Dynamics of iron metabolism in patients with bloodstream infections: a time-course clinical study.

The close relationship between infectious diseases and iron metabolism is well known, but a more detailed understanding based on current knowledge may provide new insights into the diagnosis and treatment of infectious diseases, considering the growing threat of antibiotic-resistant bacteria. This study investigated adult patients with bloodstream infections, temporal changes, and relationships between blood levels of iron and related markers, including hepcidin and lipocalin-2 (LCN2). We included 144 samples from 48 patients (mean age 72 years, 50% male), with 30 diagnosed with sepsis. During the acute phase of infection, blood levels of hepcidin and LCN2 increased rapidly, whereas iron levels decreased, with values in 95.8% of cases below the normal range (40-188 µg/dL). Later, hepcidin and LCN2 decreased significantly during the recovery phase, and the decreased iron concentrations were restored. In the case of persistent inflammation, iron remained decreased. Acute LCN2 levels were significantly higher in patients with sepsis (p < 0.01). Hypoferremia induced by increased hepcidin would reduce iron in the environment of extracellular pathogens, and the increased LCN2 would inhibit siderophores, resulting in the prevention of the pathogen's iron acquisition in each manner during the acute phase of bloodstream infection.

Variation of respiratory and pulse events in multiple system atrophy.

INTRODUCTION: A study is eagerly awaited that will reveal the unknown mechanisms of multiple system atrophy (MSA), in which the risk of sudden death is the greatest during sleep. The blunted pulse response to nocturnal respiratory events suggests an abnormal cardiac response to a sleep-related breathing disorder. Patients with MSA have a lower pulse event index (PEI), despite a greater hypoxic burden and a similar frequency of respiratory events. However, the evidence is speculative and not directly proven, and many limitations require further study. METHODS: We conducted a retrospective analysis of 26 patients with MSA who had undergone overnight oximetry between April 2016 and December 2022. RESULTS: The median 4% oxyhemoglobin desaturation index (ODI) was 11.6/h, the 6-bpm PEI was 8.9/h, and the PEI/ODI ratio was as low as 0.91. There were three patients with suspected sudden death; all had low PEI/ODI ratios. The PEI/ODI ratio was followed over time in seven patients, all of whom had a decrease in the ratio. However, the PEI was higher than the ODI in 12/26 (46%) of the patients. CONCLUSION: A low PEI/ODI ratio, reflecting a blunted pulse response to nocturnal respiratory events in patients with MSA, may indicate a worse prognosis. This finding and the significance of the longitudinal decrease in the PEI/ODI ratio will require a prospective study.

Continuous positive airway pressure treatment reduces renal tubular damage in patients with obstructive sleep apnea: A retrospective single-center cohort study.

BACKGROUND: Chronic intermittent hypoxia (IH) plays a significant role in the pathogenesis of obstructive sleep apnea (OSA) comorbidities. The prevalence of chronic kidney disease is higher in patients with OSA than the general population, and renal function decline is well correlated with renal tubular injury. However, little is known about the impact of OSA-induced chronic IH on the renal tubules. METHODS: We conducted a retrospective survey of clinical records performing multiple regression analysis and cluster analysis with particular attention to the 3% oxygen desaturation index (ODI) and urinary N-acetyl-ß-d-glucosaminidase (NAG). RESULTS: In patients with suspicion of OSA, urinary NAG creatinine ratio (UNCR) was elevated as their 3% ODI increased (n = 197, p < 0.001), and the elevated UNCR decreased following CPAP treatment in patients with OSA (n = 46, p = 0.014). Multiple regression analysis showed that 3% ODI was associated with UNCR. Cluster analysis identified three clusters of patients with OSA, including two younger age clusters, one of which was characterized by high BMI, high 3% ODI, and high prevalence of major comorbidities. In a comparative analysis of younger age cases (age ≤ 55, n = 82), the UNCR level was higher in patients with severe 3% ODI (3% ODI > 40 events/h, n = 24) (p = 0.014). CONCLUSIONS: Our results indicate that even at younger ages, OSA patients with severe chronic IH and major comorbidities are susceptible to renal tubular damage. Early treatment with CPAP may attenuate renal tubular injury and progression toward end-stage renal disease.

