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Background: Approximately 30% to 50% of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer develop brain metastasis (BMs). Pyrotinib has shown promising efficacy in these patients. However, real-world evidence supporting its use is scarce. Therefore, we evaluate the efficacy and safety of pyrotinib-based regimens in the real world., Materials and Methods: We enrolled patients with BMs from various healthcare facilities in China's Shandong region and used an updated breast-graded prognostic assessment (breast-GPA) to predict survival outcomes., Results: Efficacy and toxicity were assessed in 101 patients. Overall, the median progression-free survival (PFS) was 11.0 months (95% CI, 7.6-14.4 months). PFS was shorter in patients with a breast-GPA of 0 to 2.0 (P< .001). Previous treatment with pertuzumab plus trastuzumab (P = .039) and varying numbers of BMs (P = .028) had a significant positive correlation with PFS. Additionally, radiotherapy (P = .033) for BMs, especially pyrotinib concurrent with radiotherapy (P = .013), significantly prolonged the PFS. In patients with a breast-GPA of 0 to 2.0, a significant difference in PFS was observed depending on whether the brain was the first metastatic site (P< .001). Furthermore, a breast-GPA (0-2.0 vs. 2.5-4.0), and radiotherapy for BMs were found to be independent predictors of PFS. Overall, the objective response rate was 42.6%, while the disease control rate was 88.1%. Diarrhea emerged as the most common adverse event., Conclusion: Pyrotinib-based therapy is effective and tolerable in human epidermal growth factor receptor 2-positive metastatic breast cancer with BMs. Patients who underwent radiotherapy for BMs, particularly those who received pyrotinib concurrently with radiotherapy, exhibited a more favorable prognosis., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish the optimal first-line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2-Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan-HER inhibitor, in the context of NSCLC are still undergoing investigation., Materials and Methods: In this study, we conducted a retrospective data collection of HER2-Mutated advanced LUAD who received first-line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first-line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression-free survival (PFS)., Results: In the final analysis, 89 patients were included in the first-line cohort and 30 patients were included in the pyrotinib cohort. In the first-line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p-value < 0.05). Furthermore, patients with a first-line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p-value = 0.0490)., Conclusions: In the first-line treatment of HER2-Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first-line treatment may potentially derive more benefit from pyrotinib., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Conflicts of interest None disclosed.

Background: Prevention of Plasmodium vivax malaria recurrence is essential for malaria elimination in Brazil. We evaluated the real-world effectiveness of an updated treatment algorithm for P vivax radical cure in the Brazilian Amazon., Methods: In this non-interventional observational study, we used retrospective data from the implementation of a P vivax treatment algorithm at 43 health facilities in Manaus and Porto Velho, Brazil. The treatment algorithm consisted of chloroquine (25 mg/kg over 3 days) and point-of-care quantitative glucose-6-phosphate dehydrogenase (G6PD) testing followed by single-dose tafenoquine 300 mg (G6PD normal, aged ≥16 years, not pregnant and not breastfeeding), 7-day primaquine 0·5 mg/kg per day (G6PD intermediate or normal, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month), or primaquine 0·75 mg/kg per week for 8 weeks (G6PD deficient, aged ≥6 months, not pregnant, and not breastfeeding or breastfeeding for >1 month). P vivax recurrences were identified from probabilistic linkage of routine patient records from the Brazilian malaria epidemiological surveillance system. Recurrence-free effectiveness at day 90 and day 180 was estimated using Kaplan-Meier analysis and hazard ratios (HRs) by multivariate analysis. This clinical trial is registered with ClinicalTrials.gov, NCT05096702, and is completed., Findings: Records from Sept 9, 2021, to Aug 31, 2022, included 5554 patients with P vivax malaria. In all treated patients of any age and any G6PD status, recurrence-free effectiveness at day 180 was 75·8% (95% CI 74·0-77·6) with tafenoquine, 73·4% (71·9-75·0) with 7-day primaquine, and 82·1% (77·7-86·8) with weekly primaquine. In patients aged at least 16 years who were G6PD normal, recurrence-free effectiveness until day 90 was 88·6% (95% CI 87·2-89·9) in those who were treated with tafenoquine (n=2134) and 83·5% (79·8-87·4) in those treated with 7-day primaquine (n=370); after adjustment for confounding factors, the HR for recurrence following tafenoquine versus 7-day primaquine was 0·65 (95% CI 0·49-0·86; p=0·0031), with similar outcomes between the two treatments at day 180 (log-rank p=0·82). Over 180 days, median time to recurrence in patients aged at least 16 years who were G6PD normal was 92 days (IQR 76-120) in those treated with tafenoquine and 68 days (52-94) in those treated with 7-day primaquine., Interpretation: In this real-world setting, single-dose tafenoquine was more effective at preventing P vivax recurrence in patients aged at least 16 years who were G6PD normal compared with 7-day primaquine at day 90, while overall efficacy at 180 days was similar. The public health benefits of the P vivax radical cure treatment algorithm incorporating G6PD quantitative testing and tafenoquine support its implementation in Brazil and potentially across South America., Funding: Brazilian Ministry of Health, Municipal and State Health Secretariats; Fiocruz; Medicines for Malaria Venture; Bill & Melinda Gates Foundation; Newcrest Mining; and the UK Government., Translation: For the Portuguese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SD, PGD, IB-F, and EJ are employees of Medicines for Malaria Venture. DBP declares grants from Butantan, PATH, and Janssen, payment for lectures or presentations from GSK, and support for attending meetings and travel from Janssen. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory lesion of the breast that mimics breast cancer or infection. Immunological pathogenesis is strongly suggested for the disease., Reason for the Report: The treatment remains controversial, comprising a spectrum from observation or NSAIDs to immunosuppressive agents and surgery. Intractable cases are not uncommon and represent a major treatment challenge. Therefore in this study, we examine the effect of a topical immunomodulator agent, imiquimod, on refractory IGM. Patient 1 had IGM for 9 months and had not responded to the existing treatments. She responded to a 7-week course of imiquimod. In patient 2, the disease had begun 4 months sooner and had been resistant to all treatments; it responded to imiquimod after 4 weeks. Ulcers appeared on the skin of both patients but resolved safely., Outcome: Both patients were very satisfied with the results. Imiquimod can be an appropriate local treatment with limited adverse effects in refractory IGM. We propose similar studies to assess the efficacy of imiquimod in IGM further, paying attention to the possibility of developing skin wounds., (© 2023. The Author(s), under exclusive licence to Tehran University of Medical Sciences.)

Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

A single 300 mg dose of tafenoquine (an 8-aminoquinoline), in combination with a standard 3-day course of chloroquine, is approved in several countries for the radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged ≥ 16 years. Despite this, questions have arisen on the optimal dose of tafenoquine. Before the availability of tafenoquine, a 3-day course of chloroquine in combination with the 8-aminoquinoline primaquine was the only effective radical cure for vivax malaria. The World Health Organization (WHO)-recommended standard regimen is 14 days of primaquine 0.25 mg/kg/day or 7 days of primaquine 0.5 mg/kg/day in most regions, or 14 days of primaquine 0.5 mg/kg/day in East Asia and Oceania, however the long treatment courses of 7 or 14 days may result in poor adherence and, therefore, low treatment efficacy. A single dose of tafenoquine 300 mg in combination with a 3-day course of chloroquine is an important advancement for the radical cure of vivax malaria in patients without glucose-6-phosphate dehydrogenase (G6PD) deficiency, as the use of a single-dose treatment will improve adherence. Selection of a single 300 mg dose of tafenoquine for the radical cure of P. vivax malaria was based on collective efficacy and safety data from 33 studies involving more than 4000 trial participants who received tafenoquine, including over 800 subjects who received the 300 mg single dose. The safety profile of single-dose tafenoquine 300 mg is similar to that of standard-dosage primaquine 0.25 mg/kg/day for 14 days. Both primaquine and tafenoquine can cause acute haemolytic anaemia in individuals with G6PD deficiency; severe haemolysis can lead to anaemia, kidney damage, and, in some cases, death. Therefore, relapse prevention using an 8-aminoquinoline must be balanced with the need to avoid clinical haemolysis associated with G6PD deficiency. To minimize this risk, the WHO recommends G6PD testing for all individuals before the administration of curative doses of 8-aminoquinolines. In this article, the authors review key efficacy and safety data from the pivotal trials of tafenoquine and argue that the currently approved dose represents a favourable benefit-risk profile., (© 2024. The Author(s).)

Purpose: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients., Patients and Methods: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms., Results: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated., Conclusions: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted., (©2024 American Association for Cancer Research.)

Background: The de-escalation treatment in patients with low-risk HER2-positive early breast cancer (eBC) is an attractive strategy to avoid unnecessary treatment and improve the quality of life of patients. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor (TKI), has shown efficacy in patients with advanced HER2-positive breast cancer. Meanwhile, nanoparticle albumin-bound (nab)-paclitaxel reveals survival benefit over solvent-based paclitaxel and eliminates the toxicities associated with the solvent. However, the efficacy and safety of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for low-risk HER2 + eBC patients have not been evaluated., Methods: This is a multicenter, open-label, single-arm phase II study. A sample size of 261 patients with tumor ≤ 3 cm, lymph node-negative (N0) or micrometastatic (N1mi), HER2 + breast cancer will be recruited. Eligible patients will receive nab-paclitaxel 260 mg/m 2 once every 3 weeks for 12 weeks and pyrotinib 400 mg once daily for one year. The primary endpoint is invasive disease-free survival. A sub-study will be conducted to investigate different prophylactic strategies for diarrhea, which is the most common adverse event of pan-HER TKIs. One hundred and twenty patients from the main study will be randomly (1:1) allocated to receive loperamide either during the first cycle (4 mg tid on days 1-7, then 4 mg bid on days 8-21) or the first 2 cycles (4 mg tid on days 1-7, then 4 mg bid on days 8-42). The primary endpoint of the sub-study is the incidence of grade ≥ 3 diarrhea., Discussion: This is the first prospective study of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for patients with low-risk HER2-positive eBC. It would probably provide robust evidence for de-escalating strategy of HER2-positive eBC and appropriate management for pyrotinib-related diarrhea., Trial Registration: ClinicalTrials.gov Identifier: NCT04659499 . Registered on December 9, 2020., (© 2022. The Author(s).)

Background: Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax., Methods: This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUC [0-∞] ) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496., Findings: Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC (0-∞) was 73·8 (90% prediction interval [PI] 46·9-117·0) μg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4-139·0) μg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9-174·0) μg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6-151·0) μg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6-98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study., Interpretation: For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting., Funding: GlaxoSmithKline and Medicines for Malaria Venture., Translations: For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests IDV and TTH report funding from GlaxoSmithKline and Medicines for Malaria Venture for the TEACH clinical trial. AM, HS, VMR, JJB, TBE, KR, MT, KM, SWJ, NG and LKT are employees of GlaxoSmithKline and hold shares in the company. JAG is a former employee of GlaxoSmithKline and holds shares in the company. SD is an employee of Medicines for Malaria Venture. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2 -amplified non-small cell lung cancer (NSCLC)., Patients and Methods: In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety., Results: The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression., Conclusions: Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2 -amplified patients with NSCLC., (©2021 American Association for Cancer Research.)

Brain metastasis is a common cause of death in HER2-positive breast cancer patients. Currently, it is mainly treated by whole-brain radiotherapy. Pyrotinib is an irreversible pan-ErbB inhibitor, which has demonstrated promising tumor-suppressing activity and acceptable tolerance in previous phase trials. In the present study, we evaluated the efficacy of pyrotinib on HER2-positive brain metastatic breast cancer patients treated with whole-brain radiotherapy. A total of 20 such patients were separated into pyrotinib plus capecitabine and capecitabine-only groups in a 1:1 ratio. All patients met either the primary or secondary endpoints. Oral admission of pyrotinib together with radiotherapy can significantly increase the overall response rate, progression-free survival, time to progression and duration of response of HER2+ brain metastatic breast cancer patients, without causing extra adverse events. In addition, pyrotinib can enhance the radiosensitivity of in-vitro cultured HER2+ breast cancer cell lines. The outcome of our study suggests that pyrotinib might be an effective medication to enhance the tumor radiosensitivity of HER2-positive brain metastatic breast cancer patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy., Methods: This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate., Discussion: The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds., Trial Registration: ClinicalTrials.gov Identifier: NCT04382300 . Registered on May 11, 2020., (© 2021. The Author(s).)

Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia., Methods: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored., Results: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures., Conclusion: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.

Purpose: To determine whether reproxalap, a novel reactive aldehyde species (RASP) inhibitor, is safe and effective for the treatment of the signs and symptoms of dry eye disease (DED). Methods: In a randomized double-masked parallel-group Phase 2a trial of 3 topical ocular reproxalap formulations (0.1% ophthalmic solution, 0.5% ophthalmic solution, and 0.5% lipid ophthalmic solution), 51 patients with DED were randomly assigned 1:1:1 at a single US site. Eyes were treated bilaterally 4 times daily for 28 days, and standard DED signs and symptoms were assessed at baseline and after 7 and 28 days of dosing. Tear RASP levels were assessed at baseline and at day 28. Results: The effect of treatment on DED signs and symptoms was similar across the treatment arms, and pooled data from the 28-day treatment period demonstrated significant improvement from baseline in Symptom Assessment in Dry Eye Disease score ( P  = 0.003), Ocular Discomfort Scale score ( P  < 0.0001), Ocular Discomfort Score and 4-Symptom Questionnaire overall score ( P  = 0.0004), Schirmer's test ( P  = 0.008), tear osmolarity ( P  = 0.003), and lissamine green total staining score ( P  = 0.002). Improvements in DED symptoms were evident within 1 week of therapy, and effect sizes generally approached or exceeded 0.5. No significant changes in safety measures were observed. Conclusion: The results suggest that the novel RASP inhibitor reproxalap has the potential to mitigate the signs and symptoms of DED, and may represent a new, rapidly and broadly active treatment approach for DED (NCT03162783).

