Relationship between age-related changes in mandibular third molar roots and the possibility of mental nerve paresthesia after tooth extraction.

Mental nerve paresthesia is a serious postoperative complication of mandibular third molar extraction. It appears that no study has examined the relationship between the surface morphology of the mandibular third molar roots and the possibility of mental nerve paresthesia following tooth extraction. Therefore, the root morphology of the mandibular third molars was examined according to age using dental cone beam computed tomography (CBCT), and the possibility of mental nerve paresthesia following tooth extraction was evaluated. The study included 1216 patients who had undergone mandibular third molar extractions. The root morphology of 1534 teeth in 791 patients who had CBCT performed before surgery was studied. Factors evaluated were age, complete or incomplete formation of the mandibular third molar roots, periodontal ligament atrophy of the mandibular third molar roots, hypercementosis, and mandibular canal deformation. Mandibular third molar root formation was completed between the ages of 19 and 30 years. Complete formation of the mandibular third molar roots (P = 0.002) and deformation of the mandibular canal (P < 0.001) were identified as risk factors for mental nerve paresthesia. These findings suggest that the risk of mental nerve paresthesia could be reduced if the extraction of third molars is performed prior to complete root formation.

Colorectal endoscopic submucosal dissection: a review on patient selection and indications.

Background: The development of 'third-space'-endoscopy has paved the way towards en-bloc resection of early gastrointestinal neoplasia. Endoscopic submucosal dissection (ESD) has improved the endoscopic management of colorectal lesions by facilitating R0-resection, improving histological assessment and preventing recurrence. Methods: The purpose of this review is to provide an evidence-based overview of indications for which ESD should be considered within colorectal endoscopy. Results: The development of ESD has partially bridged the gap between endoscopy and surgery, but depends heavily on adequate pre-resection visual evaluation, ruling out potential deep submucosal invasion. ESD should be considered for large colorectal polyps (≥20mm) and/or lesions diagnosed as harbouring high-grade dysplasia, in-situ carcinoma or superficial submucosal invasion. Not only has it found its way into our guidelines for the treatment of neuroendocrine neoplasms, ESD also seems a promising alternative for the controlled resection of large pedunculated lesions. ESD can also be applied in more challenging situations, such as in pre-treated lesions, post-surgical context and in patients with IBD, although this requires a high level of skill and expertise. Conclusions: In this review we have described the different indications for ESD and attempted to define its place within our current endoscopic armamentarium. For both non-expert and expert endoscopists, knowledge about ESD indications, patient selection and therapeutic alternatives, remains crucial in the care for patients with colorectal neoplasia.

Treatment outcomes of proton beam therapy combined with retrograde intra-arterial infusion chemotherapy for locally advanced oral cancer in the elderly.

The aim of this study was to evaluate the therapeutic efficacy and safety of proton beam therapy combined with retrograde intra-arterial infusion chemotherapy in elderly patients with locally advanced oral cancer. Between February 2009 and October 2019, 42 oral cancer patients aged ≥75 years were treated with this therapy. Median age was 80 years (range 75-90 years) and the median follow-up duration was 39 months (range 2-106 months). Of the 42 patients, 34 (81%) were diagnosed with stage IV cancer. The 3-year overall survival, local control, progression-free survival, and disease-specific survival rates were 56%, 69%, 32%, and 67%, respectively. Regarding acute toxicities, grade 3 neutropenia was observed in six patients (14%), anaemia in five (12%), acute kidney injury in one (2%), and oral mucositis in 18 (42%). Late toxicities of grade 3 were observed in seven patients: dysphagia in six (14%) and osteonecrosis of the jaw in one (2%). This study showed that proton beam therapy combined with retrograde intra-arterial infusion chemotherapy was effective for elderly patients with oral cancer, and toxicities were tolerable and manageable. The study findings suggest that this therapy is a potential treatment option for elderly oral cancer patients with difficulty in surgery and systemic chemotherapy.

Feasibility of virtual surgical simulation in the head and neck region for soft tissue reconstruction using free flap: a comparison of preoperative and postoperative volume measurement.

