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Background: The coronavirus disease-2019 (COVID-19) pandemic is associated with a heavy burden on the mental and physical health of patients, regional healthcare resources, and global economic activity. While understanding of the incidence and case-fatality rates has increased, there are limited data concerning seroprevalence of antibodies against the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in healthcare workers during the pre-pandemic period. This study aimed to quantitatively evaluate seroprevalence of SARS-CoV-2 antibodies in healthcare workers in the southern part of Kyoto city, Japan. Methods: We prospectively recruited healthcare workers from a single hospital between April 10 and April 20, 2020. We collected serum samples from these participants and quantitatively evaluated SARS-CoV-2 IgG antibody levels using enzyme-linked immunosorbent assays. Results: Five (5.4%), 15 (16.3%), and 72 (78.3%) participants showed positive, borderline, and negative serum SARS-CoV-2 IgG antibody status, respectively. We found the mean titer associated with each antibody status (overall, positive, borderline, and negative) was clearly differentiated. Participants working at the otolaryngology department and/or with a history of seasonal common cold symptoms had a significantly higher SARS-CoV-2 IgG antibody titer ( p = 0.046, p = 0.046, respectively). Conclusions: Five (5.4%) and 15 (16.3%) participants tested positive and borderline, respectively, for SARS-CoV-2 IgG antibody during the COVID-19 pre-pandemic period. These rates were higher than expected, based on government situation reports. These findings suggest that COVID-19 had already spread within the southern part of Kyoto city at the early stage of the pandemic., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Fujita, Kada, Kanai, Hata, Odagaki, Satoh-Asahara, Tagami and Yasoda.)

Background: Over the past two decades, antiresorptive agent-related osteonecrosis of the jaw (ARONJ) has become a growing concern. We examined the incidence of ARONJ and identified its risk factors in lung cancer patients in the real-world clinical setting. To our knowledge, we are the first to do so., Patients and Methods: We retrospectively analyzed lung cancer patients with bone metastases who had received anti-resorptive agents (zoledronate or denosumab) at the National Hospital Organization Kyoto Medical Center from October 2012 to September 2018. All ARONJ cases were diagnosed by the dentists according to the established diagnostic criteria., Results: A total of 171 patients were reviewed, 13 (7.6%) of whom experienced ARONJ. Among the 13 patients, six (46.2%), four (30.8%) and three (23.1%) had adenocarcinoma, squamous carcinoma and not otherwise specified, respectively. ARONJ was stage 2 in three (23.1%) patients and stage 3 in 10 (76.9%). More cycles of antiresorptive agents (odds ratio [OR] = 11.54; 95% confidence interval [CI], 2.47-53.99; P < 0.01), use of immune checkpoint inhibitors (ICIs; OR = 5.05; 95% CI, 1.56-16.37; P < 0.01) and longer survival duration (≥2 years; OR = 12.16; 95% CI, 3.17-46.65; P < 0.01) were independently associated with ARONJ in a multivariate analysis., Conclusions: The incidence of ARONJ was relatively high in lung cancer patients with bone metastases. When using antiresorptive agents, oncologists should closely monitor patients for ARONJ during the course of treatment and regularly consult with dentists, especially in patients receiving ICIs., (© 2020 John Wiley & Sons Australia, Ltd.)

