Post-treatment magnetic resonance imaging predicts outcomes of maxillary sinus cancer treatment using super-selective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy (RADPLAT).

OBJECTIVES: This study aimed to evaluate the prognostic value of magnetic resonance imaging (MRI) findings in predicting local recurrence in patients with maxillary sinus cancer treated with super-selective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy (RADPLAT). METHODS: This single-center retrospective study included consecutive patients with maxillary sinus squamous cell carcinoma, who underwent RADPLAT between October 2016 and September 2021. MRI was performed before (within 2 weeks) and 1 month after (post-treatment MRI) the start of treatment. Tumor reduction rates and pre-treatment cross-sectional areas were calculated from the maximum cross-sectional areas on pre- and post-treatment MRI T2-weighted axial images. Statistical analyses, including receiver operating characteristic analysis, were performed to assess the predictive value of the tumor reduction rates. RESULTS: Twenty-four patients were included in this study. Recurrence occurred in seven patients with a median time of 213 days. The tumor reduction rates were significantly higher in the benign post-treatment changes group compared to the recurrence group (median, 0.814 vs. 0.174; p < 0.001). The cut-off value for the reduction rate between the groups was 0.3578. No significant difference was observed in the maximum pre-treatment cross-sectional area between the groups (p = 0.664). The inter-observer agreement for the tumor areas was excellent. CONCLUSIONS: The tumor reduction rate calculated from MRI T2-weighted images may be a predictor of local recurrence in patients with maxillary sinus cancer treated with RADPLAT. Patients with lower reduction rates may benefit from early salvage surgeries.

Exclusive Transcervical Drainage for Posterior Mediastinal Abscess Originating from a Mandibular Molar.

The progression of a cervical abscess toward the mediastinum is rare but remains one of the most serious diseases, even in the era of antibiotics. A mediastinal abscess can originate from an odontogenic infection and presents a challenge for otolaryngologists and craniofacial surgeons, particularly when it spreads caudally to the tracheal bifurcation. For successful treatment of such an abscess, patients are generally referred to a thoracic surgeon for drainage. We present a distinctive case of an odontogenic infection-induced wide mediastinal abscess that could be drained only through cervical manipulation by using a sump-type tube. The patient was discharged on postoperative day 55 without any complications. This is the first report showing that descending mediastinal abscesses extending below the tracheal bifurcation could be drained by head and neck surgeons alone. The technique is easy and hence reproducible, safe, and convenient to perform.

A rare case of epithelial-myoepithelial carcinoma ex pleomorphic adenoma of the parotid gland: Radiologic-pathologic correlation.

Carcinoma ex pleomorphic adenoma is a carcinoma that arises from a primary or recurrent benign pleomorphic adenoma. The prevalence of epithelial-myoepithelial carcinoma is low, and this histological type accounting for only 1% of all salivary gland tumors. Here, we report a rare case of Epithelial-Myoepithelial Carcinoma ex pleomorphic adenoma of the parotid gland with a radiologic-pathologic correlation.

Endoscopic-assisted total maxillectomy with precise surgical margins.

In traditional open maxillectomy, identifying the posterior margin is difficult because of its deep location and bleeding from the pterygoid venous plexus. Here, we present our endoscope-assisted total en bloc maxillectomy technique and discuss its merits and demerits compared to previously reported methods. We developed an endoscope-assisted total en bloc maxillectomy procedure. We reviewed a series of total maxillectomies performed with and without endoscopic assistance to verify the advantages of endoscopic assistance over conventional total maxillectomy. We analyzed (1) the precision using the distance of the remaining pterygoid process, (2) the operation time, and (3) blood loss. The length of the remnant pterygoid process was significantly shorter in the endoscopic assistance group. The operation time and blood loss were not significantly different between the two groups. Endoscopic assistance makes total maxillectomy more precise without requiring additional time and is a reasonable option for total maxillectomies.

Structural determination of the cell wall polysaccharide LCPS-1 in Lacticaseibacillus paracasei strain Shirota YIT 9029.

