Retrospective study of risk factors for tympanic membrane perforation in the early period after intratympanic steroid injection.

OBJECTIVE: Intratympanic steroid injection (ITSI) can be an effective treatment for sudden sensorineural hearing loss or Meniere's disease. Tympanic membrane (TM) perforation after ITSI is a major complication which needs additional treatment. The purpose of this study is to assess the factors associated with TM perforation after ITSI. METHODS: We obtained the clinical data of patients who underwent ITSI treatment at the Department of Otolaryngology JR Tokyo General Hospital from April 2013 to March 2021. The data included age, sex, treated side, number of injections, average interval between injections, TM anesthesia with Zentöl solution, which contains phenol, any history of diabetes and any concurrent use of oral or intravenous steroids. We evaluated the association between these variables and TM perforation after ITSI using the Student's t-test, the chi-squared test, univariate logistic regression analysis and multivariate logistic regression analysis. TM perforation was defined as a case in which perforation was observed at least once during outpatient visits. RESULTS: Records of 205 ears in 190 patients were analyzed. The overall proportion of TM perforation in the early period after ITSI was 12.7% (26 out of 205 ears), which decreased to 9.3% (19 out of 205 ears) and 5.9% (12 out of 205 ears) at the 1- and 3-month follow-ups, respectively. The proportion of TM perforation in the early period after ITSI without TM anesthesia was 3.5% (5 ears out of 145 ears), which decreased to 1.4% (2 ears) or 0% at the 1- or 3- month follow-ups, respectively. The use of tympanic anesthetics which contain phenol was significantly associated with TM perforation in univariate logistic regression analysis (odds ratio: 15.08, 95% confidence interval: 5.34-42.56, p < 0.001) and in multivariate analysis (odds ratio: 20.76, 95% confidence interval: 6.31-68.3, p < 0.001). All TM perforation cases without TM anesthesia healed spontaneously or with paper tympanic closure treatment. TM perforation in 6 ears out of 21 ears with TM anesthesia did not heal during the follow-up. CONCLUSION: The overall proportion of TM perforations from the early period after ITSI was 12.7%, 9.3% at the 1-month post-ITSI outpatient follow-up, 5.9% at the 3-month post-ITSI outpatient follow-up. Tympanic anesthesia was significantly associated with TM perforation after ITSI, which indicated that TM anesthesia with solutions containing phenol is not recommended for ITSI.

Efficacy of pH-Sensitive Nanomedicines in Tumors with Different c-MYC Expression Depends on the Intratumoral Activation Profile.

Effective inhibition of the protein derived from cellular myelocytomatosis oncogene (c-Myc) is one of the most sought-after goals in cancer therapy. While several c-Myc inhibitors have demonstrated therapeutic potential, inhibiting c-Myc has proven challenging, since c-Myc is essential for normal tissues and tumors may present heterogeneous c-Myc levels demanding contrasting therapeutic strategies. Herein, we developed tumor-targeted nanomedicines capable of treating both tumors with high and low c-Myc levels by adjusting their ability to spatiotemporally control drug action. These nanomedicines loaded homologues of the bromodomain and extraterminal (BET) motif inhibitor JQ1 as epigenetic c-Myc inhibitors through pH-cleavable bonds engineered for fast or slow drug release at intratumoral pH. In tumors with high c-Myc expression, the fast-releasing (FR) nanomedicines suppressed tumor growth more effectively than the slow-releasing (SR) ones, whereas, in the low c-Myc tumors, the efficacy of the nanomedicines was the opposite. By studying the tumor distribution and intratumoral activation of the nanomedicines, we found that, despite SR nanomedicines achieved higher accumulation than the FR counterparts in both c-Myc high and low tumors, the antitumor activity profiles corresponded with the availability of activated drugs inside the tumors. These results indicate the potential of engineered nanomedicines for c-Myc inhibition and spur the idea of precision pH-sensitive nanomedicine based on cancer biomarker levels.

Manipulating dynamic tumor vessel permeability to enhance polymeric micelle accumulation.

