher dose, and the ability to recover can be preserved by further reducing the dose to subvolumes receiving lower dose.

GPR55, a lipid-sensing receptor, is implicated in cell cycle control, malignant cell mobilization, and tissue invasion in cancer. However, a physiological role for GPR55 is virtually unknown for any tissue type. Here, we localize GPR55 to self-renewing ductal epithelial cells and their terminally differentiated progeny in both human and mouse salivary glands. Moreover, we find GPR55 expression downregulated in salivary gland mucoepidermoid carcinomas and GPR55 reinstatement by antitumor irradiation, suggesting that GPR55 controls renegade proliferation. Indeed, GPR55 antagonism increases cell proliferation and function determination in quasiphysiological systems. In addition, Gpr55-/- mice present ~50% enlarged submandibular glands with many more granulated ducts, as well as disordered endoplasmic reticuli and with glycoprotein content. Next, we hypothesized that GPR55 could also modulate salivation and glycoprotein content by entraining differentiated excretory progeny. Accordingly, GPR55 activation facilitated glycoprotein release by itself, inducing low-amplitude Ca2+ oscillations, as well as enhancing acetylcholine-induced Ca2+ responses. Topical application of GPR55 agonists, which are ineffective in Gpr55-/- mice, into adult rodent submandibular glands increased salivation and saliva glycoprotein content. Overall, we propose that GPR55 signaling in epithelial cells ensures both the life-long renewal of ductal cells and the continuous availability of saliva and glycoproteins for oral health and food intake.

Objective: The aim of this study was to determine the effects of prolonged hyperoxia on salivary glands and salivary secretion in mice., Design: Male C57BL/6 J mice were kept in a 75% oxygen chamber (hyperoxia group) or a 21% oxygen chamber for 5 days. We measured the secretion volume, protein concentration, and amylase activity of saliva after the injection of pilocarpine. In addition, we evaluated the histological changes induced in the submandibular glands using hematoxylin and eosin and Alcian blue staining and assessed apoptotic changes using the TdT-mediated dUTP nick end labeling (TUNEL) assay. We also compared the submandibular gland expression levels of heme oxygenase-1 (HO-1), superoxide dismutase (SOD)-1, and SOD-2 using the real-time polymerase chain reaction., Results: In the hyperoxia group, salivary secretion was significantly inhibited at 5 and 10 min after the injection of pilocarpine, and the total salivary secretion volume was significantly decreased. The salivary protein concentration and amylase activity were also significantly higher in the hyperoxia group. In the histological examinations, enlargement of the mucous acini and the accumulation of mucins were observed in the submandibular region in the hyperoxia group, and the number of TUNEL-positive cells was also significantly increased in the hyperoxia group. Moreover, the expression levels of HO-1, SOD-1, and SOD-2 were significantly higher in the hyperoxia group., Conclusion: Our results suggest that hyperoxia reduces salivary secretion, and oxidative stress reactions might be involved in this., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (non-specific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD.

Mucins are heavily glycosylated proteins with high molecular mass, and are involved in various diseases including infection, inflammation, and cancer. As easy separation method, such as gel electrophoresis, however, does not exist for mucins, due to their large molecular sizes and heterogeneities. In 2009, we published a supported molecular matrix electrophoresis (SMME) method that can be used to characterize mucins. For SMME analysis, mucins have been enriched by ultrafiltration of trypsin digests using a 100 KDa cutoff filter. However, this enrichment results in a loss of protein identification capability using proteomic approaches. In this study, we describe a simple enrichment of mucins without trypsinization for SMME analysis. The enrichment was developed using a porcine submandibular gland and then was applied to study and compare mouse submandibular glands between young and aged mice. From mouse submandibular glands, hyaluronic acid and some mucins were observed by SMME. One of the mucins was identified as MUC10 by proteomic analysis of the band on the SMME membrane and immunostaining using anti-MUC10 antibody. A major O-glycan of MUC10 was determined to be NeuAcα2-3Galβ1-3GalNAc. Furthermore, our experiments revealed that the concentrations of these molecules were lower in aged mice than in young mice, and that an unknown mucin-like molecule was detected only from the aged mouse submandibular gland., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice., Methods: Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction., Results: Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05)., Conclusions: ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.

