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The present study investigated the expression and role of ROR2 in small cell lung cancer (SCLC). To examine the expression of ROR2, 27 surgically resected SCLC tissue samples were immunostained for ROR2. Sixteen tissue samples were positive and some showed intratumor heterogeneity in staining intensity. The heterogeneity of ROR2 expression was also observed in tumor tissues from a PDX model of SCLC, in which there were cells with high ROR2 expression (ROR2

Neuroendocrine (NE) differentiation has been histochemically detected in normal and cancer tissues and cells. Immunohistochemical analyses have provided a more detailed understanding of NE biology and pathology. Pulmonary NE cells are a rare lung epithelial type, and small cell carcinoma of the lung (SCLC) is a high-grade NE tumor. Pulmonary NE and SCLC cells share common mechanisms for NE differentiation. Neural or NE cell lineage-specific transcription factors, such as achaete-scute homologue 1 (Ascl1) and insulinoma-associated protein 1 (INSM1), are crucial for the development of pulmonary NE cells, and NE differentiation is influenced by the balance between Ascl1 and the suppressive neural transcription factor, hairy-enhancer of split 1, a representative target molecule of the Notch signaling pathway. In this review, we discuss the importance of Ascl1 and INSM1 in identifying pulmonary NE and SCLC cells and introduce Ascl1-related molecules detected by comparative RNA-sequence analyses. The molecular classification of SCLC based on the expression of lineage-specific transcription or co-transcription factors, including ASCL1, NEUROD1, POU2F3, and YAP1, was recently proposed. We attempted to characterize these 4 SCLC subtypes using integrated immunohistochemical studies, which will provide insights into the molecular characteristics of these subtypes and clarify the inter- and intratumor heterogeneities of SCLC.

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also known as WWTR1) are core downstream effectors of the Hippo pathway, which is involved in diverse biological processes. The oncogenic effects of YAP and TAZ in non-small cell lung cancer (NSCLC) have recently been reported; however, their roles in SCLC remain unclear. Immunohistochemistry (IHC) on lung cancer tissues and Western blotting (WB) on lung cancer cell lines were performed to examine the expression of YAP1. Genome editing using CRISPR/Cas9 was then used to knockout the YAP1 gene in the H69AR cell line. An RNA-sequence analysis, gene ontology (GO) analysis, WB, cell counting assay, invasion assays, and xenograft studies were conducted on these cells to investigate the biological roles of YAP1. IHC revealed that insulinoma-associated protein 1 was expressed in most cases (28 out of 32 cases), while only four cases expressed YAP1. The knockout of YAP1 in H69AR cells, a chemically induced SCLC-Y subtype, reduced cell proliferation and invasion capacity and restored drug sensitivity. Xenograft assays revealed that the knockout of YAP1 suppressed cell proliferation. Tumor tissues showed the expression of neuroendocrine markers and a low Ki-67 index. In SCLC, YAP1 plays an important role in biological functions, such as cell proliferation, EMT, drug sensitivity, and neuroendocrine differentiation.

Although the lung is the most common site of distant metastases from head and neck squamous cell carcinoma (HNSCC), the number of reports about the effects of pulmonary metastasectomy for the treatment of lung metastasis from HNSCC is limited. Metachronous pulmonary metastases were detected in 45 HNSCC patients at Kumamoto University Hospital from 1998 to 2018. Twenty-two patients underwent an operative resection (Ope group) and 23 underwent chemotherapy (Chemo group). The 3-year overall survival (OS) rate and median OS were evaluated. The effects of adjuvant chemotherapy after pulmonary metastasectomy and of new drugs (cetuximab and nivolumab), in the chemo group were also assessed. The 3-year OS rates and median OS were: Ope, 66.1% and 31.5 months; Chemo, 39.7% and 18 months, respectively. In the Ope group, addi-tional recurrences were significantly fewer in the patients who underwent adjuvant chemotherapy post-surgery versus the patients who underwent surgery alone (p = 0.013). In the Chemo group, the 3-year OS rate of the patients who received new drugs was significantly better than that of the patients who did not (p = 0.021). Adjuvant chemotherapy after pulmonary metastasectomy may be a preferable treatment option for preventing recurrences. Cetuximab and nivolumab have a potential to improve OS.

Background Lenvatinib, a multi-tyrosine kinase inhibitor (TKI), has been proven to be an effective treatment option for patients with unresectable thyroid carcinoma. However, it causes certain adverse effects (AEs), and discontinuation or dose reduction of the drug is almost unavoidable. Few studies have investigated the impact of the length, dose, or interruption of lenvatinib administration on the prognosis of patients with unresectable thyroid carcinoma. Here, we aimed to verify the significance of our efforts to continue lenvatinib therapy to the longest duration possible with a reasonable daily dose and minimum discontinuation period in patients with unresectable thyroid carcinoma. Methods The clinical records of 42 patients with unresectable thyroid carcinoma treated with lenvatinib between 2015 and 2020 were retrospectively studied. Results The Cox proportional hazard model-based analysis indicated that the overall survival (OS) of patients treated with a mean dose of lenvatinib

Simple Summary Recurrent laryngeal nerve (RLN) is the second most common structure invaded by primary or metastatic thyroid cancer. However, little is known about the optimal procedure for maintaining vocal function in patients with unilateral RLN involvement in thyroid cancer. This study aimed to evaluate various parameters of vocal function to establish the optimal management of thyroid cancer patients with unilateral RLN involvement. Based on our findings, we propose that for optimal management of unilateral RLN involvement in thyroid cancer, first, sharp dissection should be performed, and if this is impossible, a simultaneous RLN reconstruction procedure should be adopted whenever possible. These findings may help improve management of RLN involvement in patients with thyroid cancer and ensure vocal function preservation. Abstract We aimed to determine the optimal management of recurrent laryngeal nerve (RLN) involvement in thyroid cancer. We enrolled 80 patients with unilateral RLN involvement in thyroid cancer between 2000 and 2016. Eleven patients with preoperatively functional vocal folds (VFs) underwent sharp tumor resection to preserve the RLN (shaving group). Thirty-three patients underwent RLN reconstruction with RLN resection (reconstruction group). We divided the reconstruction group into two subgroups based on preoperative VF mobility (normal-reconstruction and paralyzed-reconstruction subgroups). In the cases where RLN reconstruction was difficult, phonosurgeries including arytenoid adduction (AA), with or without thyroplasty type I, or nerve muscle pedicle implantation with AA were performed later (phonosurgery group). We evaluated and compared vocal function among the evaluated periods and different groups. Postoperative vocal function in the shaving and normal-reconstruction subgroups was favorable. There were no significant differences between the two groups. In the paralyzed-reconstruction and phonosurgery groups, postoperative vocal function was significantly improved, and vocal function in the paralyzed-reconstruction subgroup was significantly better than that in the phonosurgery group. For optimal management of unilateral RLN involvement in thyroid cancer, first, sharp dissection should be performed, and if this is impossible, a simultaneous RLN reconstruction procedure should be adopted whenever possible.

We propose a construction and calibration method of an absolute coordinate system for lithography tools. In the conventional overlay control system, subsequent layers are overlaid on the 1st layer that could have unknown wafer distortion. This is inefficient, because the distortion of the 1st layer may be large. A high-level overlay control can be realized with the absolute coordinate system by correcting the 1st layer to zero distortion. This can be possible by using absolute alignment metrology system. In order to confirm our theory, we report experimental results of the absolute grid construction and matching accuracy among multiple lithography tools.

Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important for the formation of SCLC characteristics in a molecular subtype-specific manner. We expect that immunohistochemistry (IHC) of these molecules may facilitate the diagnosis of the specific SCLC molecular subtype and aid in the appropriate selection of individualized treatments. We attempted IHC of the four key factors and 26 candidate SCLC target molecules selected from the gene expression omnibus datasets of 47 SCLC samples, which were grouped based on positive or negative results for the four key molecules. We examined differences in the expression levels of the candidate targets and key molecules. ASCL1 showed the highest positive rate in SCLC samples, and significant differences were observed in the expression levels of some target molecules between the ASCL1-positive and ASCL1-negative groups. Furthermore, the four key molecules were coordinately and simultaneously expressed in SCLC cells. An IHC study of ASCL1-positive samples showed many candidate SCLC target molecules, and IHC could become an essential method for determining SCLC molecular subtypes.

The treatment of sensorineural hearing loss (SNHL) may be achieved via the application of a cochlear implant (CI) that allows the electrical stimulation of spiral ganglion neurons (SGNs). Nevertheless, the efficacy of CIs is limited by the degeneration of SGNs following SNHL. Although the application of exogenous neurotrophic factors has been reported to decrease SGN degeneration, non-invasive targeted drug delivery systems are required to achieve effective results. In this study, an SS-cleavable proton-activated lipid-like material [ssPalm; a neutral lipid nanoparticle (LNP)], was loaded with mRNA, and the efficacy of this material as a delivery system was investigated. Our results showed that LNPssPalm carrying brain-derived neurotrophic factor (BDNF) mRNA was suitable for the treatment of inner ear diseases, preventing the degeneration of SGNs. In conclusion, this modern nanotechnology-based bioconjugation system, LNPssPalm, is a potential non-invasive targeted therapy allowing the delivering biomaterials to specific structures within the inner ear for the treatment of SHNL.

A standalone alignment technology was developed as a fundamental solution to improve on-product overlay (OPO). It enables high performance alignment measurements, and delivers state-of-the-art feed forward corrections to exposure scanner. Dense alignment sampling and high-order field distortion correction is effective for scanner fingerprint matching and for heat related field distortions. A modeling and sampling optimization software is a powerful tool for dense sampling and high-order overlay correction with minimal throughput loss. We performed an overlay experiment using the standalone alignment technology coupled with a modeling and sampling optimization software, which demonstrates on-product overlay improvement potential for next generation manufacturing accuracy and productivity challenges.

Differentiated thyroid carcinoma (DTC) can invade the surrounding aerodigestive tract. Radical surgery for locally advanced DTC will require resection of the trachea, recurrent laryngeal nerve (RLN), inferior pharyngeal constrictor muscles (IPCMs), or a part of the esophagus. The purpose of this study was to demonstrate the effect of resection of these surrounding tissues combined with total thyroidectomy and neck dissection on swallowing function following surgery. We performed total thyroidectomy combined with neck dissection and resection of the RLN in 24 patients with DTC with extrathyroidal invasion (19 unilateral, 1 bilateral), IPCMs (n = 5), or muscle layers of esophagus (n = 9). Nine patients received a tracheostomy placement due to a window resection of the trachea for tumor invasion (n = 6) and necessary upper airway management (n = 3). We used the duration of nasogastric tube feeding to evaluate swallowing function following surgery. Patients who underwent tracheostomy or IPCM resection showed significantly longer periods of tube feeding (p = 0.0057 and 0.0017, respectively). In contrast, resection of the unilateral RLN or esophageal muscle layer showed no difference in tube feeding duration. Multiple regression analysis indicated that tracheostomy and IPCM resection were significant independent predictors of longer periods of tube feeding (p = 0.04583 and 0.00087, respectively). These results indicate that tracheostomy placement and resection of the IPCMs, together with total thyroidectomy, extends the tube feeding duration in the postoperative period.

SOX2is an oncogene in human small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) tumor. However, the roles of SOX2 in SCLC remain unclear, and strategies to selectively target SOX2 in SCLC cells have not yet been established. We herein demonstrated that SOX2 is involved in NE differentiation and tumorigenesis in cooperation with ASCL1, a lineage-specific transcriptional factor, in the classical subtype of SCLC cell lines. ASCL1 recruits SOX2, which promotes INSM1 expression. Precursor SCLC lesions were established inTrp53(-/-);CCSPrtTA; tetOCre; floxedRb1; floxedHes1mice, and the NE neoplasms induced were positive for Ascl1, Sox2, and Insm1. In contrast to the ASCL1-SOX2 signaling axis to control the SCLC phenotype in classical subtype SCLC, SOX2 targeted distinct genes, such as those related to the Hippo pathway, in ASCL1-negative, variant subtype SCLC. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 signaling axis and the clinical utility of SOX2 as a biological marker in the classical subtype of SCLC.

Study design This is a report of two patients who sustained cervical myelopathy that seemed to be associated with hypertrophic atlantodental osteoarthritis accompanying dens hypertrophy. Objectives Pathogenesis of hypertrophic osteoarthritis in the atlantodental articulation was elucidated, and these two patients were treated by C1 decompressive laminectomy with or without posterior fusion. Summary of background data One case of myelopathy resulting from the hypertrophic nonunion of the dens has been reported, but to the authors' knowledge, there have been no reports describing a case similar to those presented in this report. Methods History, physical findings, and image examination findings common to the two cases were analyzed to elucidate pathogenesis of hypertrophic osteoarthritis in the atlantodental articulation. C1 decompressive laminectomy alone was performed in one patient and additional atlantoaxial transarticular fixation in the other patient. Results Myelopathy in two patients was caused by the cervical cord compressed between the hypertrophic and sclerotic dens and the anteriorly displaced posterior arch of the atlas in the developmentally small atlas ring. Postoperative neurologic recovery was satisfactory with the atlantoaxial solid fusion. Conclusion The atlantodental hypertrophic osteoarthritis accompanying the dens hypertrophy seemed to have developed because of post-traumatic atlantoaxial instability. Their developmentally small atlas ring may be a predisposing factor toward the development of myelopathy.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

An attempt was made to employ the plasma-energized jet (PEN-jet) generated by pulsed arc discharge, one of the atmospheric-pressure mesoplasmas, for removal of machine oil from the surface of electrically-grounded aluminum (Al) alloy substrate under open atmosphere. Three types of nozzle configurations were examined; a metal nozzle, ceramic nozzle, and electrically-floated metal nozzle. Electric input power to the pulsed arc plasma discharge was 700 W constant. First, free-burning of the PEN-jet was observed as a function of air gas flow. When the PEN-jets were irradiated to the clean substrate, the PEN-jet with the metal nozzle caused substrate damage by the arc spot due to transferring arc discharge. Then the PEN-jet with the ceramic nozzle was irradiated to the oily substrate. The adhesion strength of sealant and water contact angle of the treated surface were then measured. As a result, these values of the oily substrate treated by the PEN-jet were almost the same as those of clean substrate. The treated surface was analyzed by Fourier transform infrared spectroscopy, Raman spectroscopy, and reflectance spectroscopy. Their spectral profiles clearly indicated oil removal from the surface by PEN-jet.