Background: Despite recent intensification of control measures, Plasmodium vivax poses a major challenge for malaria elimination efforts. Liver-stage hypnozoite parasites that cause relapsing infections can be cleared with primaquine; however, poor treatment adherence undermines drug effectiveness. Tafenoquine, a new single-dose treatment, offers an alternative option for preventing relapses and reducing transmission. In 2018, over 237,000 cases of malaria were reported to the Brazilian health system, of which 91.5% were due to P. vivax., Methods and Findings: We evaluated the impact of introducing tafenoquine into case management practices on population-level transmission dynamics using a mathematical model of P. vivax transmission. The model was calibrated to reflect the transmission dynamics of P. vivax endemic settings in Brazil in 2018, informed by nationwide malaria case reporting data. Parameters for treatment pathways with chloroquine, primaquine, and tafenoquine with glucose-6-phosphate dehydrogenase deficiency (G6PDd) testing were informed by clinical trial data and the literature. We assumed 71.3% efficacy for primaquine and tafenoquine, a 66.7% adherence rate to the 7-day primaquine regimen, a mean 5.5% G6PDd prevalence, and 8.1% low metaboliser prevalence. The introduction of tafenoquine is predicted to improve effective hypnozoite clearance among P. vivax cases and reduce population-level transmission over time, with heterogeneous levels of impact across different transmission settings. According to the model, while achieving elimination in only few settings in Brazil, tafenoquine rollout in 2021 is estimated to improve the mean effective radical cure rate from 42% (95% uncertainty interval [UI] 41%-44%) to 62% (95% UI 54%-68%) among clinical cases, leading to a predicted 38% (95% UI 7%-99%) reduction in transmission and over 214,000 cumulative averted cases between 2021 and 2025. Higher impact is predicted in settings with low transmission, low pre-existing primaquine adherence, and a high proportion of cases in working-aged males. High-transmission settings with a high proportion of cases in children would benefit from a safe high-efficacy tafenoquine dose for children. Our methodological limitations include not accounting for the role of imported cases from outside the transmission setting, relying on reported clinical cases as a measurement of community-level transmission, and implementing treatment efficacy as a binary condition., Conclusions: In our modelling study, we predicted that, provided there is concurrent rollout of G6PDd diagnostics, tafenoquine has the potential to reduce P. vivax transmission by improving effective radical cure through increased adherence and increased protection from new infections. While tafenoquine alone may not be sufficient for P. vivax elimination, its introduction will improve case management, prevent a substantial number of cases, and bring countries closer to achieving malaria elimination goals., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: “NN, MW, DV, and RL received funding from Medicines for Malaria Venture (MMV) to evaluate the impact of roll-out of tafenoquine in Brazil.”

Background: Severe asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling., Methods and Results: Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice., Conclusion: This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab., Methods: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m 2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805., Findings: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related., Interpretation: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy., Funding: Jiangsu Hengrui Medicine and National Key R&D Program of China., Translations: For the Chinese translation of the abstract see Supplementary Materials section., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction : A century-long history in 8-aminoquinolines, the only anti-malaria drug class preventing malaria relapse, has resulted in the approval of tafenoquine by the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) and to date registration in Brazil and Thailand. Tafenoquine is an alternative anti-relapse treatment for vivax malaria and malaria prophylaxis. It should not be given in pregnancy, during lactation of infants with glucose-6-phosphate dehydrogenase (G6PD) unknown or deficient status, and in those with G6PD deficiency or psychiatric illness. Areas covered : This systematic review assesses tafenoquine associated adverse events in English-language, human clinical trials. Meta-analysis of commonly reported adverse events was conducted and grouped by comparison arms. Expert opinion : Tafenoquine, either for radical cure or prophylaxis, is generally well tolerated in adults. There is no convincing evidence for neurologic, ophthalmic, and cardiac toxicities. Psychotic disorder which has been attributed to higher doses is a contraindication for the chemoprophylaxis indication and psychiatric illness is a warning for the radical cure indication. Pregnancy assessment and quantitative G6PD testing are required. The optimal radical curative regimen including the tafenoquine dose along with its safety for parts of Southeast Asia, South America, and Oceania needs further assessment.

Intracellular calcium (Ca 2+ ) homeostasis is a vital process to nerve cell survival and function with an intricate regulatory network. It is well established that the endoplasmic reticulum (ER) is a major intraneuronal Ca 2+ storage and that the sarco/endoplasmic reticulum (SR/ER) calcium (Ca 2+ )-ATPase (SERCA) pump is a key regulator of cytosolic Ca 2+ levels. SERCA pumps play a critical role in brain pathophysiology, thus SERCA comprises an emerging pharmacological target for the treatment of brain diseases. Interestingly, preclinical studies in rodents suggest that chronic pharmacological activation of SERCA2 by the quinoline derivative CDN1163 comprises a potential pharmacotherapeutic target in Alzheimer's and Parkinson's diseases. As little is known about the behavioral and neurochemical consequences of CDN1163 administration, in the current study we investigated the potential effects of acute (i.e., at 1 h) and chronic (i.e., 17 days) CDN1163 administration (i.e., 10 mg/kg and 20 mg/kg; intraperitoneally) on locomotor activity and relevant affective behaviors, as well as on monoaminergic neurotransmission in naïve C57BL/6J mice of both sexes. Interestingly, chronic, but not acute, CDN1163 administration induced anxiogenic and depressive-like behavioral effects in mice, as assessed in the open field (OF) test and the forced swim test (FST), respectively. In addition, chronic CDN1163 administration induced sustained sex- and brain region-dependent noradrenergic and serotonergic neurochemical effects ex vivo. Taken together, present findings support the critical role of SERCA-dependent Ca 2+ handling in regulating behavior and neurochemical activity, and further highlight the need to consider sex in the development of SERCA-targeting pharmacotherapies for the treatment of debilitating brain disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The aim of this study was to evaluate the effectiveness of lapatinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer., Methods: We retrospectively reviewed the medical records of patients who received lapatinib for salvage treatment at any line setting from January 1, 2007 to August 31, 2019 at Shandong Cancer Hospital and Institute., Results: A total of 115 (89.1%) patients were included in the study. In the overall cohort, the median disease-free survival (DFS) was 19.0 months; the median progression-free survival (PFS), 6.3 months; and median overall survival (OS), 88.0 months, with 32.2% of patients alive at 5 years. In the second line setting, the median PFS among trastuzumab, lapatinib, and trastuzumab plus lapatinib were 4.2 months, 5.2 months, and 7.3 months, respectively ( P = 0.004). No significant differences between the median PFSs and OSs of the different line salvage treatments with lapatinib was observed (all P > 0.05). For brain metastasis patients, the median PFSs in first line, second line, and more than 3 lines were 7.2 months, 4.5 months, and 6.3 months, respectively., Conclusions: Our findings suggest that patients would benefit more from trastuzumab plus lapatinib than from lapatinib or trastuzumab alone for second line treatment in the advanced stages of the disease. Lapatinib could be used as an alternative selection for HER2-positive metastasic breast cancer patients when there is disease progression after trastuzumab or pyrotinib treatment, which is used as part of China's national health insurance.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327., (© 2020 by The American Society of Hematology.)

