Ken-ichi Nibu

The Role of Molecular Testing in the Differential Diagnosis of Salivary Gland Carcinomas

Salivary gland neoplasms are a morphologically heterogenous group of lesions that are often diagnostically challenging. In recent years, considerable progress in salivary gland taxonomy has been reached by the discovery of tumor type-specific fusion oncogenes generated by chromosome translocations. This review describes the clinicopathologic features of a selected group of salivary gland carcinomas with a focus on their distinctive genomic characteristics. Mammary analog secretory carcinoma is a recently described entity characterized by a t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 fusion. Hyalinizing clear cell carcinoma is a low-grade tumor with infrequent nodal and distant metastasis, recently shown to harbor an EWSR1-ATF1 gene fusion. The CRTC1-MAML2 fusion gene resulting from a t(11;19)(q21;p13) translocation, is now known to be a feature of both low-grade and high-grade mucoepidermoid carcinomas associated with improved survival. A t(6;9)(q22-23;p23-34) translocation resulting in a MYB-NFIB gene fusion has been identified in the majority of adenoid cystic carcinomas. Polymorphous (low-grade) adenocarcinoma and cribriform adenocarcinoma of (minor) salivary gland origin are related entities with partly differing clinicopathologic and genomic profiles; they are the subject of an ongoing taxonomic debate. Polymorphous (low-grade) adenocarcinomas are characterized by hot spot point E710D mutations in the PRKD1 gene, whereas cribriform adenocarcinoma of (minor) salivary glands origin are characterized by translocations involving the PRKD1-3 genes. Salivary duct carcinoma (SDC) is a high-grade adenocarcinoma with morphologic and molecular features akin to invasive ductal carcinoma of the breast, including HER2 gene amplification, mutations of TP53, PIK3CA, and HRAS and loss or mutation of PTEN. Notably, a recurrent NCOA4-RET fusion has also been found in SDC. A subset of SDC with apocrine morphology is associated with overexpression of androgen receptors. As these genetic aberrations are recurrent they serve as powerful diagnostic tools in salivary gland tumor diagnosis, and therefore also in refinement of salivary gland cancer classification. Moreover, they are promising as prognostic biomarkers and targets of therapy.

Organ preservation with chemoradiation in advanced laryngeal cancer: The problem of generalizing results from randomized controlled trials

BACKGROUNDnThe primary goal of treatment in advanced laryngeal cancer is to achieve optimal oncologic outcomes while preserving function and quality of life. Combination of chemotherapy and radiation has been popularized as an alternative to surgery for patients facing total laryngectomy. However, survival analyses from large, population-based databases have not duplicated results reported from randomized trials.nnnMETHODSnA comprehensive literature review was undertaken to try to better understand the reasons why results differ among randomized trials and population cohort studies.nnnRESULTSnA variety of reasons are discussed, including differences in patient staging, selection bias, complexity bias, inconsistent terminology, patient compliance and treatment expertise.nnnCONCLUSIONSnPersonalized treatment considering all factors is critical for optimal outcomes. In general, evidence supports total laryngectomy for patients with T4 cancers. Definitive chemoradiotherapy strategies are acceptable alternatives for T3 cancers, provided that all resources for the administration of the treatment, follow-up and surgical salvage are available.

Expression of amphiregulin in mucoepidermoid carcinoma of the major salivary glands: a molecular and clinicopathological study

In mucoepidermoid carcinoma (MEC), CRTC1-MAML2 fusion indicates a favorable prognosis. Amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, has been shown to be a downstream target of CRTC1-MAML2 fusion, and to play a role in tumor growth and survival in CRTC1-MAML2-positive MEC cell lines. The aim of this study was to characterize the AREG and EGFR expression in the fusion-positive and fusion-negative MEC of the major salivary gland. The AREG and EGFR expression were studied by immunochemistry in 33 MEC cases of the major salivary glands. CRTC1-MAML2 fusion was tested by reverse-transcription polymerase chain reaction (23 CRTC1-MAML2 fusion-positive, 10 fusion-negative). Of 23 fusion-positive cases, AREG and EGFR overexpression were detected in 17 (73.9%) and 14 (60.9%) cases, respectively. Of 10 fusion-negative cases, AREG and EGFR overexpression were detected in 1 (10%) and 3 (30.0%) cases, respectively. There was a positive correlation between CRTC1-MAML2 fusion and AREG overexpression (P < .01), but not between CRTC1-MAML2 fusion and EGFR overexpression. The AREG overexpression was associated with a longer disease-free survival of the MEC patients (P = .042), but EGFR overexpression was not. In this study, we showed that AREG overexpression was detected more frequently in the CRTC1-MAML2 fusion-positive tumors than in fusion-negative tumors. Detection of AREG expression may be useful for identifying CRTC1-MAML2-positive MECs and as a marker for favorable prognosis.