The relationship between adherence to continuous positive airway pressure and nasal resistance measured by rhinomanometry in patients with obstructive sleep apnea syndrome.

Nasal breathing disorders are associated with obstructive sleep apnea (OSA) syndrome and influence the availability of continuous positive airway pressure (CPAP) therapy. However, information is scarce about the impact of nasal resistance assessed by rhinomanometry on CPAP therapy. This study aimed to examine the relationship between CPAP adherence and nasal resistance evaluated by rhinomanometry, and to identify clinical findings that can affect adherence to CPAP therapy for patients with OSA. This study included 260 patients (199 men, 61 women; age 58 [interquartile ranges (IQR) 50-66] years) with a new diagnosis of OSA who underwent rhinomanometry (before, and 1 and 3 months after CPAP introduction) between January 2011 and December 2018. CPAP use was recorded, and the good and poor CPAP adherence groups at the time of patient registration were compared. Furthermore, those with improved and unimproved pre-CPAP high rhinomanometry values were also compared. Their apnea-hypopnea index (AHI) by polysomnography at diagnosis was 45.6 (IQR 33.7-61.6)/hour, but the residual respiratory event (estimated AHI) at enrollment was 2.5 (IQR 1.4-3.9)/hour and the usage time was 318 (IQR 226-397) minutes, indicating that CPAP was effective and adherence was good. CPAP adherence was negatively correlated with nasal resistance (r = -0.188, p = 0.002). The participants were divided into good (n = 153) and poor (n = 107) CPAP adherence groups. In the poor adherence group, rhinomanometry values before CPAP introduction were worse (inspiration, p = 0.003; expiration, p = 0.006). There was no significant difference in patient background when comparing those with improved (n = 16) and unimproved (n = 12) pre-CPAP high rhinomanometry values. However, CPAP usage time was significantly longer in the improved group 1 month (p = 0.002) and 3 months (p = 0.026) after CPAP introduction. The results suggest that nasal resistance evaluated by rhinomanometry is a useful predictor of CPAP adherence, and that improved rhinomanometry values may contribute to extending the duration of CPAP use.

Oral appliance therapy for obstructive sleep apnea in multiple system atrophy with floppy epiglottis: a case series of three patients.

PURPOSE: A recent study demonstrated that continuous positive airway pressure (CPAP) may exacerbate obstructive sleep apnea (OSA) in patients with multiple system atrophy (MSA) and a floppy epiglottis (FE) as the CPAP promotes downward displacement of the epiglottis into the laryngeal inlet. In this case series, we examined the effectiveness of an oral appliance (OA) for treating OSA in three patients with MSA and an FE. METHODS: Patients with MSA were demonstrated to have an FE on fiberoptic laryngoscopy under sedation using intravenous propofol. The therapeutic intervention was fitting an OA. Polysomnography (PSG) was performed subsequently with the OA in place. RESULTS: In three patients with MSA, some parameters used to assess the severity of OSA improved with an OA. Both apnea-hypopnea index (AHI) and arousal index (ArI) decreased while wearing the OA in two cases while in the third case, apnea index (AI) and cumulative time at peripheral oxygen saturation (SpO2) below 90% (CT90) decreased, but AHI and ArI increased. The only side effects were transient TMJ discomfort, masseter muscle pain, and tooth discomfort. CONCLUSION: OA therapy using a two-piece type mandibular advancement device (MAD) may be a useful treatment intervention for patients with OSA who have MSA and FE.

Factors associated with cytomegalovirus antigenemia in patients with rheumatic disease: A retrospective study.

INTRODUCTION: This study aimed to examine the factors associated with cytomegalovirus (CMV) antigenemia and the time of onset of CMV antigenemia among patients with rheumatic diseases. METHODS: A single-center, retrospective, observational study was conducted in our institution from January 2009 to December 2017. This study included patients with rheumatic diseases who had at least one CMV antigen measurement. Multivariate analysis and receiver operating characteristic analysis was performed. RESULTS: A total of 249 patients underwent CMV antigenemia assay, and 84 (33.7%) patients tested positive. When the association between CMV antigenemia and possible associated factors was investigated, multivariate analysis showed that daily steroid dose increased the odds of having CMV [odds ratio 16.25, 95% confidence interval (CI), 5.360-49.253]. In this study, the cutoff value of daily steroid dose found in this study (0.45 mg/kg/day) was reasonable in clinical practice, and the area under the curve of the steroid dose was 0.838 [95% CI 0.781-0.882], which was the largest of the known indicators. Moreover, the median time from the start of immunosuppressive therapy to the onset of CMV antigenemia was 30 (interquartile range, 21-44) days, and most of the daily steroid users (85.7%) developed CMV antigenemia within 60 days. CONCLUSIONS: The daily steroid dose is the most important factor associated with CMV antigenemia. Therefore, monitoring and treatment strategies based on the steroid dose, especially in the initial 2 months, are important.

