Dramatic Response to Tezepelumab as an Initial Biologic Agent for Refractory Asthma Associated with Type 2 and Non-type 2 Traits.

A 74-year-old Japanese woman presented with a 45-year history of refractory asthma. She had been treated with inhaled corticosteroids, a long-acting ß2-agonist, and a long-acting muscarinic antagonist for 6 months. She also had a repeated viral infection. Her condition had been characterized as a refractory asthma associated with type 2 and non-type 2 traits. We began treatment with tezepelumab. The control of the patient's asthma symptoms and quality of life improved greatly within 1 month (changes in eosinophil count from 748 to 96 /µL, in FeNO from 32 to 17 ppb, in the Asthma Quality of Life Questionnaire score from 3.59 to 6.68, and in the Asthma Control Test score from 13 to 23). Tezepelumab was effective as an initial biologic agent for a patient with refractory asthma associated with type 2 and non-type 2 traits.

Speech-language Pathology Rehabilitation in a Case of Jefferson Fracture Complicated with Lower Cranial Nerve Palsies.

A 68-year-old man presented with a Jefferson fracture leading to lower cranial nerve palsies affecting the ninth, tenth, and twelfth cranial nerves with a traumatic basilar impression. On the X day, the patient underwent occipitocervical posterior fixation surgery; the surgery was uneventful. However, just after the surgery, epipharyngeal palsy and airway obstruction occurred. Consequently, tracheostomy was needed. On the X+8 day, speech-language pathology (SLP) therapy was initiated for decannulation. On the X+21 day, the patient could clear all the checkpoints and was decannulated. On the X+36 day, the patient was discharged home and SLP therapy was continued. On the X+171 day, his SLP therapy was halted. However, the patient continued to complain that he could not speak as fast as before, and his quality of life remained compromised. Some studies reported that lower cranial nerve palsies affecting the ninth to the twelfth cranial nerve occur in conjunction with Jefferson fractures. Thus, SLP therapy is crucial for Jefferson fracture cases.

Combination therapy with anti-programmed cell death 1 antibody plus angiokinase inhibitor exerts synergistic antitumor effect against malignant mesothelioma via tumor microenvironment modulation.

Malignant pleural mesothelioma (MPM) is an asbestos-related fatal malignant neoplasm. Although there has been no reliable chemotherapeutic regimen other than combination therapy of cisplatin and pemetrexed for two decades, combination of ipilimumab plus nivolumab brought about a better outcome in patients with MPM. Thus, cancer immunotherapy using immune checkpoint inhibitor (ICI) is expected to play a central role in the treatment of MPM. To maximize the antitumor effect of ICI, we evaluated whether nintedanib, an antiangiogenic agent, could augment the antitumor effect of anti-programmed cell death 1 (PD-1) antibody (Ab). Although nintedanib could not inhibit the proliferation of mesothelioma cells in vitro, it significantly suppressed the growth of mesothelioma allografts in mice. Moreover, combination therapy with anti-PD-1 Ab plus nintedanib reduced tumor burden more dramatically compared with nintedanib monotherapy via inducing remarkable necrosis in MPM allografts. Nintedanib did not promote the infiltration of CD8+ T cells within the tumor when used alone or in combination with anti-PD-1 Ab but it independently decreased the infiltration of tumor-associated macrophages (TAMs). Moreover, immunohistochemical analysis and ex vivo study using bone marrow-derived macrophages (BMDMs) showed that nintedanib could polarize TAMs from M2 to M1 phenotype. These results indicated that nintedanib had a potential to suppress protumor activity of TAMs both numerically and functionally. On the other hand, ex vivo study revealed that nintedanib upregulated the expression of PD-1 and PD-ligand 1 (PD-L1) in BMDMs and mesothelioma cells, respectively, and exhibited the impairment of phagocytic activity of BMDMs against mesothelioma cells. Co-administration of anti-PD-1 Ab may reactivate phagocytic activity of BMDMs by disrupting nintedanib-induced immunosuppressive signal via binding between PD-1 on BMDMs and PD-L1 on mesothelioma cells. Collectively, combination therapy of anti-PD-1 Ab plus nintedanib enhances the antitumor activity compared with respective monotherapy and can become a novel therapeutic option for patients with MPM.

