Phosphorylation of DNA-binding domains of CLOCK-BMAL1 complex for PER-dependent inhibition in circadian clock of mammalian cells.

In mammals, CLOCK and BMAL1 proteins form a heterodimer that binds to E-box sequences and activates transcription of target genes, including Period (Per). Translated PER proteins then bind to the CLOCK-BMAL1 complex to inhibit its transcriptional activity. However, the molecular mechanism and the impact of this PER-dependent inhibition on the circadian clock oscillation remain elusive. We previously identified Ser38 and Ser42 in a DNA-binding domain of CLOCK as phosphorylation sites at the PER-dependent inhibition phase. In this study, knockout rescue experiments showed that nonphosphorylatable (Ala) mutations at these sites shortened circadian period, whereas their constitutive-phospho-mimetic (Asp) mutations completely abolished the circadian rhythms. Similarly, we found that nonphosphorylatable (Ala) and constitutive-phospho-mimetic (Glu) mutations at Ser78 in a DNA-binding domain of BMAL1 also shortened the circadian period and abolished the rhythms, respectively. The mathematical modeling predicted that these constitutive-phospho-mimetic mutations weaken the DNA binding of the CLOCK-BMAL1 complex and that the nonphosphorylatable mutations inhibit the PER-dependent displacement (reduction of DNA-binding ability) of the CLOCK-BMAL1 complex from DNA. Biochemical experiments supported the importance of these phosphorylation sites for displacement of the complex in the PER2-dependent inhibition. Our results provide direct evidence that phosphorylation of CLOCK-Ser38/Ser42 and BMAL1-Ser78 plays a crucial role in the PER-dependent inhibition and the determination of the circadian period.

Characteristics of cases for which esophageal endoscopic submucosal dissection under general anesthesia is recommended.

BACKGROUND/AIMS: Esophageal endoscopic submucosal dissection (ESD) performed under general anesthesia can potentially provide more stable treatment in difficult cases than that under sedation. We evaluated the clinical characteristics and outcomes of ESD performed under general anesthesia compared with those under propofol sedation and discussed the cases in which general anesthesia is recommended. PATIENTS AND METHODS: In total, 292 lesions in 265 consecutive patients undergoing esophageal ESD at Yamaguchi University Hospital from 2013 to 2023 were included in this retrospective study. RESULTS: ESD was performed under general anesthesia for 92 lesions in 81 patients and under propofol sedation for 200 lesions in 184 patients. Tumor long-axis diameter was larger (39.8 ± 14.4 mm vs. 32.4 ± 9.9 mm, p < 0.01) and dissection speed was faster (10.5 ± 5.9 mm2/min vs. 7.5 ± 4.2 mm2/min, p < 0.01) in the general anesthesia group versus the sedation group. In the sedation group, a treatment history of pharyngeal cancer was significantly associated with a slower dissection speed (p = 0.037). The sedation group showed higher frequencies of hypoxemia (0% vs 9.8%, p < 0.01), interruption due to body movement (0% vs 13%, p < 0.01), and acute adverse events (21.7% vs 33.5%, p = 0.05). A treatment history of pharyngeal cancer was shown to be the significant factor contributing to acute adverse events (p = 0.018). CONCLUSION: Esophageal ESD under general anesthesia can be a treatment option in patients with difficulty in performing stable procedures with propofol sedation. Especially in patients with a treatment history of pharyngeal cancer in whom ESD is more difficult to be performed and who are at higher risk for acute adverse events, general anesthesia can be considered.

Impact of the preoperative nutritional status on postoperative kyphosis in geriatric patients undergoing cervical laminoplasty.