Prognostic significance of procalcitonin in small cell lung cancer.

BACKGROUND: Procalcitonin (PCT) is a serological marker whose utility has been established in infectious disease areas. Although serum calcitonin is a prognostic predictor in patients with medullary thyroid carcinoma, the clinical usefulness of PCT remains unclear in lung cancer patients. METHODS: As a discovery cohort, we retrospectively analyzed consecutive patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) who received first-line chemotherapy at our institution, and PCT blood levels were measured. As the validation cohort, PCT blood levels were prospectively evaluated in SCLC patients before first-line chemotherapy. The correlation between a PCT increase and prognosis was examined in the discovery and validation cohorts. RESULTS: Twenty-three SCLC patients and 26 NSCLC patients were enrolled as the discovery cohort, and 30 SCLC patients were enrolled as the validation cohort. The PCT level in SCLC patients was significantly higher than that in NSCLC patients. The PCT level was not associated with WBC count and weakly associated with the CRP level. In both the discovery and validation cohorts, the median survival time was significantly shorter in SCLC patients with PCT-high than in SCLC patients with PCT-normal (discovery; 11.7 vs. 89.7 months, P<0.005, validation; 9.6 vs. 22.6 months, P<0.005). CONCLUSIONS: It may be difficult to differentiate bacterial infections in SCLC patients by PCT, as PCT is elevated even in SCLC patients without infectious diseases. This is the first study to prospectively verify that pretreatment PCT levels have a significant negative correlation with prognosis in SCLC patients.

PD-1 blockade therapy augments the antitumor effects of lymphodepletion and adoptive T cell transfer.

Lymphodepleting cytotoxic regimens enhance the antitumor effects of adoptively transferred effector and naïve T cells. Although the mechanisms of antitumor immunity augmentation by lymphodepletion have been intensively investigated, the effects of lymphodepletion followed by T cell transfer on immune checkpoints in the tumor microenvironment remain unclear. The current study demonstrated that the expression of immune checkpoint molecules on transferred donor CD4+ and CD8+ T cells was significantly decreased in lymphodepleted tumor-bearing mice. In contrast, lymphodepletion did not reduce immune checkpoint molecule levels on recipient CD4+ and CD8+ T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Further analysis revealed that transfer of both donor CD4+ and CD8+ T cells was responsible for the antitumor effects of a combination therapy consisting of lymphodepletion, T cell transfer and anti-PD-1 treatment. Our findings indicate that a possible mechanism underlying the antitumor effects of lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. PD-1 blockade may reinvigorate exhausted recipient T cells and augment the antitumor effects of lymphodepletion and adoptive T cell transfer.

The Prognostic Significance of the Continuous Administration of Anti-PD-1 Antibody via Continuation or Rechallenge After the Occurrence of Immune-Related Adverse Events.