Surgical management of brain metastasis as a part of systematic metastases from adenoid cystic carcinoma of the external auditory canal: illustrative case.

BACKGROUND: Adenoid cystic carcinoma (ACC) of the external auditory canal (EAC) is a rare tumor that accounts for approximately 5% of all EAC tumors. ACC is generally known as a slow-growing tumor, but patients often experience recurrence or distant metastasis in the long clinical course. While the major pattern of recurrence is pulmonary metastasis, brain metastasis of ACC of the EAC is rare. OBSERVATIONS: The authors describe the case of a 72-year-old male who was diagnosed with ACC of the EAC. Approximately 7 years later, brain magnetic resonance imaging revealed an intra-axial homogenously enhancing mass lesion that had no direct connection with the skull base in the left frontal lobe. The patient underwent tumor resection and histopathological examination revealed a mixture of cribriform and tubular patterns. The image and pathological characteristics of the tumor were similar to those of primary ACC or ACC from other sites of origin. LESSONS: While patients with ACC of the EAC often experience recurrence or distant metastasis in the long clinical course, they survive for a relatively long period of time, even though an optimal treatment has not been established. The authors therefore recommend surgical resection for brain metastasis of ACC of the EAC to improve neurological symptoms.

Use of a highly sensitive lung cancer compact panel to detect KRAS G12D in the wash fluid from a lung tumor: A case report.

Here, we report a case of a pulmonary invasive mucinous adenocarcinoma harboring KRAS G12D, diagnosed from tumor samples containing a very small amount of tumor cells using next-generation sequencing (NGS) and the recently developed Lung Cancer Compact Panel. A 79-year-old woman without any respiratory symptoms underwent chest computed tomography, which revealed a tumor in the left lower lobe. During endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB) using a guide sheath (GS), a sufficient specimen for pathological diagnosis could not be obtained because the patient had a severe cough and pulmonary bullae located adjacent to the tumor. In the absence of EBUS transbronchial biopsy findings using a guide sheath, brush cytology was used to categorize the tumor as class II (Papanicolaou classification). However, the wash fluid from the cytological examination contained enough cells to obtain sufficient nucleic acid for use in sequencing analysis. The latter revealed KRAS G12D expression. Although the patient underwent surgery without pathological evidence, the evaluation of the surgical specimen confirmed a diagnosis of pulmonary invasive mucinous adenocarcinoma. Use of the Lung Cancer Compact Panel enabled the detection of KRAS G12D in the wash fluid of a brush cytology sample and thus a diagnosis of pulmonary invasive mucinous adenocarcinoma.

Improving the accuracy of estimating blood calcium concentration in Holstein cows using electrocardiographic variables.

We previously reported the possibility of using the electrocardiogram variable to estimate blood calcium (Ca) concentration in dairy cows based on the strong positive correlation between the blood Ca concentration and the inverse of the corrected ST peak interval (STc-1). To improve the accuracy of the estimation of blood Ca concentration, we investigated the relationship between blood Ca concentration and STc-1 for each postpartum day and available variables other than STc-1. We measured multiple variables (milk yield, calving number, age, body temperature, etc.), including serum total Ca concentration (tCa), blood ionized Ca concentration (iCa) and STc-1 in 462 Holstein cows on days 0, 1, 2, 3, 5, and 7 postpartum. A very high correlation was observed between iCa and tCa. The association between tCa and STc-1 for each postpartum day had a high coefficient of determination of 0.61-0.79 postpartum 0-2 days but decreased after the third day. In the investigation using the data from postpartum days 0-2, STc-1, heart rate interval, calving number, and age were highly correlated with tCa. In addition, a multiple regression equation was obtained with tCa as the objective variable and STc-1 and calving number as explanatory variables. The estimation accuracy was improved as compared with the simple regression equation using only STc-1 as the explanatory variable. This multiple regression equation was used for 11 cows suspected of having hypocalcemia, and it was able to correctly detect cows requiring early treatment, except for one cow.

Combination therapy with levofloxacin and cefepime to treat severe respiratory infection due to Aeromonas caviae after a near-drowning accident in river water.

