Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer

Purpose Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity. Methods Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). Results The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022). Conclusions Tryptophan metabolites may have a potential for predicting the efficacy of ICIs (AU)

Comprehensive assessment of multiple tryptophan metabolites as potential biomarkers for immune checkpoint inhibitors in patients with non-small cell lung cancer.

PURPOSE: Tryptophan metabolites have immunomodulatory functions, suggesting possible roles in cancer immunity. METHODS: Plasma tryptophan metabolites were measured using liquid chromatography/mass spectrometry before immune checkpoint inhibitors (ICIs) in patients with non-small cell lung cancer (NSCLC). RESULTS: The 19 patients with NSCLC had significantly lower levels of tryptophan (p = 0.002) and xanthurenic acid (p = 0.032), and a significantly higher level of 3-hydroxyanthranilic acid (3-HAA) (p = 0.028) compared with the 10 healthy volunteers. The patients achieving objective responses had significantly lower levels of 3-HAA than those who did not (p = 0.045). Receiver operating characteristic analyses determined that the cutoff value of 3-HAA for objective response was 35.4 pmol/mL (sensitivity: 87.5% and specificity: 83.3%). The patients with 3-HAA < 35.4 pmol/mL had significantly longer median progression-free survival (7.0 months) than those without (1.6 months, p = 0.022). CONCLUSIONS: Tryptophan metabolites may have a potential for predicting the efficacy of ICIs. REGISTRATION NUMBER: University Hospital Medical Information Network Clinical Trial Registry 000026140.

Respiratory impedance is correlated with airway narrowing in asthma using three-dimensional computed tomography.

BACKGROUND: Respiratory impedance comprises the resistance and reactance of the respiratory system and can provide detailed information on respiratory function. However, details of the relationship between impedance and morphological airway changes in asthma are unknown. OBJECTIVE: We aimed to evaluate the correlation between imaging-based airway changes and respiratory impedance in patients with asthma. METHODS: Respiratory impedance and spirometric data were evaluated in 72 patients with asthma and 29 reference subjects. We measured the intraluminal area (Ai) and wall thickness (WT) of third- to sixth-generation bronchi using three-dimensional computed tomographic analyses, and values were adjusted by body surface area (BSA, Ai/BSA, and WT/the square root (√) of BSA). RESULTS: Asthma patients had significantly increased respiratory impedance, decreased Ai/BSA, and increased WT/√BSA, as was the case in those without airflow limitation as assessed by spirometry. Ai/BSA was inversely correlated with respiratory resistance at 5 Hz (R5) and 20 Hz (R20). R20 had a stronger correlation with Ai/BSA than did R5. Ai/BSA was positively correlated with forced expiratory volume in 1 second/forced vital capacity ratio, percentage predicted forced expiratory volume in 1 second, and percentage predicted mid-expiratory flow. WT/√BSA had no significant correlation with spirometry or respiratory impedance. CONCLUSIONS & CLINICAL RELEVANCE: Respiratory resistance is associated with airway narrowing.

Type-1 polarised dendritic cells are a potent immunogen against Mycobacterium tuberculosis.

OBJECTIVE: Application of immunotherapy using dendritic cells (DCs) is considered an effective treatment strategy against persistent Mycobacterium tuberculosis infection. With the goal of developing improved therapeutic vaccination strategies for patients with tuberculosis (TB), we tested the ability of ex vivo-generated DCs to induce an effective TB antigen-specific type-1 immune response. METHODS: Monocyte-derived DCs from TB patients were induced to mature using a 'standard' cytokine cocktail (interleukin [IL] 1ß, tumour necrosis factor alpha [TNF-α], IL-6 and prostaglandin E2) or a type 1-polarised DC (DC1) cocktail (IL-1ß, TNF-α, interferon [IFN] α, IFN-γ and polyinosinic:polycytidylic acid), and were loaded with the established TB antigen 6-kDa early secretory antigenic target protein (ESAT-6). RESULTS: Although DC1s from TB patients expressed the same levels of multiple co-stimulatory molecules (CD83, CD86, CD80 and CD40) as the standard DCs (sDCs), DC1s secreted substantially higher levels of IL-12p70. Furthermore, when DCs pulsed with or without ESAT-6 were cultured with lymphocytes from the same patients, DC1s induced much higher numbers of ESAT-6-specific IFN-γ-producing T-cells than sDCs, as manifested by their superior induction of natural killer cell activation and antigen-independent suppression of regulatory T-cells. CONCLUSION: TB antigen-loaded DC1s are potent inducers of antigen-specific T-cells, which could be used to develop improved immunotherapies of TB.