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca 2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.

Introduction: In about 15% to 20% of breast cancer cases, human epidermal growth factor receptor 2 (HER2) over-expression or gene-amplification is associated with poor prognosis. Thanks to the development of target therapies, HER2 positive patients can be managed using HER2-targeting drugs. There are several kinds ofHER2 inhibitors, such as trastuzumab, lapatinib, and pyrotinib. Pyrotinib which exert different functions, of note, the latest generation of the drug, is an irreversible small-molecule tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) (HER1) and/or HER2 and/or HER4. Both lapatinib and pyrotinib potentially target EGFR and/or HER2, but in some instances, induces different responses of patients with EGFR and/or HER2 mutations. This is attributed to the different mutations in EGFR and HER2 genes, which may form distinct types of HER2 dimers, with different binding capacities to drugs., Patient Concerns: Five years ago, a patient underwent a radical mastectomy in an external hospital. Results of the resection histopathology revealed an invasive ductal carcinoma, pT3N0M0, stage IIB, HER2 positive. The lady patient received 6 cycles of adjuvant chemotherapy and was subjected to adjuvant trastuzumab therapy for 1 year. After a regular 1-year follow-up and in March 2018, she complained of chest pain and visited our hospital. We diagnosed her with metastatic breast cancer, positive for HER2., Diagnosis: positron emission tomography/computed tomography showed multiple metastases in the lung and sternum, while the breast lesions did not progress, the curative effect of which we evaluated as a progressive disease. Then, lapatinib integrated with chemotherapy was administered to the patient. After 5 cycles of the treatment, the patient experienced lower back pain. Through CT examination, it was revealed that she had multiple metastases in the lung and sternum, in addition to new metastases in the lumbar spine and right lobe of the liver. Moreover, magnetic resonance imaging revealed multiple metastases in the brain, and the disease further progressed. The results of circulating tumor DNA assays showed that other than HER2 amplification, novel EGFR-ZNF880 fusion and EGFR E114K mutations developed., Interventions: The patient was administered with a combination of pyrotinib with chemotherapy., Outcomes: After 2 months of pyrotinib treatment, the metastases of the lung, sternum, lumbar spine, and right lobe of the liver disappeared. Also, the size of the brain metastases reduced while bone metastases were relieved. The curative effect was evaluated as a partial response. Following the results of circulating tumor DNA assays, HER2 amplification, EGFR-ZNF880 fusion, and EGFR E114K mutations disappeared. However, since a small lesion was present in the brain, the patient was subjected to radiotherapy in the head. Notably, after 9 months treatment with pyrotinib, enhanced CT indicated that tumors in the breast, liver, both lungs, brain, and bone were under control. The patient continually received oral pyrotinib, however, a new brain lesion appeared 6 months later. Overall, we managed to regulate the efficacy of pyrotinib for up to 15 months., Conclusion: This case report demonstrates that EGFR-ZNF880 fusion and EGFR E114K mutations may contribute or lead to the formation of a special HER2 dimer, which is rapidly resistant to lapatinib but sensitive to pyrotinib. Of note, this is the first report that such a new fusion has been found., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Topical corticosteroids used to treat ocular inflammation are associated with a high risk of clinically significant toxicities. Therefore, corticosteroid-sparing medications to treat ocular inflammation are needed. Noninfectious anterior uveitis (NAU) is a sight-threatening ocular inflammatory condition typically treated with topical corticosteroids. This corticosteroid-controlled comparator trial examines the safety and efficacy of reproxalap, a novel inhibitor of reactive aldehyde species (RASP), for the treatment of ocular inflammation, by using NAU as a model. Methods: Forty-five patients with mild-to-moderate acute NAU were randomly assigned 1:1:1 to receive reproxalap 0.5% ophthalmic solution (4 times daily for 6 weeks), prednisolone 1% ophthalmic solution (Pred Forte ® , 4 times daily taper for 6 weeks), or a combination of reproxalap 0.5% ophthalmic solution (4 times daily for 6 weeks) and prednisolone 1% ophthalmic solution (twice daily taper for 6 weeks). Results: All treatments improved anterior cell count and grade, and no differences were observed in change from baseline between groups. Reproxalap monotherapy and combination therapy were statistically noninferior to prednisolone. The proportion of patients requiring rescue therapy was comparable across treatment groups. No safety issues were identified for reproxalap-treated patients, whereas treatment with prednisolone resulted in an average increase of intraocular pressure of ∼2 mm Hg. Conclusions: Reproxalap may be a safe and effective alternative to topical corticosteroids for patients with NAU and other forms of ocular inflammation. These results represent initial clinical evidence of the importance of RASP in ocular inflammation and the applicability of RASP inhibition to immune modulation in ocular disease. Clinical trial (NCT02406209).

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.