OBJECTIVES: Although immune checkpoint inhibitors (ICIs) have been shown to improve overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients, ICIs sometimes cause various types of immune-related adverse events (irAEs), which lead to the interruption of ICI treatment. This study aims to evaluate the clinical significance of the continuation of ICIs in NSCLC patients with irAEs and to assess the safety and efficacy of the readministration of ICIs after their discontinuation due to irAEs. METHODS: We retrospectively identified patients with advanced NSCLC who were treated with first- to third-line anti-programmed cell death-1 (PD-1) therapy from January 2016 through October 2017 at multiple institutions belonging to the Niigata Lung Cancer Treatment Group. Progression-free survival (PFS) and OS from the initiation of ICI treatment were analyzed in patients with and without irAEs, with and without ICI interruption, and with and without ICI readministration. A 6-week landmark analysis of PFS and OS was performed to minimize the lead-time bias associated with time-dependent factors. RESULTS: Of 231 patients who received anti-PD-1 antibodies, 93 patients (40%) developed irAEs. Of 84 eligible patients with irAEs, 32 patients (14%) continued ICIs, and OS was significantly longer in patients who continued ICIs than that in patients who discontinued ICIs [not reached (95% CI: NE-NE) vs. not reached (95% CI: 22.4-NE); p = 0.025]. Of 52 patients who discontinued ICIs, 14 patients (6.1%) readministered ICIs, and OS in patients with ICI readministration was significantly longer than that in patients without ICI readministration [not reached (95% CI: NE-NE) vs. not reached (95% CI: 8.4-NE); p = 0.031]. CONCLUSION: The current study demonstrated that both the continuation and readministration of ICIs after irAE occurrence improved OS compared to the permanent interruption of ICIs in NSCLC patients with ICI-related irAEs.

Optogenetic activation of DRN 5-HT neurons induced active wakefulness, not quiet wakefulness.

There has been a long-standing controversy regarding the physiological role of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) in sleep/wake architecture. Some studies have reported that 5-HT acts as a sleep-promoting agent, but several studies have suggested that DRN 5-HT neurons function predominantly to promote wakefulness and inhibit rapid eye movement (REM) sleep. Furthermore, recent studies have reported that there is a clear neurobiological difference between a waking state that includes alertness and active exploration (i.e., active wakefulness) and a waking state that is devoid of locomotion (i.e., quiet wakefulness). These states have also been shown to differ clinically in terms of memory consolidation. However, the effects of 5-HT neurons on the regulation of these two different waking states have not been fully elucidated. In the present study, we attempted to examine the physiological role of DRN 5-HT neurons in various sleep/wake states using optogenetic methods that allowed manipulation of cell-type specific neuronal activation with high temporal and anatomical precision. We crossed TPH2-tTA and TetO-ChR2(C128S) mice to obtain mice with channelrhodopsin-2 (ChR2) [C128S]-expressing central 5-HT neurons, and we activated DRN-5HT neurons or medullary 5-HT neurons. Optogenetic activation of DRN 5-HT neurons caused rapid transition from non-REM sleep to active wakefulness, not quiet wakefulness, whereas activation of medullary 5-HT neurons did not appear to affect sleep/wake states or locomotor activity. Our results may shed light on the physiological role of DRN 5-HT neurons in sleep/wake architecture and encourage further investigations of the cortical functional connectivity involved in sleep/wake state regulation.

Subsequent systemic therapy for non-small cell lung cancer patients with immune checkpoint inhibitor-related interstitial lung disease.

BACKGROUND: Although immune checkpoint inhibitors (ICIs) are effective for advanced non-small cell lung cancer (NSCLC), ICIs may cause interstitial lung disease (ILD), which results in treatment discontinuation and is sometimes fatal. Despite the high incidence of ICI-related ILD, there are few cancer treatment options for patients. This study aimed to evaluate the safety and efficacy of subsequent systemic cancer therapy in NSCLC patients with ICI-related ILD. METHODS: We retrospectively assessed NSCLC patients who received programmed cell death-1 (PD-1) inhibitors as first- to third-line therapy at participating institutions of the Niigata Lung Cancer Treatment Group from January 2016 to October 2017. RESULTS: This analysis included 231 patients, 32 (14%) of whom developed ICI-related ILD. Of these patients, 16 (7%) received subsequent systemic cancer treatments. The median overall survival (OS) tended to be longer in the systemic cancer therapy group than in the no systemic cancer therapy group [22.2 months (95% CI: 1-NE) vs. 4.5 months (95% CI: 1-NE); P=0.067]. ICI-related ILD recurred in half of the patients who received systemic cancer therapy, and the median OS tended to be shorter in patients with recurrent ICI-related ILD [22.0 months (95% CI: 1-NE) vs. 7.0 months (95% CI: 1-NE); P=0.3154]. CONCLUSIONS: According to the current study, systemic cancer treatment is effective in patients with ICI-related ILD; however, its safety is uncertain because of the high risk of ICI-related ILD recurrence and poor survival outcome following ILD recurrence.

A case of eosinophilic granulomatosis with polyangiitis showing multiple white lichen lesions on the airway mucosa.