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study.

BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.

Immunogenicity of dormancy-related antigens in individuals infected with Mycobacterium tuberculosis in Japan.

SETTING: DosR regulon genes are considered essential for Mycobacterium tuberculosis dormancy, and their products are demonstrated to have immunogenicity in M. tuberculosis-infected individuals, suggesting that DosR regulon-encoded proteins are suitable targets for vaccines to control the reactivation of dormant M. tuberculosis. OBJECTIVE: Prospective analysis of T-cell and antibody responses against DosR regulon-encoded antigens in M. tuberculosis-infected individuals in Japan to identify effective vaccine targets. DESIGN: T-cell responses against 33 DosR regulon-encoded antigens were investigated in 26 consecutive M. tuberculosis-infected individuals--14 with latent tuberculosis infection (LTBI) and 12 with active pulmonary tuberculosis (PTB)--using enzyme-linked immunosorbent spot assay, and antibody responses in 42 consecutive individuals, 14 with LTBI and 28 with PTB. RESULT: Six antigens (Rv0570, Rv1996, Rv2004c, Rv2028c, Rv2029c and Rv3133c) induced stronger T-cell responses in LTBI than in PTB, In contrast, antigen-specific antibody responses to five antigens (Rv0080, Rv1738, Rv2007c, Rv2031c and Rv2032) were found to be stronger in PTB than in LTBI cases. CONCLUSION: T-cell responses to six antigens might contribute to natural protection against dormant M. tuberculosis. These antigens are therefore considered to be potential targets of novel vaccines to control M. tuberculosis reactivation in the Japanese population.

A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis.

A nerve growth factor receptor encoded by the TRKA gene plays an important part in the formation of autonomic neurons and small sensory neurons in dorsal root ganglia and in signal transduction through its intracytoplasmic tyrosine kinase domain. Recently, three mutations in the tyrosine kinase domain of TRKA have been reported in patients with congenital insensitivity to pain with anhidrosis, which is an autosomal recessive disorder characterized by recurrent fever due to absence of sweating, no reaction to noxious stimuli, self-mutilating behavior, and mental retardation. We examined the TRKA gene in five generations of a large Japanese family with many consanguineous marriages who live in a small remote island of the southern part of Japan. We found a novel point mutation at nucleotide 1825 (A-->G transition) resulting in Met-581-Val in the tyrosine kinase domain. Two of the three affected patients were homozygous for this mutation; however, the third affected patient was heterozygous. Further analysis revealed that the third patient was a compound heterozygote with the Met-581-Val mutation in one allele and with a single base C deletion mutation at nucleotide 1726 in exon 14 in the other allele, resulting in a frameshift and premature termination codon.

[Multiple pulmonary arteriovenous malformations associated with hereditary hemorrhagic telangiectasia].

A 61-year old asymptomatic woman was admitted to our hospital for the examination of an abnormal shadow in the left lower lung lobe in 1978. Enhanced chest computed tomograms and pulmonary arteriograms revealed a pulmonary arteriovenous malformation (PAVM) composed of feeding artery and draining vein. The patient had suffered brain abscesses 3 times because of paradoxical emboli from PAVMs. A diagnosis of hereditary hemorrhagic telangiectasia (HHT) was made according to the criteria. The patient died of septic shock due to urinary tract infection by Candida albicans. We reviewed cases of PAVMs associated with HHT in the Japanese literature. In Japan, 126 HHT families and 144 HHT patients have been reported to date. PAVMs occur in approximately one-third of HHT patients in Japan. Twenty-four out of 45 patients (44.4%) had multiple PAVMs. We also discussed the diagnosis, complications, and treatment of PAVM-associated HHT.