PURPOSE: This study aimed to determine the association of preoperative malnutrition with an increased risk of cervical kyphosis after laminoplasty in geriatric patients with cervical spondylotic myelopathy (CSM). METHODS: Geriatric patients who underwent cervical laminoplasty were included. Malnutrition was defined as a geriatric nutritional risk index < 98 before surgery. The C2-7 angle and the global alignment parameters were analyzed on standing radiographs. The postoperative kyphosis was defined as a C2-7 angle < 0° during a 2-year follow-up. RESULTS: Ninety patients without preoperative kyphotic alignment were enrolled (mean age, 73.5 years old; 41.1% female). Twenty-one patients (23.3%) had malnutrition status (74.2 years old). Preoperatively, the global alignment parameters were comparable between the malnutrition and normal nutrition groups (SVA, 43.3 mm vs. 42.4 mm; T1S, 29.7° vs. 28.4°; TPA, 21.4° vs. 17.8°), with no significant difference in the C2-7 angle (15.1° vs. 15.2°). At 2 years postoperatively, the malnutrition group showed a significantly lower C2-7 angle than the normal nutrition group (9.3° vs. 15.8°, P = 0.03). Postoperative kyphosis was more prevalent in the malnutrition group (33.3% vs. 7.2%, P = 0.005). The preoperative nutritional status and C2-7 angle were independent predictors of postoperative kyphosis. The predictive C2-7 angles differed by preoperative nutritional status (malnutrition group, 11°; normal nutrition group, 7°). CONCLUSION: Among geriatric CSM patients, preoperative malnutrition was closely associated with the increased occurrence of cervical kyphosis after laminoplasty. Our results underscore the importance of preoperative nutritional assessment and management in geriatric populations undergoing cervical spine surgery, as malnutrition is a perioperative modifiable risk factor.

Estimation of salt intake from spot urine may assist the risk assessment of gastric cancer.

Daily salt intake can be estimated by measuring sodium and creatinine concentrations in spot urine. Excessive salt intake is risk factor for gastric cancer. We examined the correlation between estimated salt intake from spot urine and risk of gastric cancer. This study included gastric cancer patients who underwent treatment at our hospital and patients in whom esophagogastroduodenoscopy was performed but gastric cancer was not observed. The history of H. pylori infection was known in these patients. Spot urine was collected, and daily salt intake was estimated from urine sodium and urine creatinine. Mean estimated salt intake was significantly higher in 120 gastric cancer patients (9.18 g/day) than in 80 non-gastric cancer patients (8.22 g/day). Multivariate analysis revealed estimated salt intake and H. pylori infection to be independent risk factors for gastric cancer. Among H. pylori-infected patients, salt intake was significantly higher in gastric cancer patients (9.25 g/day) than in non-gastric cancer patients (8.01 g/day). In conclusion, salt intake estimated from spot urine was high in patients with gastric cancer, especially in H. pylori infected patients. Spot urine is a simple examination and it may be applied as a new risk assessment of gastric cancer.

[A Case of Significant Ejection Fraction Reduction and Heart Failure Induced by Osimertinib].

BACKGROUND: In recent years, osimertinib has been increasingly used as a therapeutic drug for epidermal growth factor receptor(EGFR)mutation-positive lung cancer, with heart failure rarely reported as an adverse event. We report here a case of a significantly decreased ejection fraction and heart failure that were induced by osimertinib. We consider the case important and include a discussion of relevant previous reports. CASE: The patient was a 73-year-old woman who had been on oral gefitinib as first-line treatment for EGFR mutation-positive(exon19 deletion)non-small cell lung cancer for approximately 1 year and 2 months. Thereafter, she tested positive for an EGFR resistance mutation(T790M); and accordingly, oral osimerti- nib was started at 80mg/day as second-line treatment. After continuing this treatment for 6 months with no particular adverse events, she visited our hospital and was found to have dyspnea on exertion and increased pleural effusion. Based on these findings, cancer relapse was suspected, and the patient was hospitalized for detailed examinations. She was diagnosed with heart failure based on the elevated BNP level that was found in a blood test and CT and echocardiography findings, and her ejection fraction deteriorated to 19% from a pretreatment level of 59%. The conditions improved after diuretic and b- blocker treatment. Given the absence of any possible cause of heart failure or reduced ejection fraction in her past history of illness and medication, we concluded that these conditions were induced by osimertinib. CONCLUSION: While heart failure induced by EGFR-TKIs has been rarely reported, osimertinib may cause cardiomyopathy due to human epidermal growth factor receptor type 2(HER2)inhibitory activity.

[Cooperation between Clinics and Hospitals Using a Critical Path for G-CSF Prophylaxis in Cancer Chemotherapy].

BACKGROUND: Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011. METHODS: We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital. RESULTS: Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%). CONCLUSION: Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.