The current coronavirus disease 2019 (COVID-19) pandemic is associated with a heavy burden on the mental and physical health of patients, regional healthcare resources, and global economic activity. Many patients with lung cancer are thought to be affected by this situation. Therefore, in this study, we aimed to evaluate the impact of COVID-19 pandemic on lung cancer treatment scheduling. We retrospectively reviewed the medical records of lung cancer patients who were undergoing anticancer treatment at the National Hospital Organization Kyoto Medical Center (600 beds) in Kyoto, Japan, between 1 March 2020 and 31 May 2020. After the medical records were reviewed, the patients were assigned to one of two groups, depending on whether their lung cancer treatment schedule was delayed. We assessed the characteristics, types of histopathology and treatment, and the reason for the delay. A total 15 (9.1%) patients experienced a delay in lung cancer treatment during the COVID-19 pandemic. Patients with a treatment delay received significantly more immune checkpoint inhibitor (ICI) monotherapy than patients without a treatment delay (P = 0.0057). On the contrary, no patients receiving molecular targeted agents experienced a treatment delay during the COVID-19 pandemic period (P = 0.0027). The treatments of most of the patients were delayed at their request. We determined that 9.1% lung cancer patients suffered anxiety and requested a treatment delay during the COVID-19 pandemic. Oncologists should bear in mind that patients with cancer have more anxiety than expected under unprecedented circumstances such as the COVID-19 pandemic., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Immune checkpoint inhibitors(nivolumab)have been recommended as third-line chemotherapy for advanced gastric cancer(AGC)according to the Guidelines of Gastric Cancer(5th edition). Therefore, they have been used in daily clinical practice. On the other hand, the neutrophil-lymphocyte ratio(NLR)has been reported to be associated with the prognosis of cancer patients., Methods: Twenty patients treated with nivolumab for AGC between January 2018 and November 2019 were retrospectively examined., Results: Median age of the 20 patients(18 males, 2 females)was 70 years(55- 84 years). Nivolumab was administered as second-, third-, fourth-, and fifth-line therapy in 1, 11, 7, and 1 case, respectively. The best tumor response evaluation was observed in PR 1, SD 7 and PD 10 cases. Median overall survival(OS)was 10 months, and median progression-free survival(PFS)was 3 months. No serious adverse events occurred. Compared to the NLR>2.0 group, OS significantly prolonged(2.2 months vs 21.9 months)and PFS tended to prolong(1.4 months vs 6.2 months)in the NLR≤2.0 group., Conclusion: NLR may be an effective prognostic factor in patients with AGC receiving nivolumab treatment.

Background: Spirometry is useful for evaluating respiratory health status and predicting health-related outcomes. As spirometry requires skilled technician and takes time, it is useful to find simple way for predicting lung function impairment. The aim of this study was to investigate which tests could predict lung function impairment among workers., Methods: This prospective study included workers of manufacturing industry who underwent health check-ups in 2017. Subjects underwent the chronic obstructive pulmonary disease (COPD) assessment test (CAT), spirometry, and physical fitness assessments, including handgrip strength (HGS). Lung function impairment was defined as a decline in any of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), or a FEV1/FVC ratio less than the lower limit of normal (LLN)., Results: Complete data on 475 workers (366 men, 50.4% ever smokers) were available. Lung function impairment was observed in 99 subjects (64 men). Men with lung function impairment had significantly higher rate of ever-smoking, passive smoking at home in childhood, high CAT scores, and decreased HGS, compared with those without. On multivariate analyses, ever-smoking (odds ratio [OR], 2.50; 95% confidence intervals [CI], 1.25-4.97), passive smoking at home in childhood (OR, 2.71; 95% CI, 1.16-6.32), CAT scores (OR, 1.06; 95% CI, 1.01-1.12), and HGS (OR, 0.73; 95% CI, 0.57-0.92) were independently associated with lung function impairment in men., Conclusions: Ever-smoking, passive smoking at home in childhood, high CAT scores, and decreased HGS are significantly associated with lung function impairment in men., Trial Registration: Registration number: UMIN000028011. Date of registration: July 1, 2017.