Background: Plasmodium vivax malaria has a persistent liver stage that causes relapse of the disease and continued P vivax transmission. Primaquine (PQ) is used to clear the liver stage of the parasite, but treatment is required for 14 days. Primaquine also causes haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Tafenoquine (TQ) is a new alternative to PQ with a longer half-life and can be used as a single-dose treatment., Objectives: To assess the effects of tafenoquine 300 mg (single dose) on preventing P vivax relapse., Search Methods: We searched the following up to 3 June 2020: the Cochrane Infectious Diseases Group Specialized Register; CENTRAL; MEDLINE; Embase; and three other databases. We also searched the WHO International Clinical Trial Registry Platform and the metaRegister of Controlled Trials for ongoing trials using "tafenoquine" and "malaria" as search terms up to 3 June 2020., Selection Criteria: Randomized controlled trials (RCTs) that gave TQ to prevent relapse in people with P vivax malaria. We planned to include trials irrespective of whether participants had been screened for G6PD enzyme deficiency., Data Collection and Analysis: All review authors independently extracted data and assessed risk of bias. As true relapse and reinfection are difficult to differentiate in people living in endemic areas, studies report "recurrences" of infection as a proxy for relapse. We carried out meta-analysis where appropriate, and gave estimates as risk ratios (RR) with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach., Main Results: Three individually randomized RCTs met our inclusion criteria, all in endemic areas, and thus reporting recurrence. Trials compared TQ with PQ or placebo, and all participants received chloroquine (CQ) to treat the asexual infection). In all trials, pregnant and G6PD-deficient people were excluded. Tafenoquine 300 mg single dose versus no treatment for relapse prevention Two trials assessed this comparison. TQ 300 mg single dose reduces P vivax recurrences compared to no antihypnozoite treatment during a six-month follow-up, but there is moderate uncertainty around effect size (RR 0.32, 95% CI 0.12 to 0.88; 2 trials, 504 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (2 trials, 504 participants; moderate-certainty evidence). However, we are uncertain if TQ causes more serious adverse events (2 trials, 504 participants; very low-certainty evidence). Both RCTs reported a total of 23 serious adverse events in TQ groups (One RCT reported 21 events) and a majority (15 events) were a drop in haemoglobin level by > 3g/dl (or >30% reduction from baseline). Tafenoquine 300 mg single dose versus primaquine 15 mg/day for 14 days for relapse prevention Three trials assessed this comparison. There is probably little or no difference between TQ and PQ in preventing recurrences (proxy measure for relapse) up to six months of follow-up (RR 1.04, 95% CI 0.8 to 1.34; 3 trials, 747 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (3 trials, 747 participants; moderate-certainty evidence). We are uncertain if TQ can cause more serious adverse events compared to PQ (3 trials, 747 participants; very low-certainty evidence). Two trials had higher point estimates against TQ while the other showed the reverse. Most commonly reported serious adverse event in TQ group was a decline in haemoglobin level (19 out of 29 events). Some other serious adverse events, though observed in the TQ group, are unlikely to be caused by it (Hepatitis E infection, limb abscess, pneumonia, menorrhagia)., Authors' Conclusions: TQ 300 mg single dose prevents relapses after clinically parasitologically confirmed P vivax malaria compared to no antihypnozoite treatment, and with no difference detected in studies comparing it to PQ to date. However, the inability to differentiate a true relapse from a recurrence in the available studies may affect these estimates. The drug is untested in children and in people with G6PD deficiency. Single-dose treatment is an important practical advantage compared to using PQ for the same purpose without an overall increase in adverse events in non-pregnant, non-G6PD-deficient adults., (Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P. vivax hypnozoites, has recently been approved by the US Food and Drug Administration and Australian Therapeutic Goods Administration for the radical cure of P. vivax malaria in patients 16 years and older. We conducted an exploratory pharmacogenetic analysis (GSK Study 208099) to assess the role of host genome-wide variation on tafenoquine efficacy in patients with P. vivax malaria using data from three GSK clinical trials, GATHER and DETECTIVE Part 1 and Part 2. Recurrence-free efficacy at 6 and 4 months and time to recurrence up to 6 months postdosing were analyzed in 438 P. vivax malaria patients treated with tafenoquine. Among the approximately 10.6 million host genetic variants analyzed, two signals reached genome-wide significance (P value ≤ 5 × 10). rs62103056, and variants in a chromosome 12 intergenic region, were associated with recurrence-free efficacy at 6 and 4 months, respectively. Neither of the signals has an obvious biological rationale and would need replication in an independent population. This is the first genome-wide association study to evaluate genetic influence on response to tafenoquine in P. vivax malaria.

Background: HER2 dual-blockade combined with aromatase inhibitors (AI) is a promising strategy to improve progression-free survival (PFS) in hormone receptor (HR) positive, metastatic breast cancer (MBC). Pyrotinib is a novel irreversible epidermal growth factor receptor/HER2 dual tyrosine kinase inhibitor. However, there is scarcity of data on the effectiveness and safety of pyrotinib combined with trastuzumab and AI as first-line treatment in a metastatic setting., Methods/design: The present study is a prospective, randomized, open-label trial. 198 patients with HER2+/HR+ MBC will be recruited. Eligible patients will be allocated (2:1) to either an experimental group (pyrotinib + trastuzumab + AI) or a control group (trastuzumab + AI). Allocation will be stratified by 1) time since adjuvant hormone therapy (≤ 12 months/> 12 months/no prior hormone therapy); 2) lesion sites (visceral / non-visceral). The primary endpoint is PFS., Discussion: To our knowledge, this is the first prospective randomized controlled trial to assess dual HER2-blockade with pyrotinib in the metastatic setting. This study will provide valuable evidence regarding the efficacy and safety of pyrotinib when combined with trastuzumab and an AI as first-line treatment for MBC. Moreover, it will also evaluate the feasibility of endocrine therapy as an alternative to chemotherapy in providing de-escalation therapy with less toxicity for advanced HR+/HER2+ patients., Trial Registration: ClinicalTrials.gov, ID: NCT03910712 . Registered on 10 Apr. 2019.

Tafenoquine has been licensed for the single-dose radical cure of Plasmodium vivax in adults; however, it is only recommended in patients with > 70% of normal glucose-6-phosphate dehydrogenase (G6PD) activity. Because this may hinder widespread use, we investigated sex-based treatment strategies in which all adult patients are tested with a qualitative G6PD rapid diagnostic test (RDT). Glucose-6-phosphate dehydrogenase normal males are prescribed tafenoquine in all three strategies, whereas G6PD normal females are prescribed either a low-dose 14-day primaquine regimen (PQ14, total dose 3.5 mg/kg) or a high-dose 7-day primaquine regimen (PQ7, total dose 7 mg/kg), or referred to a healthcare facility for quantitative G6PD testing before prescribing tafenoquine. Patients testing G6PD deficient are prescribed a weekly course of primaquine for 8 weeks. We compared the cost-effectiveness of these three strategies to usual care in four countries using a decision tree model. Usual care in Ethiopia does not include radical cure, whereas Afghanistan, Indonesia, and Vietnam prescribe PQ14 without G6PD screening. The cost per disability-adjusted life-year (DALY) averted was expressed through incremental cost-effectiveness ratios (ICERs). Compared with usual care, the ICERs for a sex-based treatment strategy with PQ7 for females from a healthcare provider perspective were $127 per DALY averted in Vietnam, $466 in Ethiopia, $1,089 in Afghanistan, and $4,443 in Indonesia. The PQ14 and referral options cost more while averting fewer DALYs than PQ7. This study provides an alternative cost-effective mode of rolling out tafenoquine in areas where initial testing with only a G6PD RDT is feasible.