In the head and neck region, preoperative evaluation of the free flap volume is challenging. The current study validated preoperative three-dimensional (3D) virtual surgical simulation for soft tissue reconstruction by assessing flap volume and evaluated fat and muscle volume changes at follow-up in 13 head and neck cancer patients undergoing anterolateral craniofacial resection. Patients received 3D virtual surgical simulation, and the volume of the planned defects was estimated by surgical simulation. Following en bloc resection of the tumor, the defect in the skull base was covered using a rectus abdominis myocutaneous flap. Following surgery, computed tomography scans were acquired at day 1 and at 6 and 12 months. Virtual planned defect was on average 227 ml (range, 154-315) and was 10% smaller than the actual flap volume in patients without skin involvement of the tumor. Between day 1 and 12 months post-surgery, the volume of fat and muscle tissue in the free flap dropped by 9% and 58%, respectively. Our results indicate that 3D virtual surgical simulation provides essential information in determining the accurate volume of the required free flap for surgical defect repair and may thus help improve surgical planning and functional and esthetic outcome.

Successful Steroid Therapy for Lipoid Pneumonia Developing After Allogeneic Hematopoietic Stem Cell Transplant: A Case Report.

Lipoid pneumonia is an uncommon noninfectious inflammatory lung disease characterized by lipid deposition in the alveoli, and its etiology and treatment have not been elucidated. We report the case of a 32-year-old woman who developed lipoid pneumonia 9 months after allogeneic hematopoietic stem cell transplant for chronic myelogenous leukemia in lymphoid blast crisis. She complained of progressive cough and dyspnea shortly after discontinuation of immunosuppressive therapy given for graft-vs-host disease. Computed tomography demonstrated diffuse ground-glass opacities in the lungs, and pulmonary function test revealed restrictive impairment. Bronchoalveolar lavage fluid showed milky appearance, and transbronchial lung biopsy specimen revealed foamy macrophages infiltrating the alveoli. Based on these findings, she was diagnosed as having lipoid pneumonia. Prednisolone (1 mg/kg/d) promptly improved the symptoms, pulmonary shadows, and pulmonary function. The findings and clinical course of this case suggest that lipoid pneumonia should be recognized as one of the pulmonary complications of allogeneic hematopoietic stem cell transplantation.

High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis.

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia.

Previously, we identified SETD2 loss-of-function mutations in 22% of MLL-rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes.

Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.

BACKGROUND AND PURPOSE: Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. METHODS: We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. RESULTS: The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. CONCLUSIONS: Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration.

Burst intensification by singularity emitting radiation in multi-stream flows.

Burst Intensification by Singularity Emitting Radiation (BISER) is proposed. Singularities in multi-stream flows of emitting media cause constructive interference of emitted travelling waves, forming extremely localized sources of bright coherent emission. Here we for the first time demonstrate this extreme localization of BISER by direct observation of nano-scale coherent x-ray sources in a laser plasma. The energy emitted into the spectral range from 60 to 100 eV is up to ~100 nJ, corresponding to ~1010 photons. Simulations reveal that these sources emit trains of attosecond x-ray pulses. Our findings establish a new class of bright laboratory sources of electromagnetic radiation. Furthermore, being applicable to travelling waves of any nature (e.g. electromagnetic, gravitational or acoustic), BISER provides a novel framework for creating new emitters and for interpreting observations in many fields of science.

Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth.