Selectively delivering anticancer drugs to solid tumors while avoiding their accumulation in healthy tissues is a major goal in polymeric micelle research. We have recently discovered that the extravasation and permeation of polymeric micelles occur in a dynamic manner characterized by vascular bursts followed by a brief and vigorous outward flow of fluid (called "nano-eruptions"). Nano-eruptions allow delivery of polymeric micelle-associated drugs, though delivery can be heterogeneous both among tumors and within an individual tumor, leading to suboptimal intratumoral distribution. Manipulation of nano-eruptions is expected to improve the efficiency of drug delivery systems (DDSs). By using compounds that affect the intratumoral environment, i.e. a TGF-ß inhibitor and chloroquine, the possibility of manipulating nano-eruptions to improve delivery efficiency was investigated. Both compounds were tested in a mouse xenograft model of GFP-labeled pancreatic tumor cells by tracing nano-eruption events and extravasation of size-modulated polymeric micelles in real-time through intravital confocal laser scanning microscopy. The TGF-ß inhibitor increased the number of dynamic vents, extended duration time, and generated dynamic vents with a wide range of sizes. Chloroquine did not affect the frequency of nano-eruptions, but it increased tumor vessel diameter, maximum nano-eruption area, and maximum radial increase. Both the TGF-ß inhibitor and chloroquine augmented nano-eruptions to diffuse polymeric micelles through tumor stroma, and these medications had a greater effect on the polymeric micelles with larger size, i.e. 70-nm, than on the smaller polymeric micelles having a 30-nm diameter. The results indicate that TGF-ß inhibition and chloroquine refashion the intratumoral distribution of DDSs by different mechanisms.

cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells.

Recalcitrant head and neck squamous cell carcinoma (HNSCC) usually relapses after therapy due to the enrichment of drug resistant cancer stem-like cells (CSCs). Nanomedicines have shown potential for eradicating both cancer cells and CSCs by effective intratumoral navigation for reaching particular cell populations and controlling drug delivery. The installation of ligands on nanomedicines is an attractive approach for improving the delivery to CSCs within tumors, though the development of CSC-selective ligand-receptor systems has been challenging. Herein, we found that the CSC subpopulation in HNSCC cells overexpresses αvß5 integrins, which is preferentially expressed in tumor neovasculature and cancer cells, and can be effectively targeted by using cyclic Arg-Gly-Asp (cRGD) peptide. Thus, in this study, we propose installing cRGD peptide on micellar nanomedicines incorporating cisplatin for improving their activity against CSCs and enhancing survival. Both cisplatin-loaded micelles (CDDP/m) and cRGD-installed CDDP/m (cRGD-CDDP/m) were effective against HNSCC SAS-L1-Luc cells in vitro, though cRGD-installed CDDP/m was more potent than CDDP/m against the CSC fraction. In vivo, the cRGD-CDDP/m also showed significant antitumor activity against HNSCC orthotopic tumors, i.e. SAS-L1 and HSC-2. Moreover, cRGD-CDDP/m rapidly accumulated into the lymph node metastasis of SAS-L1 tumors, effectively inhibiting their growth, and prolonging mice survival. These findings indicate cRGD-installed nanomedicines as an advantageous strategy for targeting CSCs in HNSCC, and particularly, cRGD-CDDP/m as a significant therapeutic strategy against regionally advanced HNSCC.

Eradication of CD44-variant positive population in head and neck tumors through controlled intracellular navigation of cisplatin-loaded nanomedicines.

Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth.

Laryngotracheal separation procedure for elderly patients.

A procedure for laryngotracheal separation was performed on 5 elderly patients in poor general condition to prevent habitual aspiration pneumonia. Intractable aspiration was relieved in all the patients with no major postoperative complications. In this intervention, a modification of the procedure previously reported, the anterior part of the tracheal and cricoid cartilage was removed, and the subglottic mucosa was sutured to fashion a blind pouch. This procedure could be adjusted even in cases of severe laryngoptosis or after high tracheostomy. Laryngotracheal separation is likely to be useful as a simple and safe procedure even for older patients. If this comes to be, it will serve as a valuable intervention in today's aging society.