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Background: CONVERT, a randomized, active-controlled, global, Phase 3 trial demonstrated that patients with treatment-refractory Mycobacterium avium complex (MAC) pulmonary disease were more likely to achieve culture conversion with amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) versus those continuing on GBT alone. This subgroup analysis reports the efficacy and safety of ALIS in Japanese patients enrolled in CONVERT., Methods: Japanese patients aged ≥20 years with treatment-refractory MAC pulmonary disease from Japanese sites were included. Patients were randomized to receive once-daily 590 mg ALIS + GBT or GBT alone; patients converting by Month 6 remained in the study to complete 12-month treatment followed by a 12-month off-treatment period. Nonconverters exited the study at Month 8. The primary endpoint was the proportion of patients achieving culture conversion by Month 6., Results: Of the 59 Japanese patients screened, 48 were randomized to receive ALIS + GBT (n = 34) or GBT alone (n = 14), and 41/48 (85.4 %) were women. The mean (standard deviation) age of patients was 64.5 (8.6) years, and 83.3 % of patients had bronchiectasis at baseline. By Month 6, sputum culture conversion was cumulatively achieved in 9/34 (26.5 %) patients receiving ALIS + GBT versus none receiving GBT alone. Treatment-emergent adverse events were reported in 94.1 % and 100.0 % of patients receiving ALIS + GBT and GBT alone, respectively. No deaths were reported., Conclusions: The efficacy observed in the Japanese subpopulation was largely consistent with that in the overall CONVERT study population, with more patients achieving culture conversion with ALIS + GBT versus GBT alone. Safety profiles were similar between the overall population and the Japanese subpopulation., Clinical Trial Registration: NCT02344004., Competing Interests: Declaration of competing interest Kozo Morimoto received an educational grant from Insmed G.K. to NTM-JRC, serves as a consultant to Nippon Boehringer Ingelheim Co. Ltd. and Insmed G.K., received honoraria for writing promotional material from Insmed G.K. and Nippon Boehringer Ingelheim Co. Ltd.; Mizu Nonaka received lecture fees from Insmed G.K.; Taku Nakagawa received lecture fees from Insmed Inc. and was a member of the advisory board of Insmed Inc.; Kazunari Tsuyuguchi serves as a consultant to Insmed Inc. and Asahi Kasei Pharma and received honoraria for writing promotional material from Insmed Inc., Janssen Pharmaceutical K.K., Eiken Chemical Co. Ltd., AstraZeneca K.K., Kyorin Pharmaceutical Co., Ltd., Teijin Pharma Ltd., and Oxford Immunotec K.K; Zhanna Jumadilova was a former employee of Insmed Inc. and received grants or contracts from Insmed Inc.; Dayton W. Yuen is an employee of Insmed Inc. and reports stock or stock options in Insmed Inc.; Monika Ciesielska is an employee of Insmed Inc. and reports stock or stock options in Insmed Inc.; Naoki Hasegawa serves as a consultant to Insmed Inc.; Yoshitaka Yamazaki, Jin Takasaki, and Seigo Kitada have no conflicts of interest., (Copyright © 2024 [The Author/The Authors]. Published by Elsevier B.V. All rights reserved.)

Background: Mycobacterial time to positivity (TTP) in liquid culture media has predictive value for longer term outcomes in pulmonary tuberculosis, but has not been thoroughly studied in nontuberculous mycobacterial pulmonary disease. This study sought to evaluate for association between TTP and sputum culture conversion to negative in pulmonary disease caused by Mycobacterium avium complex (MAC)., Methods: Data from the CONVERT trial (NCT02344004) that evaluated efficacy of guideline-based-therapy with or without amikacin liposome inhalation suspension in adults with refractory MAC-PD (Mycobacterium avium complex pulmonary disease) were analyzed. We evaluated TTP measures for sputum obtained prior to study treatment initiation and at monthly visits, assessing reproducibility of measures as well as association of TTP with culture conversion on treatment., Results: Data from 71 participants with at least one screening visit TTP value were analyzed. For participants who provided more than one sputum sample at a given visit, there was moderate between-sample reliability, with median intraclass correlation coefficient 0.62 (IQR 0.50, 0.70). Median TTP at screening was longer in those participants who subsequently achieved vs. did not achieve culture conversion (10.5 [IQR 9.4] days vs. 4.2 [IQR 2.8] days, p = 0.0002). Individuals with culture conversion by study treatment month 6 were more likely to have a screening TTP > 5 days compared to those who did not achieve culture conversion (OR 15.4, 95% CI 1.9, 716.7, p = 0.0037) and had increasing TTPs over time., Conclusions: TTP prior to and on treatment is associated with microbiological treatment response in patients with MAC-PD., (© 2022. The Author(s).)

Background: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001)., Research Question: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion?, Study Design and Methods: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation., Results: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment., Interpretation: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion., Trial Registry: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population. Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT. Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed. Results: In the ALIS-naive cohort, 83.3% of patients ( n  = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% ( n  = 32) had serious TEAEs; 26.7% ( n  = 24) achieved culture conversion by Month 6 and 33.3% ( n  = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients ( n  = 34/73) experienced respiratory TEAEs, and 27.4% ( n  = 20) had serious TEAEs; 9.6% ( n  = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% ( n  = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts. Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).