Background: Plasmodium vivax is a frequent cause of recurring malaria in endemic areas as in its latent stage it resides in liver, and is responsible for relapse. Treatment with 8 aminoquinoline Primaquine is given for 14 days, however studies have shown dismal results with adherence to therapy. A new long acting 8 aminoquinoline, Tafenoquine was introduced that showed efficacy and safety almost similar to Primaquine in a single dose regimen, hence giving hopes for improved compliance and help in eradicating malaria., Methods: We searched for randomized controlled trials (RCTs) that compared the efficacy of Tafenoquine with Primaquine or placebo. Our primary outcome was the recurrence of Plasmodium vivax parasitemia at 6 months and our safety outcomes included total number of adverse events as well as serious adverse events. We performed pooled data analysis by the random effects model and I2 was used to assess heterogeneity., Results: 4 RCTs were included. Our pooled analysis showed that the number of episodes of recurrence at 6 months between Tafenoquine and Primaquine (RR = 1.08, 95% CI = 0.74-1.59), and between Tafenoquine and placebo (RR = 0.17, 95%CI = 0.03-1.11) was statistically insignificant. Comparison of serious adverse events did not show any significant risk associated with the use of Tafenoquine as compared to Primaquine when analyzed till day 29, which was the time period considered to show most probable drug associated events., Conclusion: Tafenoquine as a single dose is an effective alternative to Primaquine for prevention of recurrence of P vivax malaria, with a reasonable safety profile., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Rationale: Pyrotinib is a novel dual pan-ErbB receptor tyrosine kinase inhibitor, approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). However, there was still limited information regarding specific effect of pyrotinib on HER2-positive MBC patients with phosphoinositol-3 kinase mutation., Patient Concerns: A 63-year-old woman accidentally discovered a left breast lesion. The breast cancer was diagnosed by biopsy of breast lesion and postoperative pathological examination in March, 2017. The patient was presented with HER2-positive (3+), invasive carcinoma of the left breast with lymph nodes and lung nodules metastasis, and the clinical stage was T4N2M1. However, the lesion continued to aggressive disease progression with the treatment of trastuzumab plus multiple chemotherapy regimens and traditional Chinese medicine., Diagnoses: The woman was diagnosed with invasive carcinoma of the left breast and lymph nodes and lung nodules metastasis., Interventions: The patient received 6 cycles of pyrotinib in combination with capecitabine regularly., Outcomes: Progression free survival was more than 6 months, and the patient's efficacy evaluation was partial remission., Lessons: Our clinical observations demonstrated that pyrotinib may be an effective treatment for patients with HER2-positive MBC.

In the preterm brain, accumulating evidence suggests toll-like receptors (TLRs) are key mediators of the downstream inflammatory pathways triggered by hypoxia-ischemia (HI), which have the potential to exacerbate or ameliorate injury. Recently we demonstrated that central acute administration of the TLR7 agonist Gardiquimod (GDQ) confers neuroprotection in the preterm fetal sheep at 3 days post-asphyxial recovery. However, it is unknown whether GDQ can afford long-term protection. To address this, we examined the long-term effects of GDQ. Briefly, fetal sheep (0.7 gestation) received sham asphyxia or asphyxia induced by umbilical cord occlusion, and were studied for 7 days recovery. Intracerebroventricular (ICV) infusion of GDQ (total dose 3.34 mg) or vehicle was performed from 1-4 hours after asphyxia. GDQ was associated with a robust increase in concentration of tumor necrosis factor-(TNF)-α in the fetal plasma, and interleukin-(IL)-10 in both the fetal plasma and cerebrospinal fluid. GDQ did not significantly change the number of total and immature/mature oligodendrocytes within the periventricular and intragyral white matter. No changes were observed in astroglial and microglial numbers and proliferating cells in both white matter regions. GDQ increased neuronal survival in the CA4 region of the hippocampus, but was associated with exacerbated neuronal injury within the caudate nucleus. In conclusion, our data suggest delayed acute ICV administration of GDQ after severe HI in the developing brain may not support long-term neuroprotection.

Background: Naphthoquine (NQ) is a suitable partner anti-malarial for the artemisinin-based combination therapy (ACT), which is recommended to be taken orally as a single-dose regimen. The metabolism of NQ was mainly mediated by CYP2D6, which is well-known to show gender-specific differences in its expression. In spite of its clinical use, there is limited information on the pharmacokinetics of NQ, and no data are available for females. In this study, the effect of gender on the pharmacokinetics and antiplasmodial efficacy of NQ in rodents was evaluated. The underlying factors leading to the potential gender difference, i.e., plasma protein binding and metabolic clearance, were also evaluated., Methods: The pharmacokinetic profiles of NQ were investigated in healthy male or female rats after a single oral administration of NQ. The antiplasmodial efficacy of NQ was studied in male or female mice infected with Plasmodium yoelii. The recrudescence and survival time of infected mice were also recorded after drug treatment. Plasma protein binding of NQ was determined in pooled plasma collected from male or female mice, rat or human. In vitro metabolism experiments were performed in the liver microsomes of male or female mice, rat or human., Results: The results showed that the gender of rats did not affect NQ exposure (AUC 0-t and C max ) significantly (P > 0.05). However, a significant (P < 0.05) longer t 1/2 was found for NQ in male rats (192.1 ± 47.7), compared with female rats (143.9 ± 27.1). Slightly higher but not significant (P > 0.05) antiplasmodial activity was found for NQ in male mice (ED 90 , 1.10 mg/kg) infected with P. yoelii, compared with female mice (ED 90 , 1.67 mg/kg). The binding rates of NQ to plasma protein were similar in males and females. There was no metabolic difference for NQ in male and female mice, rat or human liver microsomes., Conclusions: These results indicated that the pharmacokinetic profiles of NQ were similar between male and female rats, except for a longer t 1/2 in male rats. The difference was not associated with plasma protein binding or hepatic metabolic clearance. Equivalent antiplasmodial activity was found for NQ in male and female mice infected with P. yoelii. This study will be helpful for the rational design of clinical trials for NQ.

