Disseminated non-tuberculous mycobacterial infection caused by Mycobacterium obuense in an immunocompromised patient: a case report.

BACKGROUND: Mycobacterium obuense (M. obuense) is a rapidly growing mycobacterium (RGM) which has been considered nonpathogenic. Here, we report a case of disseminated non-tuberculous mycobacterial (NTM) infection caused by M. obuense in an immunocompromised patient. CASE PRESENTATION: A 16-year-old boy was referred to our hospital due to acute myeloid leukemia. During the treatment of leukemia, the patient exhibited continuous fever, and diffuse miliary nodules with random distribution were found on chest computed tomography. Repeated examinations of bacterial culture tests revealed sputum and urine samples to be smear-positive for acid-fast bacillus, and blood culture from a peripherally inserted central catheter line showed the growth of NTM. The NTM species was identified as M. obuense by mass spectrometry and confirmed by genome sequencing. Combination therapy with amikacin, rifampicin, azithromycin, and moxifloxacin significantly improved the patient's symptoms and radiological findings. CONCLUSION: We report a case of disseminated NTM infection caused by M. obuense for which combination anti-microbial therapy was effective. An immunocompromised host indwelling catheter is at risk of RGM bloodstream infections. Although relatively rare, M. obuense may be considered as a potential pathogen causing infectious diseases, especially in high-risk patients.

Correction to: Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer

In the original version of this article, the given names of all authors were omitted. The complete names were provided below.Takatoshi Enomoto, Akihiro Tamiya, Kinnosuke Matsumoto, Yuichi Adachi, Koji Azuma, Yuji Inagaki, Shunichi Kouno, Yoshihiko Taniguchi, Nobuhiko Saijo, Kyoichi Okishio, Shinji AtagiThe original article has been corrected.

Retrospective analysis of long-term survival factors in patients with advanced non-small cell lung cancer treated with nivolumab.

BACKGROUND: Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non-small cell lung cancer (NSCLC). However, factors associated with long-term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long-term survival in NSCLC patients treated with nivolumab, using real-world data. METHODS: We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long-term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong-term survivors and long-term survivors and performed univariate and multivariate analyses of factors associated with long-term survival. RESULTS: Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG-PS ≤1 were included in the study. Young age, ECOG-PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil-to-lymphocyte ratio (NLR) change (ΔNLR) <1 were significantly associated with long-term survival. Long-term survivors had significantly higher response and disease control rates than nonlong-term survivors. Multivariate analysis showed that ΔNLR <1 was significantly associated with long-term survival. Further, OS was significantly different between the PS 0 and PS 1 groups (median OS: 32.0 months vs. 10.6 months) and the nonincreasing NLR and increasing NLR groups (median OS: 20.8 months vs. 5.7 months). CONCLUSIONS: ΔNLR <1 was a significant long-term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab.

Diagnostic yield and safety of bronchofiberscopy for pulmonary alveolar proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a diffuse lung disease characterized by the abnormal accumulation of surfactant-like material within the alveolar spaces and distal bronchioles. If high-resolution computed tomography (HRCT) indicates the presence of PAP, a definitive diagnosis of PAP is established when consistent pathological findings are obtained. Herein, we retrospectively studied the yield and safety of bronchofiberscopy in the diagnosis of PAP. METHODS: One hundred and fifty consecutive patients with PAP were prospectively registered in the PAP cohort database of the National Hospital Organization Kinki-Chuo Chest Medical Center between January 1991 and December 2018. We examined 86 patients who underwent bronchofiberscopy with bronchoalveolar lavage (BAL) and transbronchial lung forceps biopsy (TBLB). RESULTS: The patients included 56 men and 30 women, with a median age of 57 years. All patients had autoimmune PAP, and the median level of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies was 42.8 µg/mL. The diagnostic yield was 90.7% (78/86) with BAL and 81.4% (70/86) with TBLB. The combination of BAL and TBLB increased the yield to 98.8%. Age, disease severity score, and frequency of traction bronchiectasis on HRCT were significantly different between the TBLB-positive and TBLB-negative groups. No patient developed serious complications due to bronchofiberscopy; TBLB-related complications included pneumothorax (3.5%) and minimal bleeding (7.0%). CONCLUSIONS: Bronchofiberscopy, in combination with BAL and TBLB, is an effective and safe method for the diagnosis of PAP, with a yield of 98.8%.

Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer

Purpose This study evaluated the efficacy and safety of nivolumab treatment beyond progressive disease (PD) in non-small cell lung cancer (NSCLC). Patients/methods Medical records of consecutive patients with advanced NSCLC who received nivolumab between December 2015 and December 2018 were reviewed. Clinical outcomes of three groups of eligible patients who received nivolumab as a second-line treatment after PD were compared based on Response Evaluation Criteria in Solid Tumors v1.1. We conducted subgroup analyses in patients with and without new lesions at first PD. Results Twenty-eight patients continued nivolumab treatment beyond PD (TBP). Post PD, 46 patients switched to other anti-cancer treatment (OAT), and 21 received no further anti-cancer treatment (NAT). There were no significant differences in overall survival (OS) or survival post progression (SPP) between TBP and OAT groups (OS: 15.6 vs. 13.4 months, P = .40, SPP: 12.2 vs. 9.3 months, P = .42). Subgroup analyses indicated that among patients without new lesions at first PD, SPP was longer in the TBP than in the OAT groups (12.6 vs. 9.3 months, P = .22, HR: 0.64; 95% CI 0.31‒1.31). The frequency of immune-related adverse events leading to discontinuation during nivolumab beyond PD was equivalent to that for pre-PD (10.7 vs. 12.6%). Conclusions No significant benefits were associated with continuation of nivolumab for advanced NSCLC patients. Continuation of nivolumab beyond PD could be a more useful option in patients without new lesions at first PD. Treatment-related toxicities require attention during nivolumab treatment not only before PD but also beyond PD (AU)

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

BACKGROUND: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. METHODS: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. RESULTS: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). CONCLUSION: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

Limitations of End-Tidal CO2 Measured with a Portable Capnometer to Estimate PaCO2 for Patients with Respiratory Disease.

OBJECTIVE: This study evaluated the relationship between end-tidal carbon dioxide (EtCO2) measured with a portable capnometer and PaCO2 in respiratory disease patients. MATERIAL AND METHODS: We retrospectively reviewed patients whose EtCO2, measured with a portable capnometer using a mouthpiece, and PaCO2 were simultaneously assessed at a single center from August 2017 to September 2018. The primary outcome was the relationship between EtCO2 and PaCO2. We conducted subgroup analyses in patients with interstitial lung disease (ILD), with and without O2 supplementation. The relationship between EtCO2 and PaCO2 was analyzed using Spearman's rank test and Bland-Altman analysis. RESULTS: A total of 100 patients were registered in this study. There was a moderate correlation between EtCO2 and PaCO2 (rho = 0.41). The Bland-Altman plot showed that the mean bias was 0.32 mmHg (95% CI: -1.28 to 1.92), the limits of agreement (LOA) were -15.48 and 16.13 mmHg, and the percent error was 38.49%. The LOA in patients with ILD were -15.12 and 13.75 mmHg. In patients with O2 supplementation, the mean bias was greater, and the LOA were wider than in those without O2 supplementation (mean bias: 7.17 vs. -1.18 mmHg, respectively; LOA: -14.29 and 28.62 mmHg vs. -13.82 and 11.46 mmHg, respectively). CONCLUSION: In the clinical setting, the relationship between EtCO2 and PaCO2 was poor in patients with respiratory disease, especially in those receiving O2 supplementation, compared with that reported in previous studies. It may be difficult to precisely estimate PaCO2 in patients with respiratory disease based on measurements of EtCO2.

Nivolumab treatment beyond progressive disease in advanced non-small cell lung cancer.