Effect of chlorella on rats with iron deficient anemia.

In order to determine effects of iron deficiency on the living body, rats were given the iron deficient diet (Group 1, iron content, 0.32mg/100g), the complete diet added with iron (Group 5, iron content, 32.5mg/100g), the diet added with 1% chlorella (Group 2, iron content, 2.2mg/100g), the diet added with 5% chlorella (Group 3, iron content, 7.4mg/100g), or the diet added with 10% chlorella (Group 4, iron content, 13.9mg/100g). For the first 30 days, rats of all groups were given the iron deficiency diet to make them iron deficient, and were subsequently given the respective diet during the next 30 days to observe various changes in the conditions of rats. Following results were obtained. 1) When rats were reared for 30 days with the iron deficient diet, rats of these groups became anemic and their hemoglobin concentrations and hematocrit values lowered. Rats of Groups 3, 4 and 5 fed with the diets containing certain amounts of iron rapidly recovered, while the recovery of those of Group 2 fed with less iron content diet was delayed. Group 1 fed with the iron deficient diet showed no recovery. 2) Examination of effects of these diets on the rats body weight gains revealed that the growth of Groups 1 and 2 with iron deficiency was delayed notably (p less than 0.01) as compared with Group 5 and that of Group 3 was likewise restrained (p less than 0.05). The relative organ weights of all rats were examined. The liver weight in Groups 1, 2, 3, 4 was lower than that in Group 5, while that of the spleen in Groups 1 and 2 was higher than that in Group 5. 3) The Numbers of erythrocyte decreased in Groups 1 and 2 (p less than 0.01) and increased in Groups 3 and 4 (p less than 0.01) as compared with Group 5. There was no direct relation between the iron content in the diet and the number of leukocytes and their compositions. 4) Serum iron decreased remarkably in Groups 1 and 2 (p less than 0.01) but there were no intergroup differences in blood glucose value. 5) When osmotic fragility of erythrocyte membranes was expressed in term of NaCl concentration to indicate 50% hemolysis, Groups 1, 2 and 3 apparently increased their resistance as compared with Group 5 (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Responsiveness of the ductus arteriosus to prostaglandin E1 assessed by combined cross sectional and pulsed Doppler echocardiography.

Cross sectional echocardiography combined with Doppler echocardiography was used to record either ductal morphology or the flow profile within the ductus arteriosus before and after infusion of prostaglandin E1 in 25 newborn infants with cyanotic and acyanotic congenital heart disease with ductus dependent blood flow. The ultrasound results were compared with changes in arterial oxygen tension and the overall clinical response to prostaglandin E1 seen during the same period in 24 of the 25 patients in whom the degree of ductal narrowing could be determined with the ultrasound method. At the time of the study, the ductus was widely patent or slightly narrowed in 12 patients and was closed in two patients. These patients did not respond to prostaglandin E1. There was prominent localised narrowing of the ductus in seven patients and generalised narrowing in three. After the infusion of prostaglandin E1 there was no ductal narrowing in these patients, except for one patient who had slight residual localised narrowing. There was also a considerable change in the ductal flow profiles in each patient. In these 10 patients infusion of prostaglandin E1 resulted in an increase in arterial oxygen tension, clinical improvement, or both. The present study indicates that prostaglandin E1 is effective in patients with prominent narrowing of the ductus but is not in patients in whom the ductus is widely patent or closed. Cross sectional echocardiography combined with Doppler echocardiography was useful for predicting the responsiveness of the ductus arteriosus to the infusion.