ABSTRACT
BACKGROUND: Elevated serum alkaline phosphatase (ALP) levels are a risk factor for all-cause mortality in hemodialysis patients. Traditionally in Japan, ALP measurements were conducted using the JSCC method, which yields higher ALP measurement values than the IFCC method, mainly due to its increased sensitivity to intestinal ALP. METHODS: Serum total ALP levels before and after switching the assay method from JSCC to IFCC were compared among different blood types in 521 hemodialysis patients (Study 1). The association between ALP levels measured by the JSCC method and 7-year mortality was analyzed, including blood types and liver function parameters as covariates, in 510 hemodialysis patients (Study 2). RESULTS: ALP levels measured by the JSCC method were approximately three times higher than those measured by the IFCC method, with significant elevation in patients with blood types B and O compared to those with blood types A and AB. Similarly, ALP levels measured by the IFCC method were significantly higher in patients with blood types B and O compared to those with blood types A and AB (Study 1). The highest tertile of ALP levels showed a significantly increased risk of all-cause mortality, even after adjusting for patient background. However, this significance disappeared when serum liver function-related or inflammatory markers were included as covariates (Study 2). CONCLUSION: ALP levels measured by the JSCC method are associated with life prognosis, but caution should be exercised due to their elevation in patients with blood types B and O and in those with hepatic dysfunction or inflammation.
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Rolling walkers are common walking aids for individuals with poor physical fitness or balance impairments. There is no doubt that rolling walkers are useful in assisting locomotion. On the other hand, it is arguable that walking with rolling walkers (WW) is effective for maintaining or restoring the nervous systems that are recruited during conventional walking (CW). This is because the differences and similarities of the neural control of these locomotion forms remain unknown. The purpose of the present study was to compare the neural control of WW and CW from the perspective of a split-belt adaptation paradigm and reveal how the adaptations that take place in WW and CW would affect each other. The anterior component of the ground reaction (braking) forces was measured during and after walking on a split-belt treadmill by 10 healthy subjects, and differences in the peak braking forces between the left and right sides were calculated as the index of the split-belt adaptation (the degree of asymmetry). The results demonstrated that (1) WW enabled subjects to respond to the split-belt condition immediately after its start as compared to CW; (2) the asymmetry movement pattern acquired by the split-belt adaptation in one gait mode (i.e., CW or WW) was less transferable to the other gait mode; (3) the asymmetry movement pattern acquired by the split-belt adaptation in CW was not completely washed out by subsequent execution in WW and vice versa. The results suggest unique control of WW and the specificity of neural control between WW and CW; use of the walkers is not necessarily appropriate as training for CW from the perspective of neural control.
Subject(s)
Adaptation, Physiological , Walking , Humans , Male , Adaptation, Physiological/physiology , Walking/physiology , Adult , Female , Young Adult , Walkers , Biomechanical Phenomena/physiology , Gait/physiologyABSTRACT
Regulatory T cells (Tregs) play an important role in creating an immunosuppressive microenvironment in cancer tissues. However, the mechanisms by which Tregs are activated and suppress cancer immunity remain unclear. To elucidate these mechanisms, we performed a T cell receptor (TCR) repertoire analysis of Tregs and conventional T cells in peripheral blood, draining lymph nodes (DLNs), and cancer tissues of patients with head and neck squamous cell cancer (HNSCC). We found that the TCR repertoire was skewed in cancer tissue and metastatic DLNs (M-DLNs) compared with non-metastatic DLNs, and TCR repertoire similarities in Tregs and CD8+ T cells between M-DLNs and cancer tissue were high compared with those at other sites. These results suggest that Tregs and CD8+ T cells are activated in M-DLNs and cancer tissues by cancer antigens, such as neoantigens, and shared antigens and Tregs suppress CD8+ T cell function in a cancer antigen-specific manner in M-DLNs and cancer tissue. Moreover, M-DLNs might be a source of Tregs and CD8+ T cells recruited into the cancer tissue. Therefore, targeting Tregs in M-DLNs in an antigen-specific manner is expected to be a novel immunotherapeutic strategy for HNSCCs.