Background: Sialadenitis is a nonneoplastic disease that causes salivary dysfunction. Autophagy may be involved in helping protect salivary function when the salivary gland is impaired; this process is primarily activated by sensors of innate immunity, such as Toll-like receptors and nucleotide-binding oligomerization domain (NOD)-like receptors. The role of these pattern recognition receptors (PRRs) in the regulation of salivary gland tissue defense and homeostasis has been underappreciated. This study hypothesized that NOD2 and TLR4 have a synergistic effect on the activation of autophagy in human submandibular gland (HSG) inflammation., Methods: Submandibular gland inflammation was modeled by treating HSG cell lines in vitro with muramyl dipeptide (MDP) and lipopolysaccharide (LPS) for 24 hours. The mRNA and protein expression of NOD2, TLR4 and autophagy-related proteins (ATG5, LC3, Beclin1) were evaluated by real-time PCR and Western blot. Immunohistochemistry and double immunofluorescence were used to analyze the presence, distribution and colocalization of the aforementioned indicators in HSG tissues., Result: The mRNA and protein expression of autophagy-related proteins were significantly increased in HSG cells costimulated with LPS and MDP for 24 hours. NOD2, TLR4 and the autophagy-related proteins were also highly expressed in residual acini and dilated ducts of chronic submandibular sialadenitis tissues. In addition, PRRs and autophagy markers were obviously colocalized in chronic submandibular sialadenitis tissues and HSG cells., Conclusion: TLR4 and NOD2 have unique expression sites in salivary glands, and they may synergistically activate autophagy in salivary glands under conditions of inflammation., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hereditary hemochromatosis (HH) includes various disorders in iron metabolism producing iron deposits in several organs. HH is classified according to the HFE gene mutation. HH type I is characterized by HFE gene mutation, while types II, III and IV are due to other conditions. Juvenile hemochromatosis (JH) is related to hemojuvelin mutation, which is a regulatory peptide of the hepcidin protein, which regulates iron absorption. We report a case of JH and offer a concise review of the literature. A 14-year-old girl, with no secondary sexual characteristics, presented with abdominal pain, cough and dyspnoea. Clinical examination revealed right lower lobe consolidation, pleural effusion, cardiomegaly and an ejection fraction of 20%, with no response to treatment. On autopsy she was seen to have pleural and pericardial effusion, dilated cardiomyopathy, liver cirrhosis and pancreatic fibrosis. Prussian blue stain showed iron overload in these organs. JH with hypogonadism, cardiomyopathy and cirrhosis was diagnosed., (Copyright © 2018 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: Although a role for CD4+ T cells in the pathogenesis of Sjögren's syndrome (SS) has been documented, the pathogenic significance of CD8+ T cells is unclear. The aim of this study was to investigate the role of CD8+ T cells in the development of SS., Methods: Flow cytometry and immunofluorescence analyses were utilized to detect T cell infiltration within the labial salivary glands of patients with primary SS. In parallel, p40 -/- CD25 -/- mice were used as a murine model of SS. In addition, mice with genetic knockout of CD4, CD8a, or interferon-γ (IFNγ) were crossed with p40 -/- CD25 -/- mice to study the pathogenic significance of specific lineage subpopulations, including functional salivary gland tests as well as histopathologic and serologic data. A CD8+ T cell-specific depletion antibody was used in this murine SS model to evaluate its potential as a therapeutic strategy., Results: CD8+ T cells with a tissue-resident memory phenotype outnumbered CD4+ T cells in the labial salivary glands of patients with SS, and were primarily colocalized with salivary duct epithelial cells and acinar cells. Furthermore, infiltrating CD8+ T cells with a CD69+CD103+/- tissue-resident phenotype and with a significant elevation of IFNγ production were dominant in the submandibular glands of mice in this murine SS model. CD8a knockout abrogated the development of SS in these mice. Knockout of IFNγ decreased CD8+ T cell infiltration and gland destruction. More importantly, depletion of CD8+ T cells fully protected mice against the pathologic manifestations of SS, even after the onset of disease., Conclusion: These data reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD8+ T cells may be a rational therapy for the management of SS in human subjects., (© 2018, American College of Rheumatology.)