Although it ameliorates lung cancer, immunotherapy with immune checkpoint inhibitors (ICIs) presents complications of infectious diseases, including tuberculosis. Incidence of tuberculosis during immunotherapy remains unclear. We found that 1.7% of patients developed active tuberculosis during immunotherapy at our institution. In patients with a positive interferon-gamma release assay status before ICI therapy, physicians should pay close attention to developing tuberculosis., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background/aim: The utility of nanoparticle albumin-bound paclitaxel (nab-PTX) monotherapy in patients with relapsed small-cell lung cancer (SCLC) has not been fully evaluated. We aimed to investigate the efficacy and safety of nab-PTX monotherapy in relapsed SCLC patients, including heavily treated patients., Patients and Methods: We retrospectively analysed data from 17 patients with relapsed SCLC who were treated with weekly nab-PTX monotherapy at our hospital. We also reviewed past studies on nab-PTX monotherapy for relapsed SCLC., Results: The response rate, progression-free survival, and overall survival were 29.4%, 48 days (95%CI=33-89), and 134 days (95%CI=64-223), respectively. The most common adverse event of grade ≥3 was leukopenia (17.6%), followed by neutropenia, neuropathy, fatigue, and infections. Our results were consistent with previous studies., Conclusion: The efficacy of nab-PTX monotherapy for heavily treated relapsed SCLC patients might be moderate. Further studies to improve outcomes are warranted., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: This study evaluated the efficacy and safety of retreatment with anti-programmed death 1 (anti-PD-1) antibodies in patients with advanced non-small cell lung cancer (NSCLC) after prior treatment with anti-programmed death-ligand 1 (anti-PD-L1) antibodies., Methods: Data (N = 15) on patients' characteristics, number of cycles, regimens, their best response and immune-related adverse events (irAEs) were recorded retrospectively., Results: NSCLC was initially treated with anti-PD-L1 antibody atezolizumab (N = 14) or durvalumab (N = 1). No patients had a high (≥50%) tumor expression of PD-L1. The median cycles for atezolizumab were five (range 1-15), and median progression-free survival was 2.8 and 6.0 months for atezolizumab and durvalumab, respectively. Five (33.3%) and nine (60.0%) patients showed stable and progressive disease as their best response, respectively. No differences in irAEs between anti-PD-L1 and anti-PD-1 antibodies occurred., Conclusion: Patients treated with anti-PD-L1 antibodies for NSCLC received limited benefits from retreatment with anti-PD-1 antibodies., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Disseminated nontuberculous mycobacterial (NTM) infections usually occur in severely immunosuppressed patients. These infections may also occur in previously immunocompetent patients with acquired anti-interferon-gamma antibodies (anti-IFN-γ Abs). A previously healthy 33-year-old man presented with a 3-week history of cough and fever. Chest computed tomography showed air-space consolidation in the middle lobe of the right lung and enlargement of the supraclavicular, mediastinal, and hilar lymph nodes. Tissue samples obtained via mediastinoscopy showed granuloma formation with acid-fast bacteria; cultures from the tissue revealed Mycobacterium kansasii . Accordingly, a diagnosis of disseminated M. kansasii disease was made. The positive control tested negative in the QuantiFERON-TB Gold In-tube test, suggesting the presence of anti-IFN-γ Abs. The ELISA test for anti-IFN-γ Abs demonstrated an increased titer. Antimycobacterial drug treatments were initiated after diagnosis. His symptoms improved over 2 months, and he remains well on outpatient management. Disseminated M. kansasii disease is a very rare condition suggestive of immunosuppression. Testing for anti-IFN-γ antibodies might be important in all cases of disseminated M. kansasii disease.

Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α + /CD103 + cDC1s and CD11b + cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs ( Itgax -cre × Adam10 -fl/fl; ADAM10 ∆DC ) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10 ∆DC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10 ∆DC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival., Competing Interests: The authors declare no conflict of interest.

