Brain-Specific Angiogenesis Inhibitor 3 Is Expressed in the Cochlea and Is Necessary for Hearing Function in Mice.

Mammalian auditory hair cells transduce sound-evoked traveling waves in the cochlea into nerve stimuli, which are essential for hearing function. Pillar cells located between the inner and outer hair cells are involved in the formation of the tunnel of Corti, which incorporates outer-hair-cell-driven fluid oscillation and basilar membrane movement, leading to the fine-tuned frequency-specific perception of sounds by the inner hair cells. However, the detailed molecular mechanism underlying the development and maintenance of pillar cells remains to be elucidated. In this study, we examined the expression and function of brain-specific angiogenesis inhibitor 3 (Bai3), an adhesion G-protein-coupled receptor, in the cochlea. We found that Bai3 was expressed in hair cells in neonatal mice and pillar cells in adult mice, and, interestingly, Bai3 knockout mice revealed the abnormal formation of pillar cells, with the elevation of the hearing threshold in a frequency-dependent manner. Furthermore, old Bai3 knockout mice showed the degeneration of hair cells and spiral ganglion neurons in the basal turn. The results suggest that Bai3 plays a crucial role in the development and/or maintenance of pillar cells, which, in turn, are necessary for normal hearing function. Our results may contribute to understanding the mechanisms of hearing loss in human patients.

Establishment of a new practical telesurgical platform using the hinotori™ Surgical Robot System: a preclinical study.

AIM: The recent development of new surgical robots and network telecommunication technology has opened new avenues for robotic telesurgery. Although a few gastroenterological surgeries have been performed in the telesurgery setting, more technically demanding procedures including gastrectomy with D2 lymphadenectomy and intracorporeal anastomosis have never been reported. We examined the feasibility of telesurgical robotic gastrectomy using the hinotori™ Surgical Robot System in a preclinical setting. METHODS: First, the suturing time in the dry model was measured in the virtual telesurgery setting to determine the latency time threshold. Second, a surgeon cockpit and a patient unit were installed at Okazaki Medical Center and Fujita Health University, respectively (approximately 30 km apart), and connected using a 10-Gbps leased optic-fiber network. After evaluating the feasibility in the dry gastrectomy model, robotic distal gastrectomies with D2 lymphadenectomy and intracorporeal B-I anastomosis were performed in two porcine models. RESULTS: The virtual telesurgery study identified a latency time threshold of 125 ms. In the actual telesurgery setting, the latency time was 27 ms, including a 2-ms telecommunication network delay and a 25-ms local information process delay. After verifying the feasibility of the operative procedures using a gastrectomy model, two telesurgical gastrectomies were successfully completed without any unexpected events. No fluctuation was observed across the actual telesurgeries. CONCLUSION: Short-distance telesurgical robotic surgery for technically more demanding procedure may be safely conducted using the hinotori Surgical Robot System connected by high-speed optic-fiber communication.

Deficiency of large tumor suppressor kinase 1 causes congenital hearing loss associated with cochlear abnormalities in mice.

Mammalian auditory hair cells are not spontaneously replaced. Their number and coordinated polarization are fairly well-maintained and both these factors might be essential for the cochlear amplifier. Cell cycle regulation has critical roles in regulating appropriate cell size and cell number. However, little is known about the physiological roles of the Hippo pathway, which is one of the most important signaling cascades that regulates cell growth, differentiation, and regenerative capacity in the cochlear sensory epithelium. Herein, we investigated the in vivo role of the large tumor suppressor 1 (LATS1), an essential kinase in the Hippo/yes-associated protein pathway, in the cochlea using the LATS1 knockout mice. LATS1 was expressed in hair cells and supporting cells. It was strongly expressed on the surface of the cuticular plate of the organ of Corti. We found that LATS1 knockout caused congenital hearing loss due to the irregular orientation and slightly reduced number of hair cells, whereas the number of supporting cells remained unchanged. On the surface of the hair cells, the kinocilium and stereocilia were dispersed during and after morphogenesis. However, the expression of the receptor-independent polarity regulators, such as Par3 or Gαi, was not affected. We concluded that LATS1 has an indispensable role in the maturation of mammalian auditory hair cells, but not in the development of the supporting cells, and thus, has a role in the hearing acquisition.

Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model.

Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-γ levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-γ production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited.

Risk factors for an acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis are major causes of morbidity and mortality among patients with idiopathic pulmonary fibrosis. However, acute exacerbations remain unpredictable. The aim of this study was to investigate risk factors for acute exacerbations of idiopathic pulmonary fibrosis. METHODS: We performed a retrospective cohort study of patients with idiopathic pulmonary fibrosis who visited our institutions from January 1999 to September 2014. We investigated risk factors for acute exacerbations in patients with idiopathic pulmonary fibrosis diagnosed retrospectively based on the official 2011 idiopathic pulmonary fibrosis ATS/ERS/JRS/ALAT Update Statement. RESULTS: The idiopathic pulmonary fibrosis study cohort included 65 subjects. The median follow-up period was 2.6 years. During follow-up, 24 patients (36.9 %) experienced acute exacerbations. A Kaplan-Meier curve demonstrated that the 1-year, 2-year, and 3-year incidences of acute exacerbation were 9.6, 19.2 and 31.0 %, respectively. Acute exacerbation exerted a significant impact on overall survival among those with the disease. A log-rank test showed that baseline cardiovascular diseases, higher GAP (gender, age, physiology) stage (≥II), higher serum lactate dehydrogenase level (≥180 U/L), higher serum surfactant protein-D level (≥194.7 ng/mL), higher neutrophil (≥1.77 %) and eosinophil (≥3.21 %) percentages in bronchoalveolar lavage fluid samples, and treatment with an immunosuppressive agent after diagnosis were associated with poor acute exacerbation-free probability. In the Cox analysis adjusted for treatment with an immunosuppressive agent, baseline cardiovascular diseases, higher GAP stage (≥II), and higher eosinophil percentage (≥3.21 %) in bronchoalveolar lavage fluid samples were predictors of an acute exacerbation of idiopathic pulmonary fibrosis. CONCLUSIONS: This study demonstrated that baseline cardiovascular diseases, higher GAP stage (≥II), and higher eosinophil percentage (≥3.21 %) in bronchoalveolar lavage fluid samples were associated with the onset of an acute exacerbation of idiopathic pulmonary fibrosis.

Identification of Helicobacter pylori VacA in human lung and its effects on lung cells.

OBJECTIVE: Prior reports suggested that infection with Helicobacter pylori was associated with respiratory diseases; pathogenetic mechanisms however, were not defined. We tested the hypothesis that VacA, an exotoxin of H. pylori, a gastric pathogen, was aspirated into the lung and could stimulate secretion of inflammatory cytokines by lung epithelial cells. METHODS: The presence of VacA was determined by immunohistochemistry in surgical lung biopsy tissue samples from 72 patients with interstitial pneumonia. The effects of VacA on A549 human alveolar epithelial adenocarcinoma cells and normal human bronchial epithelial cells were determined. After incubation with VacA, the secretions of cytokines were measured by Multiplex Luminex(®) Assays. RESULTS: VacA was detected with anti-VacA antibodies in bronchial epithelial cells and alveolar epithelial cells from 10 of 72 patients with interstitial pneumonia. VacA was more prevalent in lungs of patients with collagen vascular disease-associated interstitial pneumonia than in those of patients with idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia and cryptogenic organizing pneumonia. Incubation of A549 cells and normal human bronchial epithelial cells with VacA for 24 h was cytotoxic, and resulted in vacuolation. VacA induced interleukin-8 production by A549 cells and normal human bronchial epithelial cells and interleukin-6 production by A549 cells. Based on multiplex screening, interleukin-8 and interleukin-6 were the primary secretory products induced by VacA. CONCLUSIONS: H. pylori VacA is present in human lung and can induce interleukin-8 and interleukin-6 production by human lung cells. VacA could have a role in the pathogenesis of respiratory diseases by its cytotoxic effects and by inducing the secretion of interleukin-8 and interleukin-6 by targeted airway epithelial cells.

Association of elevated α-defensin levels with interstitial pneumonia in patients with systemic sclerosis.