BACKGROUND: Aeromonas spp. are gram-negative anaerobic rods that are mainly found in water. Respiratory infections due to Aeromonas sp. are rare but have a high mortality rate. CASE PRESENTATION: A 43-year-old man fell into a river following an automobile accident and almost drowned. He developed a severe respiratory infection and acute respiratory distress syndrome. Ampicillin/sulbactam was given; however, Aeromonas caviae was detected in his blood culture. Despite treatment with levofloxacin, to which A. caviae was susceptible, his condition failed to improve. However, with additional treatment with cefepime, his blood culture results were negative, and his condition improved. CONCLUSION: When a patient develops a respiratory infection after aspiration of river water, empiric antimicrobial therapy should be given as soon as possible to manage the risk of Aeromonas sp. infection.

Occurrence patterns of crop-foraging sika deer distribution in an agriculture-forest landscape revealed by nitrogen stable isotopes.

Conflicts arising from the consumption of anthropogenic foods by wildlife are increasing worldwide. Conventional tools for evaluating the spatial distribution pattern of large terrestrial mammals that consume anthropogenic foods have various limitations, despite their importance in management to mitigate conflicts. In this study, we examined the spatial distribution pattern of crop-foraging sika deer by performing nitrogen stable isotope analyses of bone collagen. We evaluated whether crop-foraging deer lived closer to agricultural crop fields during the winter and spring, when crop production decreases. We found that female deer in proximity to agricultural crop fields during the winter and spring were more likely to be crop-foraging individuals. Furthermore, the likelihood of crop consumption by females decreased by half as the distance to agricultural crop fields increased to 5-10 km. We did not detect a significant trend in the spatial distribution of crop-foraging male deer. The findings of spatial distribution patterns of crop-foraging female deer will be useful for the establishment of management areas, such as zonation, for efficient removal of them.

Irinotecan and Gemcitabine as Second-Line Treatment in Patients with Malignant Pleural Mesothelioma following Platinum plus Pemetrexed Chemotherapy: A Retrospective Study.

BACKGROUND: Cisplatin-pemetrexed combination chemotherapy is the current standard primary treatment for malignant pleural mesothelioma (MPM). It was first approved for untreated and unresectable MPM in the 2003 National Comprehensive Cancer Network (NCCN) guidelines. However, to date, standard treatments for patients with MPM who previously underwent chemotherapy, as recommended by the NCCN Malignant Pleural Mesothelioma guidelines, have been inadequate. To explore treatment options for such patients, we performed this retrospective study of patients who received irinotecan plus gemcitabine as second-line therapy for MPM. METHODS: We investigated 62 patients diagnosed with unresectable MPM between January 2008 and October 2017 who experienced recurrence following cisplatin treatment (or carboplatin) plus pemetrexed or pemetrexed monotherapy as first-line treatment, and who underwent irinotecan plus gemcitabine combination therapy as second-line treatment. Irinotecan (60 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1 and 8 every 3 weeks, including a 1-week washout period. Our endpoints were efficacy, survival period, and toxicity. RESULTS: patients' median age was 65 years (range 50-79), and the histological MPM types were epithelioid (n = 48), sarcomatoid (n = 6), biphasic (n = 6), and desmoplastic (n = 2). One patient experienced a partial response, 40 had stable disease, and 21 had progressive disease. The disease control rate was 66.1% and the response rate 2.1%. Additionally, the median progression-free and overall survival time were 5.7 and 11.3 months, respectively. The most common adverse events were neutropenia (32.2%), loss of appetite (16.1%), nausea/diarrhea (11.3%), and thrombocytopenia/phlebitis (9.7%). Grade 3 adverse events included neutropenia (12.9%) and thrombocytopenia/phlebitis (2.1%); however, all adverse events were managed with symptomatic therapy. CONCLUSIONS: Despite the fact that second-line irinotecan plus gemcitabine combination therapy did not produce marked tumor shrinkage, it achieved a relatively high disease control rate of >65% with an acceptable toxicity profile. Hence, the combination of irinotecan plus gemcitabine may be considered for MPM treatment, with consideration of combination with immune checkpoint inhibitors as a potential next step.