The neutral polysaccharides LCPS-1 and LCPS-2 play functional roles in the cell wall of the lactic acid bacterium Lacticaseibacillus paracasei strain Shirota YIT 9029 (LcS; formerly Lactobacillus casei strain Shirota YIT 9029), which has long been used as a probiotic food product. Studies have shown that LCPS-1 is associated with the immunomodulatory functions of LcS. We hypothesized that the structure of LCPS-1 is crucial for elucidating the mechanism of action of LcS on host immune responses and aimed to solve the undetermined primary structure of LCPS-1. Our results showed that LCPS-1 has a molecular weight of >400 kDa and is composed of Glc, Rha, Gal, and GlcNAc, with a repeating structure. Using limited degradation reactions, including controlled Smith and deamination degradations, we obtained key fragments with low molecular weight. Subsequently, their structures were analyzed using NMR spectra and other analytical techniques. Further, we integrated the results for each key fragment to derive the complete structure of LCPS-1. Our results indicated that the most probable structure of LCPS-1 is composed of two types of units (X, Y), each with a basic structure of seven sugars in which the C2-position of Rha is substituted with an acetyl group. The structure of X is {6[Glcß1-2] Galα1-3[2-OAc] Rhaß1-4Glcß1-4[Rhaα1-3] [Glcα1-6] Glcß1-} and that of Y is {6[Glcß1-2] Galα1-3[2-OAc] Rhaß1-4Glcß1-4[Rhaα1-3] [Glcα1-6)] GlcNAcß1-}, which can be expressed as (X6Y12)n. In this study, we identified the primary structure of LCPS-1, and our results may enable an improved understanding of the immunomodulatory abilities of LcS.

Wall teichoic acid-dependent phagocytosis of intact cell walls of Lactiplantibacillus plantarum elicits IL-12 secretion from macrophages.

Selected lactic acid bacteria can stimulate macrophages and dendritic cells to secrete IL-12, which plays a key role in activating innate and cellular immunity. In this study, we investigated the roles of cell wall teichoic acids (WTAs) displayed on whole intact cell walls (ICWs) of Lactiplantibacillus plantarum in activation of mouse macrophages. ICWs were prepared from whole bacterial cells of several lactobacilli without physical disruption, and thus retaining the overall shapes of the bacteria. WTA-displaying ICWs of several L. plantarum strains, but not WTA-lacking ICWs of strains of other lactobacilli, elicited IL-12 secretion from mouse bone marrow-derived macrophages (BMMs) and mouse macrophage-like J774.1 cells. The ability of the ICWs of L. plantarum to induce IL-12 secretion was abolished by selective chemical elimination of WTAs from ICWs, but was preserved by selective removal of cell wall glycopolymers other than WTAs. BMMs prepared from TLR2- or TLR4-deficient mouse could secret IL-12 upon stimulation with ICWs of L. plantarum and a MyD88 dimerization inhibitor did not affect ICW-mediated IL-12 secretion. WTA-displaying ICWs, but not WTA-lacking ICWs, were ingested in the cells within 30 min. Treatment with inhibitors of actin polymerization abolished IL-12 secretion in response to ICW stimulation and diminished ingestion of ICWs. When overall shapes of ICWs of L. plantarum were physically disrupted, the disrupted ICWs (DCWs) failed to induce IL-12 secretion. However, DCWs and soluble WTAs inhibited ICW-mediated IL-12 secretion from macrophages. Taken together, these results show that WTA-displaying ICWs of L. plantarum can elicit IL-12 production from macrophages via actin-dependent phagocytosis but TLR2 signaling axis independent pathway. WTAs displayed on ICWs are key molecules in the elicitation of IL-12 secretion, and the sizes and shapes of the ICWs have an impact on actin remodeling and subsequent IL-12 production.

Critical roles of a housekeeping sortase of probiotic Bifidobacterium bifidum in bacterium-host cell crosstalk.

Bifidobacterium bifidum YIT 10347 (BF-1) is adhesive in vitro. Here we studied the molecular aspects of the BF-1 adhesion process. We identified and characterized non-adhesive mutants and found that a class E housekeeping sortase was critical for the adhesion to mucin. These mutants were significantly less adhesive to GCIY cells than was the wild type (WT), which protected GCIY cells against acid treatment more than did a non-adhesive mutant. The non-adhesive mutants aberrantly accumulated precursors of putative sortase-dependent proteins (SDPs). Recombinant SDPs bound to mucin. Disruption of the housekeeping sortase influenced expression of SDPs and pilus components. Mutants defective in a pilin or in an SDP showed the same adhesion properties as WT. Therefore, multiple SDPs and pili seem to work cooperatively to achieve adhesion, and the housekeeping sortase is responsible for cell wall anchoring of its substrates to ensure their proper biological function.

