Clinicopathological findings, prognosis, and Epstein-Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders.

BACKGROUND: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). METHODS: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. RESULTS: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). CONCLUSIONS: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Highly expressed tumoral emmprin and stromal CD73 predict a poor prognosis for external auditory canal carcinoma.

Squamous cell carcinoma of the external auditory canal (SCC-EAC) is rare and has a poor prognosis. The SCC-EAC cases with high-grade tumor budding (TB) or poorly differentiated clusters (PDCs) are associated with shorter survival than those with low-grade TB or PDCs. Extracellular matrix metalloproteinase inducer (emmprin) is a protein expressed in tumor cells that stimulates the production of MMP-2 by stromal fibroblasts to facilitate tumor invasion. Recently, we reported that emmprin forms a complex with CD73 to regulate MMP-2 production from fibroblasts in vitro. Here, we examined the association of emmprin and CD73 expression with TB or PDCs as well as with survival in 34 biopsy specimens of SCC-EAC patients. High tumoral emmprin expression was associated with high-grade TB, whereas high stromal CD73 expression was associated with high-grade PDCs. Furthermore, concurrent elevated expression of tumoral emmprin and stromal CD73 was determined to be an independent poor prognostic factor. In immunoprecipitation analyses, complex formation between emmprin and CD73 was demonstrated in vitro. Production of MMP-2 from fibroblasts was more abundant when cocultured with tumor cells than from fibroblasts cultured alone. Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells. The colocalization of emmprin and CD73 was enhanced in not only the peripheral cells of the tumor cell clusters that interact with fibroblasts but also in the cells of intratumor clusters. Overall, this study provides novel insights into the roles of emmprin, CD73, and MMP-2 in tumor invasiveness.

Two-layer anti-reflection coating with mullite and polyimide foam for large-diameter cryogenic infrared filters.

We have developed a novel two-layer anti-reflection (AR) coating method for large-diameter infrared (IR) filters made of alumina, for use at cryogenic temperatures in millimeter wave measurements. Thermally sprayed mullite and polyimide foam (Skybond Foam) are used as the AR material. An advantage of the Skybond Foam is that the index of refraction is chosen between 1.1 and 1.7 by changing the filling factor. Combination with mullite is suitable for wide-band millimeter wave measurements with sufficient IR cutoff capability. We present the material properties, fabrication of a large-diameter IR filter made of alumina with this AR coating method, and characterizations at cryogenic temperatures. This technology can be applied to a low-temperature receiver system with a large-diameter focal plane for next-generation cosmic microwave background polarization measurements, such as POLARBEAR-2 (PB-2).

Two-year evolution of quality of life following radiotherapy and/or chemotherapy in patients with head and neck cancer.

Objective: This study aims to elucidate the trajectory of quality of life (QoL) over a two-year period after radiotherapy and/or chemotherapy for head and neck cancer (HNC), addressing the gap in long-term QoL information. Methods: Employing a prospective longitudinal observational design, we tracked 58 HNC patients who underwent radiotherapy and/or chemotherapy, analyzing their QoL using Short-Form 36-Item Health Survey version 2 (SF36v2), the European Organization for Research and Treatment of Cancer quality of life (EORTC-QLQ-C30), and the European Organization for Research and Treatment of Cancer quality of life head and neck-35 (EORTC-QLQ-H&N35) questionnaires for two years post-discharge. The data underwent repeated measures analysis of variance. Results: Over the two-year follow-up, 10 patients (17.2%) succumbed, and 8 (13.8%) dropped out. SF36v2 physical and role-social component summary scores declined during treatment, requiring 1-2 years for recovery. The mental component summary score remained stable. EORTC-QLQ-30 revealed global health status recovery within one year post-discharge. EORTC-QLQ-H&N35 items like "swallowing," "senses problems," "trouble with social eating," "dry mouth," "sticky saliva," "coughing," and "felt ill" worsened pre-discharge. "Trouble with social contact" improved within a year, while "pain," "swallowing," "senses problems," "trouble with social eating," and "coughing" improved within two years. "Dry mouth" and "sticky saliva" persisted throughout the two-year follow-up, common symptoms of HNC and treatment side effects. Conclusions: Recovery of specific QoL aspects in HNC patients treated with radiotherapy and/or chemotherapy may require up to two years. Prolonged monitoring and management of oral symptoms could enhance QoL. Future research should extend follow-up beyond two years for comprehensive interventions enhancing patient QoL.