BACKGROUND: Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc). Although the pathogenesis of SSc-ILD is not well understood, neutrophils may play a pivotal role in this process. Neutrophils store azurophil granules that contain defensins, antimicrobial peptides that function in regulating the inflammatory response, and IL-8, a potent chemoattractant for neutrophils. The present study evaluated the levels of defensins and IL-8 in patients with SSc-ILD to determine their roles in disease pathogenesis. METHODS: Defensins (also known as human neutrophil peptides, HNPs) and IL-8 levels were measured in the serum and bronchoalveolar lavage fluid (BALF) of 33 patients with SSc-ILD and in 20 healthy controls by using ELISA. RESULTS: BALF analysis revealed a significant increase in HNPs in SSc-ILD patients (median; 240.0 pg/mL) than that of healthy controls (79.7 pg/mL). Additionally, IL-8 levels were higher in SSc-ILD patient serum and BALF as compared to healthy controls (16.4 pg/mL vs. 5.8 pg/mL and 15.4 pg/mL vs. 14.5 pg/mL, respectively). However, plasma HNPs levels were relatively unchanged. HNP and IL-8 levels in patient BALF displayed a significant positive correlation significantly correlated (r = 0.774, p <0.01), and which also correlated with clinical disease parameters--such as ILD biomarkers, pulmonary function tests, ratio of neutrophils and eosinophils in BALF, tricuspid regurgitation peak gradient (TRPG), and the extent of high-resolution computed tomography (HRCT) findings in the lung. Levels of plasma HNPs and serum IL-8 did not show a significant correlation with any clinical parameter. SSc-ILD progression was evaluated by pulmonary function tests, but no association was observed between VC change ratios and HNPs or IL-8 levels. CONCLUSIONS: BALF levels of HNPs and IL-8 were higher in SSc-ILD than in healthy controls, and are associated with various clinical disease parameters. Further studies are needed to clarify the role of defensins and IL-8 in SSc-ILD pathogenesis.

Comparison of pulmonary involvement between patients expressing anti-PL-7 and anti-Jo-1 antibodies.

Anti-PL-7 is an anti-tRNA synthetase antibody, and interstitial lung disease (ILD) is the most frequent complication of anti-PL-7-associated antisynthetase syndrome. However, the features of ILD have not been fully elucidated. The present study retrospectively compares 7 and 15 patients who were positive for anti-PL-7 and anti-Jo-1 antibodies, respectively. The features of ILD did not significantly differ between the two groups, but the ratio of lymphocytes in bronchoalveolar lavage fluid was higher in the Jo-1 than in the PL-7 group. High-resolution computed tomography revealed nonspecific interstitial pneumonia in all patients in the PL-7 group and organizing pneumonia in four of the 15 patients in the Jo-1 group. These findings suggest that pulmonary complications slightly differ between patients expressing anti-PL-7 and anti-Jo-1 antibodies. Further studies are required to clarify the features of ILD associated with PL-7.

[Chondroblastoma of the Temporal Bone Removed Using a Middle Cranial Fossa Approach].

We report a case of chondroblastoma of the middle cranial fossa, probably arising from the (infra) mandibular fossa, and expanding to the attic and external auditory canal that was successfully removed using a middle cranial fossa approach. No recurrences occurred during an 8-year postoperative follow-up period. Initial biopsy findings suggested a pathological diagnosis of giant cell tumor that was later confirmed to be a chondroblastoma based on an immunohistochemical study of S-100. This case study suggests a profound understanding of the clinical features, histopathological characteristics, and possible treatment. of chondroblastoma.

Prevotella intermedia induces severe bacteremic pneumococcal pneumonia in mice with upregulated platelet-activating factor receptor expression.