Background and Objectives: Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease., Methods: In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg., Results: Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (C max ) was < 2 mg/L and median area under the concentration-time curve (AUC 0-24 ) was < 20 mg·h/L, suggesting low systemic exposure at both time points. Exposure estimates were similar between Japanese and White patients. The median unchanged amikacin fraction excreted in urine was < 10% of inhaled dose throughout the TR02-112 study, indicating that relatively small amounts reached systemic circulation. Median t 1/2 was 5.5 h. Amikacin concentrations were much higher in sputum than in serum, demonstrating the ability to achieve higher drug concentration at the site of infection. Median sputum amikacin concentrations in the CONVERT study were high at 1-4 h postdose (range 242-426 μg/g) and decreased by 8 h (median 7 μg/g)., Conclusions: Systemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin., Trial Registration: ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the second most prescribed therapeutic drug class in the United States after analgesics. Although these agents are used predominantly to reduce cholesterol concentrations in patients with hyperlipidemia, numerous studies have investigated the pleiotropic effects of statins and their potential in the prevention and/or treatment of other disease states, including cancer. Many theories have been proposed as to how statins may affect the risk or development of malignancies, prompting a clinical review of the literature. Studies have revealed statins to be associated with both increased and decreased cancer risk. Most of the published studies have been observational and retrospective in nature, and most prospective trials evaluated cancer as a secondary end point or adverse event, making it difficult to determine causality. Although most of the available evidence suggests a possible beneficial effect of statins on cancer, further study is needed with better designed trials and/or increased efforts in evaluating cancer as secondary end points in all statin trials until definite conclusions regarding statin effects on cancer risk and occurrence can be made.

The present study aims to investigate the potential therapeutic role of interleukin-10 (IL-10) in small-for-size liver transplantation. A syngenic rat orthotopic liver transplantation model was performed using either whole or 40% liver volume of Lewis rats as grafts according to the experimental design. IL-10 was given to the 40% grafts right after reperfusion, and also at 24 and 48 hours after transplantation. When no treatment was given, less than 40% of the small-for-size grafts survived indefinitely, whereas IL-10 treatment could increase the long-term survival rate of the small-for-size grafts to 80%. The 40% grafts presented with extensive areas of necrosis and increased number of apoptotic cells at the early phases after reperfusion. In addition, upregulation of plasma protein carbonyl content (PCC) levels was also detected in the 40% graft group. IL-10 treatment suppressed the upregulation of allograft inflammatory factor-1 (AIF-1) on macrophages in the 40% grafts, and at the same time, decreased the levels of plasma PCC, and improved the histology and function of the 40% grafts. The expression of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-alpha, and caspase 9 in the 40% grafts were upregulated after reperfusion, whereas the augmentation could be suppressed by the administration of IL-10. Finally, IL-10 culture could block AIF-1-mediated NO production and downregulate the expression of iNOS and TNF-alpha in a macrophage cell line. In conclusion, IL-10 rescued the small-for-size liver grafts by its antiinflammatory properties, through inhibition of AIF-1 mediated proinflammatory and proapoptotic activities of the macrophages during the early period after ischemia/reperfusion.

Background: Diagnosis of nasopharyngeal carcinoma (NPC) at an early disease stage is important for successful treatment and improving the outcome of patients. The use of serum protein profiles and a classification tree algorithm were explored to distinguish NPC from noncancer., Methods: Serum samples were applied to metal affinity protein chips to generate mass spectra by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Protein peak identification and clustering were performed using the Biomarker Wizard software. Proteomic spectra of serum samples from 50 NPC patients and 54 noncancer controls were used as a training set and a classification tree with 6 distinct protein masses was generated by using Biomarker Pattern software. The validity of the classification tree was then challenged with a blind test set including another 20 NPC patients and 25 noncancer controls., Results: The software identified an average of 93 mass peaks/spectrum and 6 of the identified peaks were used to construct the classification tree. The classification tree correctly determined 83% (123 of 149) of the test samples with 83% (58 of 70) of the NPC samples and 82% (65 of 79) of the noncancer samples. In a combination of the serum protein profiles with Epstein-Barr (EBV) nuclear antigen 1 (EBNA1 IgA) test, the diagnostic sensitivity and specificity were increased to 99% and 96%, respectively., Conclusions: The results suggest that SELDI-TOF-MS serum protein profiles could discriminate NPC from noncancer. The combination of serum protein profiles with an EBV antibody serology test could further improve the accuracy of NPC screening., (Copyright 2006 American Cancer Society.)

This study aims to investigate the immunological status of small-for-size liver allografts and possible mechanism that contributes to the accelerated immune response in these allografts. Eight experimental groups were: whole isografts; 40% isografts; whole allografts, no treatment; 40% allografts, no treatment; whole allografts with sodium salicylate intraperitoneal injection, D0-3; 40% allografts with sodium salicylate, D0-3; whole allografts with FK506 intramuscular injection D0-3, and 40% allografts with FK506, D0-3. The 40% allografts survived significantly shorter than whole allografts (p=0.02). At 72 h after reperfusion, a higher number of macrophages infiltrated into the periportal area of small-for-size allografts than whole allografts. Remarkable up-regulation of interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-10 (IL-10) and interferon-gamma (IFN-gamma) messenger RNA (mRNA) levels were detected in small-for-size allografts within 24 h after reperfusion. Sodium salicylate administration reduced IL-1beta and IFN-gamma mRNA in both small-for-size and whole allografts, but it could decrease IL-2 and IL-10 mRNA levels only in small-for-size allografts. In vitro study revealed that CD80, CD86 and CD11b expression on macrophages was augmented after IL-1beta stimulation, whereas the up-regulation could be blocked by sodium salicylate. In conclusion, early activation of macrophages as a result of graft injury might play an important role in the accelerated acute rejection process in small-for-size allografts.