A 70-year-old man, treated for asthma for 2 years and chronic sinusitis for several months, presented with fever, numbness in the lower limbs, heaviness in the head, gross hematuria, and black stools. He also had eosinophilia, elevated serum IgG4 levels, high levels of myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA), and pulmonary infiltrative shadows. Bronchoscopy revealed multiple white flattened lesions (white moss) on the airway mucosa, suggesting mycobacterial infection or malignancy. A biopsy from tracheal mucosa revealed airway inflammation with marked eosinophil infiltration. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) and treated with steroids, and all findings improved. However, a year and a half after the initiation of treatment, eosinophils and IgE gradually increased; subjective symptoms, such as asthma symptoms and numbness in the lower limbs, worsened; and ANCA, which had been negative, turned positive. Therefore, we suspected disease relapse and anti-IL-5 antibody (mepolizumab) treatment was initiated. Thereafter, ANCA turned negative again, eosinophils and IgE normalized, and subjective symptoms decreased. The presence of airway mucosal lesions in EGPA is relatively rare, and we report this case as a valuable case owing to the interesting bronchoscopic findings that are worth comprehending as a respiratory physician.

Efficacy of the new ß-D-glucan measurement kit for diagnosing invasive fungal infections, as compared with that of four conventional kits.

BACKGROUND: Each of the currently available (1→3)-ß-D-glucan (BDG) measurement kits follows a different measurement method and cut-off value. Comparisons of diagnostic performance for invasive fungal infections (IFIs) are desirable. Additionally, ecological considerations are becoming increasingly important in the development of new measurement kits. METHODS: The plasma BDG levels in clinical samples were measured using the following currently available kits: the Fungitec G test MKII, the Fungitec G test ES, Fungitell, the ß-Glucan test Wako, and the newly developed Wako kit (Wako-Eu). Wako-Eu uses a pre-treatment solution that conforms to European regulations for the registration, evaluation, authorisation, and restriction of chemicals. The values obtained for the samples using each kit were studied and compared. RESULTS: Of the 165 patients evaluated, 12 had IFIs, including pneumocystis pneumonia, aspergillosis, and candidiasis. BDG values obtained using the kits were moderately correlated with each other. Clinical diagnoses of the evaluated cases indicated that 21 false positives were diagnosed by at least one kit. The sensitivity of the Fungitell kit was relatively low, but those of the other four were over 90%. The specificity was above 90% for all kits. For positive predictive value, the Wako and the Wako-Eu methods were superior to the others owing to fewer false positive results. CONCLUSIONS: The newly developed Wako-Eu method, which considers ecological concerns, shows diagnostic performance equivalent to that of its predecessor. To improve the diagnostic accuracy of IFIs, it is necessary to interpret the results carefully, giving due consideration to the characteristics of each measurement kit.

A case of bronchiolitis obliterans after living-donor renal transplantation.

We herein report the case of a 20 year-old-man who developed bronchiolitis obliterans after living-donor renal transplantation. The patient presented with dyspnea on exertion and wheezing two years after renal transplantation, and spirometry showed an obstructive pattern. Surgical lung biopsy revealed subepithelial fibrosis that constricted and obstructed the intrabronchiolar space. Based on these findings, the patient was diagnosed with bronchiolitis obliterans. He was prescribed bronchodilators and azithromycin, and he achieved stable respiratory function for two years. The differential diagnosis of respiratory symptoms after renal transplantation includes opportunistic infection and drug-induced lung injury; however, bronchiolitis obliterans should also be considered.

Chronic Hypercapnic Respiratory Failure in an Adult Patient with Silver-Russell Syndrome.

A 31-year-old woman who was clinically diagnosed with Silver-Russell syndrome (SRS) in childhood was admitted with complaints of dyspnea. She had hypercapnic respiratory failure accompanied by nocturnal hypoventilation. Computed tomography revealed systemic muscle atrophy and superior mesenteric artery syndrome; however, the bilateral lung fields were normal. She was treated with nocturnal noninvasive positive pressure ventilation and showed improvement of respiratory failure. In this case, loss of methylation on chromosome 11p15 and maternal uniparental disomy of chromosome 7, which are the common causes of SRS, were not detected. This is a rare case of adult SRS manifesting as chronic hypercapnic respiratory failure.

