Significance of Continuous Low-Dose Lenvatinib for the Treating of the Patients with Unresectable Thyroid Carcinoma.

The tyrosine kinase inhibitor lenvatinib has been confirmed as an effective treatment option for patients with unresectable thyroid carcinoma. We conducted a retrospective analysis of the significance of the effect of continued lenvatinib treatment for the longest duration possible at a reasonable daily dose and with a minimum discontinuation period in 42 patients with unresectable thyroid carcinoma treated with lenvatinib between 2015 and 2020. A Cox proportional hazard model-based analysis revealed that the overall survival of the patients treated with a <8 mg/day mean dose of lenvatinib was significantly better than that of the patients treated with 8-24 mg/day (hazard ratio [HR] 0.38 for 1.14-4.54 mg/day, and HR 0.01 for 4.56-7.97 mg/day) adjusted for various factors (e.g., sex, age, drug interruption period). The cumulative dose of lenvatinib administered tended to be higher in the patients treated with low doses (< 8 mg/day) than in the patients treated with relatively high doses (8-24 mg/day). Considering its adverse events, the continuation of lenvatinib treatment with an adequate daily dose and drug interruption may help prolong the survival of patients with unresectable thyroid carcinoma.

Treatment Outcomes of Pulmonary Metastases from Head and Neck Squamous Cell Carcinoma.

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.

Swallowing dysfunction following surgery for well-differentiated thyroid cancer with extrathyroid invasion.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: These results indicate that tracheostomy placement and resection of the IPCMs, together with total thyroidectomy, extends the tube feeding duration in the postoperative period.

Mouse otocyst transuterine gene transfer restores hearing in mice with connexin 30 deletion-associated hearing loss.

Although numerous causative genes for hereditary hearing loss have been identified, there are no fundamental treatments for this condition. Herein, we describe a novel potential treatment for genetic hearing loss. Because mutations or deletions in the connexin (Cx) genes are common causes of profound congenital hearing loss in both humans and mice, we investigated whether gene supplementation therapy using the wild-type Cx gene could cure hearing loss. We first generated inner ear-specific connexin 30 (Cx30)-deficient mice via the transuterine transfer of Cx30-targeted short hairpin RNA (shRNA-Cx30) into otocysts. The inner ear-specific Cx30-deficient mice mimicked homozygous Cx30-deficient mice both histologically and physiologically. Subsequently, we cotransfected the shRNA-Cx30 and the wild-type Cx30 gene. The cotransfected mice exhibited Cx30 expression in the cochleae and displayed normal auditory functions. Next, we performed the transuterine transfer of the wild-type Cx30 gene into the otocysts of homozygous Cx30-deficient mice, thereby rescuing the lack of Cx30 expression in the cochleae and restoring auditory functioning. These results demonstrate that supplementation therapy with wild-type genes can restore postnatal auditory functioning. Moreover, this is the first report to show that Cx-related genetic hearing loss is treatable by in vivo gene therapy.

Therapeutic outcomes of laryngeal closure and laryngostomy in children with recurrent pneumonia.

PURPOSE: Children with medical complexity frequently experience difficulty breathing and swallowing and occasionally develop aspiration pneumonia. Long-term intubation may cause fatal trachea-innominate artery fistula (TIF). In the present study, we retrospectively evaluated the efficacy of laryngeal closure and laryngostomy in children with medical complexity. MATERIALS AND METHODS: Laryngeal closure and laryngostomy were performed in eight children with severe neuromuscular disorders who were incapable of oral ingestion and verbal communication. The laryngostoma was placed at a higher position compared to that in conventional tracheostomies for easier management of the airway and to prevent TIF. RESULTS: Aspiration was successfully prevented postoperatively in all cases. Laryngocutaneous fistula formation was not observed. Two patients successfully achieved oral ingestion capability and tracheal cannulas were removed in two patients. Among the six patients who needed a mechanical ventilator before surgery, two patients were weaned from mechanical ventilation. Five patients were successfully discharged from the hospital. Although two patients died because of their primary condition, pneumonia exacerbation was not observed in any of the patients. CONCLUSION: Compared to the conventional tracheostomy, our procedure improved airway management and function in children with medical complexity and reduced the risk of TIF.

Optimal Management of the Unilateral Recurrent Laryngeal Nerve Involvement in Patients with Thyroid Cancer.

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.

Pharyngocutaneous fistula caused by dried 'Kombu' (edible seaweed) after total laryngectomy.

The most common early complication after total laryngectomy is pharyngocutaneous fistula (PCF). However, there are no reports of PCF after total laryngectomy caused by 'Kombu' (edible seaweed) as a foreign body in the digestive tract. A 68-year-old Japanese man had undergone total laryngectomy 5 years previously. He presented with PCF, neck swelling and pain. Video endoscopy showed that a dark green foreign body obstructed the digestive tract. PCF was successfully treated via emergency surgery comprising abscess drainage, foreign body removal and fistula closure. The foreign body was kombu. Clinicians who perform total laryngectomy should know the potential dangers of consuming hygroscopic food items that can cause bolus obstruction of the upper digestive tract and pharyngeal abscess and perforation.

Delayed transmastoid facial nerve decompression surgery in patients with Ramsay-Hunt syndrome presenting with neurophysiologically complete paralysis.

