Outcomes of regenerative treatment for over 200 patients with tympanic membrane perforation.

OBJECTIVE: To evaluate outcomes of a regenerative treatment (RT) for over 200 patients with tympanic membrane perforation (TMP). The RT-TMP method involves a gelatin sponge, basic fibroblast growth factor (bFGF) and fibrin glue. METHODS: The study population included 216 patients and 234 ears (male: female =100:116; age 1-93 years). All enrolled patients were treated with RT-TMP in which TMP edges were disrupted mechanically and a gelatin sponge immersed in bFGF was inserted into the perforation. Fibrin glue was then dripped over the sponge. Patient outcomes including TMP closure rates, change in hearing level, and complications were obtained from retrospective medical chart reviews. The TMP was examined three or more weeks after surgery. The treatment was repeated up to 4 times until complete TMP closure was achieved. RESULTS: After mechanical disruption, the perforation size was Grade I, ≤1/3 of entire TM area in 22 ears (9.4 %), Grade II, 1/3-2/3 of entire TM in 77 ears (32.9 %) and Grade III, ≥2/3 of entire TM area in 135 ears (57.7 %). The overall TMP closure rates were 97.0 % (227/234). Complete TMP closure was achieved in 68.8 % (161/234), 22.6 % (53/234), 4.7 % (11/234) and 0.9 % (2/234) of ears after 1, 2, 3 and 4 treatments, respectively. In 7 of 234 ears (3.0 %), the TMPs were not closed completely after 4 treatments. There was no correlation between TMP size after mechanical disruption and number of treatments required to achieve complete closure (Fisher's exact test p = 0.70). The mean air-conduction hearing threshold at low frequency improved from 57.3 ± 16.7 dB before treatment to 37.3 ± 16.0 dB (p < 0.0001) after closure of TMPs. For middle and high frequencies, the improvement was 49.0 ± 19.3 dB to 36.9 ± 17.9 dB (p < 0.0001) and 57.7 ± 22.9 dB to 49.2 ± 23.3 dB (p < 0.0001), respectively. The mean air-bone gaps also improved significantly, and were within 10 dB at 250 Hz, 500 Hz and 1 kHz, and 11 dB at 2 kHz. One or more complications occurred in 32 patients (32/216; 14.8 %). The most common complication was formation of an epithelial pearl (16 ears; 6.8 %), followed by severe TM retraction (9 ears; 3.8 %) and otitis media with effusion (6 ears; 2.6 %). There were no serious complications that caused deterioration of the patient's general condition. CONCLUSION: Our results showed that RT-TMP had high success rates for TMP closure and good hearing improvement and produced no severe complications that could affect general health status. This novel therapy is simple, safe and minimally invasive, and could help improve the quality of life in patients with TMP.

Diagnosing Middle Ear Malformation by Pure-Tone Audiometry Using a Three-Dimensional Finite Element Model: A Case-Control Study.

BACKGROUND: Hearing loss caused by middle ear malformations is treated by tympanoplasty to reconstruct the acoustic conduction system. The mobility of the ossicles plays a crucial role in postoperative success. However, identifying the location of ossicular malformation based solely on preoperative audiograms is challenging due to the complex relationship between fixation location, deformity levels, and ossicular mobility. METHODS: Middle ear finite element models for simulating ossicular malformations were created, and the results were compared with the actual preoperative audiograms. RESULTS: This approach objectively diagnosed ossicular fixation and disarticulation, bypassing traditional criteria reliant on physician examination or imaging. CONCLUSION: This study suggests that future research should focus on developing a diagnostic framework utilizing large-scale data.

