Inferior Surface Leukoplakia of Vocal Folds: Risk of Recurrence: A Preliminary Study.

OBJECTIVES: This study aimed to identify vocal fold leukoplakia (VFL) lesions on the inferior surface as a risk factor for recurrence. METHODS: This was a retrospective study with data collected from 2001 to 2018. The study comprised 37 patients with VFL, divided into the nonrecurrent and recurrent groups. We examined the clinicopathological characteristics and the surgical procedures performed in each patient. RESULTS: Among the 37 patients, 15 (40.5%) had residual (3) or recurrent (12) VFL. Of those patients with and without recurrence, 8 of 12 (66.7%) and 6 of 22 (27.3%), respectively, had inferior surface lesions of the vocal fold at the initial operation (P = .036). Recurrences were significantly higher in patients with inferior surface lesions. Other evaluated factors did not show significance for recurrence. CONCLUSION: The presence of VFL lesions on the inferior surface is a significant risk factor for recurrence.

Posterior Cervical Intramuscular Schwannoma Within the Trapezius Muscle: A Case Report.

Schwannomas are benign soft tissue tumors derived from the Schwann cells of the peripheral nerves. An intramuscular schwannoma arising within the trapezius muscle in the posterior neck is rare. We report a case of a 31-year-old woman with an intramuscular schwannoma in the trapezius muscle. A painless and smooth-surfaced mass from 10 years ago was evident on palpation in the right posterior neck. Ultrasonography revealed an oval mass with clear borders and slight internal blood flow. No continuous hypoechoic lesions were noted at the tip of the mass. Magnetic resonance imaging of the neck revealed a mass in the right posterior cervical trapezius muscle with isointensity on T1-weighted imaging and heterointensity on T2-weighted imaging. Based on these findings, a schwannoma was suspected. Ultrasonography guided fine needle aspiration cytology revealed no significant findings. During surgery, a white-colored, encapsulated-tumor mass was found in the trapezius muscle. Histopathologically, hypocellular and hypercellular areas of fusiform cells were conspicuous, and nuclear palisading was observed in a part of the hypercellular region, confirming the diagnosis of schwannoma. To our knowledge, this is an extremely rare report of an intramuscular schwannoma within the trapezius muscle; herein, we report its clinical, radiological, and pathological features.

Human Papillomavirus Vaccination as an Adjuvant Therapy for Recurrent Respiratory Papillomatosis: Additional Case Series.

Prevention of the recurrence of recurrent respiratory papillomatosis (RRP), a neoplasm of the respiratory tract, is a challenge. Human papillomavirus (HPV) vaccine has been expected to suppress the aggressiveness of RRP. However, there has been insufficient data to verify whether HPV vaccination can serve as an adjuvant therapy option for RRP. The aim of this study was to add our data on the efficacy of HPV vaccination for RRP to the academic discipline. Twenty-four RRP patients were treated with a combination therapy of surgery and three sessions of quadrivalent HPV vaccine. The patients' clinical courses, which were HPV infection status changes, intersurgical interval, and disease severity score (Derkay's site score), were statistically analyzed before and after combination therapy. Twelve of the 24 (52.5%) RRP patients who were HPV-DNA positive turned negative after the combination therapy. The mean of intersurgical interval was significantly extended from 6.85 ± 4.49 months to 30.5 ± 27.6 months after the therapy (P <0.01). The median of Derkay's score of the participants also significantly decreased from 7.5 (interquartile range, 5-12) to 1 (interquartile range, 0-4.25) after the therapy (P <0.01). Thus, combination therapy comprising of surgery and HPV vaccination can postpone the recurrence and lessen the severity of RRP.

Thyroid hyalinizing trabecular adenoma with a high thyroglobulin level: a case report.