OBJECTIVES: We have previously demonstrated that dental pulp stem cells (DPSCs) isolated from mature teeth by granulocyte colony-stimulating factor (G-CSF)-induced mobilization method can enhance angiogenesis/vasculogenesis and improve pulp regeneration when compared with colony-derived DPSCs. However, the efficacy of this method in immature teeth with root-formative stage has never been investigated. Therefore, the aim of this study was to examine the stemness, biological characteristics, and regeneration potential in mobilized DPSCs compared with colony-derived DPSCs from immature teeth. MATERIALS AND METHODS: Mobilized DPSCs isolated from immature teeth were compared to colony-derived DPSCs using methods including flow cytometry, migration assays, mRNA expression of angiogenic/neurotrophic factor, and induced differentiation assays. They were also compared in trophic effects of the secretome. Regeneration potential was further compared in an ectopic tooth transplantation model. RESULTS: Mobilized DPSCs had higher migration ability and expressed more angiogenic/neurotrophic factors than DPSCs. The mobilized DPSC secretome produced a higher stimulatory effect on migration, immunomodulation, anti-apoptosis, endothelial differentiation, and neurite extension. In addition, vascularization and pulp regeneration potential were higher in mobilized DPSCs than in DPSCs. CONCLUSIONS: G-CSF-induced mobilization method enhances regeneration potential of colony-derived DPSCs from immature teeth.

Subacute sarcoid myositis with ocular muscle involvement; a case report and review of the literature.

Sarcoidosis is a chronic granulomatous disease that can affect multiple organs. The lungs, eyes, and skin are known to be highly affected organs in sarcoidosis. There have been reports based on random muscle biopsy that 32-80% of systemic sarcoidosis comprises noncaseating granulomas; however, muscle involvement in sarcoidosis is generally asymptomatic and has an unknown frequency. We describe a case of acute to subacute sarcoid myositis of the skeletal and extraocular muscles. Typical ophthalmic involvement (manifested by infiltration of the ocular adnexa, intraocular inflammation, or infiltration of the retrobulbar visual pathways) and extraocular sarcoid myositis (as with the present case) is infrequently reported. It is important to keep in mind the rare yet perhaps underestimated entity of sarcoid myositis, and to utilize muscle biopsy and imaging tests for appropriate diagnosis and management of patients with sarcoidosis.

Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer.

BACKGROUND: T-cell infiltration in tumors has been used as a prognostic tool in non-small-cell lung cancer (NSCLC). However, the influence of smoking habit and histological type on tumor-infiltrating lymphocytes (TILs) in NSCLC remains unclear. PATIENTS AND METHODS: We evaluated the prognostic significance of TILs (CD4+, CD8+, CD20+, and FOXP3+) according to histological type and smoking habit using automatic immunohistochemical staining and cell counting in 218 patients with NSCLC. RESULTS: In multivariate survival analyses of clinical, pathological, and immunological factors, a high ratio of FOXP3+ to CD4+ T cells (FOXP3/CD4) [hazard ratio (HR): 4.46, P < 0.01 for overall survival (OS); HR: 1.96, P < 0.05 for recurrence-free survival (RFS)] and a low accumulation of CD20+ B cells (HR: 2.45, P = 0.09 for OS; HR: 2.86, P < 0.01 for RFS) were identified as worse prognostic factors in patients with adenocarcinoma (AD). In non-AD, a low number of CD8+ T cells were correlated with an unfavorable outcome (HR: 7.69, P < 0.01 for OS; HR: 3.57, P < 0.02 for RFS). Regarding smoking habit in AD, a high FOXP3/CD4 ratio was poorly prognostic with a smoking history (HR: 5.21, P < 0.01 for OS; HR: 2.38, P < 0.03 for RFS), whereas a low accumulation of CD20+ B cells (HR: 4.54, P = 0.03 for OS; HR: 2.94, P < 0.01 for RFS) was confirmed as an unfavorable factor in non-smokers with AD. CONCLUSIONS: A low number of CD8+ T cells in non-AD, a high FOXP3/CD4 ratio in smokers with AD, and a low number of CD20+ B cells in non-smokers with AD were identified as independent unfavorable prognostic factors in resected NSCLC. Evaluating the influence of histological type and smoking habit on the immunological environment may lead to the establishment of immunological diagnosis and appropriate individualized immunotherapy for NSCLC.

Usefulness of immunocytochemistry using a Breast Marker antibody cocktail targeting P63/cytokeratin7/18/cytokeratin5/14 for fine needle aspiration of the breast: a retrospective cohort study of 139 cases.