A prospective study of palonosetron for prevention of chemotherapy-induced nausea and vomiting in malignant lymphoma patients following highly emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is a troublesome issue in chemotherapy for cancer patients. A second-generation 5HT3 receptor antagonist (5HT3RA), palonosetron, is effective and safe for the prevention of CINV in breast cancer patients treated with cyclophosphamide and anthracycline, but there is little data for malignant lymphoma. We conducted a prospective phase 2 study at a single institution to clarify the efficacy and safety of palonosetron in lymphoma patients. METHODS: Chemotherapy-naïve lymphoma patients who were treated with highly emetogenic chemotherapy (HEC) received a single intravenous bolus of palonosetron, 0.75 mg/body, before chemotherapy on day 1 during the first course of chemotherapy. The occurrence of CINV was assessed using the Multinational Association for Supportive Care in Cancer (MASCC) antiemesis tool, which was recorded by patients during the first course of chemotherapy. RESULTS: A total of 59 patients were enrolled, and 49 patients were eligible and evaluated. The complete response (CR) rate was 93.9% (95% confidence interval 83.1-98.7%) at 0-120 h post-chemotherapy. The proportion of patients who developed nausea of any grade and vomiting at 0-120 h post-chemotherapy was 34.7 and 6.1%, respectively. Although treatment-related adverse events were observed in 36 (73.5%) patients, these were mild and they recovered by the next cycle of chemotherapy. CONCLUSION: The present study demonstrated that a single dose of palonosetron was highly effective and safe for the prevention of CINV in lymphoma patients.

Impact of Indoxyl Sulfate on Coronary Plaques in Patients on Hemodialysis.

Serum indoxyl sulfate (IS; a uremic toxin) levels, which are significantly higher in patients with chronic kidney disease, including those undergoing hemodialysis, than in the robust, are associated with both cardiovascular disease (CVD) and CVD-related mortality. Furthermore, coronary artery calcium (CAC) is an independent predictor of cardiovascular events in patients undergoing hemodialysis. This study aimed to interpret the association between serum IS levels and coronary plaque burden (CPB) or CAC.A total of 30 consecutive patients on hemodialysis, who underwent 320-row coronary multidetector computed tomography (MDCT) angiography for suspected coronary artery disease, were enrolled in this prospective study. Coronary artery percent atheroma volume (a CPB marker) and percent calcium volume (a CAC marker) assessed using MDCT were evaluated. Furthermore, various oxidative and inflammatory markers typified by serum IS levels at a dialysis-free day were measured. Using these data, we investigated correlation between the inflammatory marker IS and CPB or CAC.Multivariable analysis indicated that serum IS levels were positively correlated with CAC [partial regression coefficient, 2.89; 95% confidence interval (CI), 0.35-5.43; P = 0.03] but not with CPB, even after adjustment for cofounders. Composite cardiovascular events, namely, as all-cause death, non-fatal myocardial infarction, disabling stroke, and hospital admission for other cardiovascular events, were reported to be 50% in all patients (95% CI, 32.1-67.9).In patients undergoing hemodialysis, serum IS levels were significantly associated with CAC but not with CPB.

Inhibitory FcγRIIb-Mediated Soluble Antigen Clearance from Plasma by a pH-Dependent Antigen-Binding Antibody and Its Enhancement by Fc Engineering.

Fc engineering can modulate the Fc-FcγR interaction and thus enhance the potency of Abs that target membrane-bound Ags, but it has not been applied to Abs that target soluble Ags. In this study, we revealed a previously unknown function of inhibitory FcγRII in vivo and, using an Ab that binds to Ag pH dependently, demonstrated that the function can be exploited to target soluble Ag. Because pH-dependent Ab dissociates Ag in acidic endosome, its Ag clearance from circulation reflects the cellular uptake rate of Ag/Ab complexes. In vivo studies showed that FcγR but not neonatal FcR contributes to Ag clearance by the pH-dependent Ab, and when Fc binding to mouse FcγRII and III was increased, Ag clearance was markedly accelerated in wild-type mice and FcR γ-chain knockout mice, but the effect was diminished in FcγRII knockout mice. This demonstrates that mouse FcγRII efficiently promotes Ab uptake into the cell and its subsequent recycling back to the cell surface. Furthermore, when a human IgG1 Fc variant with selectively increased binding to human FcγRIIb was tested in human FcγRIIb transgenic mice, Ag clearance was accelerated without compromising the Ab half-life. Taken together, inhibitory FcγRIIb was found to play a prominent role in the cellular uptake of monomeric Ag/Ab immune complexes in vivo, and when the Fc of a pH-dependent Ab was engineered to selectively enhance human FcγRIIb binding, the Ab could accelerate soluble Ag clearance from circulation. We assume such a function would enhance the therapeutic potency of Abs that target soluble Ags.