Successful management of temporary veno-venous extracorporeal membrane oxygenation for a pediatric lung transplant recipient with bronchiolitis obliterans syndrome awaiting lung re-transplantation: a case report.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation is an uncommon strategy in Japan owing to the severe donor shortage and absence of urgent allocation policy. Moreover, the use of veno-venous (VV) ECMO for immunosuppressed patients is controversial; thus, applying ECMO to patients who await lung re-transplantation is challenging. CASE PRESENTATION: A 16-year-old lung transplant recipient with grade 3 bronchiolitis obliterans syndrome was waitlisted for lung re-transplantation. Eleven months later, he fell into severe respiratory acidosis with hypercapnia, which were not resolved with mechanical ventilation. VV ECMO was introduced to minimize lung stress and strain. Tracheostomy was additionally performed on day 5 after the start of ECMO, and respiratory condition swiftly improved; hence, the weaning process from VV ECMO began on day 9. Rehabilitation became implementable, and bilateral re-lung transplantation was successfully performed 6 months after the ECMO treatment. No critical complication related to the precedent use of ECMO was noted. CONCLUSIONS: VV ECMO can be a feasible treatment option even for lung transplant candidates awaiting re-transplantation for a prolonged period. Introduction of ECMO and tracheostomy in the early deterioration stage may be crucial to successful subsequent patient management.

[A Surgical Case of Currarino Syndrome with Syringomyelia].

Currarino syndrome is characterized by a triad of anorectal malformations, sacral defects, and presacral masses. Although it is not extremely rare, this report presents a surgical case of Currarino syndrome with syringomyelia and discusses related literature. The patient is a girl, aged 2 years and 2 months, who presented with marked constipation, chronic cystitis, and lower limb weakness. After examining the patient through magnetic resonance imaging, we diagnosed her with rectal compression due to meningocele and syringomyelia. The base of the meningocele was detached, and the spinal cord was untethered. One week after surgery, her lower limb weakness and constipation improved. Following up on symptoms and performing imaging is essential to determine a treatment plan for Currarino syndrome. (Received 28 February, 2023; Accepted 22 March, 2023; Published 1 August, 2023).

Survey of Food Intake in Patients with Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a vascular disease that involves asymptomatic progressive expansion of the abdominal aorta. Aneurysm rupture is associated with a high mortality rate. Dietary conditions may be associated with the development and rupture of AAA. However, the relationship between nutrition and AAA is not completely understood. In this study, a nutrition survey was conducted using a brief self-administered diet history questionnaire (BDHQ) to evaluate the relationship between AAA and dietary habits. One-hundred and twenty-six Japanese people participated in the nutrition survey. Food intake status was analyzed in four groups: the analyzed group-1 (all men), analyzed group-2 (men with smoking history), analyzed group-3 (all women) and analyzed group-4 (women without smoking history). In group-2 and group-3, the intake of citrus fruits was significantly lower in the AAA group than in the non-AAA group. In group-2, the intake of soybean and soybean products was significantly lower in the AAA group than in the non-AAA group. In analyzed group-3, the intake of other vegetables (vegetables except for green and yellow vegetables and soybeans) and seafood was significantly lower in the AAA group than in the non-AAA group. This study suggests that AAA onset may be associated with low intake of fruits, soybeans, vegetables, and seafood.

Long-term exposure to high-concentration dexamethasone in the inner ear via intratympanic administration.

The first-line treatment for inner ear disorders is usually oral/systemic steroids. Intratympanic steroid therapy is an alternative option; however, it requires multiple office visits owing to the short residence time of steroids in the inner ear (systemic: 24 h, intratympanic: 2-3 h). Therefore, intratympanic injections of higher steroid concentrations could result in longer drug exposure, providing better treatment outcomes. This study aimed to develop a prototype for high-concentration steroids and examine their safety and feasibility in vivo. Using wild-type Institute for Cancer Research mice, high-concentration steroids (50 mg/mL dexamethasone), typical steroid concentrations (3.3 mg/mL dexamethasone), and sterile saline were administrated into the middle ear cavity via tympanic membrane injection. Auditory brainstem response analysis, vestibular function tests, and morphological analyses were performed to examine the safety and utility of High-conc Dex. One month post-injection, the frequency-averaged auditory brainstem response thresholds of high-dose dexamethasone-treated mice were not significantly different from those of low-dose dexamethasone- and saline-treated mice at all tested frequencies. Furthermore, the total points on vestibular function tests were similar between the three groups. Morphologically, no damage to the inner ear/middle ear mucosa was observed in all groups. Two months post-injection, dexamethasone could still be detected in the high-dose dexamethasone group. Altogether, our data successfully demonstrates the feasibility and safety of high-dose dexamethasone for in vivo use in the middle ear and ensure that the drug localizes to the inner ear. Further research is warranted to develop this new treatment strategy and further characterize its effects in vivo.