Cause and occurrence timing of osteoradionecrosis of the jaw: a retrospective study focusing on prophylactic tooth extraction

PurposeThis retrospective study aimed to analyze the relationship between tooth extraction and osteoradionecrosis (ORN) occurrence. The irradiation field, dose, and time interval between radiotherapy (RT) and ORN were reviewed. We also discuss appropriate guidelines for prophylactic tooth extraction.MethodsA total of 33 patients treated for grade ≥2 (clinical) ORN in our department from 2002 to 2014 were enrolled. The following epidemiological data were retrospectively gathered: age, sex, histological diagnosis, primary tumor sites, radiation dose, chemotherapy, site of ORN, relationship between tooth extraction and ORN occurrence, and time interval between tooth extraction and the initiation or end of RT.ResultsTwenty-one percent of ORN cases resulted from tooth extraction. The most common site of ORN (82xa0%) was the mandibular molar region. About half of ORN cases (49xa0%) occurred within 2xa0years after RT. All patients who received tooth extraction after RT developed ORN (100xa0%) independently of time interval between tooth extraction and the end of RT (median interval, 37.5xa0months; range, 27–120xa0months). In contrast, only 50xa0% of patients who received tooth extraction before RT developed ORN. There may have been an association between the irradiation field and the site of ORN developmentConclusionsORN occurrence due to tooth extraction was 21xa0%. Occurrence timing of ORN did not depend on time interval between tooth extraction and the end of RT. The irradiation field is certainly related to the site of ORN; therefore, prophylactic tooth extraction should be performed in consideration of the proposed radiation field and dose.

Japanese Clinical Practice Guideline for Head and Neck Cancer

OBJECTIVEnThe first revision of Japanese Clinical Practice Guideline for Head and Neck Cancer was made in 2013 by the clinical practice guideline committee of Japan Society for Head and Neck Cancer, in response to the revision of the TNM classification.nnnMETHODSn34 CQs (Clinical Questions) were newly adopted to describe the diagnosis and treatment methods currently considered most appropriate, and offered recommendation grade made by the consensus of the committee. A comprehensive literature search was performed for studies published between 2001 and 2012 using PubMed. Qualified studies were analyzed and the results were evaluated, consolidated and codified by all the committee members.nnnRESULTSnElective neck dissection (ND) does contribute to improvement in survival and should be performed for patients with high-risk tongue cancer. At present, no research has clearly demonstrated the utility of superselective arterial infusion chemotherapy. However, depending on the site and stage of the cancer, combination with radiotherapy may be useful for preserving organ function or improving survival rate. Concurrent CDDP chemotherapy and adjuvant radiotherapy contributes to improvement of survival rate as an adjuvant therapy for advanced squamous cell carcinoma of the head and neck in patients at high risk of recurrence. The anti-EGFR antibody cetuximab (Cmab) has an additive effect with radiotherapy. However, the indication must be carefully considered since this treatment has not been compared with the standard treatment of chemoradiotherapy. Cmab has been shown to have an additive effect with chemotherapy (CDDP/5-FU) in patients with unresectable metastatic or recurrent cancer. Preoperative and postoperative oral care may reduce the risk of postoperative complications such as surgical wound infection and pneumonia in head and neck cancers. Rehabilitation soon after ND for cervical lymph node metastasis is recommended for maintaining and restoring shoulder function.nnnCONCLUSIONSnIn this article, we described most relevant guidelines and CQs for the diagnosis and treatment of head and neck cancer in Japan. These guidelines are not intended to govern therapies that are not shown here, but rather aim to be used as a guide in searching for the most appropriate treatment for individual patient.

Association of impaired renal function and poor prognosis in oropharyngeal squamous cell carcinoma

Renal function influences decisions regarding treatment for patients with oropharyngeal squamous cell carcinoma (SCC). However, the importance of renal function in oropharyngeal SCC has not yet been reported.

Modified partial maxillary swing approach for myxofibrosarcoma in pterygopalatine fossa.

Extirpation of tumors arising in the pterygopalatine fossa is challenging because of its anatomic complexity.

Focal hyperintensity in the dorsal brain stem of patients with cerebellopontine angle tumor: A high-resolution 3 T MRI study

Focal hyperintensity (FHI) in the dorsal brain stem on T2-weighted images of patients with cerebellopontine angle (CPA) tumor was thought to indicate degeneration of the vestibular nucleus and to be specific to vestibular schwannoma. The purpose of this study was to evaluate FHI by using high-resolution 3 Tesla magnetic resonance imaging (3u2009T MRI) and the relation to clinical characteristics. We retrospectively reviewed the clinical data and MRI of 45 patients with CPA tumors (34 vestibular schwannomas and 11 other tumors). FHI in the dorsal brain stem was found in 25 (55.6%) patients (20 vestibular schwannomas and 5 other tumors). For the vestibular schwannomas, the factors contributing to positive FHI were age (pu2009=u20090.025), max CPA (pu2009=u2009u2009<u20090.001), hearing ability (Pu2009=u20090.005), and canal paresis (pu2009=u2009u2009<u20090.001) in the univariate analysis. Multivariate regression analysis showed that max CPA (pu2009=u20090.029) was a significant factor of positive FHI. In other CPA tumors, these factors were not significant predictors. With the use of 3u2009T MRI, FHI was observed more frequently than previously reported. Our results suggest that FHI is not a specific indicator of vestibular schwannoma and is related to not only vestibular function but also other factors.