Aim: To evaluate the efficacy and safety of re-treatment with anti-programmed death (PD)-L1 antibody (atezolizumab) after anti-PD-1 antibody (nivolumab/pembrolizumab) treatment in advanced non-small cell lung cancer (NSCLC) patients., Patients and Methods: We retrospectively reviewed 18 NSCLC patients who received atezolizumab after anti-PD-1 antibody treatment. Data on patient characteristics, number of cycles of anti-PD-1 antibody and atezolizumab, regimens between anti-PD-1 antibody and atezolizumab, best response, and immune-related adverse events (irAEs) were collected and analyzed., Results: Nine patients a had high (≥50%) PD-L1 expression. The median number of cycles of atezolizumab was 3 (range=2-7). The median progression-free survival was 2.9±1.8 months. Seven (38.9%) and 11 (61.1%) patients had stable and progressive disease, respectively. No patient achieved partial or complete response. There were no significant differences in the occurrence of irAEs between anti-PD-1 antibodies and atezolizumab., Conclusion: Preliminary results showed that patients previously treated with anti PD-1 antibodies received only limited benefit from subsequent atezolizumab., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This case involved a 28-year-old female with rectal cancer in the inner pelvis. Two courses of SOX plus Cmab therapy, and 4 courses of FOLFOX-Cmab therapy were administered as preoperative chemotherapies, which resulted in a reduction in the major lesion. Subsequently, laparoscopic low anterior resection and dissection of the bilateral lymph nodes were performed. After the surgery, adjuvant chemotherapy with FOLFOX was administered. Afterwards, the patient developed severe anal pain and visited us for treatment. The severe anal pain continued even after FOLFOX treatment and increased with defecation. A side effect of oxaliplatin was suspected, and sLV5FU chemotherapy was administered. As a result, the anal pain disappeared. Thus, the pain was considered to be induced by oxaliplatin. While peripheral neuropathy is a widely known side effect of oxaliplatin, this case was considered to be unique because anal pain occurs very rarely with oxaliplatin treatment.