Background: Treatment of bronchopulmonary dysplasia in preterm infants is challenging due to its multifactorial origin. In rodent models of neonatal lung injury, selective inhibition of phosphodiesterase 4 (PDE4) has been shown to exert anti-inflammatory properties in the lung. We hypothesized that GSK256066, a highly selective, inhalable PDE4 inhibitor, would have beneficial effects on lung injury and inflammation in a triple hit lamb model of Ureaplasma parvum (UP)-induced chorioamnionitis, prematurity, and mechanical ventilation. Methods: Twenty-one preterm lambs were surgically delivered preterm at 129 days after 7 days intrauterine exposure to UP. Sixteen animals were subsequently ventilated for 24 hours and received endotracheal surfactant and intravenous caffeine citrate. Ten animals were randomized to receive twice a high (10 μg/kg) or low dose (1 μg/kg) of nebulized PDE4 inhibitor. Results: Nebulization of high, but not low, doses of PDE4 inhibitor led to a significant decrease in pulmonary PDE activity, and was associated with lung injury and vasculitis, influx of neutrophils, and increased proinflammatory cytokine messenger RNA levels. Conclusion: Contrary to our hypothesis, we found in our model a dose-dependent proinflammatory effect of an inhaled highly selective PDE4 inhibitor in the lung. Our findings indicate the narrow therapeutic range of inhaled PDE4 inhibitors in the preterm population.

Purpose of Review: This is a review of tafenoquine, a new antimalarial drug. Here we examine the recent literature supporting the use of tafenoquine and summarize the opportunities and challenges for its well tolerated use worldwide., Recent Findings: Tafenoquine was recently approved by the US Food and Drug Administration for the treatment of dormant liver stage (hypnozoite) in Plasmodium vivax and for malaria prophylaxis. Single-dose tafenoquine provides equivalent efficacy to 14 days of primaquine for radical cure in P. vivax, and it can be dosed weekly to prevent malaria. However, tafenoquine can only be used in patients with normal G6PD activity and is contraindicated in children and during pregnancy or in lactating mothers with infants of deficient or unknown G6PD status., Summary: Tafenoquine's long half-life allows a single dose to achieve radical cure, and weekly dosing for chemoprophylaxis to provide an exciting therapeutic option for patient care and as a new weapon for malaria control/eradication programs. Global implementation of tafenoquine will require the development and validation of a robust, low-cost diagnostic to reliably identify G6PD-deficient individuals. In addition, studies on tafenoquine safety in children are needed.

Introduction: Tafenoquine has been recently registered for the prevention of relapse in Plasmodium vivax malaria., Objective: This study assessed the pharmacodynamic effects of 300-mg single-dose tafenoquine on the retina., Methods: This phase I, prospective, multicenter, randomized, single-masked, placebo-controlled, parallel-group study was conducted between 2 February 2016 and 14 September 2017 at three US study centers. Adult healthy volunteers were randomized (2:1) to receive either a single 300-mg oral dose of tafenoquine or matched placebo on day 1. Ophthalmic assessments, including spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF), were conducted at baseline and day 90 and evaluated for pre-determined endpoints by an independent, masked reading center., Results: One subject in each group met the composite primary endpoint for retinal changes identified with SD-OCT or FAF, i.e., one out of 306 (0.3%) with tafenoquine, one out of 161 (0.6%) with placebo. Both cases had unilateral focal ellipsoid zone disruption at day 90 with no effect on best-corrected visual acuity. The tafenoquine-treated subject had this abnormality at baseline, and was enrolled in error. There was no difference in ophthalmic safety between tafenoquine and placebo., Conclusion: There was no evidence of any pharmacodynamic effect of 300-mg single-dose tafenoquine on the retina or any short-term clinically relevant effects on ophthalmic safety. This clinical trial is registered with ClinicalTrials.gov (identifier: NCT02658435).

Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC)., Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers., Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naïve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P = 0.006)., Conclusions: In a population largely naïve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC., (©2019 American Association for Cancer Research.)

Purpose: Ophthalmic safety observations are reported from a clinical trial comparing tafenoquine (TQ) efficacy and safety versus sequential chloroquine (CQ)/primaquine (PQ) for acute Plasmodium vivax malaria., Methods: In an active-control, double-blind study, 70 adult subjects with microscopically confirmed P. vivax malaria were randomized (2:1) to receive 400 mg TQ × 3 days or 1500 mg CQ × 3 days then 15 mg PQ × 14 days., Main Outcome Measures: clinically relevant changes at Day 28 and Day 90 versus baseline in the ocular examination, color vision evaluation, and corneal and retinal digital photography., Results: Post-baseline keratopathy occurred in 14/44 (31.8%) patients with TQ and 0/24 with CQ/PQ (P = 0.002). Mild post-baseline retinal findings were reported in 10/44 (22.7%) patients receiving TQ and 2/24 (8.3%) receiving CQ/PQ (P = 0.15; treatment difference 14.4%, 95% CI - 5.7, 30.8). Masked evaluation of retinal photographs identified a retinal hemorrhage in one TQ patient (Day 90) and a slight increase in atrophy from baseline in one TQ and one CQ/PQ patient. Visual field sensitivity (Humphrey™ 10-2 test) was decreased in 7/44 (15.9%) patients receiving TQ and 3/24 (12.5%) receiving CQ/PQ; all cases were < 5 dB. There were no clinically relevant changes in visual acuity or macular function tests., Conclusions: There was no evidence of clinically relevant ocular toxicity with either treatment. Mild keratopathy was observed with TQ, without conclusive evidence of early retinal changes. Eye safety monitoring continues in therapeutic studies of low-dose tafenoquine (300 mg single dose)., Clinical Trial Registration: Clinicaltrials.gov identifier: NCT01290601.

Background: Tafenoquine was recently approved for chemoprophylaxis of malaria. Its specific activity against liver and blood stages of Plasmodium species has been separately characterized in animals but not in humans., Methods: In this randomized, double-blind, placebo-controlled study, 16 malaria-naive, glucose-6-phosphate dehydrogenase-normal participants aged 20-42 years received tafenoquine chemoprophylaxis prior to challenge with blood stage Plasmodium falciparum. Participants were randomly assigned to either tafenoquine (n = 12) or placebo (n = 4) and took blinded study medication (single 200-mg dose) on days 1, 2, 3, and 10, followed by intravenous inoculation with approximately 2800 P. falciparum parasitized erythrocytes on day 13. The primary endpoint was the number of participants requiring rescue treatment with artemether/lumefantrine due to the onset of parasitemia as determined by quantitative polymerase chain reaction., Results: None of the 12 participants who received tafenoquine developed parasitemia, whereas all placebo participants developed parasitemia (P = .0005). Two cases of mild hemoglobin decrease and a single case of mild hyperbilirubinemia occurred in the tafenoquine group., Conclusions: Tafenoquine chemoprophylaxis is safe and effective in preventing malaria in healthy nonimmune participants challenged with blood stage P. falciparum., Clinical Trials Registration: Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12617000102370., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Malaria chemoprophylaxis has become increasingly prominent now that it is used for vulnerable populations in endemic regions in addition to nonimmune travelers to those regions. The objective would be a drug with > 95% efficacy and that is easily tolerated, including in children and pregnant women. For individuals who prefer weekly rather than daily drug administration, a further objective is a product that is administered weekly. The deficiencies of present agents are parasite resistance to chloroquine, neuropsychiatric liability of mefloquine, the need for daily dosing for atovaquone-proguanil, and daily dosing plus adverse reactions for doxycycline. A primaquine analogue, tafenoquine, has a 17-day half-life and was approved for weekly prophylaxis in the United States and in Australia in 2018. Weekly tafenoquine was equal to mefloquine in efficacy in nonimmunes. The tafenoquine label contains a contraindication for preexisting psychosis, but not for the broad number of other neuropsychiatric disorders which are listed as contraindications in the mefloquine label. As an 8-aminoquinoline, tafenoquine is contraindicated for glucose-6-phosphate dehydrogenase (G6PD)-deficient persons or in pregnancy if the fetus might be G6PD deficient. Other possible significant adverse reactions for tafenoquine are declines in hemoglobin levels reported in some G6PD-normal patients, asymptomatic elevations in methemoglobin, and minor psychiatric events. The lack of broad neuropsychiatric adverse reactions suggests that tafenoquine may have a role as the weekly prophylactic of choice for G6PD-normal persons.