Full-Endoscopic Transcervical Ventral Decompression for Pathologies of Craniovertebral Junction: Case Series.

Odontoidectomy is very effective for the decompression of the ventral craniovertebral junction (CVJ). Various approaches are available for the direct ventral decompression of the CVJ. Because there are many disadvantages of open transoral approach, endoscopic odontoidectomy was developed. There are 3 approaches in endoscopic odontoidectomy. We report transcervical retropharyngeal endoscopic approach for the ventral CVJ in this paper. Three patients with different pathologies received operations using this approach. The decompression was enough and surgical invasion was less in all patients. Each endoscopic approach has some advantages and different working regions due to their approach trajectories, but transcervical retropharyngeal approach is very familiar for our neurospinal surgeons and has a relatively large working area. This approach might have the chance to take the place of open transoral approach for endoscopic spinal surgeons.

Tumor-associated macrophage-derived inflammatory cytokine enhances malignant potential of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an asbestos-related aggressive malignant neoplasm. Due to the difficulty of achieving curative surgical resection in most patients with MPM, a combination chemotherapy of cisplatin and pemetrexed has been the only approved regimen proven to improve the prognosis of MPM. However, the median overall survival time is at most 12 mo even with this regimen. There has been therefore a pressing need to develop a novel chemotherapeutic strategy to bring about a better outcome for MPM. We found that expression of interleukin-1 receptor (IL-1R) was upregulated in MPM cells compared with normal mesothelial cells. We also investigated the biological significance of the interaction between pro-inflammatory cytokine IL-1ß and the IL-1R in MPM cells. Stimulation by IL-1ß promoted MPM cells to form spheroids along with upregulating a cancer stem cell marker CD26. We also identified tumor-associated macrophages (TAMs) as the major source of IL-1ß in the MPM microenvironment. Both high mobility group box 1 derived from MPM cells and the asbestos-activated inflammasome in TAMs induced the production of IL-1ß, which resulted in enhancement of the malignant potential of MPM. We further performed immunohistochemical analysis using clinical MPM samples obtained from patients who were treated with the combination of platinum plus pemetrexed, and found that the overexpression of IL-1R tended to correlate with poor overall survival. In conclusion, the interaction between MPM cells and TAMs through a IL-1ß/IL-1R signal could be a promising candidate as the target for novel treatment of MPM (Hyogo College of Medicine clinical trial registration number: 2973).

Adenosine Deaminase in Pleural Effusion and Its Relationship with Clinical Parameters in Patients with Malignant Pleural Mesothelioma.

Pleural effusion adenosine deaminase (ADA) levels are elevated in various diseases. We investigated whether pleural effusion ADA levels differ among patients with malignant pleural mesothelioma (MPM), lung cancer (LC), and benign diseases, including tuberculous pleurisy. We examined 329 patients from February 2002 to July 2013. There were 131 MPM cases with ADA levels of 32.29 IU/L; 117 LC cases with ADA levels of 21.12 IU/L; 54 benign disease cases with ADA levels of 20.98 IU/L. A significant difference existed in pleural effusion ADA levels between MPM and benign disease patients. Pleural effusion ADA levels were significantly higher in MPM patients.

A superior vena cava aneurysm discovered by chance at regular physical examination.

A superior vena cava (SVC) aneurysm is a rare disease that can be confused with upper mediastinal tumor. A 57-year-old female visited our hospital regarding an abnormal shadow in her mediastinum on a chest X-ray. Upon closer examinations, which included three-dimensional computed tomography, we diagnosed it as a SVC aneurysm. Since her SVC aneurysm was regarded as fusiform type at low risk of rupture and thrombosis, she has been managed conservatively and is free from any complications to date. Thus, it is important to keep SVC aneurysms in mind during routine examinations.

Clinical outcome and radiological findings after cervical open door laminoplasty with titanium basket.