Thyroid hyalinizing trabecular adenoma (HTA) is a rare and borderline tumor of follicular origin. It is characterized by a trabecular growth pattern and marked intratrabecular hyalinization. Excessively elevated thyroglobulin levels have not been reported previously in cases without bilateral lung metastases. Here, we present a case of a 54-year-old woman with chronic thyroiditis with a 50-mm tumor in the left lobe of the thyroid gland, which was observed on ultrasonography. Her thyroglobulin level was found to be elevated at 684 ng/ml. Since fine needle aspiration cytology could not exclude possible malignancy, she underwent thyroid lobectomy; the final diagnosis was thyroid HTA. Two weeks after resection, her thyroglobulin level showed negative conversion. To our knowledge, this is the first report of a patient with a thyroid HTA exhibiting a thyroglobulin level as high as that for a patient with hyalinizing trabecular carcinoma.

Parotid Gland Non-Sebaceous Lymphadenoma: A Case Report.

We here report a rare salivary gland tumor, a non-sebaceous lymphadenoma (NSLA), in the parotid gland with positive technetium-99m (99mTc) pertechnetate scintigraphy and cervical masses that was difficult to distinguish from malignant lymphoma preoperatively. A 65-year-old Japanese woman presented to our institution with a painless left parotid mass that had been gradually enlarging for three months. Computed tomography and magnetic resonance imaging showed a solid mass (30 mm) in the tail of the left parotid gland with three swellings (each 10 mm) on the periphery of the parotid gland. A low grade malignant lymphoma was diagnosed by fine needle aspiration cytology. Gallium-67 scintigraphy showed mild positivity. On 99mTc pertechnetate scintigraphy, the mild accumulation remained after oral stimulation with a mixture of ascorbic acid and calcium pantothenate. The patient underwent superficial parotidectomy with removal of the cervical masses. Our findings in this patient suggest that 99mTc positivity may constitute a clue to the preoperative diagnosis of NSLA that has pathologically overlapping sites with Warthin tumor.

In search of a longitudinal animal model of evoked swallow function.

BACKGROUND: A malfunction or impairment of swallow function can potentiate aspiration events and interfere with both quality of life and survival. Establishing an animal model for swallow research would provide a better understanding of its pathophysiology and would also allow for the development and validation of physiologically based clinical interventions to improve swallow function. Two requirements define the ideal model for longitudinal exploration: 1) identification of species similar to human in form and function; and 2) provision for reliable and reproducible evoked swallow under general anesthesia and one that would also support a longitudinal study design. OBJECTIVE: We hypothesize that an anesthetized porcine model under dexmedetomidine-based or ketamine-based anesthesia will support a reproducible and stable evoked swallow response. METHODS: Seven neutered male Yorkshire pigs were anesthetized using combinations of dexmedetomidine-based or ketamine-based anesthesia for induction and maintenance of anesthesia during the experimental portion of our study. Single stimulation of iSLN or vagus nerve, bilateral simultaneous single stimulation of iSLN or vagus nerve, and stimulus trains applied to afferent nerves were performed. RESULTS: None of the seven pigs demonstrated evoked swallow events, both during inhalational anesthesia (1.0 MAC) or during post-washout intravenous anesthesia (dexmedetomidine, ketamine/fentanyl or ketamine alone). CONCLUSION: Our results support a high degree of organizational neurophysiologic complexity characterizing the swallow reflex and highlight the challenges and limitations of intraoperative study in survival models. LEVEL OF EVIDENCE: NA Laryngoscope, 2018.

Long-term prognosis and factors associated with damage accrual in Japanese patients with systemic lupus erythematosus.