Subject(s)
CD8-Positive T-Lymphocytes , Head and Neck Neoplasms , Lymph Nodes , Squamous Cell Carcinoma of Head and Neck , T-Lymphocytes, Regulatory , T-Lymphocytes, Regulatory/immunology , Humans , Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/pathology , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/pathology , Lymph Nodes/pathology , Lymph Nodes/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Male , Tumor Microenvironment/immunology , Lymphatic Metastasis/pathology , Lymphatic Metastasis/immunology , Female , Middle Aged , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/pathology , Aged , Receptors, Antigen, T-Cell/immunologyABSTRACT
Self-assembly processes are widely used in nature to form hierarchically organized structures, prompting us to investigate such processes at the macroscopic scale. We report an unprecedented approach toward the self-assembly of alkyl-fullerene (C60) derivatives into a hexagonal array of hemispherical microparticles akin to the morphology of a compound eye. The method includes casting solvated alkyl-C60compound on an air/water interface followed by controlled evaporation of the solvent under atmosphere-sealed conditions. This leads to the formation of a thin film floating on water with a diameter of up to 1.3 centimeters and exhibiting a hexagonally-packed hemispherical structure with a diameter of approximately 38µm. Various measurements of the formed film reveal that amorphousness is necessary for suppressing uncontrollable crystallization, which affects the microparticle size and film formation mechanism. We tested the feasibility of this approach for the self-assembly of a relatively common C60derivative, [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM), resulting in the formation of a film with a similar pattern of hexagonally-packed larger microparticles approximately 152µm in size of diameter.
ABSTRACT
PURPOSE: Given the uncertainty surrounding the abscopal effect (AE), it is imperative to identify promising treatment targets. In this study, we aimed to explore the incidence of AE when administering radiotherapy to patients with oligoprogressive solid tumours while they are undergoing treatment with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: In this multicentre prospective observational study, oligoprogressive disease was defined as a < 20% increase in lesions compared to > 2 months before enrolment. We enrolled patients who requested radiotherapy during the ICI rest period between 2020 and 2023. AE was considered present if ≥ 1 non-irradiated lesion decreased by ≥ 30% before the next line of systemic therapy started. RESULTS: Twelve patients were included in this study; the common primary lesions were in the lungs (four patients) and kidneys (three patients). AEs were observed in six (50%) patients, with a median time to onset of 4 (range 2-9) months after radiotherapy. No significant predictors of AEs were identified. Patients in the AE group had a significantly better 1-year progression-free survival (PFS) rate than those in the non-AE group (p = 0.008). Two patients from the AE group were untreated and progression-free at the last follow-up. Four (33%) patients experienced grade 2 toxicity, with two cases attributed to radiotherapy and the other two to ICI treatment. No grade 3 or higher toxicities were observed in any category. CONCLUSION: Patients with oligoprogressive disease may be promising targets with potential for AEs. AEs can lead to improved PFS and, in rare cases, to a certain progression-free period without treatment. Irradiating solid tumours in patients with oligoprogressive disease during immune checkpoint inhibitor therapy may be a promising target with the potential for abscopal effects (AEs). AEs can lead to improved progression-free survival and, in rare cases, to a certain progression-free period without treatment.
Subject(s)
Lung Neoplasms , Neoplasms , Radiation Oncology , Humans , Immune Checkpoint Inhibitors/therapeutic use , Neoplasms/drug therapy , Neoplasms/radiotherapy , Kidney , Progression-Free Survival , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapyABSTRACT
Mycobacterium abscessus subsp. abscessus (MABA) is refractory and sometimes fatal especially in an immunocompromised patient. Also, MABA-associated pneumothorax is an extremely rare complication. We report a case of MABA pulmonary infection complicated pneumothorax treated successfully. A 69-year-old Japanese female with immunosuppressed systemic sclerosis-associated interstitial lung disease experienced left-sided secondary spontaneous pneumothorax. MABA was detected in the pleural effusion and blood culture. Microbial sensitivity test showed the MABA was sensitive to only amikacin, sitafloxacin, and clofazimine. Combination therapy with these antibiotics including azithromycin achieved remission within three weeks. In the treatment of MABA infection, compliance with microbial sensitivity test is crucial.