Combination therapy of cisplatin with cilastatin enables an increased dose of cisplatin, enhancing its antitumor effect by suppression of nephrotoxicity.

Cisplatin, one of the most active anticancer agents, is widely used in standard chemotherapy for various cancers. Cisplatin is more poorly tolerated than other chemotherapeutic drugs, and the main dose-limiting toxicity of cisplatin is its nephrotoxicity, which is dose-dependent. Although less toxic methods of cisplatin administration have been established, cisplatin-induced nephrotoxicity remains an unsolved problem. Megalin is an endocytic receptor expressed at the apical membrane of proximal tubules. We previously demonstrated that nephrotoxic drugs, including cisplatin, are reabsorbed through megalin and cause proximal tubular cell injury. We further found that cilastatin blocked the binding of cisplatin to megalin in vitro. In this study, we investigated whether cilastatin could reduce cisplatin-induced nephrotoxicity without influencing the antitumor effects of cisplatin. Nephrotoxicity was decreased or absent in mice treated with cisplatin and cilastatin, as determined by kidney injury molecule-1 staining and the blood urea nitrogen content. Combined with cilastatin, a twofold dose of cisplatin was used to successfully treat the mice, which enhanced the antitumor effects of cisplatin but reduced its nephrotoxicity. These findings suggest that we can increase the dose of cisplatin when combined with cilastatin and improve the outcome of cancer patients.

Disseminated Varicella-zoster Virus Infection Causing Fatal Pneumonia in an Immunocompromised Patient with Chronic Interstitial Pneumonia.

Viral pneumonia caused by varicella-zoster virus (VZV) infection is a rare but important complication, especially regarding varicella infections. Although disseminated cutaneous herpes zoster (DCHZ) is often associated with visceral diseases, there have been few reports of DCHZ-related pneumonia. We herein report a rare case of a lethal disseminated VZV infection that caused severe pneumonia in a Japanese patient who had chronic interstitial pneumonia. Physicians should consider the possibility of VZV-related pneumonia, especially in patients with a medical history of hematopoietic stem cell transplantation and immunosuppressive therapy.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Retrospective analysis of antitumor effects and biomarkers for nivolumab in NSCLC patients with EGFR mutations.

Although the blockade of programmed cell death 1 (PD-1)/PD-ligand (L) 1 has demonstrated promising and durable clinical responses for non-small-cell lung cancers (NSCLCs), NSCLC patients with epidermal growth factor receptor (EGFR) mutations responded poorly to PD-1/PD-L1 inhibitors. Previous studies have identified several predictive biomarkers, including the expression of PD-L1 on tumor cells, for PD-1/PD-L1 blockade therapies in NSCLC patients; however, the usefulness of these biomarkers in NSCLCs with EGFR mutations has not been elucidated. The present study was conducted to evaluate the predictive biomarkers for PD-1/PD-L1 inhibitors in EGFR-mutated NSCLCs. We retrospectively analyzed 9 patients treated with nivolumab for EGFR-mutated NSCLCs. All but one patient received EGFR-tyrosine kinase inhibitors before nivolumab treatment. The overall response rate and median progression-free survival were 11% and 33 days (95% confidence interval (CI); 7 to 51), respectively. Univariate analysis revealed that patients with a good performance status (P = 0.11; hazard ratio (HR) 0.183, 95% CI 0.0217 to 1.549), a high density of CD4+ T cells (P = 0.136; HR 0.313, 95% CI 0.045 to 1.417) and a high density of Foxp3+ cells (P = 0.09; HR 0.264, 95% CI 0.0372 to 1.222) in the tumor microenvironment tended to have longer progression-free survival with nivolumab. Multivariate analysis revealed that a high density of CD4+ T cells (P = 0.005; HR<0.001, 95% CI <0.001 to 0.28) and a high density of Foxp3+ cells (P = 0.003; HR<0.001, 95% CI NA) in tumor tissues were strongly correlated with better progression-free survival. In contrast to previous studies in wild type EGFR NSCLCs, PD-L1 expression was not associated with the clinical benefit of anti-PD-1 treatment in EGFR-mutated NSCLCs. The current study indicated that immune status in the tumor microenvironment may be important for the effectiveness of nivolumab in NSCLC patients with EGFR mutations.