Resolution of Laryngeal Ulceration with Prednisolone Therapy in a Patient with Crohn's Disease.

A 23-year-old man diagnosed with Crohn's disease (CD) was treated with infliximab. He developed new-onset sore throat and dysphagia during admission, and nasopharyngoscopy revealed epiglottic ulceration. Laryngeal ulceration was considered as an extraintestinal manifestation of CD owing to treatment failure with antibiotics and hydrocortisone. This strongly suggested that laryngeal ulceration was a complication of CD because of the rapid improvement in the symptoms and lesions after prednisolone administration. Furthermore, this treatment process demonstrated the superior anti-inflammatory effect of prednisolone over that of hydrocortisone and supported the assumption of inflammation related to CD.

A Rare Case of Tracheal Crystal-Storing Histiocytosis Associated with Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue.

Crystal-storing histiocytosis (CSH) is a rare non-neoplastic histiocytic lesion with abnormal accumulation of immunoglobulin (Ig) light chain. CSH is associated with Ig overproduction by B-lymphoproliferative disorders (B-LPDs) or by persistent inflammatory diseases. Eighteen cases of pulmonary CSH have been reported. However, no case reports of tracheal CSH have been published. In this patient, we found a solitary tracheal tumor in an asymptomatic 60-year-old man on chest computed tomography scan. Histologically, the tumor comprised two different lesions. One lesion showed diffuse proliferation of spindle-shaped histiocytes with abundant eosinophilic granular cytoplasm. With immunohistochemistry, the histiocytic cells were positive for CD68, CD163 and Ig kappa light chain, and the cytoplasm was weakly positive for anaplastic lymphoma kinase (ALK) protein. Fluorescence in situ hybridization indicated no split signals for the ALK gene. Electron microscopy demonstrated many elongated or rhomboid-shaped dense crystals in the cytoplasm of histiocytes. The second lesion showed proliferation of CD20-positive small atypical lymphocytes mixed with Ig kappa chain-positive plasma cells. A diagnosis of CSH and concomitant mucosa-associated lymphoid tissue lymphoma was made. In this patient, unexpected ALK protein was detected in infiltrating histiocytes. Therefore, careful assessment of the ALK protein and gene was necessary to differentiate from other histiocytic disorders.

Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein-Barr virus+ diffuse large B-cell lymphoma.

Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.

Management of tracheostomy in COVID-19 patients: The Japanese experience.

OBJECTIVE: Involvement in the tracheostomy procedure for COVID-19 patients can lead to a feeling of fear in medical staff. To address concerns over infection, we gathered and analyzed experiences with tracheostomy in the COVID-19 patient population from all over Japan. METHODS: The data for health-care workers involved in tracheostomies for COVID-19-infected patients were gathered from academic medical centers or their affiliated hospitals from all over Japan. RESULTS: Tracheostomies have been performed in 35 COVID-19 patients with a total of 91 surgeons, 49 anesthesiologists, and 49 surgical staff members involved. Twenty-eight (80%) patients underwent surgery more than 22 days after the development of COVID-19-related symptoms (11: 22-28 days and 17: ≥29 days). Thirty (85.7%) patients underwent surgery ≥ 15 days after intubation (14: 15-21 days, 6: 22-28 days, and 10: ≥29 days). Among the total of 189 health-care workers involved in the tracheostomy procedures, 25 used a powered air-purifying respirator (PAPR) and 164 used a N95 mask and eye protection. As a result, no transmission to staff occurred during the 2 weeks of follow-up after surgery. CONCLUSION: No one involved in tracheostomy procedures were found to have been infected with COVID-19 in this Japanese study. The reason is thought to be that the timing of the surgery was quite late after the infections, and the surgery was performed using appropriate PPE and surgical procedure. The indications for and timing of tracheostomy for severe COVID-19 patients should be decided through multidisciplinary discussion.