Development of an orally-administrable tumor vasculature-targeting therapeutic using annexin A1-binding D-peptides.

We previously reported that IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminus, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the ANXA1 N-terminus as target. We then identified peptide sequences, synthesized them as D-amino acids, and designated the resulting peptide dTIT7, which we showed bound to the ANXA1 N-terminus. Whole body imaging of mouse brain tumor models injected with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered dTIT7/geldanamycin (GA) conjugates suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that ANXA1-binding D-peptide can be developed as an orally-administrable tumor vasculature-targeted therapeutic.

Multisite studies for validation and improvement of a highly efficient culture assay for detection of undifferentiated human pluripotent stem cells intermingled in cell therapy products.

BACKGROUND AIMS: The Multisite Evaluation Study on Analytical Methods for Non-Clinical Safety Assessment of Human-Derived Regenerative Medical Products (MEASURE) is a Japanese experimental public-private partnership initiative, which aims to standardize methodology for tumorigenicity evaluation of human pluripotent stem cell (hPSC)-derived cell therapy products (CTPs). Undifferentiated hPSCs possess tumorigenic potential, and thus residual undifferentiated hPSCs are one of the major hazards for the risk of tumor formation from hPSC-derived CTPs. Among currently available assays, a highly efficient culture (HEC) assay is reported to be one of the most sensitive for the detection of residual undifferentiated hPSCs. METHODS: MEASURE first validated the detection sensitivity of HEC assay and then investigated the feasibility of magnetic-activated cell sorting (MACS) to improve sensitivity. RESULTS: The multisite experiments confirmed that the lower limit of detection under various conditions to which the human induced pluripotent stem cell lines and culture medium/substrate were subjected was 0.001%. In addition, MACS concentrated cells expressing undifferentiated cell markers and consequently achieved a detection sensitivity of 0.00002%. CONCLUSIONS: These results indicate that HEC assay is highly sensitive and robust and that the application of MACS on this assay is a promising tool for further mitigation of the potential tumorigenicity risk of hPSC-derived CTPs.

Direct visualization of the extracellular binding structure of E-cadherins in liquid.

E-cadherin is a key Ca-dependent cell adhesion molecule, which is expressed on many cell surfaces and involved in cell morphogenesis, embryonic development, EMT, etc. The fusion protein E-cad-Fc consists of the extracellular domain of E-cadherin and the IgG Fc domain. On plates coated with this chimeric protein, ES/iPS cells are cultivated particularly well and induced to differentiate. The cells adhere to the plate via E-cad-Fc in the presence of Ca2+ and detach by a chelating agent. For the purpose of clarifying the structures of E-cad-Fc in the presence and absence of Ca2+, we analyzed the molecular structure of E-cad-Fc by AFM in liquid. Our AFM observations revealed a rod-like structure of the entire extracellular domain of E-cad-Fc in the presence of Ca2+ as well as trans-binding of E-cad-Fc with adjacent molecules, which may be the first, direct confirmation of trans-dimerization of E-cadherin. The observed structures were in good agreement with an X-ray crystallographic model. Furthermore, we succeeded in visualizing the changes in the rod-like structure of the EC domains with and without calcium. The biomatrix surface plays an important role in cell culture, so the analysis of its structure and function may help promote cell engineering based on cell recognition.

Overcoming the blood-brain barrier by Annexin A1-binding peptide to target brain tumours.

BACKGROUND: Annexin A1 is expressed specifically on the tumour vasculature surface. Intravenously injected IF7 targets tumour vasculature via annexin A1. We tested the hypothesis that IF7 overcomes the blood-brain barrier and that the intravenously injected IF7C(RR)-SN38 eradicates brain tumours in the mouse. METHODS: (1) A dual-tumour model was generated by inoculating luciferase-expressing melanoma B16 cell line, B16-Luc, into the brain and under the skin of syngeneic C57BL/6 mice. IF7C(RR)-SN38 was injected intravenously daily at 7.0 µmoles/kg and growth of tumours was assessed by chemiluminescence using an IVIS imager. A similar dual-tumour model was generated with the C6-Luc line in immunocompromised SCID mice. (2) IF7C(RR)-SN38 formulated with 10% Solutol HS15 was injected intravenously daily at 2.5 µmoles/kg into two brain tumour mouse models: B16-Luc cells in C57BL/6 mice, and C6-Luc cells in nude mice. RESULTS: (1) Daily IF7C(RR)-SN38 injection suppressed tumour growth regardless of cell lines or mouse strains. (2) Daily injection of Solutol-formulated IF7C(RR)-SN38 led into complete disappearance of B16-Luc brain tumour in C57BL/6 mice, whereas this did not occur in C6-Luc in nude mice. CONCLUSIONS: IF7C(RR)-SN38 crosses the blood-brain barrier and suppresses growth of brain tumours in mouse models. Solutol HS15-formulated IF7C(RR)-SN38 may have promoted an antitumour immune response.