PURPOSE: This study evaluated the efficacy and safety of nivolumab treatment beyond progressive disease (PD) in non-small cell lung cancer (NSCLC). PATIENTS/METHODS: Medical records of consecutive patients with advanced NSCLC who received nivolumab between December 2015 and December 2018 were reviewed. Clinical outcomes of three groups of eligible patients who received nivolumab as a second-line treatment after PD were compared based on Response Evaluation Criteria in Solid Tumors v1.1. We conducted subgroup analyses in patients with and without new lesions at first PD. RESULTS: Twenty-eight patients continued nivolumab treatment beyond PD (TBP). Post PD, 46 patients switched to other anti-cancer treatment (OAT), and 21 received no further anti-cancer treatment (NAT). There were no significant differences in overall survival (OS) or survival post progression (SPP) between TBP and OAT groups (OS: 15.6 vs. 13.4 months, P = .40, SPP: 12.2 vs. 9.3 months, P = .42). Subgroup analyses indicated that among patients without new lesions at first PD, SPP was longer in the TBP than in the OAT groups (12.6 vs. 9.3 months, P = .22, HR: 0.64; 95% CI 0.31‒1.31). The frequency of immune-related adverse events leading to discontinuation during nivolumab beyond PD was equivalent to that for pre-PD (10.7 vs. 12.6%). CONCLUSIONS: No significant benefits were associated with continuation of nivolumab for advanced NSCLC patients. Continuation of nivolumab beyond PD could be a more useful option in patients without new lesions at first PD. Treatment-related toxicities require attention during nivolumab treatment not only before PD but also beyond PD.

Experimental time-reversed adaptive Bell measurement towards all-photonic quantum repeaters.

An all-optical network is identified as a promising infrastructure for fast and energy-efficient communication. Recently, it has been shown that its quantum version based on 'all-photonic quantum repeaters'-inheriting, at least, the same advantages-expands its possibility to the quantum realm, that is, a global quantum internet with applications far beyond the conventional Internet. Here we report a proof-of-principle experiment for a key component for the all-photonic repeaters-called all-photonic time-reversed adaptive (TRA) Bell measurement, with a proposal for the implementation. In particular, our TRA measurement-based only on optical devices without any quantum memories and any quantum error correction-passively but selectively performs the Bell measurement only on single photons that have successfully survived their lossy travel over optical channels. In fact, our experiment shows that only the survived single-photon state is faithfully teleported without the disturbance from the other lost photons, as the theory predicts.

Fundamental rate-loss trade-off for the quantum internet.

The quantum internet holds promise for achieving quantum communication-such as quantum teleportation and quantum key distribution (QKD)-freely between any clients all over the globe, as well as for the simulation of the evolution of quantum many-body systems. The most primitive function of the quantum internet is to provide quantum entanglement or a secret key to two points efficiently, by using intermediate nodes connected by optical channels with each other. Here we derive a fundamental rate-loss trade-off for a quantum internet protocol, by generalizing the Takeoka-Guha-Wilde bound to be applicable to any network topology. This trade-off has essentially no scaling gap with the quantum communication efficiencies of protocols known to be indispensable to long-distance quantum communication, such as intercity QKD and quantum repeaters. Our result-putting a practical but general limitation on the quantum internet-enables us to grasp the potential of the future quantum internet.

All-photonic intercity quantum key distribution.

Recent field demonstrations of quantum key distribution (QKD) networks hold promise for unconditionally secure communication. However, owing to loss in optical fibres, the length of point-to-point links is limited to a hundred kilometers, restricting the QKD networks to intracity. A natural way to expand the QKD network in a secure manner is to connect it to another one in a different city with quantum repeaters. But, this solution is overengineered unless such a backbone connection is intercontinental. Here we present a QKD protocol that could supersede even quantum repeaters for connecting QKD networks in different cities below 800 km distant. Nonetheless, in contrast to quantum repeaters, this protocol uses only a single intermediate node with optical devices, requiring neither quantum memories nor quantum error correction. Our all-photonic 'intercity' QKD protocol bridges large gaps between the conventional intracity QKD networks and the future intercontinental quantum repeaters, conceptually and technologically.

Quantum benchmark via an uncertainty product of canonical variables.