Upper extremity muscle tone and response of tidal volume during manually assisted breathing for patients requiring prolonged mechanical ventilation.

[Purpose] The aim of the present study was to examine, in patients requiring prolonged mechanical ventilation, if the response of tidal volume during manually assisted breathing is dependent upon both upper extremity muscle tone and the pressure intensity of manually assisted breathing. [Subjects] We recruited 13 patients on prolonged mechanical ventilation, and assessed their upper extremity muscle tone using the modified Ashworth scale (MAS). The subjects were assigned to either the low MAS group (MAS≤2, n=7) or the high MAS group (MAS≥3, n=6). [Methods] The manually assisted breathing technique was applied at a pressure of 2 kgf and 4 kgf. A split-plot ANOVA was performed to compare the tidal volume of each pressure during manually assisted breathing between the low and the high MAS groups. [Results] Statistical analysis showed there were main effects of the upper extremity muscle tone and the pressure intensity of the manually assisted breathing technique. There was no interaction between these factors. [Conclusion] Our findings reveal that the tidal volume during the manually assisted breathing technique for patients with prolonged mechanical ventilation depends upon the patient's upper extremity muscle tone and the pressure intensity.

Test-retest reliability of expiratory abdominal compression with a handheld dynamometer in patients with prolonged mechanical ventilation.

[Purpose] The present study aimed to examine the test-retest reliability of expiratory abdominal compression with a handheld dynamometer in patients with prolonged mechanical ventilation. [Subjects and Methods] We recruited 18 patients with prolonged mechanical ventilation. All patients had impaired consciousness. The mode of the ventilator was synchronized intermittent mandatory ventilation. The abdomen above the navel was vertically compressed using a handheld dynamometer in synchronization with expiration. Expiratory abdominal compression was performed two times. We measured the tidal volume during expiratory abdominal compression. There was an interval of 5 minutes between the first and second measurements. Intraclass correlation coefficient (ICC) and Bland-Altman analysis were performed to examine the test-retest reliability of expiratory abdominal compression with a handheld dynamometer. [Results] The test-retest reliability of expiratory abdominal compression was excellent (ICC(1, 1): 0.987). Bland-Altman analysis showed that there was no fixed bias and no proportional bias. [Conclusion] The findings of this study suggest that expiratory abdominal compression with a handheld dynamometer is reliable and useful for patients with respiratory failure and prolonged mechanical ventilation.

Parameters affecting the tidal volume during expiratory abdominal compression in patients with prolonged tracheostomy mechanical ventilation.

[Purpose] The aim of this study was to clarify physical parameters affecting the tidal volume during expiratory abdominal compression in patients with prolonged tracheostomy mechanical ventilation. [Methods] Eighteen patients with prolonged mechanical ventilation were included in this study. Expiratory abdominal compression was performed on patients lying in a supine position. The abdomen above the navel was vertically compressed in synchronization with expiration and released with inspiration. We measured the tidal volume during expiratory abdominal compression. [Results] The mean tidal volume during expiratory abdominal compression was higher than that at rest (430.6 ± 127.1 mL vs. 344.0 ± 94.3 mL). The tidal volume during expiratory abdominal compression was correlated with weight, days of ventilator support, dynamic compliance and abdominal expansion. Stepwise multiple regression analysis revealed that weight (ß = 0.499), dynamic compliance (ß = 0.387), and abdominal expansion (ß = 0.365) were factors contributing to the tidal volume during expiratory abdominal compression. [Conclusion] Expiratory abdominal compression increased the tidal volume in patients with prolonged tracheostomy mechanical ventilation. The tidal volume during expiratory abdominal compression was influenced by each of the pulmonary conditions and the physical characteristics.