OBJECTIVES: To determine the efficacy of delayed transmastoid facial nerve decompression in patients with Ramsay Hunt Syndrome (RHS) presenting with complete facial paralysis. METHODS: Twenty-five RHS patients with complete facial nerve paralysis presenting electroneuronographic (ENoG) degeneration ≥90% underwent transmastoid facial nerve decompression more than 3 weeks after the onset of paralysis. The principal features measured were 12 months pre- and post-operative House-Brackmann (HB) grades and the presence of a direct intraoperative neural response (INR) prior to decompression procedure. Correlations between these parameters, and the time between symptom onset and surgery (within or later than 30 and 50 d) were statistically analyzed. RESULTS: Of the 25 patients 13 (52%) exhibited good recovery (HB grade I or II) at 12 months-post-operatively. The timing of decompression generally did not significantly influence outcome but patients treated within 50 d of symptom onset enjoyed better outcomes than those treated later (p = .047). The presence of an INR significantly influenced outcomes (p = .0003). CONCLUSIONS: The success of delayed transmastoid facial nerve decompression in RHS patients was not affected between 25-30 and 30-40 d from symptom onset but was compromised when the delay was >50 d. The presence or absence of an INR was a good predictor of post-operative prognosis.

Transplanting mouse induced pluripotent stem cells into mouse otocysts in vivo.

The otocyst is an attractive target for studying treatment strategies for genetic hearing loss and for understanding inner ear development. We have previously reported that trans-uterine supplemental gene therapy in vivo into the otocysts of mice, which had a loss of function mutation in a causative gene of deafness, was able to prevent putative hearing loss. We herein set out to clarify the feasibility of allogenic cell transplantation into the mouse otocysts in vivo. We transplanted naive mouse-derived induced pluripotent stem cells (miPSCs) into the otocysts of wild type mice or connexin (Cx) 30 deficient mice, at embryonic day 11.5 (E11.5). The transplanted m-iPSCs survived in the lumens of the inner ears at E13.5 and E15.5 in wild type mice. In the Cx30 deficient mouse, the transplanted cells survived similarly, with some of the transplanted cells migrating into the lining cells of the lumens of the inner ears at E13.5 and showing tumorigenic cell proliferation at E15.5. In addition, engrafted cells appear to be able to differentiate after the cell transplantation. Our results suggest that otocyst transplanted cells survived and differentiated. A Cx30 deficiency may facilitate cell migration. These findings may offer some hope for cell transplantation therapy for profound genetic hearing loss caused by a Cxs deficiency.

Protein transduction therapy into cochleae via the round window niche in guinea pigs.

Cell-penetrating peptides (CPPs) are short sequences of amino acids that facilitate the penetration of conjugated cargoes across mammalian cell membranes, and as such, they may provide a safe and effective method for drug delivery to the inner ear. Simple polyarginine peptides have been shown to induce significantly higher cell penetration rates among CPPs. Herein, we show that a peptide consisting of nine arginines ("9R") effectively delivered enhanced green fluorescent protein (EGFP) into guinea pig cochleae via the round window niche without causing any deterioration in auditory function. A second application, 24 hours after the first, prolonged the presence of EGFP. To assess the feasibility of protein transduction using 9R-CPPs via the round window, we used "X-linked inhibitor of apoptosis protein" (XIAP) bonded to a 9R peptide (XIAP-9R). XIAP-9R treatment prior to acoustic trauma significantly reduced putative hearing loss and the number of apoptotic hair cells loss in the cochleae. Thus, the topical application of molecules fused to 9R-CPPs may be a simple and promising strategy for treating inner ear diseases.

Neurogenesis of the spiral ganglion cells in the cochlea requires the transcriptional cofactor TIS21.

The molecular mechanisms controlling the proliferation and differentiation of spiral ganglion cells (SGCs) in the inner ear are still largely unknown. TIS21 is a transcriptional cofactor that shows antiproliferative, antiapoptotic, and prodifferentiative effects on neural progenitor cells. To investigate the function of TIS21 during SGC development, we analyzed SGC neurogenesis from embryonic day 13.5 (E13.5) to postnatal day 4 (P4) in Tis21-GFP knock-in mice, in which the protein-encoding exon of the Tis21 gene was replaced by EGFP. Through E13.5 to P4, we found fewer SGCs in homozygous Tis21-GFP knock-in mice than in wild-type mice. Our results suggest that TIS21 is required for development of SGCs. Deleting Tis21 may affect progenitor cells or neuroblasts at the beginning of cochlear-vestibular ganglion formation and would consequently lead to a decrease in the number of SGCs.

Protein transduction into the mouse otocyst using arginine-rich cell-penetrating peptides.

The mouse otocyst, an anlage of the inner ear, is an attractive experimental target for developing treatment modalities for congenital inner ear diseases and for studying inner ear development. Poly-arginine (6-12 residues) is a cell-penetrating peptide and can be used to deliver cargo into cells. Here, we achieved transutero delivery of enhanced green fluorescent protein (EGFP) fused to a nine-arginine peptide into mouse embryonic otocysts. The EGFP signal was detected both in the lining cells of the otocysts and in their vicinity at 18 h post injection. Mice injected with EGFP fused to a nine-arginine peptide had normal auditory and vestibular functions. These data suggest that protein transduction using poly-arginine may be a useful alternative strategy to commonly used gene delivery methods for delivering therapeutically relevant molecules to the developing inner ear.