Predictive factors of acute sensorineural hearing loss in adult Japanese patients for clinical application by primary care doctors: a cross-sectional study.

BACKGROUND: Several methods are used for hearing loss screening; however, their benefits are uncertain. In this study, we aimed to determine the predictive factors of acute sensorineural hearing loss for clinical application by primary care doctors. METHODS: This retrospective, cross-sectional study included 365 patients with acute sensorineural hearing loss without prior therapy. The patients' clinical data, demographic information, and medical histories were obtained, and they were asked about comorbidities. In addition, we assessed lifestyle factors such as stress level, alcohol consumption, marital status, and socioeconomic level. Logistic regression analysis was performed to investigate the diagnostic predictive ability of the selected factors associated with acute sensorineural hearing loss. The hearing levels of all patients were evaluated using pure tone audiometry. RESULTS: We identified significant predictive factors for acute sensorineural hearing loss. The absence of hyperacusis was a predictive factor for sudden sensorineural hearing loss. Younger age, female sex, and marital status were predictive factors for acute low-tone hearing loss. High body mass index, high socioeconomic level, low alcohol consumption, high stress level, hyperacusis, and vertigo/dizziness were predictive factors for Ménière's disease. High body mass index and ear fullness were predictive factors for perilymph fistula. Low stress level was a predictive factor for acoustic tumours. CONCLUSIONS: Our findings can be used to distinguish between the types of acute sensorineural hearing loss. Symptoms, physical status, and lifestyle factors identified during this study are useful markers for predicting acute sensorineural hearing loss occurrence.

Hearing Outcomes and Complications of Cochlear Implantation in Elderly Patients over 75 Years of Age.

OBJECTIVE: Populations are aging in many countries, and the proportion of elderly people with severe to profound hearing loss is increasing in parallel with the increasing average life span. The objective of this study was to investigate the outcomes of cochlear implant (CI) surgery in elderly patients compared to those in younger patients. METHODS: The outcomes of CI surgery were retrospectively investigated for 81 adults (32 men and 49 women) who underwent CI surgery at our hospital. They were divided according to age at the time of implantation into the younger group (<75 years of age; n = 49) or elderly group (≥75 years of age; n = 32). RESULTS: The mean sentence recognition score on the CI-2004 Japanese open-set test battery (±standard deviation) was 82.9% ± 24.1 in the younger group and 81.9% ± 23.2 in the elderly group, with no significant difference between the groups (Mann-Whitney U test). The incidence of major complications that required surgical treatment was not significantly different between the groups (4.1% vs. 6.2%, respectively). Thus, there were no severe complications that could affect general health status in either group. Three patients in each group died for reasons unrelated to CI surgery during follow-up. The proportion of patients who were alive and continued to use the CI five years after surgery was 92.8% and 91.5%, respectively. CONCLUSION: Our results show good speech recognition and a low incidence of major complications in elderly patients. This comprehensive report on the outcomes of CI surgery in elderly patients will be helpful to the elderly with severe to profound hearing loss when deciding whether to undergo CI surgery.

Multicenter phase III trial of regenerative treatment for chronic tympanic membrane perforation.