OBJECTIVE: The Breast Marker Cocktail from Biocare Medical comprises five antibodies recognising p63, and cytokeratins (CKs) 7, 18, 5 and 14. Immunohistochemistry using this cocktail is useful for diagnosing proliferative intraductal breast lesions. However, cytology using the cocktail has not been reported. METHODS: We report 139 cases of mammary samples collected by fine needle aspiration (FNA) for which histological diagnoses were available. After cell transfer, immunocytochemistry was performed using the cocktail, and clusters of cells were classified. A cluster with no or limited CK5/14 expression (<20% of cells) was classified as a monotonous cluster. One with more than 20% of cells showing CK5/14 expression was defined as a mosaic cluster. When at least one p63-positive cell was present, we defined it as a cluster with p63. We also evaluated background p63-positive myoepithelial cell densities. RESULTS: The diagnostic sensitivity and specificity for carcinomas were 97.8% (89/91) and 91.7% (11/12), respectively, using the criterion of two or more monotonous clusters lacking p63. Two false-negative cases were triple-negative cancers; one false-positive was an apocrine papilloma. The numbers of monotonous clusters with p63 differed significantly between benign lesions, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) and invasive carcinomas (P < 0.001). The background myoepithelial cell density was significantly higher in fibroepithelial tumours than in other lesions (P < 0.001). CONCLUSIONS: Immunocytochemistry using this antibody cocktail showed good sensitivity and specificity for diagnosing breast cancers. Thus, this method is useful for mammary cytology using FNA.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Two cases of atretic cephalocele, and histological evaluation of skin appendages in the surrounding skin.

Atretic cephalocele is a small skin-covered lesion, usually located at or near the mid-line of the scalp. Histologically, it is composed of syncytial cells expressing neurone-specific enolase and epithelial membrane antigen. The syncytial cells form capillary-like structures *(pseudovascular areas) and collagenic fibrosis with densely packed collagen bundles (fibrous areas). Such findings suggest that the atretic cephalocele is a mild form of cephalocele, with its pathogenesis lying in the spectrum of neural tube closure abnormalities. However, few descriptions of abnormalities of the skin overlying and surrounding atretic cephalocele are available. We report two cases of atretic cephalocele that showed hamartomatous change in the surrounding cutaneous appendages. These findings suggest that atretic cephalocele is associated with abnormalities not only of the neural tube, but also of the surrounding skin.

Preliminary results of proton-beam therapy for stage III non-small-cell lung cancer.

BACKGROUND: We conducted a preliminary retrospective evaluation of the efficacy and toxicity of proton-beam therapy (pbt) for stage iii non-small-cell lung cancer. METHODS: Between January 2009 and August 2013, 27 patients (26 men, 1 woman) with stage iii non-small-cell lung cancer underwent pbt. The relative biologic effectiveness value of the proton beam was defined as 1.1. The beam energy and spread-out Bragg peak were fine-tuned such that the 90% isodose volume of the prescribed dose encompassed the planning target volume. Of the 27 patients, 11 underwent neoadjuvant chemotherapy. Cumulative survival curves were calculated using the Kaplan-Meier method. Treatment toxicities were evaluated using version 4 of the Common Terminology Criteria for Adverse Events. RESULTS: Median age of the patients was 72 years (range: 57-91 years), and median follow-up was 15.4 months (range: 7.8-36.9 months). Clinical stage was iiia in 14 patients (52%) and iiib in 13 (48%). The median dose of pbt was 77 GyE (range: 66-86.4 GyE). The overall survival rate in the cohort was 92.3% at 1 year and 51.1% at 2 years. Locoregional failure occurred in 7 patients, and distant metastasis, in 10. In 2 patients, initial failure was both locoregional and distant. The 1-year and 2-year rates of local control were 68.1% and 36.4% respectively. The 1-year and 2-year rates of progression-free survival were 39.9% and 21.4% respectively. Two patients experienced grade 3 pneumonitis. CONCLUSIONS: For patients with stage iii non-small-cell lung cancer, pbt can be an effective and safe treatment option.