Postoperative delirium after pharyngolaryngectomy with esophagectomy: a role for ramelteon and suvorexant.

BACKGROUND: Postoperative delirium is common after extensive surgery, and is known to be associated with sleeping medications. In this study, we aimed to investigate the relationships between sleeping medications and postoperative delirium after pharyngolaryngectomy with esophagectomy. METHODS: We performed a retrospective analysis of 65 patients who underwent pharyngolaryngectomy with esophagectomy at Shizuoka Cancer Center Hospital between January 2012 and March 2016. All data were assessed by two psychiatrists, and univariate and multivariate analyses were performed. RESULTS: Postoperative delirium developed in 9 (13.8%) patients, with most cases (77.8%) occurring between postoperative day (POD) 1 and POD 3. Of the 24 patients taking a minor tranquilizer after surgery, 8 (33.3%) became delirious, but, of the remaining 41 patients taking ramelteon with or without suvorexant, only one (2.4%) became delirious after surgery. Moreover, of the 16 patients taking both ramelteon and suvorexant, no postoperative delirium was observed. Ramelteon with or without suvorexant was significantly associated with a decreased rate of postoperative delirium compared with minor tranquilizer use (p = 0.001). Multivariate analysis confirmed that the use of ramelteon with or without suvorexant was the only significant preventive factor of postoperative delirium (odds ratio 0.060, p = 0.013). CONCLUSION: The use of ramelteon with or without suvorexant was the only significant preventive factor of postoperative delirium after pharyngolaryngectomy with esophagectomy. However, using minor tranquilizers was associated with postoperative delirium. We recommend ramelteon with or without suvorexant for preventing postoperative delirium after pharyngolaryngectomy with esophagectomy.

Comparison of Salvage Total Pharyngolaryngectomy and Cervical Esophagectomy Between Hypopharyngeal Cancer and Cervical Esophageal Cancer.

BACKGROUND: Total pharyngolaryngectomy and cervical esophagectomy (TPLCE) after chemoradiotherapy remains a challenge because of the high rate of complications and few available data on outcomes and safety. The purpose of this study was to evaluate the clinical significance of salvage TPLCE and to compare treatment outcomes between hypopharyngeal cancer and cervical esophageal cancer. METHODS: Data from 37 consecutive patients who were diagnosed with potentially resectable hypopharyngeal and cervical esophageal cancer after chemoradiotherapy were retrospectively analyzed. The survival and surgical outcomes were investigated between the hypopharyngeal cancer and cervical esophageal cancer groups. RESULTS: Twenty-six patients were included in hypopharyngeal cancer group and 11 patients were included in cervical esophageal cancer group. The baseline characteristics were balanced between the two groups. Compared to the hypopharyngeal cancer group, the cervical esophageal cancer group had significantly more frequent tracheal-related complications (p < 0.05) and stronger association of distal margin of the cervical esophagus and radiation field with tracheal ischemia after salvage surgery. CONCLUSIONS: Salvage TPLCE can offer the exclusive chance of prolonged survival. Association of tracheal ischemia with salvage TPLCE was seen more frequently for cervical esophageal cancer. Therefore, the indication for salvage TPLCE must be carefully considered to maintain the balance between curability and safety.

Risk factors for complications after pharyngolaryngectomy with total esophagectomy.