Streptococcus pneumoniae is the leading cause of respiratory infection worldwide. Although oral hygiene has been considered a risk factor for developing pneumonia, the relationship between oral bacteria and pneumococcal infection is unknown. In this study, we examined the synergic effects of Prevotella intermedia, a major periodontopathic bacterium, on pneumococcal pneumonia. The synergic effects of the supernatant of P. intermedia (PiSup) on pneumococcal pneumonia were investigated in mice, and the stimulation of pneumococcal adhesion to human alveolar (A549) cells by PiSup was assessed. The effects of PiSup on platelet-activating factor receptor (PAFR) transcript levels in vitro and in vivo were analyzed by quantitative real-time PCR, and the differences between the effects of pneumococcal infection induced by various periodontopathic bacterial species were verified in mice. Mice inoculated with S. pneumoniae plus PiSup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, spleen, and blood, and higher inflammatory cytokine levels in the bronchoalveolar lavage fluid (macrophage inflammatory protein 2 and tumor necrosis factor alpha) than those infected without PiSup. In A549 cells, PiSup increased pneumococcal adhesion and PAFR transcript levels. PiSup also increased lung PAFR transcript levels in mice. Similar effects were not observed in the supernatants of Porphyromonas gingivalis or Fusobacterium nucleatum. Thus, P. intermedia has the potential to induce severe bacteremic pneumococcal pneumonia with enhanced pneumococcal adhesion to lower airway cells.

Autopsy analyses in acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with high mortality. However, few studies have so far reviewed analyses of autopsy findings in patients with AE-IPF. METHODS: We retrospectively reviewed 52 consecutive patients with AE-IPF who underwent autopsies at five university hospitals and one municipal hospital between 1999 and 2013. The following variables were abstracted from the medical records: demographic and clinical data, autopsy findings and complications during the clinical course until death. RESULTS: The median age at autopsy was 71 years (range 47-86 years), and the subjects included 38 (73.1%) males. High-dose corticosteroid therapy was initiated in 45 (86.5%) patients after AE-IPF. The underling fibrotic lesion was classified as having the usual interstitial pneumonia (UIP) pattern in all cases. Furthermore, 41 (78.8%) patients had diffuse alveolar damage (DAD), 15 (28.8%) exhibited pulmonary hemorrhage, nine (17.3%) developed pulmonary thromboembolism and six (11.5%) were diagnosed with lung carcinoma. In addition, six (11.5%) patients developed pneumothorax prior to death and 26 (53.1%) developed diabetes that required insulin treatment after the administration of high-dose corticosteroid therapy. In addition, 15 (28.8%) patients presented with bronchopneumonia during their clinical course and/or until death, including fungal (seven, 13.5%), cytomegalovirus (six, 11.5%) and bacterial (five, 9.6%) infections. CONCLUSIONS: The pathological findings in patients with AE-IPF represent not only DAD, but also a variety of pathological conditions. Therefore, making a diagnosis of AE-IPF is often difficult, and the use of cautious diagnostic approaches is required for appropriate treatment.

A Japanese patient with Löfgren's syndrome with an HLA-DR12 allele and review of literature on Japanese patients.

Sarcoidosis is a granulomatous disorder of unknown etiology, with several clinical manifestations. Löfgren's syndrome is an acute type of sarcoidosis, characterized by the triad of arthritis, erythema nodosum, and bilateral hilar lymphadenopathy (BHL), which spontaneously resolve within about 2 years. Löfgren's syndrome is common among young white women from Nordic countries and Ireland, but it is very rare in Japan. Because the incidence of Löfgren's syndrome varies according to race, most studies on Löfgren's syndrome, including HLA typing, have been reported in Western countries. Indeed, HLA-DR3 has been reported to be associated with Löfgren's syndrome in Western countries, although the association between HLA typing and Japanese Löfgren's syndrome remains unclear. Here we present a Japanese patient with Löfgren's syndrome. A 34-year-old female patient was hospitalized with arthritis and erythema nodosum. Chest computed tomography revealed mediastinal and BHL. Endobronchial ultrasound-guided transbronchial needle aspiration showed non-caseating epithelioid cell granulomas. Löfgren's syndrome was thus diagnosed. Her ankle arthralgia and bilateral ankle swelling recovered without steroid treatment within two months, and the BHL almost completely diminished one year after admission. Her HLA genotype contains DR12. We also reviewed the literature on 11 Japanese patients with Löfgren's syndrome, showing that HLA-DR12 is present in five out of nine patients (55.6%). The relevant data were unavailable in the remaining three patients. Importantly, only 5.4% of registered donors in the Japan Marrow Donor Program are positive for this allele. We suggest the potential link between HLA-DR12 and the pathogenesis of Löfgren's syndrome in Japanese patients.