Background: Several reports have described the importance of immunological and nutritional factors in the morbidity and/or mortality of patients with tuberculosis. The aim of this study was to evaluate the association between pulmonary cavitation and immunonutritional status, assessed by parameters such as neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI), in patients with pulmonary tuberculosis., Methods: We retrospectively analyzed the data of 137 patients with culture-positive active pulmonary tuberculosis without bacterial pneumonia diagnosed at Kainan Hospital between April 2008 and March 2016. The associations between the levels of serum albumin, lymphocytes, NLR, PNI, platelet to lymphocyte ratio (PLR), and body mass index (BMI) and pulmonary cavitation were evaluated in the patients., Results: A total of 83 men and 63 women (median age, 75 years; range, 16-94 years) were included in the study. Sixty-six patients had smoking history; 55 patients had respiratory symptoms, while 44 patients did not have any symptoms. Patient׳s delay, defined as medical examination performed over 60 days after the onset of symptoms was observed in 25 patients. Univariate analysis showed that high NLR (≥ 5), high PLR (≥200), low serum albumin (<3 g/dL), high neutrophil count (≥6000/mm 3 ), and low lymphocyte count (<1000/mm 3 ) were associated with pulmonary cavitation. Multivariate analysis showed that high NLR and low serum albumin were associated with pulmonary cavitation., Conclusion: Malnutrition and increased severity of inflammation may be associated with pulmonary cavitation in patients with tuberculosis. Further studies are warranted to confirm the findings of the present study., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Backgrounds: Cancer immunotherapy using immune checkpoint inhibitors has received a remarkable amount of attention in patients with non-small cell lung cancer (NSCLC). The unique adverse effects known as immune-related adverse events (irAEs) associated with immune checkpoint inhibitors are not known however, and neither is the incidence of infectious disease among patients receiving immune checkpoint inhibitors. The aims of this study were to investigate the incidence of infections during nivolumab treatment, and the risk factors associated with infections., Methods: We retrospectively reviewed NSCLC patients who received nivolumab in two teaching hospitals (National Hospital Organization Kyoto Medical Center and Kyoto University Hospital, Kyoto, Japan) between December 2015 and June 2017. We counted any infectious diseases occurring at any time after the initiation of nivolumab until 3 months after its discontinuation. In the current study, "infectious disease" was defined as any infection requiring the administration of any antimicrobial agent., Results: Of a total of 167 NSCLC patients reviewed, 32 (19.2%) experienced infectious diseases. Of the 33 infections in 32 patients, 25 were bacterial, 2 were fungal, and 6 were viral. Twenty-seven of the patients with infections used corticosteroids during their treatment course. There was no statistically significant difference in the use of immunosuppressive agents between patients with and without infections. A history of diabetes mellitus was significantly associated with infection (odds ratio 3.61, 95% confidence interval 1.14-11.4, p = 0.028)., Conclusions: Lung cancer patients receiving nivolumab have a certain level of risk for developing infectious diseases. In the current study, a history of diabetes mellitus was an independent risk factor for infectious disease development. Clinicians should pay attention to occult infectious diseases in patients receiving lung cancer treatment with immune checkpoint inhibitors, especially those with the history of diabetes mellitus., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Combination therapy of linezolid (LZD) and rifampicin (RFP) may be more effective than monotherapy for treating gram-positive bacterial infections, but several studies have suggested that RFP decreases LZD exposures, thereby increasing the risk of therapeutic failure and emergence of LZD-resistant strains. However, the mechanism of the drug-drug interaction between LZD and RFP is unknown., Methods: We conducted a prospective, open-label, uncontrolled clinical study in Japanese patients receiving LZD and RFP to evaluate the effect of coadministered RFP on the concentration of LZD. In animal study in rats, the influence of coadministered RFP on the pharmacokinetics of LZD administered intravenously or orally was examined. Intestinal permeability was investigated with an Ussing chamber to assess whether coadministered RFP alters the absorption process of LZD in the intestine., Results: Our clinical study indicated that multiple doses of RFP reduced the dose-normalized trough concentration of LZD at the first assessment day by an average of 65%. In an animal study, we found that multiple doses of RFP significantly decreased the area under the concentration-time curve, the maximum concentration and the bioavailability of orally administered LZD by 48%, 54% and 48%, respectively. In contrast, the pharmacokinetics of intravenously administered LZD was unaffected by the RFP pretreatment. However, investigation of the intestinal permeability of LZD revealed no difference in absorptive or secretory transport of LZD in the upper, middle and lower intestinal tissues between RFP-pretreated and control rats, even though RFP induced gene expression of multidrug resistance protein 1a and multidrug resistance-associated protein 2., Conclusions: Therapeutic drug monitoring may be important for avoiding subtherapeutic levels of LZD in the combination therapy. The drug-drug interaction between LZD and RFP may occur only after oral administration of LZD, but is not due to any change of intestinal permeability of LZD., Trial Registration: UMIN, UMIN000004322. Registered 4 October 2010., Competing Interests: Protocol of this study was approved by the Ethics Committee of Kanazawa University (UMIN000004322).Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Vitamin D maintains calcium balance and has immunomodulatory effects. Only few studies have revealed the relationship between vitamin D and its associated factors in Mycobacterium avium complex (MAC) infection. This study aimed to investigate the effects of MAC infection on serum vitamin D, human cationic antimicrobial protein 18, its C-terminal 37 amino acid fragment (hCAP18/LL-37) levels, and bone mineral density (BMD).We enrolled 58 patients with MAC lung disease and 15 control participants. Serum 25-hydroxyvitamin D and hCAP18/LL-37 levels were measured via enzyme-linked immunosorbent assay. Lastly, computed tomography scan density readings of the BMD of the thoracic and lumbar vertebral bones (Th4, Th7, Th10, and L1) were assessed.No significant differences in patient characteristics and serum vitamin D levels were observed. Patients with MAC lung disease had significantly low serum hCAP18/LL-37 levels (P = .049). Moreover, low BMD of the mean thoracic and lumbar vertebrae was observed (mean Th, P = .012; L1, P = .48, respectively). A higher prevalence of scoliosis (P = .031) was observed in the participants with low BMD compared with the control participants. Based on a multivariate analysis, patients with MAC lung disease had significantly lower body mass index [odds ratio (OR), 19.1; 95% confidence interval (CI), 2.0-419.0; P < .01] and vertebral BMD (OR, 12.4; 95% CI, 1.7-160.6; P = .012) than control participants.Serum hCAP18/LL-37 level and BMD were significantly decreased in patients with MAC lung disease without relation to serum vitamin D level. The vitamin D-independent pathway might affect the waning of antimicrobial peptides and decrease in BMD.