MK615 Suppresses Hypoxia Tolerance by Up-regulation of E-cadherin in Colorectal Cancer Cells With Mutant KRAS.

BACKGROUND/AIM: The Japanese apricot "Prunus mume" is a traditional Japanese medicine. MK615, a compound extract from Prunus mume has been reported to have anti-tumor effects. Herein, we used 3D floating (3DF) culture to evaluate the anticancer effects of MK615 against human colorectal cancer (CRC) cells that contain mutant (mt) KRAS. MATERIALS AND METHODS: HKe3 cells exogenously expressing mtKRAS (HKe3-mtKRAS) were treated with MK615 in 3DF cultures. The protein levels of hypoxia-inducible factor 1 (HIF-1) and E-cadherin were quantified by western blotting. RESULTS: MtKRAS enhanced hypoxia tolerance via up-regulation of HIF-1. The expression of HIF-1 protein was suppressed by constitutive overexpression of E-cadherin in CRC HCT116 spheroids. MK615 increased the expression of E-cadherin and decreased the expression of HIF-1 in HKe3-mtKRAS. These results suggest that MK615 suppresses hypoxia tolerance by up-regulation of E-cadherin in CRC cells with mtKRAS. CONCLUSION: MK615 exhibits properties useful for the potential treatment of CRC patients with mtKRAS.

Mutant KRAS Promotes NKG2D+ T Cell Infiltration and CD155 Dependent Immune Evasion.

BACKGROUND/AIM: Roles for mutant (mt) KRAS in the innate immune microenvironment in colorectal cancer (CRC) were explored. MATERIALS AND METHODS: Human CRC HCT116-derived, mtKRAS-disrupted (HKe3) cells that express exogenous mtKRAS and allogenic cytokine-activated killer (CAK) cells were co-cultured in 3D floating (3DF) culture. The anti-CD155 antibody was used for function blocking and immuno histochemistry. RESULTS: Infiltration of CAK cells, including NKG2D+ T cells, into the deep layer of HKe3-mtKRAS spheroids, was observed. Surface expression of CD155 was found to be up-regulated by mtKRAS in 3DF culture and CRC tissues. Further, the number of CD3+ tumor-infiltrating cells in the invasion front that show substantial CD155 expression was significantly larger than the number showing weak expression in CRC tissues with mtKRAS. CD155 blockade decreased the growth of spheroids directly and indirectly through the release of CAK cells. CONCLUSION: CD155 blockade may be useful for therapies targeting tumors containing mtKRAS.

A Case of Salivary Duct Carcinoma Intracranial Invasion due to Perineural Invasion Through the Facial Nerve.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare parotid tumor that often develops as a rapidly growing mass with a poor prognosis. It has a high rate of distant metastases, sometimes with infiltration along nerves. We describe a case of SDC that originated outside the cranium and extended into the cranium along the path of the facial nerve. CASE DESCRIPTION: A 74-year-old man underwent magnetic resonance imaging at a local hospital, which revealed a tumor in the left internal acoustic canal; the patient was referred to our department. A left facial schwannoma was suspected, and magnetic resonance imaging was performed again 6 months later. Rapid tumor growth was confirmed, and the tumor was resected. The tumor displayed atypical epithelial cells with comedo necrosis and cribriform structure and was diagnosed as SDC. All residual intracranial tumors were removed using the middle fossa approach. The tumor, which was considered to be a primary tumor, was found near the stylomastoid foramen, and it was removed with the parotid gland. Five months after the initial surgery, metastasis to the trigeminal nerve was observed, and this was removed using a retrosigmoid approach, followed by radiation therapy. CONCLUSIONS: All 4 surgical specimens of this case were presented, and the path of tumor progression was examined in detail. Although the primary lesion was small, intracranial invasion along the facial nerve occurred. SDC should be considered as a tumor that can extend into the cranium, even with a small primary lesion.

Poorly Differentiated Clusters Predict a Poor Prognosis for External Auditory Canal Carcinoma.

Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is rare and offers a poor prognosis; more accurate prognostic biomarkers are required. Our laboratory recently demonstrated that tumor budding, characterized by tumor cell clusters (< 5 cells), and laminin 5-γ2 staining of SCC of the EAC are associated with shorter survival. However, clusters composed of ≥ 5 tumor cells are also found in the stroma. Previous reports of colorectal cancer suggest that poorly differentiated clusters (PDCs) are a negative prognostic indicator. Here, we report on the association between PDCs and prognosis in SCC of the EAC. PDCs and tumor budding were histopathologically and immunohistochemically (cytokeratin AE1/AE3) analyzed in 31 cases of pre-treatment biopsy SCC of the EAC. Clusters in the stroma composed of < or ≥ 5 cancer cells were defined as tumor budding or PDCs, respectively. Entire tumors were initially scanned to identify greatest PDC density. Tumors with low or high PDC density were classified as low- and high-grade, respectively. Patients with high-grade PDCs had a significantly poorer outcome than those with low-grade. Even in cases of low-grade tumor budding, those with high-grade PDCs had a poor prognosis. Multivariate analysis results indicated that high-grade PDCs were associated with poor prognosis. PDC grade can provide a more accurate prognosis than tumor budding in SCC of the EAC.

Adenoid cystic carcinoma with high-grade transformation forming spindle cell component of the submandibular gland.

Adenoid cystic carcinoma (AdCC) with high-grade transformation (AdCC-HGT) is rare, and AdCC-HGT with spindle cell component is particularly rare. The patient was a 65-year-old man with a 5 cm sized swelling of the right submandibular gland. Submandibular sialoadenectomy was performed. Histopathological findings mainly showed conventional AdCC, and minorly showed two other components: (1) the pleomorphic component, a proliferation of atypical pleomorphic epithelial cells forming solid or small clusters and accompanied by necrosis; (2) the spindle cell component, containing atypical spindle cells invading the stroma. Postoperative chemoradiotherapy was performed. Multiple right lung nodular lesions were found on the contrast-enhanced chest CT one month after the surgery. Thoracoscopic pulmonary resection was performed. The lung tumors exhibited a proliferation of atypical spindle cells, accompanied by necrosis. We considered that the spindle cell component of the AdCC-HGT of the submandibular gland developed lung metastases. The patient died seven months after submandibular sialoadenectomy due to respiratory failure. Although rare, our case highlights the importance of recognising spindle cell components in conventional AdCC; even if the area is small, these high-grade transformation areas can metastasise and become prognostic factors.

A comparison between the feeling of ear fullness and tinnitus in acute sensorineural hearing loss.

The feeling of ear fullness (FEF) occurs frequently in patients with acute sensorineural hearing loss; the same is true for tinnitus (TIN). However, the cause of FEF in these patients is unclear. This study included 171 ears of patients admitted with unilateral sudden deafness to the ENT division of Fukuoka University Hospital between January 2001 and December 2004. The results showed TIN was mainly associated with worse high-frequency hearing thresholds, where hearing loss was relatively severe, and this association became stronger after the hearing threshold stabilized. FEF was associated with the low-frequency region, where hearing loss was relatively mild, and this association disappeared after the hearing threshold stabilized. In conclusion, TIN is thought to originate in the region where hair cells are impaired; in contrast, FEF may originate from some functional factor rather than an organic lesion of the cochlea.

A rare case of dedifferentiated liposarcoma of the sinonasal cavity: A case report.

Sarcoma is an uncommon histopathological presentation of sinonasal tumors, comprising ~15% of all cases; liposarcoma is particularly uncommon. An analysis of the available medical literature revealed no prior reports of dedifferentiated liposarcoma (DDLPS) of the sinonasal cavity. This case report presents a rare case of DDLPS of the sinonasal cavity. A 40-year old six-week pregnant female was admitted with a left nasal obstruction. Endoscopic evaluation of the left nasal cavity revealed a polypoid lesion. A computed tomography scan indicated a mass invading the left nasal cavity, maxillary sinus and anterior ethmoid sinus with focal destruction of the surrounding bone. A biopsy of the tumor was performed and hematoxylin and eosin staining of the tissue sections revealed proliferation of atypical and pleomorphic spindle cells with enlarged or elongated hyperchromatic nuclei and occasional vacuolated cytoplasm arranged in short interlacing fascicles or storiform structures, accompanied by tumor necrosis. These findings were consistent with undifferentiated pleomorphic sarcoma. Immunohistochemically, the tumor cells were positive for cyclin dependent kinase 4, mouse double minute 2 homolog (MDM2) and adipophilin. Fluorescence in situ hybridization (FISH) analysis revealed amplification of the MDM2 gene. Recently, undifferentiated pleomorphic sarcoma without areas of well-differentiated liposarcoma but with MDM2 amplification is regarded as conventional DDLPS. In the present case, the tumor was diagnosed as a DDLPS due to the results of histopathological, immunohistochemical and FISH analysis.

ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line.

Excess production of reactive oxygen species (ROS) is known to cause apoptotic cell death. However, the molecular mechanisms whereby ROS induce apoptosis remain elusive. Here we show that the NHL-repeat-containing protein 2 (NHLRC2) thioredoxin-like domain protein is cleaved by caspase-8 in ROS-induced apoptosis in the HCT116 human colon cancer cell line. Treatment of HCT116 cells with the oxidant tert-butyl hydroperoxide (tBHP) induced apoptosis and reduced NHLRC2 protein levels, whereas pretreatment with the antioxidant N-acetyl-L-cysteine prevented apoptosis and the decrease in NHLRC2 protein levels seen in tBHP-treated cells. Furthermore, the ROS-induced decrease in NHLRC2 protein levels was relieved by the caspase inhibitor z-VAD-fmk. We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase-8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and CRISPR-Cas9-mediated loss of NHLRC2 resulted in an increased susceptibility of HCT116 cells to ROS-induced apoptosis. These results suggest that excess ROS production causes a caspase-8-mediated decrease in NHLRC2 protein levels, leading to apoptotic cell death in colon cancer cells, and indicate an important role of NHLRC2 in the regulation of ROS-induced apoptosis.

Apremilast Induces Apoptosis of Human Colorectal Cancer Cells with Mutant KRAS.

BACKGROUND/AIM: We previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 (PDE4B2) expression in human colorectal cancer (CRC) HCT116 cells in a three-dimensional culture (3DC). Here, we evaluated the effects of apremilast, a selective PDE4 inhibitor, on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type (wt)PDE4B2 (HKe3-wtPDE4B2), mutant (mt)PDE4B2 (kinase dead) (HKe3-wtKRAS), wtKRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS). MATERIALS AND METHODS: Apoptosis was detected by immunofluorescence using confocal laser scanning microscopy or western blot in HKe3-wtPDE4B2, HKe3-mtPDE4B2, HKe3-wtKRAS and mtKRAS cells treated with or without apremilast in 3DC. Tumourigenicity was assessed in nude mice assay using these cells. RESULTS: Apremilast did not inhibit the proliferation of HKe3-wtPDE4B2 cells or HKe3-mtKRAS in two-dimensional cultures, whereas the number of apoptotic HKe3-wtPDE4B2 cells and HKe3-mtKRAS cells increased after apremilast treatment in 3DC, leading to formation of a luminal cavity. Tumour growth in nude mice was dramatically reduced by intraperitoneal injection of apremilast. Notably, a decreased level of caspase-1 expression was observed in HKe3-wtPDE4B2 and HKe3-mtKRAS cells. CONCLUSION: Apremilast induces tumour regression in nude mice, possibly by inducing caspase-1 expression.

C-MYC and Its Main Ubiquitin Ligase, FBXW7, Influence Cell Proliferation and Prognosis in Adult T-cell Leukemia/Lymphoma.

Smoldering-type and chronic-type adult T-cell leukemia/lymphomas (ATLL) patients have relatively indolent clinical courses, but often progress into aggressive lymphoma-type and acute-type disease. We examined the roles of transcription factor C-MYC and its ubiquitin ligase FBXW7 in tumor tissues from 137 patients with ATLL. Immunohistochemical tests showed ≥50% of lymphoma cells in 78.7% (48/61) of lymphoma-type, and 64.9% (24/37) of acute-type samples expressed C-MYC, significantly higher than was seen in smoldering-type (3.6%) and chronic-type (9.1%) samples (P<0.01). Real-time polymerase chain reaction showed C-MYC mRNA expression in lymphoma-type and acute-type samples were significantly higher than in smoldering-type (P<0.01). C-MYC expression was highly correlated with its mRNA levels (ρ=0.65, P<0.0001), chromosomal amplification and duplication (ρ=0.3, P=0.045) and MIB1 labeling index (ρ=0.69, P<0.0001). Expression of FBXW7 protein and mRNA in lymphoma-type samples were significantly lower than those of smoldering-type (P<0.01 for each), and both were inversely correlated with C-MYC (protein: ρ=-0.4, P=0.0002; mRNA: ρ=-0.31, P=0.015). Seven patients with smoldering-type or chronic-type ATLL converted to acute-type, in 4 of whom C-MYC expression increased from <50% to ≥50%. Patients with ≥50% C-MYC or MIB1 had significantly worse prognosis than those with <50% C-MYC (P=0.0004) or MIB1 (P<0.0001), as did those with ≥7.5 C-MYC mRNA scores (P=0.033); whereas significantly better prognosis was associated with ≥50% FBXW7 protein (P=0.0006) or ≥0.17 FBXW7 mRNA (P=0.016). C-MYC and FBXW7 affect ATLL proliferation and progression, and low FBXW7 may increase C-MYC expression. C-MYC was a critical prognostic factor in ATLL patients.

An Alpha-kinase 2 Gene Variant Disrupts Filamentous Actin Localization in the Surface Cells of Colorectal Cancer Spheroids.

BACKGROUND/AIM: Alpha-kinase 2 (ALPK2), suggested to be a novel tumour-suppressor gene down-regulated by oncogenic KRAS, plays a pivotal role in luminal apoptosis in normal colonic crypts. The aim of this study was to determine the association between ALPK2 germline variants and colorectal cancer. MATERIALS AND METHODS: Missense single nucleotide variants in the exons of the ALPK2 gene in 2,343 consecutive autopsy cases (1,446 cases with cancer and 897 cases without cancer) were screened using HumanExome BeadChip arrays. To address the functional effect of a missense ALPK2 variant, a 3D floating cell culture was performed using HCT116-derived human colorectal cancer cells stably expressing wild-type (wt) ALPK2 (HCT116-wtALPK2) or amino acid-substituted (sub) ALPK2 (HCT116-subALPK2). RESULTS: We identified that one of the ALPK2 germline variants, rs55674018 (p.Q1853E), was significantly associated with the presence of cancer (adjusted odds ratio(OR)=4.39; 95% confidence interval(CI)=1.31-14.78, p=0.001). The p.Q1853E variant was present in the East Asian population and located in the immunoglobulin-like domain. Notably, the basolateral polarity of actin in the surface of HCT116-wtALPK2 spheroids was more attenuated compared to that of HCT116-subALPK2 spheroids. Furthermore, luminal apoptosis and cell aggregation were promoted by wtALPK2, but not by subALPK2 in 3D culture. CONCLUSION: The p.Q1853E variant of ALPK2, which had been accumulating in the Japanese population, induced a metastatic phenotype by disrupting ALPK2 function.

Feeling of ear fullness in acute sensorineural hearing loss.

CONCLUSIONS: This study revealed two characteristic findings of the feeling of ear fullness (FEF) in acute sensorineural hearing loss (ASNHL). First, that the appearance of FEF was not associated with the auditory function on audiograms; and second, that the disappearance of FEF is clearly associated with the hearing prognosis. OBJECTIVE: FEF appears frequently in patients with ASNHL. However, there are few reports on this symptom and its mechanism has yet to be clarified. So we tried to investigate the character of FEF in ASNHL. PATIENTS AND METHODS: In this study, observations were made during the period from the first medical examination to 2 months after obtaining a steady audiogram on 227 ears from unilateral ASNHL cases, and the relationship between FEF and the audiograms was analyzed. RESULTS: The FEF prevalence at the first medical examination was about 80% for any audiogram shape or hearing threshold. Moreover, the better the hearing prognosis, the higher the improvement rate of FEF.