Prognostic value of ALDH2 polymorphism for patients with oropharyngeal cancer in a Japanese population

Background Half of Japanese possess a polymorphism of aldehyde dehydrogenase 2(ALDH2), while few white individuals possess this mutation. The purpose of this study was to investigate the possibility of ALDH2 polymorphism as a prognostic factor for oropharyngeal cancer (OPC) among Japanese population. Methods We analyzed 82 Japanese patients with OPC treated between 2006 and 2011. The median observation period was 50 months. P16-staining and ALDH2 polymorphisms were investigated. To examine the frequencies of second primary pharyngeal and esophageal cancers (SPPEC),37 Japanese patients with OPC treated at Tokyo University Hospital were included for statistical analysis. Results Statistically significant differences were noted in OS among sex, age, N classification, and p16 (p = 0.045, 0.024, 0.020, 0.007, respectively). In addition, OS and DSS rates of the patients with heterozygous ALDH2 tended to be worse than those of the patients with homozygous ALDH2 (p = 0.21, 0.086, respectively). Of note, OS and DSS of the patients with p16-negative OPC and heterozygous ALDH2 was significant poorer than those of the patients with p16-positive OPC (p = 0.002, 0.006, respectively), while there was no significant difference in OS and DSS between patients with p16-positive OPC and patients with p16-negative OPC and homozygous ALDH2. Conclusions ALDH2 polymorphism might be a promising prognostic factor for Japanese patients with p16-negative OPC.

Isosorbide-Induced Decompression Effect on the Scala Media: Participation of Plasma Osmolality and Plasma Arginine Vasopressin

OBJECTIVEnThe correlation between the isosorbide-induced decompression effect on the endolymphatic space and plasma osmolality (p-OSM) or plasma arginine vasopressin (p-AVP) was investigated on comparing two different dosages of isosorbide (2.8 and 1.4u200ag/kg) to elucidate why the decompression effect is delayed with a large dose of isosorbide.nnnMATERIALS AND METHODSnTwo experiments were performed using 80 guinea pigs. Experiment 1 was designed to morphologically investigate the sequential influence of the oral intake of 1.4- and 2.8-g/kg doses of isosorbide on the endolymphatic volume. The animals used were 50 guinea pigs (control: 10, experimental: 40). All animals underwent surgical obliteration of the endolymphatic sac of the left ear. One month after the surgery, control animals were sacrificed 3u200ahours after the intake of distilled water, and experimental animals were sacrificed 3 and 6u200ahours after the isosorbide intake. All of the left temporal bone served for the quantitative assessment of changes in the endolymphatic space, and the cross-sectional area of the scala media was measured from the mid-modiolar sections of the cochlea.Experiment 2 was designed to investigate changes in p-OSM and p-AVP levels 3u200ahours after the oral intake of isosorbide. Animals used were 15 guinea pigs (control: 5, experimental: 10). The control group received the oral administration of distilled water (4u200aml/kg), and the experimental animals were subdivided into two groups consisting of 10 animals each by the dosage of isosorbide (1.4 or 2.8u200ag/kg). All animals were sacrificed for the measurement of p-OSM and p-AVP concentrations 3u200ahours after the intake of water or 70% isosorbide solution.nnnRESULTSnMorphologically, an isosorbide-induced decompression effect was noted in animals with both 1.4- and 2.8-g/kg doses of isosorbide. According to the regression analysis, however, the volumetric decrease of the endolymphatic space was more evident in cases with the small dose (1.4u200ag/kg) 3u200ahours after the intake (analysis of covariance [ANCOVA], pu200a<u200a0.001). Six hours after, the decompression effect was significantly greater in cases with the large dose (2.8u200ag/kg) (ANCOVA, pu200a<u200a0.001).Isosorbide intake caused a rise in p-OSM levels dose-dependently. The Cochran-Cox test revealed that the differences in the mean values among control and isosorbide groups were significant (pu200a<u200a0.01). Regarding the p-AVP level, a significant increase was evident in cases with the large dose (2.8u200ag/kg) (pu200a<u200a0.01, Cochran-Cox test), and not in cases with the small dose (1.4u200ag/kg).nnnCONCLUSIONnAn isosorbide-induced decompression effect of the endolymphatic space was evident in spite of two different dosages of isosorbide (2.8 and 1.4u200ag/kg). Three hours after the isosorbide intake, however, the decompression effect was more marked in the group with the small dose (1.4u200ag/kg). Since significant rises in p-OSM and p-AVP were evident in the group with the large dose, this early rise of p-AVP due to dehydration seems to be the major reason for the delayed decompression effect in cases with a large isosorbide intake.