OBJECTIVE: To evaluate the efficacy and safety of regenerative treatment for tympanic membrane perforation (TMP) using gelatin sponge, basic fibroblast growth factor (bFGF), and fibrin glue. METHODS: This was a multicenter, non-randomized, single-arm study conducted at tertiary referral centers. Twenty patients with chronic TMP (age 23-78 years, 6 males, 14 females) were registered from three institutions. All treated patients were included in the safety analysis population. The edges of the TMP were disrupted mechanically by myringotomy and several pieces of gelatin sponge immersed in bFGF were placed and fixed with fibrin glue to cover the perforation. The TMP was examined 4 ± 1 weeks later. The protocol was repeated up to four times until closure was complete. The main outcome measures were closure or a decrease in size of the TMP, hearing improvement, and air-bone gap evaluated 16 weeks after the final regenerative procedure (FRP). Adverse events (AEs) were monitored throughout the study. RESULTS: Total closure of the TMP at 16 weeks was achieved in 15 out of 20 patients (75.0%, 95% confidence interval [CI]: 50.9%-91.3%) and the mean decrease in size was 92.2% (95%CI: 82.9%-100.0%). The ratio of hearing improvement and the air-bone gap at 16 weeks after FRP were 100% (20/20; 95%CI: 83.2%-100%) and 5.3 ± 4.2 dB (p <0.0001), respectively. Thirteen out of 20 patients (65.0%) experienced at least one AE, but no serious AEs occurred. CONCLUSION: The results indicate that the current regenerative treatment for TMP using gelatin sponge, bFGF, and fibrin glue is safe and effective.

Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan.

BACKGROUND: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. PROCEDURE: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. RESULTS: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. CONCLUSIONS: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.

Complement activation associated with ADAMTS13 deficiency may contribute to the characteristic glomerular manifestations in Upshaw-Schulman syndrome.

INTRODUCTION: Upshaw-Schulman syndrome (USS) is a congenital form of thrombotic thrombocytopenic purpura (TTP) associated with loss-of-function mutations in the ADAMTS13 gene, possibly leading to aberrant complement activation and vascular injury. However, USS is extremely rare, and there have been no systematic studies correlating histopathological severity with local ADAMTS13 expression and complement activation. MATERIALS AND METHODS: Here, we compared histopathological features, ADAMTS13 immunoreactivity, and immunoreactivity of complement proteins C4d and C5b-9 among renal biopsy tissues from five USS cases, ten acquired TTP cases, and eleven controls. RESULTS: Pathological analysis revealed chronic glomerular sclerotic changes in the majority of USS cases (4 of 5), with minor glomerular pathology in the remaining case. In two of these four severe cases, more than half of the glomerular segmental sclerosis area was localized in the perihilar region. The average number of ADAMTS13-positive cells per glomerulus was significantly lower in USS cases than controls (p < 0.05). Conversely, C4d staining was significantly more prevalent in the glomerular capillary walls of USS cases than controls (p < 0.05), while C5b-9 staining did not differ significantly among groups. CONCLUSIONS: These findings suggest that the severity of glomerular injury in USS is associated with deficient ADAMTS13 expression and local complement activation, particularly in vascular regions with higher endothelial shear stress. We suggest that C4d immunostaining provides evidence for complement-mediated glomerular damage in USS.

Application of Regenerative Treatment for Tympanic Membrane Perforation With Cholesteatoma, Tumor, or Severe Calcification.