ABSTRACT
Coronary artery calcification (CAC) is associated with cardiovascular disease (CVD). CAC might contain calcium oxalate, and a high serum oxalate (SOx) concentration is associated with cardiovascular mortality in dialysis patients. We assessed the associations between SOx and CAC or CVD events in Japanese hemodialysis patients. This cross-sectional and retrospective cohort study was done in 2011. Seventy-seven hemodialysis patients' Agatston CAC score was measured, and serum samples were collected. SOx concentrations were measured in 2021 by using frozen samples. Also, new-onset CVD events in 2011-2021 were retrospectively recorded. The association between SOx concentration and CAC score ≥ 1000, and new-onset CVD events were examined. Median SOx concentration and CAC score were 266.9 (229.5-318.5) µmol/L and 912.5 (123.7-2944), respectively. CAC score ≥ 1000 was associated with SOx [adjusted odds ratio (OR) 1.01, 95% confidence interval (CI), 1.00-1.02]. The number of new-onset CVD events was significantly higher in patients with SOx ≥ median value [hazard ratio (HR) 2.71, 95% CI 1.26-6.16]. By Cox proportional hazard models, new-onset CVD events was associated with SOx ≥ median value (adjusted HR 2.10, 95% CI 0.90-4.91). SOx was associated with CAC score ≥ 1000 and new-onset CVD events in Japanese hemodialysis patients.
Subject(s)
Cardiovascular Diseases , Coronary Artery Disease , Vascular Calcification , Humans , Retrospective Studies , Coronary Vessels , Oxalates , Cross-Sectional Studies , East Asian People , Coronary Angiography , Renal Dialysis/adverse effects , Coronary Artery Disease/complications , Cardiovascular Diseases/etiology , Cardiovascular Diseases/complications , Vascular Calcification/etiology , Vascular Calcification/complications , Risk FactorsABSTRACT
OBJECTIVES/HYPOTHESIS: Some people who practice singing on a daily basis may be able to produce a voice higher than the upper limit of the normal range (extra high voice), but there is much regarding the movement of the larynx that remains unknown. We have been conducting dynamic analysis of the larynx using multi-row detection computed tomography (MD-CT) at our university and report herein an analysis of the extra high voice. STUDY DESIGN: Observational. METHODS: Images of a normal male participant capable of extremely high-frequency speech (the highest speech range is C7 [2093 Hz] and the singing application range is up to B5 [988 Hz]) during speech were captured by MD-CT. The acquisition time was 2 seconds, and the rise of the voice from low to high and then to very high tones was recorded. Ten frames per second were analyzed as three-dimensional images. RESULTS: In the fundamental frequency range from A3 to D5 (220-587 Hz), laryngeal elevation movements were observed as the voice rose in pitch. However, posterior upward displacement of the laryngeal cartilage was observed as the frequency range increased from E5 to B5 (659-988 Hz). CONCLUSIONS: In the E5-B5 range, laryngeal movements were different from those observed in the previous range. MD-CT analysis is useful in the study of this range because it allows visualization of laryngeal movements that are unclear using endoscopy or external examination.
ABSTRACT
BACKGROUND: Dialysis patients often take multiple oral medications, leading to a high pill burden. Phosphate binders (PBs) account for a large proportion of this daily pill burden (DPB). The relationship between DPB and mortality risk remains unclear, and we hypothesized that this relationship might be influenced by the proportion of PBs to all medications. METHODS: We divided DPB into those derived from PBs and non-PB drugs and analyzed the association with mortality risk over a 7-year period in 513 chronic hemodialysis patients using a baseline model. RESULTS: The median (interquartile range) DPB from all drugs was 15.8 (11.2-21.0) pills/day/patient, and the median ratio of PB pills to all drug pills was 29.3 (13.7-45.9)% at baseline. During a median observation period of 5.2 years, 161 patients (31.4%) died. Kaplan-Meier analysis showed no significant difference in all-cause mortality between PB users and non-users. However, a significant survival advantage was observed in the highest tertile of DPB from PBs compared to the lowest tertile. Conversely, the highest tertile of DPB from non-PB drugs was associated with worse survival. Consequently, the highest tertile of the ratio of PBs to all pills was associated with better survival. This association remained significant even after adjusting for patient characteristics in the Cox proportional hazards model. However, when serum nutritional parameters were included as covariates, the significant association disappeared. CONCLUSIONS: Dialysis patients prescribed a higher rate of PB pills to all medications exhibited a lower mortality risk, possibly due to their better nutritional status.