Background: Tafenoquine, an 8-aminoquinoline, is now indicated for causal prophylaxis against all human malarias and as radical curative (anti-relapse) treatment against Plasmodium vivax and Plasmodium ovale. As with other 8-aminoquinolines, tafenoquine causes hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (hemizygous males and homozygous females) and is contraindicated in this population. Those with intermediate G6PD activity (heterozygous females) are also at risk for hemolysis. Awareness of how to prescribe tafenoquine in relation to G6PD status is needed so it can be used safely., Methods: A standard literature search was performed on varying combinations of the terms tafenoquine, Arakoda, Kodatef, Krintafel, Kozenis, primaquine, G6PD deficiency, malaria prophylaxis and radical cure. The data were gathered and interpreted to review how tafenoquine should be prescribed in consideration of the G6PD status of an individual and traveller., Results: Tafenoquine should only be given to those with G6PD activity >70% of the local population median. Qualitative G6PD tests are sufficient for diagnosing G6PD deficiency in males. However, in females quantitative G6PD testing is necessary to differentiate deficient, intermediate and normal G6PD statuses. Testing for G6PD deficiency is mandatory before tafenoquine prescription. Measures can be taken to avoid tafenoquine administration to ineligible individuals (i.e. due to G6PD status, age, pregnancy and lactation). Primaquine is still necessary for some of these cases. This review provides actions that can be taken to diagnose and manage hemolysis when tafenoquine is given inadvertently to ineligible individuals., Conclusion: Attention to G6PD status is required for safe prescription of tafenoquine. A high index of suspicion is needed if hemolysis occurs. Clinicians should seek evidence-based information for the management and treatment of iatrogenicy hemolysis caused by 8-aminoquinolines., (© International Society of Travel Medicine 2019. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

A rapid increase in Candida albicans infection and drug resistance has caused an emergent need for new clinical strategies against this fungal pathogen. In this study, we evaluated the inhibitory activity of a series of 2-alkylaminoquinoline derivatives against C. albicans isolates. A total of 28 compounds were assessed for their efficacy in inhibiting the yeast-to-hypha transition, which is considered one of the key virulence factors in C. albicans Several compounds showed strong activity to decrease the morphological transition and virulence of C. albicans cells. The two leading compounds, compound 1 (2-[piperidin-1-yl]quinolone) and compound 12 (6-methyl-2-[piperidin-1-yl]quinoline), remarkably attenuated C. albicans hyphal formation and cytotoxicity in a dose-dependent manner, but they showed no toxicity to either C. albicans cells or human cells. Intriguingly, compound 12 showed an excellent ability to inhibit C. albicans infection in the mouse oral mucosal infection model. This leading compound also interfered with the expression levels of hypha-specific genes in the cyclic AMP-protein kinase A and mitogen-activated protein kinase signaling pathways. Our findings suggest that 2-alkylaminoquinoline derivatives could potentially be developed as novel therapeutic agents against C. albicans infection due to their interference with the yeast-to-hypha transition., (Copyright © 2019 American Society for Microbiology.)

Background: Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib., Patients and Methods: Using patient-derived organoids and xenografts established from an HER2-A775&#95;G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented., Results: Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P = 0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P = 0.0471) and T-DM1 (P = 0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, -52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2-mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months., Conclusion: Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy., Clinical Trial Registration: NCT02535507., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Treatment of Plasmodium vivax malaria requires the clearing of asexual parasites, but relapse can be prevented only if dormant hypnozoites are cleared from the liver (a treatment termed "radical cure"). Tafenoquine is a single-dose 8-aminoquinoline that has recently been registered for the radical cure of P. vivax., Methods: This multicenter, double-blind, double-dummy, parallel group, randomized, placebo-controlled trial was conducted in Ethiopia, Peru, Brazil, Cambodia, Thailand, and the Philippines. We enrolled 522 patients with microscopically confirmed P. vivax infection (>100 to <100,000 parasites per microliter) and normal glucose-6-phosphate dehydrogenase (G6PD) activity (with normal activity defined as ≥70% of the median value determined at each trial site among 36 healthy male volunteers who were otherwise not involved in the trial). All patients received a 3-day course of chloroquine (total dose of 1500 mg). In addition, patients were assigned to receive a single 300-mg dose of tafenoquine on day 1 or 2 (260 patients), placebo (133 patients), or a 15-mg dose of primaquine once daily for 14 days (129 patients). The primary outcome was the Kaplan-Meier estimated percentage of patients who were free from recurrence at 6 months, defined as P. vivax clearance without recurrent parasitemia., Results: In the intention-to-treat population, the percentage of patients who were free from recurrence at 6 months was 62.4% in the tafenoquine group (95% confidence interval [CI], 54.9 to 69.0), 27.7% in the placebo group (95% CI, 19.6 to 36.6), and 69.6% in the primaquine group (95% CI, 60.2 to 77.1). The hazard ratio for the risk of recurrence was 0.30 (95% CI, 0.22 to 0.40) with tafenoquine as compared with placebo (P<0.001) and 0.26 (95% CI, 0.18 to 0.39) with primaquine as compared with placebo (P<0.001). Tafenoquine was associated with asymptomatic declines in hemoglobin levels, which resolved without intervention., Conclusions: Single-dose tafenoquine resulted in a significantly lower risk of P. vivax recurrence than placebo in patients with phenotypically normal G6PD activity. (Funded by GlaxoSmithKline and Medicines for Malaria Venture; DETECTIVE ClinicalTrials.gov number, NCT01376167 .).