OBJECTIVE: Using a single-center cohort of Japanese patients with SLE, we attempted to clarify the long-term outcome and factors associated with damage accrual using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). METHODS: We examined a cohort of 557 patients who had been referred to Niigata University Hospital and diagnosed as having SLE between 1961 and 2013. The patients' data at the latest visit were collected from their clinical records, and causes of death were defined on the basis of those data. Survival from the time of diagnosis was calculated by the Kaplan-Meier method. The SDI was calculated and analyzed using Spearman's correlation coefficient and stepwise multiple regression analysis to reveal the factors associated with any organ damage. RESULTS: Data from 458 of the patients were successfully obtained. The overall 5-year survival rate was 92.2%, and patients diagnosed after 2000 had a significantly high 5-year survival rate of 96.4%. Stepwise multiple regression analysis selected serum creatinine levels (B = 0.6051, p < 0.0001), age (standardized beta = 0.2762, p < 0.001), hypertension (standardized beta = 0.2267, p < 0.001), and antiphospholipid antibody syndrome (standardized beta = 0.1533, p = 0.005) as positive independent variables, whereas administration of bisphosphonate (standardized beta = - 0.1295, p = 0.016) was selected as a negative independent variable. CONCLUSION: These results suggest that Japanese patients with SLE have a favorable long-term prognosis, and also indicate that disease control as well as management of chronic complications such as hypertension and osteoporosis has possible effects for prevention of organ damage.

Expression of von Hippel-Lindau tumor suppressor protein (pVHL) characteristic of tongue cancer and proliferative lesions in tongue epithelium.

BACKGROUND: Patients with tongue cancer frequently show loss of heterozygosity (LOH) of the von Hippel-Lindau (VHL) tumor suppressor gene. However, expression of VHL protein (pVHL) in tongue cancer has rarely been investigated and remains largely unknown. We performed immunohistochemical staining of pVHL in tongue tissues and dysplasia, and examined the association with LOH and its clinical significance. METHODS: Immunohistochemical staining of pVHL in formalin-fixed, paraffin-embedded sections of cancerous and other tissues from 19 tongue cancer patients showed positivity for LOH of VHL in four samples, negativity in four samples, and was non-informative in 11 samples. The staining pattern of pVHL was also compared with those of cytokeratin (CK) 13 and CK17. RESULTS: In normal tongue tissues, pVHL staining was localized to the cytoplasm of cells in the basal layer and the area of the spinous layer adjacent to the basal layer of stratified squamous epithelium. Positive staining for pVHL was observed in the cytoplasm of cancer cells from all 19 tongue cancer patients. No differences as a result of the presence or absence of LOH were found. Notably, cytoplasm of poorly differentiated invasive cancer cells was less intensely stained than that of well and moderately differentiated invasive cancer cells. pVHL staining was also evident in epithelial dysplasia lesions with pVHL-positive cells expanding from the basal layer to the middle of the spinous layer. However, no CK13 staining was noted in regions of the epithelium, which were positive for pVHL. In contrast, regions with positive staining for CK17 closely coincided with those positive for pVHL. CONCLUSIONS: Positive staining for pVHL was observed in cancerous areas but not in normal tissues. pVHL expression was also detected in lesions of epithelial dysplasia. These findings suggest that pVHL may be a useful marker for proliferative lesions.

HPV-Positive Oropharyngeal Cancer Via p16 Immunohistochemistry in Japan.

OBJECTIVES: Human papillomavirus (HPV) has emerged as a driving cause of head and neck cancer, but investigations outside the West are limited. A p16 immunohistochemistry is a commonly used biomarker for HPV cancers. We sought to investigate the pathology and rates of HPV head and neck oropharyngeal cancer in Japan via p16 immunohistochemistry at 2 institutions in Japan. METHODS: Fifty-nine oropharyngeal specimens from 2 university hospitals in Japan were examined for morphology and p16 immunohistochemistry. The rate of p16 positivity was then determined, and the 2 groups were compared for differences in age, smoking history, gender, and stage of presentation and mortality. RESULTS: The rate of p16 positivity among the oropharyngeal specimens was 29.5%. There were important differences in the pathology compared to morphology usually seen in the US. The patients with p16+ cancer tended to be younger. There was no significant difference in smoking status. Patients with p16+ cancers trended toward better survival. CONCLUSION: There appears to be a geographical difference in HPV rates of oropharyngeal cancers with persistently lower rates in Asian countries when compared to Western Europe and the US. Conclusions about HPV head and neck squamous cell carcinoma (HNSCC) in Western countries may not be generalizable across the globe at this time.

Cervical branch of the facial nerve approach for retrograde parotidectomy compared with anterograde parotidectomy.

CONCLUSION: The cervical branch of the facial nerve approach for parotidectomy is an excellent surgical technique that can reduce the incidence of facial nerve paralysis, surgical time, and surgical blood loss. OBJECTIVE: To develop and evaluate a surgical technique for parotidectomy that can reduce the incidence of facial nerve paralysis. METHODS: Retrograde parotidectomy following identification of the cervical branch of the facial nerve in 90 subjects was compared with standard anterograde parotidectomy in 100 subjects. RESULTS: Retrograde parotidectomy with a cervical branch approach was associated with significant decreases in the incidence of facial nerve paralysis, surgical time, and surgical blood loss, compared with anterograde parotidectomy.

Anti-matrix metalloproteinase-9 DNAzyme decreases tumor growth in the MMTV-PyMT mouse model of breast cancer.

INTRODUCTION: Despite continued improvements in diagnosis, surgical techniques, and chemotherapy, breast cancer patients are still overcome by cancer metastasis. Tumor cell proliferation, invasion and metastasis are mediated, at least in part, through degradation of basement membrane by neutral matrix metalloproteinases (MMP) produced by tumor and stromal cells. Evidence suggests that MMP-9 plays a significant role in breast tumor cell invasion and metastasis. DNAzymes or catalytic oligonucleotides are new classes of gene targeting molecules that bind and cleave a specific mRNA, resulting in decreased protein expression. METHODS: The application of anti-MMP-9 DNAzyme (AM9D) for the treatment of primary and metastatic breast cancer was evaluated in vitro and in vivo using MDA-MB-231 cells and the MMTV-PyMT transgenic breast cancer mouse model. Spontaneously developed mammary tumors in MMTV-PyMT transgenic mice were treated intratumorally with naked AM9D, once a week for 4 weeks. The stability of DNAzyme was determined in vitro and in vivo using fluorescently labeled DNAzyme. RESULTS: AM9D specifically inhibited expression of MMP-9 in MDA-MB-231 cells resulting in reduced invasive property of these cells by 43%. Weekly intratumoral treatment of spontaneously developed mammary tumors in MMTV-PyMT transgenic mice was sufficient to significantly reduce the rate of tumor growth and final tumor load in a dose dependent and statistically significant manner (P < 0.05). This decrease in tumor growth was correlated with decreased MMP-9 protein production within the treated tumor tissues. Tumors treated with AM9D were also less vascularized and contained more apoptotic cells compared to control and untreated tumors. CONCLUSIONS: These results show that targeting and down regulation of MMP-9 by AM9D could prove useful as a therapy against breast carcinoma tumor growth and invasion.

Serum soluble α-klotho in hemodialysis patients.

BACKGROUND: The extracellular domain of klotho is cleaved and released into various extracellular fluids, such as blood, urine, and cerebrospinal fluid, as soluble α-klotho (sαKl). METHODS: We measured sαKl in 53 hemodialysis patients and 20 healthy controls to examine its role in mineral metabolism. RESULTS: The sαKl level of the hemodialysis patients was 430 pg/ml (386 - 540 pg/ml, which was lower than that of healthy controls 740 pg/ml (550 - 913 pg/ml, p < 0.01). The serum sαKl level showed a positive correlation with serum phosphorus (P) (σ = 0.33, p = 0.014), while serum corrected Ca tended to be negatively correlated with sαKl (σ = -0.26, p = 0.06). Both parameters showed the same trends in healthy subjects. However, there was no significant association between serum sαKl and age (σ= 0.21, p = 0.14), intact PTH (σ = -0.08, p= 0.55), whole PTH (σ = -0.08, p = 0.59), or FGF23 (σ = -0.07, p = 0.62). Multiple regression analysis showed that P was independently associated with the serum sαKl levels (total adjusted R2 = 0.18, p = 0.02). CONCLUSIONS: The sαKl level was lower in hemodialysis patients than in healthy persons. Serum P level was independently associated with the serum sαKl level.

Pharyngeal squamous cell papilloma in adult Japanese: comparison with laryngeal papilloma in clinical manifestations and HPV infection.

A number of reports have investigated the relationship between laryngeal papilloma and human papilloma virus (HPV) infection. On the other hand, it is unclear whether the HPV infection is involved in the occurrence of pharyngeal papilloma. We hypothesized that HPV infection was involved in the occurrence of pharyngeal papilloma similarly to laryngeal papilloma. To verify this hypothesis, we investigated the presence of HPV infection. Furthermore, clinical manifestations of pharyngeal papilloma, which had rarely been reported, were discussed. A male-to-female ratio, solitary or multiple occurrences, and koilocytosis were examined in cases with pharyngeal papilloma. HPV DNA was examined with unfixed surgically resected specimens of pharyngeal papilloma. A screening test by the liquid-phase hybridization method was carried out for the HPV high-risk group (16, 18, 31, 33, 35, 39, 45, 51, 56, 58, 59, and 68) and HPV low-risk group (6, 11, 42, 43, 44). As a control, 15 cases with laryngeal papilloma for which the same screening test was carried out were employed. Pharyngeal papilloma occurred as a solitary lesion more often, whereas laryngeal papilloma occurred as multiple tumors more frequently. The HPV infection rate was 0% in pharyngeal papilloma cases, which was in stark contrast with 66.7% in the HPV low-risk group in laryngeal papilloma cases. Pharyngeal papilloma occurred as a solitary lesion in females more frequently. Contrary to our hypothesis, the involvement of HPV infection was unlikely in the occurrence of pharyngeal papilloma.

High iFGF23 level despite hypophosphatemia is one of the clinical indicators to make diagnosis of XLH.

X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. Deletion of Phex leads to increased serum fibroblast growth factor23 (FGF23) levels in mouse. The aim is to assure the clinical usefulness of FGF23 determination in the diagnosis of XLH. Participants were 21 patients with XLH having abnormalities in PHEX from 13 kindred (PtPHEX: 1 to 42 years old; 10 males, 11 females) and 55 healthy controls (1 month to 18 years old; 27 males, 28 females). Temporal changes in FGF23 were determined by a single oral phosphate administration in PtPHEX and an ad lib diet in controls. Reference ranges of intact FGF23 (iFGF23) for children were determined. iFGF23 level which distinguish between controls and PtPHEX were validated. Correlations between iFGF23 and the severity of XLH (gender, age of onset, bone deformity, The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmPO(4)/GFR), inorganic phosphate (IP), Alkaline Phosphatase (ALP), therapeutic dose) were investigated. Increasing tendency after phosphate administration and no general tendency after breakfast in iFGF23 were observed. Reference range (5(th) and 95(th) percentiles) of iFGF23 for children (12.9 and 51.2 pg/mL) was similar to that for adults. iFGF23 were above the reference range in 19 of 21 PtPHEX (40 to 4710 pg/mL). iFGF23 did not correlate with any index of severity of XLH. Relatively high iFGF23 despite hypophosphatemia is one of the clinical indicators to diagnose XLH.

Fatal acute pancreatitis associated with reactive AA amyloidosis in rheumatoid arthritis with end-stage renal disease: a report of three cases.

We report three cases of fatal pancreatitis associated with systemic AA amyloidosis in rheumatoid arthritis (RA). All of the patients showed end-stage renal failure, and hemodialysis was introduced during the course of treatment. Autopsy was performed on two of the three patients, and this revealed amyloid deposition on the vascular walls in the pancreas. It was strongly suggested that the acute pancreatitis in all three patients was attributable to deposition of amyloid in vascular and pancreatic tissues. Acute pancreatitis is considered to be a rare complication of end-stage amyloidosis associated with RA, and is frequently fatal. It is important to treat RA patients intensively to avoid such deposition of amyloid.

Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice.