Subject(s)
Kidney Failure, Chronic , Renal Dialysis , Humans , Renal Dialysis/adverse effects , Cohort Studies , Follow-Up Studies , Phosphorus , PhosphatesABSTRACT
Radical temporal bone resection (TBR) for lateral skull base malignancies is technically challenging because of the vital anatomical structures located at the medial part of the temporal bone and their limited exposure. A possible solution is to adopt an additional endoscopic approach for medial osteotomy to reduce blind spots. The authors aimed to describe a combined exoscopic and endoscopic approach (CEEA) for cranial dissection in radical TBR and to determine the usefulness of the endoscopic approach to the medial aspect of the temporal bone. Having utilized the CEEA in for cranial dissection in radical TBR since 2021, the authors included 5 consecutive patients who underwent the procedure between 2021 and 2022. All surgeries were successful and resulted in no significant complications. The additional use of an endoscope improved visualization of the middle ear in 4 patients and that of the inner ear and carotid canal in 1 patient, enabling precise and safe cranial dissection. Furthermore, surgeons experienced reduced intraoperative postural stress with CEEA than with a microscopic approach. The main advantage of CEEA in radical TBR was the extension of the viewing angles of the endoscope, which allowed observation of the medial aspect of the temporal bone and limited tumor exposure and injury to vital structures. Given the other benefits of exoscopes and endoscopes, including compact size, ergonomics, and surgical field accessibility, CEEA proved to be an efficient treatment option for cranial dissection in radical TBR.
Subject(s)
Neurosurgical Procedures , Skull Base , Humans , Skull Base/surgery , Neurosurgical Procedures/methods , Endoscopes , Osteotomy , Temporal Bone/surgery , Endoscopy/methodsABSTRACT
Neck dissection for cervical lymph node metastasis is an established procedure for head and neck cancer (HNC). However, with the advent of immunotherapy, head and neck surgical oncologists need to rethink removing all lymph nodes, including those with immune function. We investigated the anti-cancer immune response of the cervical lymph nodes in four patients with human papillomavirus type 16 (HPV16)-positive head and neck squamous cell carcinoma. Using lymphocytes extracted from local, metastatic, and non-metastatic lymph nodes and peripheral blood from these patients, we performed an intracellular flow cytometric cytokine assay using anti-IFNγ and anti-TNF-α monoclonal antibodies to detect HPV16 E6- and E7-specific T cells. HPV status and p16 immunostaining were determined by in situ detection using the HPV RNAscope method and immunohistochemistry. In one case, E6-specific and E7-specific CD8+ T cells were detected in proximal metastatic nodes and distal non-metastatic nodes. This finding suggests that non-metastatic nodes should be preserved for their immune function during neck dissection and that the immune function of non-metastatic lymph nodes is important when administering immunotherapy. In this context, head and neck surgical oncologists treating HNC should consider the place of immunotherapy and neck dissection in the treatment of HNC.
ABSTRACT
In the treatment of head and neck cancer, cisplatin is often used as a therapeutic agent; however, its efficacy is limited and it can cause renal dysfunction as an adverse effect. For this reason, the use of cisplatin is limited in elderly patients with reduced renal function. Recently, artemisinin, which was developed as an antimalarial drug, was found to have antitumor effects and is effective in combination with other anticancer drugs. In the present study, the antitumor effects of artemisinin and its derivatives as well as their combination with cisplatin and iron on head and neck squamous cell carcinoma cell lines, were investigated. Cell viability was determined by a cell viability assay, the cell cycle was analyzed by flow cytometry, cell death was assessed with annexin V and propidium iodide staining, and western blotting was used to analyze retinoblastoma protein (Rb), phosphorylated (p)Rb, and other cell cycleassociated molecules. A total of four artemisinin compounds were examined and it was found that artesunate and dihydroartemisinin had a significant inhibitory effect on growth. It was also identified that the combination of artesunate, cisplatin, and iron inhibited cell proliferation and caused S/G2M cell cycle arrest. In addition, western blotting of Rb, a molecule involved in the cell cycle, showed that artesunate induced the loss of not only Rb but also pRb. These results suggested that artesunate is a useful drug in combination with cisplatin.
Subject(s)
Artemisinins , Head and Neck Neoplasms , Humans , Aged , Cisplatin/pharmacology , Artesunate/pharmacology , Squamous Cell Carcinoma of Head and Neck , Cell Proliferation , Artemisinins/pharmacology , Cell Cycle , Apoptosis , Head and Neck Neoplasms/drug therapy , IronABSTRACT
All-trans retinoic acid (ATRA) is used as standard induction therapy for acute promyelocytic leukemia (APL), but it is contraindicated for patients on hemodialysis. We present a case of a patient with APL on hemodialysis, intubated, and with marked disseminated intravascular coagulation (DIC) who was successfully treated with ATRA. A 49-year-old man was transferred to our hospital and admitted into the intensive care unit due to renal dysfunction, DIC, and pneumonia. Promyelocytes were noted in the peripheral blood, and he was diagnosed with APL after bone-marrow examination. Because of renal dysfunction, only Ara-C was used but with a reduced dose. The patient's condition improved, and he was extubated and withdrawn from dialysis on the 5th day of hospitalization. The patient suffered from APL syndrome during induction therapy, which necessitated ATRA withdrawal and steroid administration. Remission was achieved after induction therapy, and the patient is currently on maintenance therapy. There are few cases of patients with APL on hemodialysis who were treated with ATRA; hence, it is necessary to review the treatment plan for these patients.