We present an uncertainty-relation-type quantum benchmark for continuous-variable (CV) quantum channels that works with an input ensemble of Gaussian-distributed coherent states and homodyne measurements. It determines an optimal trade-off relation between canonical quadrature noises that is unbeatable by entanglement breaking channels and refines the notion of two quantum duties introduced in the original papers of CV quantum teleportation. This benchmark can verify the quantum-domain performance for all one-mode Gaussian channels. We also address the case of stochastic channels and the effect of asymmetric gains.

All-photonic quantum repeaters.

Quantum communication holds promise for unconditionally secure transmission of secret messages and faithful transfer of unknown quantum states. Photons appear to be the medium of choice for quantum communication. Owing to photon losses, robust quantum communication over long lossy channels requires quantum repeaters. It is widely believed that a necessary and highly demanding requirement for quantum repeaters is the existence of matter quantum memories. Here we show that such a requirement is, in fact, unnecessary by introducing the concept of all-photonic quantum repeaters based on flying qubits. In particular, we present a protocol based on photonic cluster-state machine guns and a loss-tolerant measurement equipped with local high-speed active feedforwards. We show that, with such all-photonic quantum repeaters, the communication efficiency scales polynomially with the channel distance. Our result paves a new route towards quantum repeaters with efficient single-photon sources rather than matter quantum memories.

Combined chemotherapy with gemcitabine and carboplatin for metastatic urothelial carcinomas in patients with high renal insufficiency.

BACKGROUND: This was a retrospective study to evaluate the activity and toxicity of a combined chemotherapeutic regimen of gemcitabine and carboplatin (GCa) in patients with metastatic urothelial carcinomas (UCs) with special regard to patients with highly impaired renal function. METHODS: Eleven patients whose creatinine clearance was 30 ml/min or under and who had been diagnosed with metastatic UC were treated with GCa. The patient cohort comprised 4 males and 7 females, with a median age of 74 (range 67-84) years. The median follow-up was 19 (range 1-58) months. RESULTS: Five of the 11 patients (45%) showed an objective response, with 2 achieving a clinically complete response and 3 a partial response with GCa. The grade 3/4 toxicity of the regimen was primarily hematological, including anemia (55%), neutropenia (45%), and thrombocytopenia (45%). Four patients (36%) could not complete the treatment in total. Grade 3 pneumonitis was found in one patient, and the treatment was terminated. Grade 4 febrile neutropenia occurred in the patient on hemodialysis, and the patient was forced to discontinue the chemotherapy. Another 2 patients also called off the treatment due to a pulmonary adverse event and an elevation of serum creatinine, respectively. CONCLUSIONS: GCa appears to be effective for the treatment of metastatic UCs in patients with impaired renal function, but it is necessary to pay attention to the occurrence of severe adverse events.

Modified FOLFOX6 chemotherapy in patients with metastatic urachal cancer.

BACKGROUND: To improve the prognosis of patients with urachal cancer and establish an effective chemotherapeutic regimen for distant metastases. METHODS: We conducted a retrospective study to evaluate the efficacy and safety of a modified combination of 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) therapy in patients with metastatic urachal cancer. RESULTS: Five patients were treated with mFOLFOX6. Their median age was 65 years (range 41-80). The median follow-up time was 42 months (range 18-46). Two of the 5 patients (40%) showed an objective response: 1 achieved a clinically complete response and 1 a partial response. The grade 3/4 toxicity associated with this regimen was primarily neutropenia, but febrile neutropenia was not observed. Oxaliplatin treatment was discontinued because of a grade 2 allergic reaction in 1 patient. Grade 2 peripheral sensory neuropathy caused by oxaliplatin was observed in 2 patients, and the OPTIMOX (stop and go) approach had to be adopted. CONCLUSIONS: mFOLFOX6 appears to be effective for the treatment of metastatic urachal cancer.

Knockdown of Akt isoforms by RNA silencing suppresses the growth of human prostate cancer cells in vitro and in vivo.