OBJECTIVE: To apply regenerative treatment for tympanic membrane (TM) perforation to patients with severe calcification of the TM, cholesteatomas, or tumors localized to the tympanic cavity. STUDY DESIGN: Controlled clinical pilot study. SETTING: General hospitals. PATIENTS: Forty-five patients (age: 8-85; M = 19, F = 26) were selected from patients with or without TM perforation for the regenerative treatment. Twenty-five patients had cholesteatomas, 3 had tumors, and 17 had severe TM calcification. Patients were classified into three groups based on TM perforation size: less than 1/3 of the TM as Grade I (n = 5), 1/3 to 2/3 as Grade II (n = 19), and over 2/3 as Grade III (n = 21). Twenty patients who underwent standard tympanoplasty type I were selected as historical controls. MATERIALS AND METHODS: Materials for the TM repair included gelatin sponge with basic fibroblast growth factor and fibrin glue. After lesions were removed through the TM perforation, gelatin sponge immersed in basic fibroblast growth factor was placed over the perforation. Fibrin glue was then dripped onto the sponge. Treatment efficacy was evaluated 6 months posttreatment. RESULTS: Complete closure of the TM perforation was achieved in 91% (n = 41/45) of the patients in this regenerative treatment. Improvement in average hearing levels and air-bone gap were much better with this treatment than in the historical control group. CONCLUSION: This new regenerative therapy is useful not only for patients with simple TM perforations but also for those with cholesteatomas, tumors, or severe calcification without requiring conventional surgical procedures. This regenerative therapy is an easy, safe, cost-effective, and minimally-invasive treatment.

Acute Myositis Associated with Concurrent Infection of Rotavirus and Norovirus in a 2-Year-Old Girl.

Rotavirus and norovirus are common pathogens associated with gastroenteritis in children. Although rotavirus occasionally induces central nervous system disease, only 3 cases with rotavirus-induced acute myositis have been reported in the English literature. We recently treated a female patient with acute myositis associated with gastroenteritis induced by concurrent infection with rotavirus and norovirus. Having suffered from gastroenteritis for 3 days, she suddenly developed myositis affecting her lower extremities with concomitant creatine kinase elevation. Herein, we present our patient and review the previous cases including those reported in the Japanese literature.

Ex Vivo Expanded Allogeneic Mesenchymal Stem Cells With Bone Marrow Transplantation Improved Osteogenesis in Infants With Severe Hypophosphatasia.

Patients with severe hypophosphatasia (HPP) develop osteogenic impairment with extremely low alkaline phosphatase (ALP) activity, resulting in a fatal course during infancy. Mesenchymal stem cells (MSCs) differentiate into various mesenchymal lineages, including bone and cartilage. The efficacy of allogeneic hematopoietic stem cell transplantation for congenital skeletal and storage disorders is limited, and therefore we focused on MSCs for the treatment of HPP. To determine the effect of MSCs on osteogenesis, we performed multiple infusions of ex vivo expanded allogeneic MSCs for two patients with severe HPP who had undergone bone marrow transplantation (BMT) from asymptomatic relatives harboring the heterozygous mutation. There were improvements in not only bone mineralization but also muscle mass, respiratory function, and mental development, resulting in the patients being alive at the age of 3. After the infusion of MSCs, chimerism analysis of the mesenchymal cell fraction isolated from bone marrow in the patients demonstrated that donor-derived DNA sequences existed. Adverse events of BMT were tolerated, whereas those of MSC infusion did not occur. However, restoration of ALP activity was limited, and normal bony architecture could not be achieved. Our data suggest that multiple MSC infusions, following BMT, were effective and brought about clinical benefits for patients with lethal HPP. Allogeneic MSC-based therapy would be useful for patients with other congenital bone diseases and tissue disorders if the curative strategy to restore clinically normal features, including bony architecture, can be established.

Regenerative treatment for soft tissue defects of the external auditory meatus.