A 90-year-old woman was referred to our hospital because of dyspnea with pleural effusion that was detected using a chest X-ray. Pleural fluid cell block specimens from the left pleural effusion were shown to be an adenocarcinoma harboring an epidermal growth factor receptor(EGFR)gene mutation(L858R). Erlotinib was administered and the patient responded to treatment for 15 months. Subsequent re-accumulation of the left pleural effusion was detected, and re-evaluation using cell block specimens revealed EGFR T790M mutation positivity. Osimertinib was initiated and the patient responded to treatment for 11 months. Re-evaluation of the left pleural effusion upon failure of osimertinib treatment revealed EGFR T790M mutation negativity. Hence this report summarizes the case of osimertinib therapy being administered to a 90-year-old patient who had EGFR T790M mutation positivity based on a pleural fluid cell block.

Purpose: After approval of anti-programmed cell death (PD)-1 antibodies, treatment for non-small cell lung cancer (NSCLC) has drastically changed. However, even in patients with favorable effects, therapeutic efficacy does not last long. Recently, retreatment with anti-PD-1 antibody has received attention. The aim of this study was to evaluate the efficacy and safety of retreatment with pembrolizumab in NSCLC patients previously treated with nivolumab., Patients and Methods: We retrospectively reviewed NSCLC patients retreated with pembrolizumab who were previously treated with nivolumab. We collected the following data: patient characteristics, number of cycles of nivolumab and pembrolizumab, treatment interval between nivolumab and pembrolizumab, best response, and immune-related adverse events., Results: Twelve patients were reviewed. The median number of cycles of nivolumab was 12.5 (range 2-32 cycles). Seven patients (58.3%) achieved a partial response (PR) and two patients (16.7%) achieved stable disease (SD). Eight patients (66.7%) received cytotoxic chemotherapy between nivolumab and pembrolizumab. The median number of cycles of chemotherapy treatment was 4 (range 1-9 cycles). The median number of cycles of pembrolizumab was 3.5 (range 1-17 cycles). One patient (8.3%) achieved PR and four patients (33.3%) achieved SD as their best response to pembrolizumab. All patients showing response to pembrolizumab had very high (≥ 80%) tumor PD-Ligand 1 expression., Conclusions: This study suggested that retreatment with anti-PD-1 antibody is a reasonable option for selected NSCLC patients.

Background/aim: It remains challenging to select patients with non-small cell carcinoma (NSCLC) for nivolumab monotherapy. We evaluated whether early termination of nivolumab monotherapy correlated with pretreatment neutrophil/lymphocyte ratio (NLR) and prognostic nutritional index (PNI)., Patients and Methods: Twenty patients received nivolumab monotherapy for NSCLC with wild-type epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) during 2016. Early termination and continued therapy were defined as ≤5 and ≥6 cycles of monotherapy, respectively., Results: Early termination and continued therapy groups included 9 and 11 patients, respectively. High pretreatment NLR and low pretreatment PNI were significantly associated with early termination of nivolumab, both in an overall analysis (p<0.001 and p=0.016) and in subgroup analyses of patients with performance scores of 0-1 and ≥30 days of pretreatment drug holidays., Conclusion: High NLR and low PNI were associated with early termination of nivolumab monotherapy, suggesting they might be useful biomarkers for treatment selection., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Recently, CO 2 utilization technology, including artificial photosynthesis, has received much attention. In this field, CO 2 is used as a feedstock for fuels, polymers and in other chemical processes. Of note are malic enzymes (MEs) which catalyze the reaction of malic acid to pyruvic acid and CO 2 with the co-enzyme NADP + , and catalyze the reverse reaction of pyruvic acid and CO 2 to malic acid with the co-enzyme NADPH. Thus, MEs are also an attractive biocatalyst for carbon-carbon bond formation from CO 2 . Studies of the visible light-induced malic acid production from pyruvic acid and CO 2 using an electron donor, a photosensitizer, an electron mediator, ferredoxin-NADP + reductase, NADP + , and ME have been reported. However, modification of these systems is required, as they are very complicated. In this study, the visible light-induced carbon-carbon bond formation from pyruvic acid and CO 2 with ME using the photoreduction of 1,1'-diphenyl-4,4'-bipyridinium salt derivatives as a novel electron mediator with water-soluble tetraphenylporphyrin tetrasulfonate (H 2 TPPS) in the presence of triethanolamine (TEOA) as an electron donor was developed. When a sample solution containing TEOA, H 2 TPPS, 1,1'-diphenyl-4,4'-bipyridinium salt derivative, pyruvic acid, and ME in CO 2 -saturated bis-tris buffer was irradiated, the major product was oxaloacetic acid. Thus, a visible light-induced photoredox system for carbon-carbon bond formation from CO 2 with ME using 1,1'-diphenyl-4,4'-bipyridinium salt derivative as an electron mediator was developed.