The serine/threonine kinase Akt has three highly homologous isoforms in mammals: Akt1, Akt2, and Akt3. Recent studies indicate that Akt is often constitutively active in many types of human malignancy. Here we investigated the expression and function of Akt isoforms in human prostatic carcinoma cells. Initially, we used Western blotting to examine Akt expression in four human prostate cancer cell lines. Next, small-interfering RNAs (siRNAs) specific for Akt isoforms were used to elucidate their role on the in vitro and in vivo growth of prostate cancer cells. Expression of Akt1 and Akt2 was detected in all cells tested, but Akt3 was expressed only in cancer cells that did not express androgen receptors. All synthetic siRNAs against Akt isoforms suppressed their expression and inhibited the growth of cancer cells in vitro. Furthermore, atelocollagen-mediated systemic administration of siRNAs significantly reduced the growth of tumors that had been subcutaneously xenografted. These results suggest that targeting Akt isoforms could be an effective treatment for prostate cancers.

An artificial extracellular matrix created by hepatocyte growth factor fused to IgG-Fc.

The design of artificial extracellular matrices (ECM) has attracted much attention in tissue engineering and regenerative medicine as well as in molecular biology research. A recombinant hepatocyte growth factor (HGF), fused to an immunoglobulin G (IgG) Fc region (abbreviated as AeHGF-Fc) was constructed and confirmed by Western blot assay. Almost similar amounts of HepG2 cells adhered to AeHGF-Fc-coated surface compared to collagen-coated one with large morphological changes. Immobilized AeHGF-Fc continuously activated Akt in HepG2 cells whereas Akt activation induced by soluble HGF rapidly decreased with time, indicating that immobilized AeHGF-Fc follows different signal transduction pathways compared to soluble HGF.

Anti-tumor effect of small interfering RNA targeting the androgen receptor in human androgen-independent prostate cancer cells.

Early phase prostate cancer is usually androgen-dependent, with the androgen/androgen receptor (AR) signaling pathway playing a central role. At this stage, the cancer responds well to androgen ablation therapy, but prostate cancers eventually acquire androgen independence and more aggressive phenotypes. Several studies, however, have shown that the majority of tumors still express functional AR, which is often amplified and mutated. To determine if the AR is a plausible therapeutic target, we investigated the anti-tumor effect of small interfering RNAs targeting the AR (siAR) in the human prostate cancer cells, LNCaP and 22Rv1, which express mutated AR. In both types of cells, transfection of siAR suppressed mutated AR expression and significantly reduced cell growth. Furthermore, atelocollagen-mediated systemic siAR administration markedly inhibited the growth of 22Rv1 cells subcutaneously xenografted in castrated nude mice. These results suggest that the AR is still a key therapeutic target even in androgen-independent prostate cancer (AIPC). Silencing of AR expression in AIPC opens promising therapeutic perspectives.

Effects of galantamine on L-NAME-induced behavioral impairment in Y-maze task in mice.

Nitric oxide (NO) may play a role in the established processes of learning and memory. We examined the effects of N(omega)-nitro-L-arginine methylester (L-NAME), a nonselective inhibitor of NO synthase (NOS), on the performance of mice in a Y-maze task. L-NAME (100 mg/kg) markedly impaired spontaneous alternation behavior. However, galantamine (0.5 mg/kg) significantly attenuated this l-NAME-induced impairment. To clarify the molecular basis underlying galantamine's protective effects against L-NAME-induced impairment of spontaneous alternation behavior, we tested the ability of mecamylamine, an antagonist of nicotinic ACh receptor (nAChR), and scopolamine, an antagonist of muscarinic ACh receptor, to reduce galantamine's protective effects, and found that only the former had such an ability. Galantamine significantly also reduced L-NAME-induced decreases in NOx levels. However, mecamylamine cancelled galantamine's efficacy in countering the L-NAME-induced decrease in NOx levels. In the present study, we have determined that galantamine's protection against L-NAME-induced impairment of spontaneous alternation behavior in the Y-maze task might be mediated mainly by NOergic activation via the nAChR-related pathway.