Objective: To validate the role of α-synuclein (AS) pathology in submandibular gland (SMG) as a biomarker for Parkinson disease (PD)., Methods: We performed ultrasonography (USG) guided core needle biopsy of SMG in PD patients and procured SMG biopsy tissues or surgical excision specimens from non-PD patients as controls. Then, we compared AS deposition in the SMG tissues between the PD patients and the controls. We recruited 16 PD patients in this study. In each individual, two core needle biopsy tissues were obtained from the left submandibular gland under USG guidance. Fourteen sex and age-matched controls who did not have PD and dementia but received a core needle biopsy or surgical resection of the SMG due to SMG diseases were procured from the pathology archive. Biopsy tissues and surgical specimens were immuno-stained with serine 129 phosphorylated AS (pAS) antibody for microscopic examination. pAS deposition in neural structures such as ganglion cells and neurites was considered as positive., Results: No serious complication occurred during and after the SMG biopsy. We found glandular parenchyma and neural structures in all biopsied SMG tissues from the patients and the controls. Nine out of 16 PD patients (56.2%) were positive for pAS staining, while none of the controls were positive (0%)., Conclusions: SMG core needle biopsy can reliably and safely obtain sufficient glandular parenchyma and neural structures to evaluate the α-synuclein pathology. AS pathology in SMG has high specificity and good sensitivity as a biomarker for PD., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives/hypothesis: Submandibular gland tumors (SMGTs) are rare and characterized by heterogeneity in histologic profiles. The aim of the present study was to retrieve data on submandibular gland (SMG) malignancies and identify factors influencing survival., Study Design: Retrospective study., Methods: A multicenter, retrospective study on patients who underwent primary surgery for SMGTs at three referral centers was performed., Results: Among 204 patients with SMGTs, 50 (24.5%) with SMG malignancies were analyzed in detail. Definitive pT status was: 21 (42%) pT1, 14 (28%) pT2, 10 (20%) pT3, and five (10%) pT4. Nodal metastases and perineural spread were diagnosed in 15 (30%) and 25 (50%) patients, respectively. High-grade lesions were identified in 32 (64%) patients. Follow-up status, available for 49 (98%) patients, was as follows: 23 (47%) patients were alive without disease, 11 (22.5%) died of disease, five (10.2%) alive with disease, and 10 (20.4%) died of other causes. Five- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 66.4% and 57.1%, 76.6% and 72.1%, 69.1% and 62.4%, respectively. At univariate analysis, OS, DSS, and RFS were influenced by pT status, pN status, and perineural spread. OS and RFS were also affected by the presence of facial palsy and pain. RFS was negatively influenced by positive margins. Multivariate analysis confirmed that OS, DSS, and RFS were independently affected by perineural spread, whereas nodal involvement influenced only RFS., Conclusions: The malignancy rate of SMGTs is comparable to that reported for parotid tumors. Most patients presented with high-grade lesions. pT status, pN status, and perineural spread significantly affected prognosis., Level of Evidence: 4 Laryngoscope, 128:2745-2750, 2018., (© 2018 The American Laryngological, Rhinological and Otological Society, Inc.)