Effects of recombinant human soluble thrombomodulin on neutrophil extracellular traps in the kidney of a mouse model of endotoxin shock.

Objectives: Sepsis is a life-threatening condition characterized by multi-organ dysfunction due to host immune system dysregulation in response to an infection. During sepsis, neutrophils release neutrophil extracellular traps (NETs) as part of the innate immune response. However, excessive NETs play a critical role in the development of organ failure during sepsis. Although recombinant human soluble thrombomodulin (rTM) can inhibit NET formation in the lungs and liver of a mouse model of endotoxin shock, its effects on the kidneys are unclear. Methods: The specific effects of NETs and rTM on the renal cortex and renal medulla were examined in a mouse model of endotoxin shock generated by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS), followed by i.p. injection of rTM or an identical volume of saline 1 h later. Results: LPS injection increased serum creatinine, blood urea nitrogen, and histone H3 levels. However, rTM administration significantly decreased histone H3 and citrullinated histone H3 (citH3) levels. Immunohistochemical analysis revealed no significant changes in citH3 quantity in the renal cortex of any group. However, in the renal medulla, the increase in citH3 induced by LPS was abolished in the LPS+rTM group. Conclusions: Our findings demonstrate that rTM can suppress NETs in the renal medulla of mice with endotoxin-induced acute kidney injury.

Association of circulating histone H3 and high mobility group box 1 levels with postoperative prognostic indicators in intensive care unit patients: a single-center observational study.

Objectives: Damage associated molecular patterns (DAMPs) levels are associated with sepsis severity and prognosis. Histone and high mobility group box 1 (HMGB1) levels are also potential indicators of prognosis. We investigated the relationship between serum histone H3 and HMGB1 levels and the illness severity score and prognosis in postoperative patients. Methods: Postoperative serum histone H3 and HMGB1 levels in 39 intensive care unit (ICU) patients treated at our institution were measured. The correlation between peak histone H3 and HMGB1 levels in each patient and clinical data (age, sex, surgical time, length of ICU stay, and survival after ICU discharge), which also included the patients' illness severity score, was examined. Results: Histone H3 but not HMGB1 levels were positively correlated with surgical time, the Sequential Organ Failure Assessment score, the Japanese Association for Acute Medicine acute phase disseminated intravascular coagulation diagnosis score, and the length of ICU stay. Both histone H3 and HMGB1 levels were negatively correlated with age. However, survival post-ICU discharge was not correlated with histone H3 or HMGB1 levels. Conclusions: Histone H3 levels are correlated with severity scores and the length of ICU stay. Serum histone H3 and HMGB1 levels are elevated postoperatively. These DAMPs, however, are not prognostic indicators in postoperative ICU patients.

[A case of transient auditory agnosia and schizophrenia].

We report a case of transient functional auditory agnosia and schizophrenia and discuss their relationship. A 30-year-old woman with schizophrenia reporting bilateral hearing loss was found in history taking to be able to hear but could neither understand speech nor discriminate among environmental sounds. Audiometry clarified normal but low speech discrimination. Otoacoustic emission and auditory brainstem response were normal. Magnetic resonance imaging (MRI) elsewhere evidenced no abnormal findings. We assumed that taking care of her grandparents who had been discharged from the hospital had unduly stressed her, and her condition improved shortly after she stopped caring for them, returned home and started taking a minor tranquilizer.

Physical and physiological effects on otoacoustic emissions in hypobaric hypoxia.

Tinnitus and dizziness are symptoms of acute mountain sickness. We investigated the mechanism by which high altitude (i.e. hypobaric hypoxia) affects inner ear function by measuring transient evoked otoacoustic emissions (TEOAE) and distortion product otoacoustic emissions (DPOAE) under conditions of normobaric normoxia (1,013 hPa; 760 mm Hg) and hypobaric hypoxia (540 hPa; 405 mm Hg). The possibility that air pressure effects on the eustachian tube impacted our findings was excluded by the use of tympanograms. The nonphysiological effects of hypobaric hypoxia on TEOAE and DPOAE were also assessed using an ear simulator. Under conditions of hypobaric hypoxia, both TEOAE and DPOAE levels were reduced. The amount of reduction that occurred was approximately 4 dB in the total echo power and signal-to-noise ratio of the TEOAE, and in the 2f(1) - f(2) element level of the DPOAE. Stimulus levels that were measured using an ear simulator were also reduced by approximately 4 dB under conditions of hypobaric hypoxia. These results do not indicate that stimulus levels affected TEOAE and DPOAE levels because these levels were actually only slightly affected by changes in the stimulus level. Instead, this reduction was likely due to the nonphysiological hypobaric effects of the sound pressure emitted from the tympanic membrane. We conclude that the impact of hypobaric hypoxia on cochlear function was negligible up to pressures of 540 hPa.