BACKGROUND: Pharyngolaryngectomy with total esophagectomy (PLTE) is an effective surgical treatment for synchronous or metachronous hypopharyngeal or laryngeal cancer and thoracic esophageal cancer, although it is more invasive than esophagectomy and total pharyngolaryngectomy. The aim of this study was to identify risk factors for complications after PLTE. METHODS: From November 2002 to December 2014, a total of 8 patients underwent PLTE at the Shizuoka Cancer Center Hospital, Shizuoka, Japan. We investigated the clinicopathological characteristics, surgical procedures, and postoperative complications of these patients. RESULTS: Of the 8 patients, 5 underwent one-stage PLTE and 3 underwent staged PLTE. There was no mortality in this study. Two cases of tracheal necrosis, two of anastomotic leakage, and one of ileus were observed as postoperative complications. Two patients who underwent one-stage PLTE with standard mediastinal lymph node dissection developed tracheal necrosis and severe anastomotic leakage. CONCLUSION: One-stage PLTE and standard mediastinal lymph node dissection were identified as the risk factors for severe postoperative complications. Staged PLTE or transhiatal esophagectomy should be considered when PLTE is performed and standard mediastinal lymph node dissection should be avoided when one-stage PLTE is performed with transthoracic esophagectomy.

Incidence and risk factors for postoperative delirium after major head and neck cancer surgery.

BACKGROUND: Postoperative delirium is a common and serious complication after extensive surgery. This study aimed to investigate the incidence and risk factors for postoperative delirium after major head and neck cancer surgery. METHODS: A retrospective analysis was performed for 293 patients who underwent major head and neck cancer surgery lasting >6 h at our institution between January 2012 and November 2015. All data were assessed by two psychiatrists. Univariate and multivariate analyses were performed. RESULTS: Postoperative delirium developed in 50 (17.1%) patients; most cases (84.0%) of postoperative delirium were observed between postoperative day (POD) 1 and POD 3. Multivariate analysis revealed that an age >70 years was the significant risk factor for postoperative delirium incidence after major head and neck cancer surgery; the multivariate hazard ratio was 3.935 (95% confidence interval 1.873-8.265, p < 0.001). CONCLUSIONS: Most cases of postoperative delirium after major head and neck cancer surgery were observed between POD 1 and POD 3, and a multivariate analysis revealed that an age >70 years was a significant risk factor for postoperative delirium incidence. Clinicians should pay particular attention to the possibility of delirium incidence during the first 3 days after surgery for patients aged >70 years.

Design of a Vitronectin-Based Recombinant Protein as a Defined Substrate for Differentiation of Human Pluripotent Stem Cells into Hepatocyte-Like Cells.

Maintenance and differentiation of human pluripotent stem cells (hPSCs) usually requires culture on a substrate for cell adhesion. A commonly used substratum is Matrigel purified from Engelbreth-Holm-Swarm sarcoma cells, and consists of a complex mixture of extracellular matrix proteins, proteoglycans, and growth factors. Several studies have successfully induced differentiation of hepatocyte-like cells from hPSCs. However, most of these studies have used Matrigel as a cell adhesion substrate, which is not a defined culture condition. In an attempt to generate a substratum that supports undifferentiated properties and differentiation into hepatic lineage cells, we designed novel substrates consisting of vitronectin fragments fused to the IgG Fc domain. hPSCs adhered to these substrates via interactions between integrins and the RGD (Arg-Gly-Asp) motif, and the cells maintained their undifferentiated phenotypes. Using a previously established differentiation protocol, hPSCs were efficiently differentiated into mesendodermal and hepatic lineage cells on a vitronectin fragment-containing substrate. We found that full-length vitronectin did not support stable cell adhesion during the specification stage. Furthermore, the vitronectin fragment with the minimal RGD-containing domain was sufficient for differentiation of human induced pluripotent stem cells into hepatic lineage cells under completely defined conditions that facilitate the clinical application of cells differentiated from hPSCs.

Primary adenoid cystic carcinoma of the nasolacrimal duct treated with proton beam therapy.

Primary malignant tumors of the lacrimal passage, particularly of the nasolacrimal duct, are rare. We describe a 72-year-old woman who presented with lacrimation 5 years previously. She had pain and bloody and purulent lacrimation, and a mass was identified in the inferior meatus. Accordingly, she was diagnosed with primary adenoid cystic carcinoma of the nasolacrimal duct. She was treated with proton beam therapy and showed a favorable response. Owing to the long-term risks of recurrence and distant metastasis, adenoid cystic carcinoma requires sufficient follow-up.