Traditional neck dissection for oral squamous cell carcinoma (OSCC) involves removal of the submandibular salivary gland. Several studies have cited the low incidence of direct gland invasion by tumours and have recommended gland-sparing neck dissection. In this study, a detailed audit of level Ib involvement in OSCC was performed in order to assess the feasibility of submandibular gland-sparing in neck dissection; the rate of direct involvement by the primary tumours, the involvement of periglandular level Ib nodes, and their determinants were investigated. A total of 586 neck dissection specimens obtained between 2005 and 2014 from patients operated on at the study institution for floor of mouth, tongue, and buccal primaries, were evaluated for direct invasion of the gland and periglandular lymphadenopathy. Of 226 node-positive patients, 21 (9.3%) had direct gland invasion by tumour. Risk factors were tumour diameter >4cm (P=0.002) and depth of invasion >10mm (P=0.003). Determinants of periglandular lymphadenopathy were depth of invasion >10mm (P<0.001), perineural invasion (P=0.02), lymphovascular invasion (P=0.014), and moderate/poor differentiation (P<0.0001). Gland-sparing neck dissection is safe in early tumours (pT1pN0-1), with a good chance of minimizing xerostomia without radiotherapy. Larger tumours without clear evidence of submandibular gland invasion or suspicious level Ib lymphadenopathy may be considered for gland preservation, however the oncological safety is unclear., (Copyright © 2018 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate the mechanisms driving fibrosis in the submandibular glands (SMG) of patients with IgG4-related disease (IgG4-RD). Immunohistochemistry showed that many fibroblast-like cells expressing IL-6, IL-18, TSLP, IL-33, and MMP1 were present in SMG from the affected patients. SMG fibroblasts were derived from patients with or without IgG4-RD and were cultured in vitro. Expression of IL-6, IL-18, TSLP, IL-33 and MMP1, the secretion of IL-6 and G2/M phase were upregulated in the fibroblasts from the affected patients. By treatment with inflammatory cytokines IL-1β, TNFα or TGF-β after treatment with or without the NF-κB inhibitor curcumin, curucumin blocked the production and secretion of IL-6 upregulated by IL-1β, TNFα, or TNFα/TGF-β in all fibroblasts. Wnt1-inducible signaling protein 1 (WISP1), which can enhance fibroblasts proliferation, was also more abundantly expressed in affected fibroblasts, while treatment with IL-6 induced WISP1, treatment with WISP1 increased the G2/M phase, and curucumin inhibited WISP1 induced by TNFα/TGF-β in unaffected fibroblasts. IL-33 in affected fibroblasts was induced by IL-1β, TNFα, or TNFα/TGF-β, while the effect of IL-1β or TNFα/TGF-β was blocked by curcumin. These results suggest fibrosis in the SMG of affected patients is closely linked to the proliferation of fibroblasts following induction of IL-6 and WISP1 by inflammatory cytokines. The Th2 cytokines TSLP and IL-33 are also upregulated in affected SMG, and thus may cause chronic inflammation and IgG4 accumulation.

The ductal system of the salivary gland has long been postulated to be resistant to radiation-induced damage, a common side effect incurred by head and neck cancer patients receiving radiotherapy. Yet, whether the ducts are capable of regenerating after genotoxic injury, or whether damage to ductal cells induces lineage plasticity, as has been reported in other organ systems, remains unknown. Here, using the murine salivary gland, we show that two ductal progenitor populations, marked exclusively by KRT14 and KIT, maintain non-overlapping ductal compartments after radiation exposure but do so through distinct cellular mechanisms. KRT14 + progenitor cells are fast-cycling cells that proliferate in response to radiation-induced damage in a sustained manner and divide asymmetrically to produce differentiated cells of the larger granulated ducts. Conversely, KIT + intercalated duct cells are long-lived progenitors for the intercalated ducts that undergo few cell divisions either during homeostasis or after gamma radiation, thus maintaining ductal architecture with slow rates of cell turnover. Together, these data illustrate the regenerative capacity of the salivary ducts and highlight the heterogeneity in the damage responses used by salivary progenitor cells to maintain tissue architecture., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

The case of a fine-needle aspiration biopsy (FNAB) of the patient's salivary gland lesions is considered a rapid, simple, reliable, minimal invasive procedure with markedly rare complications. Herein, we report a case of bleeding from the region of the Wharton's duct after a procedure of a FNAB on the patient's submandibular gland. To our knowledge, this is the first case of bleeding from a salivary duct after a FNAB. For this reason, it is important to recognize that bleeding from the salivary duct after a FNAB can be a rare occurrence., (© 2018 Wiley Periodicals, Inc.)

Congenital dilatation of the submandibular duct also known as imperforate submandibular duct is a rare condition of unknown etiology, clinically characterized as a well-defined, fluctuant swelling in the floor of the mouth, and microscopically defined as a cystic cavity covered with pseudostratified columnar epithelium consistent with a dilated salivary duct. A 1-month-old female presented with a translucent, smooth cystic swelling in the floor of the mouth causing breastfeeding difficulty. The lesion was surgically excised and microscopically, a cystic cavity lined with pseudostratified columnar epithelium was observed. The final diagnosis was congenital dilatation of the submandibular duct. Dentists and otolaryngologists should consider congenital dilatation of the submandibular duct when evaluating fluctuant swelling in the floor of the month of infants., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht.