[A case of scirrhous gastric cancer in which cancer cells were first identified in the ascites by immunostaining using the cell transfer technique].

This was a case of a woman in her 60s with the chief complaint of an abnormal stomach X-ray at the screening. Although suspected to be scirrhous gastric cancer, gastric biopsy revealed Group 1, and cytology in accumulated ascites and open surgery was initially Class II, but cancer cells in the ascites were confirmed for the first time by subsequent immunostaining using the cell transfer technique. Undifferentiated advanced gastric cancer, peritoneal dissemination, and lymphatic metastasis were pathologically observed. This case suggests the effectiveness of immunostaining when the results of ascites cytology are different from the clinical picture.

Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma.

BACKGROUND: Toll-like receptor 3 (TLR3) ligand which activates TLR3 signaling induces both cancer cell death and activates anti-tumor immunity. However, TLR3 signaling can also harbor pro-tumorigenic consequences. Therefore, we examined the status of TLR3 in cholangiocarcinoma (CCA) cases to better understand TLR3 signaling and explore the potential therapeutic target in CCA. METHODS: The expression of TLR3 and receptor-interacting protein kinase 1 (RIPK1) in primary CCA tissues was assayed by Immunohistochemical staining and their associations with clinicopathological characteristics and survival data were evaluated. The effects of TLR3 ligand, Poly(I:C) and Smac mimetic, an IAP antagonist on CCA cell death and invasion were determined by cell death detection methods and Transwell invasion assay, respectively. Both genetic and pharmacological inhibition of RIPK1, RIPK3 and MLKL and inhibitors targeting NF-κB and MAPK signaling were used to investigate the underlying mechanisms. RESULTS: TLR3 was significantly higher expressed in tumor than adjacent normal tissues. We demonstrated in a panel of CCA cell lines that TLR3 was frequently expressed in CCA cell lines, but was not detected in a nontumor cholangiocyte. Subsequent in vitro study demonstrated that Poly(I:C) specifically induced CCA cell death, but only when cIAPs were removed by Smac mimetic. Cell death was also switched from apoptosis to necroptosis when caspases were inhibited in CCA cells-expressing RIPK3. In addition, RIPK1 was required for Poly(I:C) and Smac mimetic-induced apoptosis and necroptosis. Of particular interest, high TLR3 or low RIPK1 status in CCA patients was associated with more invasiveness. In vitro invasion demonstrated that Poly(I:C)-induced invasion through NF-κB and MAPK signaling. Furthermore, the loss of RIPK1 enhanced Poly(I:C)-induced invasion and ERK activation in vitro. Smac mimetic also reversed Poly(I:C)-induced invasion, partly mediated by RIPK1. Finally, a subgroup of patients with high TLR3 and high RIPK1 had a trend toward longer disease-free survival (p = 0.078, 28.0 months and 10.9 months). CONCLUSION: RIPK1 plays a pivotal role in TLR3 ligand, Poly(I:C)-induced cell death when cIAPs activity was inhibited and loss of RIPK1 enhanced Poly(I:C)-induced invasion which was partially reversed by Smac mimetic. Our results suggested that TLR3 ligand in combination with Smac mimetic could provide therapeutic benefits to the patients with CCA. Video abstract.

Efferent feedback minimizes cochlear neuropathy from moderate noise exposure.

Although protective effects of the cochlea's efferent feedback pathways have been well documented, prior work has focused on hair cell damage and cochlear threshold elevation and, correspondingly, on the high sound pressure levels (>100 dB SPL) necessary to produce them. Here we explore the noise-induced loss of cochlear neurons that occurs with lower-intensity exposures and in the absence of permanent threshold shifts. Using confocal microscopy to count synapses between hair cells and cochlear nerve fibers, and using measurement of auditory brainstem responses and otoacoustic emissions to assess cochlear presynaptic and postsynaptic function, we compare the damage from a weeklong exposure to moderate-level noise (84 dB SPL) in mice with varying degrees of cochlear de-efferentation induced by surgical lesion to the olivocochlear pathway. Such exposure causes minimal acute threshold shifts and no chronic shifts in mice with normal efferent feedback. In de-efferented animals, there was up to 40% loss of cochlear nerve synapses and a corresponding decline in the amplitude of the auditory brainstem response. Quantitative analysis of the de-efferentation in inner versus outer hair cell areas suggested that outer hair cell efferents are the most important in minimizing this neuropathy, presumably by virtue of their sound-evoked feedback reduction of cochlear amplification. The moderate nature of this acoustic overexposure suggests that cochlear neurons are at risk even in everyday acoustic environments, so the need for cochlear protection is plausible as a driving force in the design of this feedback pathway.

Salivary gland cancer organoids are valid for preclinical genotype-oriented medical precision trials.

Salivary gland cancers (SGCs) are heterogeneous tumors, and precision oncology represents a promising therapeutic approach; however, its impact on SGCs remains obscure. This study aimed to establish a translational model for testing molecular-targeted therapies by combining patient-derived organoids and genomic analyses of SGCs. We enrolled 29 patients, including 24 with SGCs and 5 with benign tumors. Resected tumors were subjected to organoid and monolayer cultures, as well as whole-exome sequencing. Organoid and monolayer cultures of SGCs were successfully established in 70.8% and 62.5% of cases, respectively. Organoids retained most histopathological and genetic profiles of their original tumors. In contrast, 40% of the monolayer-cultured cells did not harbor somatic mutations of their original tumors. The efficacy of molecular-targeted drugs tested on organoids depended on their oncogenic features. Organoids recapitulated the primary tumors and were useful for testing genotype-oriented molecular targeted therapy, which is valuable for precision medicine in patients with SGCs.

Contralateral-noise effects on cochlear responses in anesthetized mice are dominated by feedback from an unknown pathway.

Suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) by contralateral noise is used in humans and animals to assay the strength of sound-evoked negative feedback from the medial olivocochlear (MOC) efferent pathway. However, depending on species and anesthesia, contributions of other feedback systems to the middle or inner ear can cloud the interpretation. Here, contributions of MOC and middle-ear muscle reflexes, as well as autonomic feedback, to contra-noise suppression in anesthetized mice are dissected by selectively eliminating each pathway by surgical transection, pharmacological blockade, or targeted gene deletion. When ipsilateral DPOAEs were evoked by low-level primaries, contra-noise suppression was typically ~1 dB with contra-noise levels around 95 dB SPL, and it always disappeared upon contralateral cochlear destruction. Lack of middle-ear muscle contribution was suggested by persistence of contra-noise suppression after paralysis with curare, tensor tympani cauterization, or section of the facial nerve. Contribution of cochlear sympathetics was ruled out by studying mutant mice lacking adrenergic signaling (dopamine ß-hydroxylase knockouts). Surprisingly, contra-noise effects on low-level DPOAEs were also not diminished by eliminating the MOC system pharmacologically (strychnine), surgically, or by deletion of relevant cholinergic receptors (α9/α10). In contrast, when ipsilateral DPOAEs were evoked by high-level primaries, the contra-noise suppression, although comparable in magnitude, was largely eliminated by MOC blockade or section. Possible alternate pathways are discussed for the source of contra-noise-evoked effects at low ipsilateral levels.

Tumor necroptosis is correlated with a favorable immune cell signature and programmed death-ligand 1 expression in cholangiocarcinoma.

Necroptosis, a regulated form of necrosis, has emerged as a novel therapeutic strategy that could enhance cancer immunotherapy. However, its role in tumorigenesis is still debated because recent studies have reported both anti- and pro-tumoral effects. Here, we aimed to systematically evaluate the associations between tumor necroptosis (mixed lineage kinase domain-like protein, MLKL; phosphorylated MLKL, pMLKL; and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3, RIPK1-RIPK3 interaction) and tumor-infiltrating immune cells (CD8+ and FOXp3+ T cells and CD163+ M2 macrophages) and tumor PD-L1 by immunohistochemistry in 88 cholangiocarcinoma (CCA) patients who had undergone surgical resection. Their associations with clinicopathological characteristics, survival data, and prognosis were evaluated. MLKL was found to be an unfavorable prognostic factor (p-value = 0.023, HR = 2.070) and was inversely correlated with a clinically favorable immune cell signature (high CD8+/high FOXp3+/low CD163+). Both pMLKL and RIPK1-RIPK3 interaction were detected in CCA primary tissues. In contrast to MLKL, pMLKL status was significantly positively correlated with a favorable immune signature (high CD8+/high FOXp3+/low CD163+) and PD-L1 expression. Patients with high pMLKL-positive staining were significantly associated with an increased abundance of CD8+ T cell intratumoral infiltration (p-value = 0.006). Patients with high pMLKL and PD-L1 expressions had a longer overall survival (OS). The results from in vitro experiments showed that necroptosis activation in an RMCCA-1 human CCA cell line selectively promoted proinflammatory cytokine and chemokine expression. Jurkat T cells stimulated with necroptotic RMCCA-1-derived conditioned medium promoted PD-L1 expression in RMCCA-1. Our findings demonstrated the differential associations of necroptosis activation (pMLKL) and MLKL with a clinically favorable immune signature and survival rates and highlighted a novel therapeutic possibility for combining a necroptosis-based therapeutic approach with immune checkpoint inhibitors for more efficient treatment of CCA patients.

Whole exome sequencing and establishment of an organoid culture of the carcinoma showing thymus-like differentiation (CASTLE) of the parotid gland.

Carcinoma showing thymus-like differentiation (CASTLE) is a rare tumor, especially in the parotid gland. We encountered a CASTLE of the parotid gland and analyzed its clinicopathological features, as well as the genotype using whole exome sequencing (WES). Moreover, we successfully established an organoid culture cell line from the primary tumor tissue. The patient was a 23-year-old woman who underwent superficial parotidectomy with peripheral neck dissection, followed by radiotherapy. Pathologically, the resected specimen showed atypical epithelioid nests and trabeculae with squamous differentiation, separated by thick fibrous septa, accompanied by dense lymphocytes and plasma cell infiltration. Immunohistochemistry revealed that the tumor cells were positive for AE1/AE3, p40, p63, p16, CK5/6, and CD5, and the background lymphocytes were positive for CD5 and CD99. Based on these findings, the tumor was diagnosed as CASTLE. WES uncovered five nonsynonymous and splicing somatic mutations, namely, FREM2 p.Val861Phe, CLK3 p.Phe376Leu, DLGAP1 p.Lys294Asn, NOX1 p.Val165Met, and PSG9 c.430 + 4A > T. Organoid culture cells preserved the histopathological characteristics of the epithelioid component of CASTLE and harbored all five somatic mutations detected in the primary tumor. In conclusion, for the first time to the best of our knowledge, we successfully analyzed a comprehensive genotype and established an organoid culture cell line of a parotid gland CASTLE, which should serve for analyzing the nature of this rare tumor.

[Two cases of MPO-ANCA-positive otitis media associated with facial palsy].

We report two cases of otitis media positive for antimyeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) associated with facial palsy. Case 1: A 73-year-old man treated for 3 months for bilateral otitis media with effusion had left facial nerve palsy and deteriorated bone conduction hearing in both ears. Blood analysis showed elevated MPO-ANCA to 134 EU. Case 2: A 66-year-old woman treated for about one year for bilateral otitis media with effusion and fluctuating mixed hearing loss had bilateral facial nerve palsy and a blood test positive for MPO-ANCA at 67 EU. Both were diagnosed with otitis media caused by ANCA-related vasculitis. After prednisolone and cyclophosphamide administration for half a year, blood test results were negative for MPO-ANCA. Both recovered almost completely from facial nerve palsy and bone conductive hearing loss partially improved except in one hearing-impaired ear. ANCA-related vasculitis of the temporal bone should thus be considered in those with intractable otitis media and deteriorated bone conduction hearing before the occurrence of facial palsy.

Parotid secretory carcinoma with high-grade transformation.

Here we present a patient with a parotid secretory carcinoma (SC) with high-grade transformation. A 65-year-old female was referred to our hospital due to a gradually growing right parotid tumor discovered initially about 4 years earlier. MRI imaging detected a right parotid tumor 50 mm in the longer axis. Fine needle aspiration cytology indicated a class III tumor. Nine months after her initial visit, she revisited our department because of pain, trismus and facial paralysis. MRI detected a tumor 69 mm in the longer axis and 64 mm in the shorter axis and a biopsy specimen revealed parotid cancer. Furthermore, positron emission tomography revealed a synchronous small cell lung cancer (SCLC). Chemoradiotherapy for the SCLC was performed followed by an extended total parotidectomy for the parotid SC. Histological findings and ETV6-FISH analysis confirmed a parotid SC with high-grade transformation. Two months after the surgery, CT revealed a loco-regional recurrence and proton beam therapy (70.2 GyE/26 Fr) was performed. Three months after the proton beam therapy, CT indicated pleural effusion and lung metastasis, and fine needle aspiration cytology revealed the metastatic SC. Eight months after the surgery, the patient died due to the lung metastasis of SC.

Clinical utility of apparent diffusion coefficient and diffusion-weighted magnetic resonance imaging for resectability assessment of head and neck tumors with skull base invasion.

BACKGROUND: The usefulness of apparent diffusion coefficient (ADC) and diffusion-weighted magnetic resonance imaging (DWI) in the detection of malignant tumors has been reported. The purpose of this study is to clarify the role of ADC and DWI for diagnosis of skull base tumors. METHODS: A total of 27 patients with head and neck tumors with skull base invasions undergoing skull base surgery were enrolled in this study. Pathological findings of dural invasion and bone invasion were compared with the diagnostic imaging. RESULTS: Advanced magnetic resonance imaging techniques revealed that ADC values in regions of pathological bone and dural invasions were significantly lower than in regions of no invasion. The area under the curve of ADC in bone invasions and dural invasions were 0.957 and 0.894, respectively. CONCLUSIONS: Our findings indicate that ADC and DWI are useful tools for the diagnosis of head and neck tumors with skull base invasion.

Management of adenoid cystic carcinoma of the head and neck: a single-institute study with over 25-year follow-up.

BACKGROUND: Adenoid cystic carcinoma is a rare malignant tumor arising from exocrine glands such as the major and minor salivary glands of the paranasal sinuses or the external auditory canal. Although multiple retrospective clinical studies of ACC have been reported to date, clinical questions, such as 1) long-term prognosis beyond 20 years, 2) usefulness and suitability for treatment of therapeutic interventions, 3) therapeutic goal to aim for, and 4) prognosis by recurrence sites, are still unclear. METHODS: To improve understanding and management of adenoid cystic carcinoma of the head and neck (ACC), a retrospective study with 58 new ACC cases between 1991 and 2016 was performed. The median observation period was 66.8 months (range 3-316 months). The overall clinical stages were as follows: I, 6.9%; II, 25.9%; III, 19.0%; and IV, 48.2%. Histology was cribriform/tubular type (C-T type) in 62.0% and solid type in 27.5%. The main treatment strategy was definitive surgery, which was performed in 75.2% of cases. RESULTS: Overall 10-year, 20-year, and 25-year survivals were 63.7, 27.3, and 20.0%, respectively. Similarly, disease-specific survival (DSSs) was 65.7, 51.2, and 38.4%, respectively, and disease-free survival was 25.2, 9.4, and 9.4%, respectively. Conducting surgery (HR: 0.19, 95% CI: 0.06-0.61, p = 0.005) and C-T type (HR: 0.32, 95% CI: 0.11-0.93, p = 0.036) were independent prognostic predictors of DSS. DSS was significantly prolonged after salvage surgery for both locoregional recurrence (p = 0.004) and lung metastatic recurrence (p = 0.012, vs best supportive care). CONCLUSIONS: In ACC cases, both initial surgical treatment and repetitive surgical resection of resectable recurrent lesions, including both locoregional and lung metastases, resulted in longer survival. The major goal of treatment for ACC may be long-term survival including cancer-bearing survival, resulting in either natural death or intercurrent-disease death, since judging cure of ACC is almost impossible. TRIAL REGISTRATION: Retrospectively registered.

Immunohistochemical pattern of c-MYC protein judged as "+/(weak)+/-" by a new notation correlates with MYC gene nontranslocation in large B-cell lymphoma.

Immunohistochemistry is not only the most important tool for pathologists to establish a final diagnosis, but it can also inform decisions regarding optimal treatment methods. However, there is no universal standard notation for expressing immunohistochemical findings. For a diagnosis of malignant lymphoma, it is important to confirm the presence or absence of MYC translocation and communicate these results to a clinical audience. However, the criteria for selecting cases for fluorescence in situ hybridization (FISH) analysis to confirm MYC translocation are ill defined. We therefore devised a notation that we termed proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation) based on the cellular proportion showing different antigen-antibody reactivity in immunohistochemistry (CPAR) and used it to examine the relationship between MYC translocation and the proportion of c-MYC+ lymphoma cells. We reviewed 82 cases diagnosed as diffuse large B-cell lymphoma or diffuse large B-cell lymphoma coexisting with grade 3A to 3B follicular lymphoma. The most common notation was "+/(weak)+/-" (49/82 cases [59.8%]); cases that were CPAR positive, weakly positive, and negative for tumor cells each accounted for about one-third of the total. Unexpectedly, no MYC translocation was observed by FISH in this group. Thus, FISH is not needed even if more than half of cells are c-MYC positive by PRIME notation. This is the first report describing a correspondence between immunohistochemical findings and chromosomal abnormality, reflecting findings at the protein and gene levels, respectively.

[Significant factors affecting the operation time for benign parotid tumor].

Tumors of the parotid gland are fairly frequent among head and neck tumors. Parotidectomy for benign tumors is necessary for diagnosis and therapy. Furthermore, acquiring the skill for this operation is a significant step in the training course of an otolaryngologist Thus, it is useful to analyze the operation time and determine the factors affecting it to evaluate the progress in the operation skill. To measure the operation time and determine the factors affecting it, 71 cases, including 43 cases of pleomorphic adenomas and 28 cases Warthin's tumor, were retrospectively reviewed to the determine if the operation time depended on the age, sex, operated side, presence of complications, BMI, bleeding volume, tumor size, tumor location, exposure of branches of the facial nerve, and experience of the surgeon. Multivariate analysis was used to determine the factors correlated with the operation time. The results revealed that the bleeding volume, tumor size, tumor location and experience of the surgeon were significantly correlated with the operation time, whereas age, sex, operated side, presentation of complications and BMI showed no correlation with the operation time. Furthermore, surgeons with the experience of operating 20-39 cases took almost the same time for the operation as the surgeon with the experience of operating more than 40 cases. Taken together, to shorten the operation time, the inexperienced surgeon should start with smaller tumors and surgery in the superficial lobe in the initial training period, and supervision by well-experienced supervised surgeons is required until 30-40 are undertaken.

Concurrent isolated IgG2-positive membranous nephropathy and malignant B-cell lymphoma.

A recent systematic review showed that hematological malignancy is often complicated by membranous nephropathy (MN). Histologically, the deposition of IgG subclasses other than IgG4 may imply secondary MN, such as malignancy-associated MN (M-MN). We describe a very rare case of concurrent isolated IgG2-positive MN and B-cell lymphoma. An 83-year-old woman was hospitalized at our institute for facial and lower extremity edema persisting for 2 months. Laboratory tests showed urinary protein level of 10.8 g/day, serum albumin level of 1.6 g/dl, and serum creatinine level of 2.34 mg/dl. Soon after diagnosis of nephrotic syndrome, treatment with corticosteroid was initiated, but it proved to be ineffective. Renal biopsy showed isolated IgG2-positive MN with highly infiltrated CD20-positive lymphoid cells in the kidney. Computed tomography revealed systemic lymphadenopathy, and aberrant B-cells with immunoglobulin light chain restriction were detected in peripheral blood and bone marrow, which led to the diagnosis of mature B-cell lymphoma. Although rituximab (375 mg/m2/week) was administered, the patient suddenly died from gastrointestinal bleeding on day 40 of hospitalization. It is, thus, necessary to consider hematological malignancy when a diagnosis of MN is made. Further studies are expected to elucidate the pathogenesis and to help establish the adequate treatment for this rare situation.

Infantile hemangiopericytoma of the tongue-Efficacy of ex utero intrapartum treatment procedure and combined-modality therapy.

Here we present an extremely rare case of giant infantile hemangiopericytoma (HPC) of the tongue diagnosed prenatally by fetal ultrasonography and MR imaging. Due to airway stenosis, the patient was delivered by the ex utero intrapartum treatment (EXIT) procedure at 36 weeks of pregnancy. Initial diagnosis was infantile hemangioma based on physical examination, diagnostic imaging and the high incidence of hemangioma. The tumor was resistant to conservative treatments. Due to severe tumor hemorrhage, the nutrient vessel was embolized by endovascular treatment on the 73th day after birth. Two days after embolization, a hemiglossectomy was performed. Histological analysis after surgery diagnosed infantile HPC with microscopically positive stumps. After receiving adjuvant chemotherapy, the patient has had no recurrence after 53 months with normal speech and swallowing function resulting in normal growth. Our findings support that infantile HPC is one of the differential diagnosis of infantile hemangioma. The EXIT procedure could be effective for infants with upper respiratory stenosis by head and neck tumor diagnosed prenatally. Though complete resection is required for infantile HPC, our report suggests that a conservative surgical approach followed by adjuvant chemotherapy should be used for giant head and neck infantile HPC.

Clinicopathological features of melanotic neuroectodermal tumor of infancy: Report of two cases.

Melanotic neuroectodermal tumor of infancy (MNTI) is an extremely rare, pigmented neoplastic entity of neural crest origin. Histological and immunohistochemical profiles indicate the presence of two components, small rounded neuroblast-like cellular areas and areas with large melanin-containing cells which consist of combination of neural, melanocytic, and epithelial cell types. Here we present two interesting cases of infants with MNTI which have different clinicopathological features. The first case is a 3-month-old female with rapidly growing MNTI involving the lacrimal sac and inferior wall of the orbital cavity, treated with total maxillectomy without orbital exenteration followed by chemotherapy. The second case is a 7-month-old male with slow-growing maxillary MNTI treated with complete surgical excision. In the female patient, histological findings revealed a predominance of neuroblast-like cellular areas and a high Ki67 index indicating rapid cellular proliferation. In the male patient however, large melanin-containing cells were dominant in this slow-growing tumor. These findings support the presence of two different types of MNTI, rapid-growing and slow-growing types, determined by the component of neuroblast-like cellular areas.

Effects of contralateral noise on the 20-Hz auditory steady state response--magnetoencephalography study.

The auditory steady state response (ASSR) is an oscillatory brain response, which is phase locked to the rhythm of an auditory stimulus. ASSRs have been recorded in response to a wide frequency range of modulation and/or repetition, but the physiological features of the ASSRs are somewhat different depending on the modulation frequency. Recently, the 20-Hz ASSR has been emphasized in clinical examinations, especially in the area of psychiatry. However, little is known about the physiological properties of the 20-Hz ASSR, compared to those of the 40-Hz and 80-Hz ASSRs. The effects of contralateral noise on the ASSR are known to depend on the modulation frequency to evoke ASSR. However, the effects of contralateral noise on the 20-Hz ASSR are not known. Here we assessed the effects of contralateral white noise at a level of 70 dB SPL on the 20-Hz and 40-Hz ASSRs using a helmet-shaped magnetoencephalography system in 9 healthy volunteers (8 males and 1 female, mean age 31.2 years). The ASSRs were elicited by monaural 1000-Hz 5-s tone bursts amplitude-modulated at 20 and 39 Hz and presented at 80 dB SPL. Contralateral noise caused significant suppression of both the 20-Hz and 40-Hz ASSRs, although suppression was significantly smaller for the 20-Hz ASSRs than the 40-Hz ASSRs. Moreover, the greatest suppression of both 20-Hz and 40-Hz ASSRs occurred in the right hemisphere when stimuli were presented to the right ear with contralateral noise. The present study newly showed that 20-Hz ASSRs are suppressed by contralateral noise, which may be important both for characterization of the 20-Hz ASSR and for interpretation in clinical situations. Physicians must be aware that the 20-Hz ASSR is significantly suppressed by sound (e.g. masking noise or binaural stimulation) applied to the contralateral ear.

Carcinoma cuniculatum mimicking leukoplakia of the mandibular gingiva.

Carcinoma cuniculatum (CC) is a rare variant of low-grade squamous cell carcinoma (SCC), and occurrence in the oral cavity is quite unusual. CC has a papillomatous keratinized surface like verrucous carcinoma, but CC has a propensity for aggressive local invasion, especially into the bone. Therefore, CC can be quite difficult to remove surgically. A 68-year-old man presented with a case of CC mimicking verrucous leukoplakia in the mandibular gingiva. Repeated biopsies showed no malignancy. Local resection was performed, and histological examination revealed the presence of well-differentiated SCC. Additional hemi-mandibulectomy was performed and the final histological diagnosis was CC. Local recurrence was detected at the 14-month follow-up examination. Chemotherapy with docetaxel was not effective, and he died of aspiration pneumonia. CC of the oral cavity is a rare entity and the diagnosis is hard to establish. Misdiagnosis could result in inadequate removal and local recurrence. Complete resection with a safety margin is essential because of the tendency for local invasion.

Atypical carcinoid of the larynx and expressions of proteins associated with molecular targeted therapy.

OBJECTIVE: We reported an extremely rare case of atypical laryngeal carcinoid, and examined the expression of several proteins for application of molecular targeted therapy. METHOD: Case report and review of the literature concerning atypical carcinoid arising from the larynx. The expressions of proteins were determined by immunohistochemical analysis. RESULTS: We present here a case of atypical laryngeal carcinoid in a 79-year-old Japanese man, which was completely resected, and with no evidence of recurrence. On immunohistochemical analysis, neoplastic elements revealed, strong positivity for platelet-derived growth factor receptor α (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2), and epidermal growth factor receptor (EGFR), and were mild positivity for KIT. CONCLUSION: Our findings suggest that atypical laryngeal carcinoid could be completely removed if it is located in the limited lesion. PDGFRα, VEGFR2, and EGFR expressions in this case provide the evidence that atypical laryngeal carcinoid is the candidate for molecular targeted therapy, although further investigations are necessary.

Eosinophilic inflammation in the middle ear induces deterioration of bone-conduction hearing level in patients with eosinophilic otitis media.

OBJECTIVE: Eosinophilic otitis media (EOM) is characterized by the extensive accumulation of eosinophils in the middle ear mucosa and middle ear effusion and is usually associated with bronchial asthma. Eosinophilic otitis media patients show gradual or sudden deterioration of hearing. In our previous study, we reported that high-tone loss was more frequently found and more severe in EOM patients than in control patients with chronic otitis media. These findings suggest that not only bacterial infection but also eosinophilic inflammation in the middle ear may damage the inner ear. The present study was performed to determine whether eosinophilic inflammation is indeed related to deterioration of bone-conduction hearing level (BCHL). PATIENTS: Fifty-five ears of 28 patients with EOM associated with bronchial asthma were included in this study. Middle ear effusion (MEE) samples were collected from all the patients, and the concentrations of eosinophilic cationic protein (ECP) and immunoglobulin E (IgE) were measured by fluorescence enzyme immunoassay. The BCHLs at 2 and 4 kHz for the worse-hearing ear of each patient were correlated with the concentrations of ECP and IgE. RESULTS: The concentration of IgE in MEE significantly and positively correlated with BCHL at 2 and 4 kHz. The ears with a higher concentration of ECP in MEE also tended to show deterioration of BCHL at 4 kHz. Other clinical risk factors for BCHL deterioration were male sex, long duration of EOM, association with bacterial infection, severe inflammatory changes of the middle ear mucosa, and high serum IgE concentration. CONCLUSION: Eosinophilic-inflammation-related substances such as ECP and IgE are closely related to the deterioration of BCHL at high frequencies. Particularly, IgE concentration in MEE is a good indicator of BCHL elevation. We should always pay attention to the hearing acuity of EOM patients with the risk factors.