Lower blood return temperature than core temperature as a causal factor of decreased cardiac output assessed by transpulmonary thermodilution during blood purification.

We aimed to evaluate whether cardiac output assessed by transpulmonary thermodilution during blood purification is affected by the difference between the blood return temperature and core temperature. We applied different blood return temperatures using a thermostat bath during blood purification in four pigs. After the blood return temperature stabilized and blood purification process stopped, the cardiac output assessed by transpulmonary thermodilution was measured. The thermostat bath was set at 35°C, 40°C, 45°C, and 50°C, with the order changed at random; four measurements were made at each temperature. Cardiac function was evaluated by echocardiography when ice-cold saline was administered in a pig. A decrease in the blood return temperature resulted in decreased cardiac output assessed by transpulmonary thermodilution, whereas an increase resulted in increased cardiac output assessed by transpulmonary thermodilution. Echocardiography revealed that the change in the blood return temperature did not affect the left ventricular ejection fraction.

Vildagliptin-induced ground-glass nodules mimicking lung metastases in a cancer patient receiving Lactobacillus probiotic supplementation.

The association between gut microbiota and the lung immune system has been attracting increasing interest. Here, we report a case of pancreatic cancer in which the dipeptidyl peptidase-4 inhibitor vildagliptin induced unusual manifestations of interstitial pneumonia, possibly under the influence of Lactobacillus paraplantarum probiotic supplementation. Chest computed tomography and positron emission tomography showed multiple ground-glass nodules (GGNs) mimicking metastatic lung cancer. Transbronchial biopsy specimens showed mild fibrosis and infiltration of lymphocytes consisting of more CD4+ than CD8+ cells. The CD4+ cells did not include FOXP3+ regulatory T cells. Bronchoalveolar lavage confirmed lymphocytosis with a markedly increased CD4+ /CD8+ ratio of 7.4. The nodules disappeared shortly after vildagliptin and probiotics were withheld. If unusual interstitial pneumonia is observed in some cancer patients, physicians should pay careful attention to their medication history, including probiotic supplements.

Dynamics of blood neutrophil-related indices during nivolumab treatment may be associated with response to salvage chemotherapy for non-small cell lung cancer: A hypothesis-generating study.

Several recent studies have shown that salvage chemotherapy following PD-1 blockade produces high antitumor activity in some patients with non-small lung cancer (NSCLC). However, the underlying synergistic mechanisms remain uncertain. The blood neutrophil-to-lymphocyte ratio (NLR) and absolute neutrophil count (ANC) can reflect the number of circulating myeloid-derived suppressor cells and tumor-associated neutrophils. The immunosuppressive status of the tumor microenvironment could be monitored by the time-series patterns of NLR and ANC. The dynamics of NLR and ANC during nivolumab treatment were retrospectively explored in 15 patients: 8 patients receiving subsequent salvage chemotherapy (2 groups: 3 non-responders and 5 responders), and 7 responders to nivolumab alone (2 groups: 4 partial response and 3 complete response). The dynamics of NLR and ANC during nivolumab differed among these four groups (NLR P = 0.045, ANC P = 0.067). NLR and ANC during nivolumab treatment increased over time in non-responders to salvage chemotherapy, with an inverse relationship between drug response and NLR or ANC at four to six weeks among the four groups. We hypothesize that the early dynamics of NLR and ANC during nivolumab may be associated with the late efficacy of subsequent salvage chemotherapy. Further studies involving a large cohort are needed to confirm these findings, which could provide insight into the role of myeloid immunosuppressor cells in combination PD-1 blockade and chemotherapy.