Subject(s)
Acute Kidney Injury , Leukemia, Promyelocytic, Acute , Male , Humans , Middle Aged , Leukemia, Promyelocytic, Acute/drug therapy , Remission Induction , Tretinoin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Renal DialysisABSTRACT
In 15-20% of cases, Graves' disease (GD) shifts to Hashimoto's thyroiditis (HT), while the shift from HT to GD is rare. We present a case of a patient in whom HT shifted to GD, along with a literature review. A 50-year-old woman with myxedema was diagnosed with Hashimoto's disease due to hypothyroidism and the presence of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb); she also had thyroid stimulating antibodies (TSAb) without any signs of GD. Although thyroid hormone replacement therapy improved her thyroid function, 2 months later, hyperthyroidism appeared and did not improve after discontinuation of the replacement therapy. The patient was diagnosed with GD, which improved with antithyroid agent administration. To date, only 50 cases regarding conversion from HT to GD have been reported. The median age is 44 years (range, 23-82 years), and the median time of conversion is 7 years (range, 0.1-27 years). The male-to-female ratio of HT conversion to GD is 1:9, closer to that of regular GD (1:10) than that of general HT (1:18). All patients received thyroid hormone replacement therapy for hypothyroidism due to HT. Continuous evaluation of TSAb levels is recommended in HT, particularly in cases of TSAb-positive and those under replacement, since it may help predict conversion to GD. Evaluating the clinical characteristics of patients with HT preceding GD is crucial to ensure appropriate treatment and reduce the risk of adverse events.
Subject(s)
Graves Disease , Hashimoto Disease , Hyperthyroidism , Hypothyroidism , Thyroiditis, Autoimmune , Humans , Male , Female , Young Adult , Adult , Middle Aged , Aged , Aged, 80 and over , Hashimoto Disease/complications , Hashimoto Disease/diagnosis , Hashimoto Disease/drug therapy , Graves Disease/complications , Graves Disease/drug therapyABSTRACT
Primary and metastatic malignancies arising in the sinuses are rare and histologically diverse. The role of fine-needle aspiration cytology (FNAC) and the cytomorphologic characteristics of these tumors have not been specifically addressed. We described two cases of suspected malignant maxillary sinus tumors in 85- and 90-year-old patients with comorbid conditions, both of whom underwent tissue biopsies that failed to yield a definitive diagnosis. We performed FNAC after imaging confirmed that the malignant tumors were outside the maxillary sinus. The 85- and 90-year-old patients were diagnosed with squamous cell carcinoma (SCC) and adenocarcinoma, respectively. In the latter, the cell block method was used to prepare the specimen, rendering individual cells identifiable. Atypia of the histological structure was confirmed without the influence of cell duplication, a known weakness of FNAC. Thus, the diagnosis was made quickly. We believe that FNAC would be utilized more frequently for the definitive diagnosis of sinonasal tumors as the technique and diagnostic technology improve further.
ABSTRACT
Walking with pulling force fields acting at the body center of mass (in the forward or backward directions) is compatible with inclined walking and is used in clinical practice for gait training. From the perspective of known differences in the motor strategies that underlie walking with the respective force fields, the present study elucidated whether the adaptation acquired by walking on a split-belt treadmill with either one of the force fields affects subsequent walking in a force field in the opposite directions. Walking with the force field induced an adaptive and de-adaptive behavior of the subjects, with the aspect evident in the braking and propulsive impulses of the ground reaction force (difference in the peak value between the left and right sides for each stride cycle) as parameters. In the parameters, the adaptation acquired during walking with a force field acting in one direction was transferred to that in the opposite direction only partially. Furthermore, the adaptation that occurred while walking in a force field in one direction was rarely washed out by subsequent walking in a force field in the opposite direction and thus was maintained independently of the other. These results demonstrated possible independence in the neural functional networks capable of controlling walking in each movement task with an opposing force field.
Subject(s)
Gait , Walking , Humans , Mechanical Phenomena , Adaptation, Physiological , Acclimatization , Biomechanical PhenomenaABSTRACT
Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC.