Comparison of changes in tidal volume associated with expiratory rib cage compression and expiratory abdominal compression in patients on prolonged mechanical ventilation.

[Purpose] This study was designed to compare and clarify the relationship between expiratory rib cage compression and expiratory abdominal compression in patients on prolonged mechanical ventilation, with a focus on tidal volume. [Subjects and Methods] The subjects were 18 patients on prolonged mechanical ventilation, who had undergone tracheostomy. Each patient received expiratory rib cage compression and expiratory abdominal compression; the order of implementation was randomized. Subjects were positioned in a 30° lateral recumbent position, and a 2-kgf compression was applied. For expiratory rib cage compression, the rib cage was compressed unilaterally; for expiratory abdominal compression, the area directly above the navel was compressed. Tidal volume values were the actual measured values divided by body weight. [Results] Tidal volume values were as follows: at rest, 7.2 ± 1.7 mL/kg; during expiratory rib cage compression, 8.3 ± 2.1 mL/kg; during expiratory abdominal compression, 9.1 ± 2.2 mL/kg. There was a significant difference between the tidal volume during expiratory abdominal compression and that at rest. The tidal volume in expiratory rib cage compression was strongly correlated with that in expiratory abdominal compression. [Conclusion] These results indicate that expiratory abdominal compression may be an effective alternative to the manual breathing assist procedure.

Capsule formation induced by flow.

Physical compartments are essential for the origin of life. While lipid vesicles are commonly regarded as precursors of cell membranes, we propose a simpler and more primitive model based on proteinoids. Proteinoids are macromolecules formed by the thermal polymerization of amino acids, mimicking primitive proteins. They self-assemble into spherical microspheres in water. Under a temperature gradient, proteinoid microspheres (PM) dissolve and flow, forming microcapsules with thin shells. The mechanism of this process has not yet been elucidated. We hypothesize that it involves the interplay between the dissolution and flow of PM. We tested our hypothesis by applying forced flow to the PM and observing capsule formation. We found that neither heat nor flow alone can produce capsules, confirming our hypothesis. We conclude that flow-induced capsule formation is a general phenomenon and a plausible model for the origin of physical compartments in early life.

Inner and outer penetrating spinal cord injuries lead to distinct overground walking in mice.

Spinal cord injury (SCI) is a devastating mechanical trauma. Although locomotion of model animals that mimic contusion SCI was actively examined, locomotion after penetrating SCI caused by sharp objects was not extensively studied. Severity of walking difficulty after partial transection of the spinal cord including penetrating SCI likely depends on the regions affected. Therefore, we compared beam walking and overground walking between mice after penetrating SCI at inner spinal cord region and mice with the injury at the outer region. Mice with the both penetrating SCIs did not display changes in beam walking. When appearance and movements of hindlimbs during overground walking was rated using Basso Mouse Scale for locomotion (BMS), however, mice with inner penetrating SCI showed low score shortly after the SCI. However, the score became high at later time points, as seen in contusion SCI mice. By contrast, BMS score did not decrease shortly after the outer penetrating SCI. However, the score became low 3 weeks after the SCI. As quantitative values during overground walking, movement duration in an open field were shorter at 1 day after the two penetrating SCIs. However, slower moving speed and fewer number of movement at 1 day were specific to mice with inner and outer penetrating SCIs, respectively. Moreover, BMS score was correlated with walking distance in open field only in mice with inner penetrating SCI. Thus, inner and outer penetrating SCI cause difficulty in overground walking with different severity and progress.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography revealed the course of granulocyte-colony stimulating factor-associated aortitis: A case report.

A 72-year-old man with diffuse large B-cell lymphoma underwent fluorine-18 fluorodeoxyglucose (FDG) PET/CT, revealing lymphoma lesions and no evidence of aortitis. The patient received chemotherapy and was treated with granulocyte colony-stimulating factor (G-CSF) for neutropenia. During chemotherapy, the patient underwent PET/CT again, revealing FDG accumulation and wall thickening at the aortic arch, which suggested aortitis. The patient was only experiencing fatigue. G-CSF-associated aortitis was suspected, and the original G-CSF was switched to another G-CSF while continuing chemotherapy. Three months later, the third round of PET/CT showed that FDG accumulation and wall thickening of the aortic arch vanished. PET/CT may be useful for not only the diagnosis but follow-up of G-CSF-associated aortitis. Radiologists should recognize incidental aortitis on PET/CT in patients receiving G-CSF administration.