Fibroblast growth factor 23 (FGF-23) plays causative roles in the development of several hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia. Patients with hypophosphatemic rickets/osteomalacia often complain of muscle weakness and bone pain that severely affect daily activities of these patients. The purpose of this study was to examine whether anti-FGF-23 antibodies, which have been shown to improve hypophosphatemia and rachitic changes of juvenile Hyp mice in a murine model of XLH, also ameliorate hypophosphatemic osteomalacia and affect muscle force and spontaneous motor activity in adult Hyp mice. Repeated injections of anti-FGF-23 antibodies increased serum phosphate and 1,25-dihydroxyvitmain D levels and enhanced mineralization of osteoid in adult Hyp mice, whereas bone length did not change. We found that grip strength was weaker and that spontaneous movement was less in adult Hyp mice than in wild-type mice. In addition, FGF-23 antibodies increased grip strength and spontaneous movement. These results suggest that the inhibition of excess FGF-23 action not only ameliorates hypophosphatemia and impaired mineralization of bone but also improves muscle weakness and daily activities of patients with FGF-23-related hypophosphatemic rickets/osteomalacia.

Association between fibroblast growth factor 23 and left ventricular hypertrophy in maintenance hemodialysis patients. Comparison with B-type natriuretic peptide and cardiac troponin T.

BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a novel bone-derived phosphate-regulating hormone, and serum FGF-23 levels are associated with mortality among hemodialysis (HD) patients. However, the pathophysiological role of FGF-23 in those patients remains unclear, so the association between serum FGF-23 levels and known cardiac biomarkers or echocardiographic measurements were investigated in long-term HD patients without cardiac symptoms. METHODS AND RESULTS: The 87 consecutive patients treated in a single HD center (51 males, 36 females; mean age 64 years, mean HD duration 5.8 years) were included in this study. Comprehensive echocardiography was performed after HD. Blood samples were obtained before HD. Serum FGF-23 levels in dialysis patients were 1,171±553pg/ml. In univariate analysis, serum phosphate (r=0.443, P<0.001) and calcium levels (r=0.256, P=0.04), left ventricular mass index (LVMI) (r=0.268, P=0.039) were significantly associated with FGF-23 levels. Neither the B-type natriuretic peptide (BNP) nor the cardiac troponin T level was correlated with FGF-23. In multivariate regression analysis, only LVMI (ß=0.287, P=0.031, confidence interval (CI) 0.390-8.040) and phosphate levels (ß=0.419, P=0.001, CI 57.12-207.7) and calcium levels (ß=0.277, P=0.025, CI 24.95-360.1) remained significantly correlated with FGF-23. CONCLUSIONS: Beside BNP, FGF-23 was identified as a factor that is significantly associated with LVMI. FGF-23 could be a novel biomarker of left ventricular overload, which is closely associated with the increased risk of death in HD patients.

Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease.

Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with early chronic kidney disease (CKD) and are postulated to cause low blood levels of 1,25-dihydroxyvitamin D, as well as normal phosphate levels. In order to provide more direct evidence for the pathophysiological role of FGF23 in the settings of mineral ion homeostasis typically seen in early CKD, we studied rats with progressive CKD treated with anti-FGF23 neutralizing antibody. Without antibody treatment, rats with CKD exhibited high circulating levels of FGF23 and parathyroid hormone, low 1,25-dihydroxyvitamin D, and normal serum phosphate levels, accompanied by increased fractional excretion of phosphate. Antibody treatment, however, lessened fractional excretion of phosphate, thus increasing serum phosphate levels, and normalized serum 1,25-dihydroxyvitamin D by increased 1α-OHase and decreased 24-OHase expressions in the kidney. These antibody-induced changes were followed by increased serum calcium levels, leading to decreased serum parathyroid hormone. Hence, our study shows that FGF23 normalizes serum phosphate and decreases 1,25-dihydroxyvitamin D levels in early-stage CKD, and suggests a pathological sequence of events for the development of secondary hyperparathyroidism triggered by increased FGF23, followed by a reduction of 1,25-dihydroxyvitamin D and calcium levels, thereby increasing parathyroid hormone secretion.