Subject(s)
Carcinoma, Mucoepidermoid , Salivary Gland Neoplasms , Humans , DNA-Binding Proteins/genetics , Trans-Activators/genetics , Carcinoma, Mucoepidermoid/pathology , In Situ Hybridization, Fluorescence , Cisplatin , Transcription Factors/genetics , Biopsy , Cell Line, Tumor , Fluorouracil/pharmacology , Salivary Gland Neoplasms/pathology , Oncogene Proteins, Fusion/geneticsABSTRACT
Recently, the usefulness of serum uromodulin (sUmod) as a novel renal biomarker has been attracting attention. Clinical evidence regarding sUmod measurements has been accumulated by analyzing cross-sectional data. However, little is known about the longitudinal data on sUmod. Therefore, we decided to investigate the variability of sUmod in patients with acute kidney injury due to different causes. High concentrations of sUmod have been observed in patients with acute tubular injury (ATI) and/or acute interstitial nephritis (AIN). sUmod could be used as an auxiliary diagnostic tool for ATI and AIN.
ABSTRACT
Regulatory T-cells (Tregs) play a major role in suppressing anti-tumor immune responses. Mogamulizumab, an anti-CC chemokine receptor type 4 (CCR4) monoclonal antibody, depletes effector Tregs (eTregs). However, the clinical efficacy of mogamulizumab was limited in phase Ia/Ib studies for solid tumors (NCT01929486); the finding suggests that mogamulizumab may also deplete beneficial CCR4+CD8+ T-cells in patients. Therefore, we focused on CTLs and aimed to identify a way to protect CCR4+ CTLs. Here, we evaluated the association of CCR4 expression in cytotoxic T-lymphocytes (CTLs) with antigen and cytokine stimulations and kinase inhibition using cytomegalovirus antigen instead of tumor antigen. CCR4 expression in CTLs was induced by antigen stimulation (mean 3.14-29.0%), enhanced by transforming growth factor-ß1 (TGF-ß1) (mean 29.0-51.2%), and downregulated by trametinib with (mean 51.2-11.4%) or without TGF-ß1 treatment (mean 29.0-6.98%). Phosphorylation of ERK in CD8+ T-cells was suppressed by trametinib. Regarding the effect on immunological function of CTL, trametinib reduced cytokine production but not affected cytotoxicity. Importantly, trametinib alleviated CTL reduction by anti-CCR4 antibody without affecting eTreg depletion because CCR4 expression in eTregs was not downregulated. In conclusion, combination therapy with trametinib may improve the clinical efficacy of mogamulizumab.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Mouth Neoplasms , Humans , T-Lymphocytes, Regulatory , Transforming Growth Factor beta1/metabolism , CD8-Positive T-Lymphocytes/metabolism , T-Lymphocytes, Cytotoxic/metabolism , Carcinoma, Squamous Cell/metabolism , Squamous Cell Carcinoma of Head and Neck/metabolism , Mouth Neoplasms/drug therapy , Mouth Neoplasms/metabolism , Receptors, CCR4/metabolism , Head and Neck Neoplasms/metabolismABSTRACT
For decades, no clear consensus existed on the standard treatment option for malignant tumors of the external auditory canal, an extremely rare disease. Here we report the case of a 55-year-old female patient with secretory carcinoma that originated from the left external auditory canal. Magnetic resonance imaging (MRI) at baseline showed that the tumor had extended to the medulla oblongata despite surgical and radiation treatments for more than 20 years from the initial diagnosis. Based on the results of a next-generation sequencing test of a formalin-fixed paraffin-embedded surgical specimen indicating that the tumor harbored ETV6-NTRK3 fusion, the patient was enrolled in a global basket study of larotrectinib, an oral selective tropomyosin receptor kinase (TRK) inhibitor. Three weeks after the start of larotrectinib treatment, MRI showed only small remnants of the tumor in the medulla oblongata and the patient's headache before the treatment had disappeared. Subsequent MRI after 12 weeks of treatment confirmed the complete disappearance of the tumor. The patient repeated grade 2 flu-like symptoms related to treatment, but did not experience any other grade 2 or worse treatment-related adverse events. TRK inhibitors, such as larotrectinib, exert potent antitumor activity against neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors in a tumor-agnostic manner. To the best of our knowledge, this is the first report on NTRK fusion-positive secretory carcinoma of the external auditory canal, and this report provides a valuable insight into the management of the extremely rare but now treatable malignancy.