OBJECTIVE: To establish a regenerative treatment for soft tissue defects of the external auditory meatus (EAM) without conventional surgical therapy. STUDY DESIGN: Controlled clinical pilot study. SETTING: General hospitals. PATIENTS: Sixty-five patients with new or old EAM defects without active inflammation were selected. Ages ranged from 12 to 87 years (average age of 58 yr). INTERVENTION: Therapeutic nonsurgical treatment of EAM defects. Gelatin sponge, basic fibroblast growth factor (b-FGF), fibrin glue, and water proof transparent dressing were used in the repair procedure. Patients were divided into 2 groups: treatment with (n = 54) and without (n = 11) b-FGF. After mechanically disrupting the edge of the EAM defect, gelatin sponge immersed in b-FGF was placed over the defect and covered with fibrin glue. In cases of extensive EAM defects, the EAM was filled with gelatin sponge/b-FGF, and the auricle was wrapped in water proof dressing. Two or 3 weeks postprocedure, crust over the defect was removed. If complete defect closure was not achieved after 1 treatment course, the treatment was repeated. MAIN OUTCOME MEASURE: Evaluation of complete closure of EAM defects 3 months posttreatment. RESULTS: Complete closure of the EAM defect was achieved within 3 treatment courses in 92.6% (50/54) and 18.2% (2/11) of the patients with or without b-FGF, respectively. No inflammation/infection or severe sequelae were observed. CONCLUSION: This study demonstrated the effectiveness of combining gelatin sponge, b-FGF, and fibrin glue for EAM defect regeneration. This innovative regenerative therapy is an easy, simple, cost-effective and minimally invasive method for treating EAM defects.

Ectopic neuroblastoma in monozygotic twins with different ages of onset: possible twin-to-twin metastasis in utero with distinct genetic alterations after birth.

We describe neuroblastoma (NB) in monozygotic twins whose ages at the onset of the disease had a 3-year interval. The primary tumor site of twin 1 was the adrenal gland, whereas that of twin 2 was the jejunum/mesentery. MYCN amplification, DNA index, ALK mutation, and copy number alterations of DNA were different between each primary tumor. NB in ectopic sites may have resulted from twin-to-twin metastasis through vascular anastamoses in the placenta. The pathogenesis of this NB involved a premalignant stage of NB during the fetal development and subsequent molecular alterations after birth, resulting in NBs that were phenotypically similar but genetically different.

Therapy-related Ph+ leukemia after both bone marrow and mesenchymal stem cell transplantation for hypophosphatasia.

Bone marrow (BM) transplantation (BMT) is one of the treatment strategies for congenital metabolic disease, but leukemia secondary to intensive cytoreductive treatment is a major concern. Besides BM cells, mesenchymal stem cells (MSC) are also used for transplantation. An 8-month-old girl with hypophosphatasia underwent transplantation of haploidentical BM cells followed by two transplants of MSC obtained from her father to facilitate osteogenesis. Fludarabine(Flu)/cyclophosphamide (CPA)/anti-thymocyte globulin were used for myeloablative conditioning, but the patient developed therapy-related leukemia harboring t(9;22)(q34;q11.2); minor BCR-ABL (t-leukemia with Ph) at the age of 32 months. At the age of 40 months she underwent a second BM and third MSC transplant from the same donor. Thereafter, she achieved complete histological and molecular remission. The present case suggests that the combination of cytotoxic agents (Flu/CPA) and MSC led to t-leukemia with Ph as a consequence of chromosome instability and suppression of host anti-tumor immunity.

A case with sacrococcygeal primitive myxoid mesenchymal tumor of infancy: a case report and review of the literature.

A girl, aged 19 months, presented with a sacrococcygeal tumor that developed at 5 months after birth and gradually enlarged. Serum tumor marker levels were negative. Ultrasound imaging showed abundant blood flow in the tumor. However, neither computed tomography (CT) nor magnetic resonance imaging (MRI) showed contrast agent incorporation. The surgically resected tumor consisted of immature cells with myxoid stroma and proliferating small blood vessels. Immunostaining showed extensive vimentin expression. However, smooth muscle actin, muscle-specific actin, and S-100 protein expression was negative. Neither the ETV6-NTRK3 fusion gene nor the FUS gene rearrangement was detected. Thus, the patient was diagnosed with a primitive myxoid mesenchymal tumor of infancy. This tumor primarily consisted of a mucosal stroma with a low absorption on CT, a low signal on T1-weighted MRI, and a high signal on T2-weighted MRI. A diagnosis of primitive myxoid mesenchymal tumor of infancy should be considered in cases of soft tissue tumors in infants that show prominent vascularity but little contrast enhancement on MRI or CT.