Heronamides are biosynthetically related metabolites isolated from marine-derived actinomycetes. Heronamide C shows potent antifungal activity by targeting membrane phospholipids possessing saturated hydrocarbon chains with as-yet-unrevealed modes of action. In spite of their curious hypothesized biosynthesis and fascinating biological activities, there have been conflicts in regard to the reported stereochemistries of heronamides. Here, we describe the asymmetric total synthesis of the originally proposed and revised structures of heronamide C, which unambiguously confirmed the chemical structure of this molecule. We also demonstrated nonenzymatic synthesis of heronamides A and B from heronamide C, which not only proved the postulated biosynthesis, but also confirmed the correct structures of heronamides A and B. Investigation of the structure-activity relationship of synthetic and natural heronamides revealed the importance of both long-range stereochemical communication and the 20-membered macrolactam ring for the biological activity of these compounds., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Blood coagulation factors play an essential role in pregnancy. We describe a 30-year-old pregnant woman whose course was complicated by dysfibrinogenemia with polymorphism of fibrinogen AαThr312Ala (rs6050) GG genotype. She was admitted to our hospital for genital bleeding and a huge subchorionic hematoma at 6 gestational weeks. Her first pregnancy and delivery had been uneventful, whereas her second and third pregnancies had resulted in spontaneous abortions with massive subchorionic hematomas. Her fibrinogen activity level was 125 mg/dl and this was lower than her fibrinogen antigen level. We administered tranexamic acid early in the pregnancy, and the subchorionic hematoma diminished in size in accordance with the increase of her fibrinogen level. At 16 gestational weeks, her D-dimer levels were elevated, and heparin treatment was initiated as an alternative. A male infant was delivered at 36 gestational weeks. Intrapartum hemorrhage was 600 g. Patients with coagulation abnormalities are often asymptomatic in the absence of pregnancy. However, when they become pregnant, the spontaneous abortion rate is high. Careful observation and effective management of coagulation abnormalities are essential for such patients to carry their pregnancies to term.

Background: Patients with pulmonary Mycobacterium avium complex (MAC) disease are often co-infected with various pathogenic microorganisms. This study aimed to determine the prevalence of co-infection with non-MAC pathogens and the risk factors associated with co-infection in patients with pulmonary MAC disease., Methods: We retrospectively reviewed the patient characteristics, microbiological results and chest CT findings in 275 patients with pulmonary MAC who visited the Kyoto University Hospital from January 2001 to May 2013. We defined chronic pathogenic co-infection as the isolation of non-MAC pathogens from sputum samples taken on more than two visits that occurred at least 3 months apart., Results: The participants were predominantly female (74.5%) and infected with M. avium (75.6%). Chronic co-infection with any pathogen was observed in 124 patients (45.1%). Methicillin-sensitive Staphylococcus aureus (MSSA; n=64), Pseudomonas aeruginosa (n=35) and Aspergillus spp (n=18) were the most prevalent pathogens. The adjusted factors were chronic obstructive pulmonary disease (COPD; OR=4.2, 95% CI 1.6 to 13.1) and pulmonary M. intracellulare disease (OR=2.2, 95% CI 1.1 to 4.4) in chronic co-infections; COPD (OR=4.2, 95% CI 2.1 to 31.4), long duration of MAC disease (OR=2.2, 95% CI 1.2 to 4.4) and nodules (OR=3.5, 95% CI 1.2 to 13.2) in chronic MSSA co-infection; COPD (OR=7.5, 95% CI 2.1 to 31.4) and lower lobe involvement (OR=9.9, 95% CI 2.0 to 90.6) in chronic P. aeruginosa co-infection; and use of systemic corticosteroids (OR=7.1, 95% CI 1.2 to 50.9) and pulmonary M. intracellulare disease (OR=4.0, 95% CI 1.1 to 14.5) in chronic Aspergillus spp co-infection., Conclusions: Patients with pulmonary MAC disease frequently had chronic co-infections with pathogenic microorganisms such as MSSA, P. aeruginosa and Aspergillus. The risk factors for chronic co-infection were COPD and pulmonary M. intracellulare disease.