OBJECT: Cervical laminoplasty, which is well described in the Japanese literature, is the gold standard for decompressing multilevel spinal cord compression. Several spacers have been introduced to provide enough decompression of the spinal canal and reconstruct the stable posterior elements. The purpose of this study was to retrospectively evaluate radiological outcomes after open door laminoplasty using the titanium spacer (Laminoplasty Basket: L-Basket; Ammtec, Tokyo). METHODS: Between July 2014 and June 2016, 31 patients with cervical spondylotic disease, including OPLL, were underwent open door laminoplasty with this device. All patients were clinically assessed by JOA score. The average follow-up period was 48.9 months with a range of 37-60 months. Postoperative radiological evaluation revealed bone union on both the open side and the gutter side from 12 months to 36 months after surgery on computed tomography. RESULTS: The clinical outcome improved from 10.9 points on the Japanese Orthopaedic Association scale to 15.8 points at 3 months after surgery and there were no significant major complications such as the implant failure. The bone union rate of the gutter side was 85.9% (85/99) at 1 year, 96.0% (95/99) at 3 years after surgery and of the open side was 57.6% (57/99) at 1 year, 89.9% (89/99) at 3 years after surgery. Circumferential fusion was confirmed 85.9% (85/99) of the time. CONCLUSION: This titanium spacer seemed to have the potential of promoting bone union between the spacer and both lamina, and lateral mass in cervical laminoplasty which is a safe procedure with satisfactory clinical results.

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest.

Small-cell lung cancer (SCLC) is characterized by one of neuroendocrine tumors, and is a clinically aggressive cancer due to its rapid growth, early dissemination, and rapid acquisition of multidrug resistance to chemotherapy. Moreover, the standard chemotherapeutic regimen in SCLC has not changed for three decades despite of the dramatic therapeutic improvement in non-SCLC. The development of a novel therapeutic strategy for SCLC has become a pressing issue. We found that expression of Eph receptor A2 (EphA2) is upregulated in three of 13 SCLC cell lines and five of 76 SCLC tumor samples. Genetic inhibition using siRNA of EphA2 significantly suppressed the cellular proliferation via induction of cell cycle arrest in SBC-5 cells. Furthermore, small molecule inhibitors of EphA2 (ALW-II-41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC.

Augmented Reality Visualization-guided Microscopic Spine Surgery: Transvertebral Anterior Cervical Foraminotomy and Posterior Foraminotomy.

OBJECTIVE: We describe intraoperative augmented reality (AR) imaging to obtain a microscopic view in spine keyhole surgery. BACKGROUND: Minimally invasive keyhole surgery has been developed even for spine surgery, including transvertebral anterior cervical foraminotomy and posterior cervical laminoforaminotomy. These methods are complex and require a skillful technique. Therefore, inexperienced surgeons hesitate to perform keyhole surgeries. The technology used in surgery is rapidly advancing, including intraoperative imaging devices that have enabled AR imaging and facilitated complicated surgeries in many fields. However, data are not currently available on the use of AR imaging in spine surgery. The purpose of this article was to introduce the utility of AR for spine surgery. METHODS: We performed O-arm intraoperative imaging to create an augmented imaging model in navigation systems. Navigation data were linked to a microscope to merge the live view and AR. Augmented reality imaging shows the model plan in the real-world surgical field. We used this novel method in patients who underwent both keyhole surgeries. RESULTS: We successfully performed both surgeries using the AR visualization guide. CONCLUSIONS: The AR navigation system facilitates complicated keyhole surgeries in patients who undergo spine surgery. STUDY DESIGN: Technical report.

Clinical and Radiological Outcomes of Microscopic Lumbar Foraminal Decompression: A Pilot Analysis of Possible Risk Factors for Restenosis.