"Bloomy rind sign" in varicella-zoster virus brainstem meningoencephalitis.

The bloomy rind sign, characterized by band-like abnormalities along the surface of the brainstem on magnetic resonance imaging without contrast enhancement, has been considered a specific imaging marker for leptomeningeal metastasis from lung adenocarcinoma. In this study, we describe the case of an 85-year-old male with a 3-week history of headache, fever, and progressive cognitive impairment. The patient was diagnosed with varicella-zoster virus brainstem meningoencephalitis and magnetic resonance imaging revealed hyperintensities along the brainstem surface on fluid-attenuated inversion recovery and diffusion-weighted imaging that mimicked a bloomy rind sign. However, the patient showed no signs of lung cancer or meningeal carcinomatosis. This case suggests that the bloomy rind sign is not exclusive to leptomeningeal metastasis but can also be observed in other conditions, such as central nervous system infections.

Adrenal ganglioneuroma with nodal metastases on 123I-MIBG SPECT/CT and 18F-FDG PET/CT.

Ganglioneuroma is a well-differentiated tumor originating from neural crest cells of the sympathetic nervous system. Although benign, a few cases have been reported that ganglioneuroma can metastasize to other sites. We report a case of adrenal ganglioneuroma with para-aortic nodal metastases with low FDG and MIBG uptake. In order to avoid unnecessary wide excision or aggressive medication, it is important to consider the possibility of ganglioneuroma preoperatively even if with metastases.

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a nonhemophilic state.

BACKGROUND: Emicizumab, a factor (F) VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment option for people with hemophilia A (PwHA). However, a small proportion of PwHA still experience bleeds even under emicizumab prophylaxis, as observed in the long-term outcomes of clinical studies. A more potent BsAb may be desirable for such patients. OBJECTIVES: To identify a potent BsAb to FIXa and FX, NXT007, surpassing emicizumab by in vitro and in vivo evaluation. METHODS: New pairs of light chains for emicizumab's heavy chains were screened from phage libraries, and subsequent antibody optimization was performed. For in vitro evaluation, thrombin generation assays were performed with hemophilia A plasma. In vivo hemostatic activity was evaluated in a nonhuman primate model of acquired hemophilia A. RESULTS: NXT007 exhibited an in vitro thrombin generation activity comparable to the international standard activity of FVIII (100 IU/dL), much higher than emicizumab, when triggered by tissue factor. NXT007 also demonstrated a potent in vivo hemostatic activity at approximately 30-fold lower plasma concentrations than emicizumab's historical data. In terms of dose shift between NXT007 and emicizumab, the in vitro and in vivo results were concordant. Regarding pharmacokinetics, NXT007 showed lower in vivo clearance than those shown by typical monoclonal antibodies, suggesting that the Fc engineering to enhance FcRn binding worked well. CONCLUSION: NXT007, a potent BsAb, was successfully created. Nonclinical results suggest that NXT007 would have a potential to keep a nonhemophilic range of coagulation potential in PwHA or to realize more convenient dosing regimens than emicizumab.

[A case with double primary cancers in both lung and nasal cavity].

Our patient, a 77-year-old male, underwent a medical examination for lower back pain. A careful investigation revealed two large tumors both in his lung and nose. The diagnosis was well-differentiated squamous cell carcinoma by biopsy in both sides. Radiation therapy(36 Gy)was performed on his nasal cavity, and nasal tumor volume was reduced considerably. Because the primary lesion could not be determined we used docetaxel chemotherapy which can be applied for both lung cancer and head and neck cancer. As a result, dissociation of the treatment's effect was seen, and we suspected the presence of overlapping cancer in both lung and nasal cavity. We could not use immunostaining to identify the primary lesion in squamous cell carcinoma as we did for adenocarcinoma. In this case we could infer the presence of overlapping cancer over the course of treatment with chemotherapy.