Rationale: Polyclonal and mixed mycobacterial Mycobacterium avium complex (MAC) infection is observed in pulmonary MAC disease. Human living environments contain multiple species or genotypes of nontuberculous mycobacterial strains and are considered sources of infection., Objectives: To investigate the association of environmental exposure with polyclonal and mixed mycobacterial infection in pulmonary MAC disease after adjustments for potential confounding diseases and conditions and radiographic findings., Methods: We collected two separate sputum samples from 102 patients and single sputum samples from 18 patients in whom the second MAC strain was not isolated in our prospective cohort of pulmonary MAC disease. MAC isolates from sputum samples and patients' residential soils were used for variable number of tandem repeats (VNTR) analyses. Polyclonal and mixed mycobacterial MAC infections were defined as having different VNTR genotypes and other mycobacterial species, respectively. Monoclonal MAC infection was defined as all isolates showing a single VNTR genotype. Associations of the type of infection with clinical and radiographic findings and environmental exposure were measured., Measurements and Main Results: Polyclonal and mixed mycobacterial MAC and monoclonal infections were observed in 42 and 78 patients, respectively. By stepwise regression analysis, patients with polyclonal and mixed mycobacterial MAC infections were associated with history of asthma (odds ratio [OR], 11.56; 95% confidence interval [CI], 1.41-255.77; P = 0.021), high soil exposure (≥2 h/wk; OR, 4.31; 95% CI, 1.72-11.45; P < 0.01), shower use in a bathroom (OR, 4.57; 95% CI, 1.28-23.23; P = 0.018), and swimming in a pool (OR, 9.69; 95% CI, 1.21-206.92; P < 0.01)., Conclusions: Environmental exposure was associated with polyclonal and mixed mycobacterial MAC infection in pulmonary MAC disease.

We describe a 45-year-old woman with minute signet ring cell carcinoma occurring in a gastric hyperplastic polyp. A biopsy specimen obtained from the gastric hyperplastic polyp revealed signet ring cell carcinoma. Endoscopic mucosal resection (EMR) was performed to confirm the diagnosis. Histological examination of the EMR specimen revealed focal signet ring cell carcinoma in the hyperplastic polyp. There are few cases of gastric hyperplastic polyp associated with signet ring cell carcinoma.

Aim: To evaluate the effectiveness of endoscopic submucosal dissection using an insulation-tipped diathermic knife (IT-ESD) for the treatment of patients with over 20 mm early gastric cancer (EGC)., Methods: A total of 112 patients with over 10 mm EGC were treated with IT-ESD at Sumitomo Besshi Hospital and Shikoku Cancer Center in the 5 year period from January 2002 to December 2006, including 40 patients with over 20 mm EGC. We compared patient backgrounds, the one-piece resection rate, complete resection (CR) rate, operation time, bleeding rate, perforation rate between patients with over 20 mm EGC [over 20 mm group (21-40 mm)] and the remaining patients (under 20 mm group)., Results: We found no significant difference in the rate of underlying cardiopulmonary disease (over 20 mm group vs under 20 mm group, 5.0% vs 5.6%), one-piece resection rate (95% vs 96%), CR rate (85% vs 89%), operation time (72.3 min vs 66.5 min), bleeding rate (5% vs 4.2%), and perforation rate (0% vs 1.4%) between the 2 groups. Three patients in each group had submucosal invasion and two in each groups underwent additional surgery., Conclusion: There was no significant difference in the outcome resulting from IT-ESD between the 2 groups. Our study proves that IT-ESD is a feasible treatment for patients with over 20 mm mucosal gastric cancer although the long-term outcome should be evaluated in the future.