A single-center retrospective comparative study was designed to identify the risk factors for restenosis of lumbar foraminal stenosis (LFS) after microscopic foraminal decompression (MFD). 21 consecutive patients who underwent single-level MFD with an average of 19-month follow-up were divided into two study groups based on clinical outcomes; group 1 (7 patients with poor outcomes requiring revision surgery), group 2 (14 patients with good outcomes with no revision surgery required). Changes of lumbar spinal alignment on plain standing radiographs were compared and analyzed between two study groups to investigate the pathology and risk factors associated with restenosis after MFD. Preoperative disc wedging (DW) angle was significantly larger in group 1 than in group 2 (3.5 ± 1.0° vs 1.1 ± 0.2°, P < 0.01). Postoperatively, disc height (DH) and foraminal height (FH) decreased (P < 0.05), and DW deteriorated (P < 0.01) significantly in group 1, while there were no significant changes in group 2. Lumbar lordosis (LL) remarkably improved postoperatively in group 2 (24.7 ± 8.0 to 32.0 ± 7.0, P < 0.001), contrary to limited improvement in group 1 (25.1 ± 9.2 to 27.0 ± 12.0, P = 0.45). Postoperative LL is a predictive factor for restenosis after MFD. Decrease in DH or progression of DW was contributing to restenosis. LFS presenting with large DW and lumbar degenerative kyphosis should be excluded from surgical indications for MFD without instrumented fusion, considering the high recurrence rate.

Balloon Kyphoplasty under Three-dimensional Radiography Guidance.

Percutaneous balloon kyphoplasty (PBKP) is generally performed under two-dimensional (2D) radiography guidance (lateral- and anteroposterior (A-P) views) using C-arm fluoroscopy. However, 2D images taken by single-plane or bi-plane fluoroscopy cannot provide information regarding axial views, particularly the Z axis. Lack of information regarding the Z axis prevents the creation of three-dimensional (3D) images. Currently, there has been a progress in interventional X-ray systems, and they are capable of providing 3D radiographic images using a rotational angiography mode which is used to create 3D angiographies. In this report, we described the usefulness of 3D radiography guidance. Patients treated by PBKP was designed to evaluate the efficacy of 3D radiography guidance. These patients experienced osteoporotic vertebral fractures with severe pain. We retrospectively analyzed patients who underwent PBKP from February to December 2016. All patients had a single-level vertebral fracture and underwent surgery by 2D or 3D radiography guidance. We performed 16 patients in 3D radiography guidance, and 10 patients in traditional 2D radiography guidance. This 3D radiography guided PBKP increase the amount of the polymethyl methacrylate (PMMA) injection compared with ordinary 2D method. As a result, postoperative vertebral height and alignment were significantly improved. Both groups have no complication. To confirm the final results and make PBKP more effective, 3D radiography guidance is feasible and safe for balloon kyphoplasty.

Blunt cardiac injury due to trauma associated with snowboarding: a case report.

BACKGROUND: Cardiac trauma is associated with a much higher mortality rate than injuries to other organ systems, even though cardiac trauma is identified in less than 10% of all trauma admissions. Here we report blunt trauma of the left atrium due to snowboarding trauma. CASE PRESENTATION: A 45-year-old Asian man collided with a tree while he was snowboarding and drinking. He lost consciousness temporarily. An air ambulance was requested and he was transported to an advanced critical care center. On arrival, a pericardial effusion was detected by a focused assessment with sonography for trauma. His presenting electrocardiogram revealed normal sinus rhythm and complete right bundle branch block. Laboratory findings included a white blood cell count of 13.5 × 103/µl, serum creatine kinase level of 459 IU/l, and creatine kinase-myocardial band level of 185 IU/l. Enhanced computed tomography showed a large pericardial effusion and bleeding from his left adrenal gland. There were no pelvic fractures. A diagnosis of cardiac tamponade due to blunt cardiac injury and left adrenal injury due to blunt trauma was made. Subsequently, emergency thoracic surgery and transcatheter arterial embolization of his left adrenal artery were performed simultaneously. A laceration of the left atrial appendage in the lateral wall of his left ventricle was detected intraoperatively and repaired. His postoperative course progressed favorably, although a pericardial effusion was still detected on chest computed tomography on hospital day 35. His electrocardiogram showed normal sinus rhythm and the complete right bundle branch block pattern changed to a narrow QRS wave pattern. He was discharged on hospital day 40. CONCLUSIONS: The present case report illustrates two points: (1) severe injuries resulted from snowboarding, and (2) complete right bundle branch block was caused by blunt cardiac injury. The present report showed blunt trauma of the left atrium with complete right bundle branch block as an electrocardiogram change due to snowboarding trauma. To detect cardiac trauma in snowboarding accidents, an examination of an electrocardiogram is required in all patients who might have a bruised chest.