Non-Small Cell Lung Cancer, Version 4.2024.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for the treatment of patients with NSCLC, including diagnosis, primary disease management, surveillance for relapse, and subsequent treatment. The panel has updated the list of recommended targeted therapies based on recent FDA approvals and clinical data. This selection from the NCCN Guidelines for NSCLC focuses on treatment recommendations for advanced or metastatic NSCLC with actionable molecular biomarkers.

Mesothelioma: Pleural, Version 1.2024.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito.

Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.

Mesothelioma: Peritoneal, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term "malignant" is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, Version 2.2023.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.

Transmissibility of clinically relevant atovaquone-resistant Plasmodium falciparum by anopheline mosquitoes.

Rising numbers of malaria cases and deaths underscore the need for new interventions. Long-acting injectable medications, such as those now in use for HIV prophylaxis, offer the prospect of a malaria "chemical vaccine", combining the efficacy of a drug (like atovaquone) with the durability of a biological vaccine. Of concern, however, is the possible selection and transmission of drug-resistant parasites. We addressed this question by generating clinically relevant, highly atovaquone-resistant, Plasmodium falciparum mutants competent to infect mosquitoes. Isogenic paired strains, that differ only by a single Y268S mutation in cytochrome b, were evaluated in parallel in southeast Asian (Anopheles stephensi) or African (Anopheles gambiae) mosquitoes, and thence in humanized mice. Fitness costs of the mutation were evident along the lifecycle, in asexual parasite growth in vitro and in a progressive loss of parasites in the mosquito. In numerous independent experiments, microscopic exam of salivary glands from hundreds of mosquitoes failed to detect even one Y268S sporozoite, a defect not rescued by coinfection with wild type parasites. Furthermore, despite uniformly successful transmission of wild type parasites from An. stephensi to FRG NOD huHep mice bearing human hepatocytes and erythrocytes, multiple attempts with Y268S-fed mosquitoes failed: there was no evidence of parasites in mouse tissues by microscopy, in vitro culture, or PCR. These studies confirm a severe-to-lethal fitness cost of clinically relevant atovaquone-resistant P. falciparum in the mosquito, and they significantly lessen the likelihood of their transmission in the field.

Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) provide recommended management for patients with NSCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. Patients with metastatic lung cancer who are eligible for targeted therapies or immunotherapies are now surviving longer. This selection from the NCCN Guidelines for NSCLC focuses on targeted therapies for patients with metastatic NSCLC and actionable mutations.

Whole Blood Transfusion for Severe Malarial Anemia in a High Plasmodium falciparum Transmission Setting.

BACKGROUND: Severe malaria resulting from Plasmodium falciparum infection is the leading parasitic cause of death in children worldwide, and severe malarial anemia (SMA) is the most common clinical presentation. The evidence in support of current blood transfusion guidelines for patients with SMA is limited. METHODS: We conducted a retrospective cohort study of 911 hospitalized children with SMA in a holoendemic region of Zambia to examine the association of whole blood transfusion with in-hospital survival. Data were analyzed in adjusted logistic regression models using multiple imputation for missing data. RESULTS: The median age of patients was 24 months (interquartile range, 16-30) and overall case fatality was 16%. Blood transfusion was associated with 35% reduced odds of death in children with SMA (odds ratio, 0.65; 95% confidence interval, .52-.81; P = .0002) corresponding to a number-needed-to-treat (NNT) of 14 patients. Children with SMA complicated by thrombocytopenia were more likely to benefit from transfusion than those without thrombocytopenia (NNT = 5). Longer storage time of whole blood was negatively associated with survival and with the posttransfusion rise in the platelet count but was not associated with the posttransfusion change in hemoglobin concentration. CONCLUSIONS: Whole blood given to pediatric patients with SMA was associated with improved survival, mainly among those with thrombocytopenia who received whole blood stored for <4 weeks. These findings point to a potential use for incorporating thrombocytopenia into clinical decision making and management of severe malaria, which can be further assessed in prospective studies, and underline the importance of maintaining reliable blood donation networks in areas of high malaria transmission.

Cytosolic and Mitochondrial Hsp90 in Cytokinesis, Mitochondrial DNA Replication, and Drug Action in Trypanosoma brucei.

Trypanosoma brucei subspecies cause African sleeping sickness in humans, an infection that is commonly fatal if not treated, and available therapies are limited. Previous studies have shown that heat shock protein 90 (Hsp90) inhibitors have potent and vivid activity against bloodstream-form trypanosomes. Hsp90s are phylogenetically conserved and essential catalysts that function at the crux of cell biology, where they ensure the proper folding of proteins and their assembly into multicomponent complexes. To assess the specificity of Hsp90 inhibitors and further define the role of Hsp90s in African trypanosomes, we used RNA interference (RNAi) to knock down cytosolic and mitochondrial Hsp90s (HSP83 and HSP84, respectively). Loss of either protein led to cell death, but the phenotypes were distinctly different. Depletion of cytosolic HSP83 closely mimicked the consequences of chemically depleting Hsp90 activity with inhibitor 17-AAG. In these cells, cytokinesis was severely disrupted, and segregation of the kinetoplast (the massive mitochondrial DNA structure unique to this family of eukaryotic pathogens) was impaired, leading to cells with abnormal kinetoplast DNA (kDNA) structures. Quite differently, knockdown of mitochondrial HSP84 did not impair cytokinesis but halted the initiation of new kDNA synthesis, generating cells without kDNA. These findings highlight the central role of Hsp90s in chaperoning cell cycle regulators in trypanosomes, reveal their unique function in kinetoplast replication, and reinforce their specificity and value as drug targets.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 2.2021.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

Therapeutic Efficacy of Artemether-Lumefantrine for Uncomplicated Falciparum Malaria in Northern Zambia.

Artemether-lumefantrine (AL) is a first-line agent for uncomplicated malaria caused by Plasmodium falciparum. The WHO recommends periodic therapeutic efficacy studies of antimalarial drugs for the detection of malaria parasite drug resistance and to inform national malaria treatment policies. We conducted a therapeutic efficacy study of AL in a high malaria transmission region of northern Zambia from December 2014 to July 2015. One hundred children of ages 6 to 59 months presenting to a rural health clinic with uncomplicated falciparum malaria were admitted for treatment with AL (standard 6-dose regimen) and followed weekly for 5 weeks. Parasite counts were taken every 6 hours during treatment to assess parasite clearance. Recurrent episodes during follow-up (n = 14) were genotyped to distinguish recrudescence from reinfection and to identify drug resistance single nucleotide polymorphisms (SNPs) and multidrug resistance protein 1 (mdr1) copy number variation. Day 7 lumefantrine concentrations were measured for correspondence with posttreatment reinfection. All children who completed the parasite clearance portion of the study (n = 94) were microscopy-negative by 72 hours. The median parasite elimination half-life was 2.7 hours (interquartile range: 2.1-3.3). Genotype-corrected therapeutic efficacy was 98.8% (95% CI: 97.6-100). Purported artemisinin and lumefantrine drug resistance SNPs in atp6, 3D7_1451200, and mdr1 were detected but did not correlate with parasite recurrence, nor did day 7 lumefantrine concentrations. In summary, AL was highly effective for the treatment of uncomplicated falciparum malaria in northern Zambia during the study period. The high incidence of recurrent parasitemia was consistent with reinfection due to high, perennial malaria transmission.

Evidence of Microbiome-Drug Interaction between the Antimalarial Lumefantrine and Gut Microbiota in Mice.

The antimalarial drug lumefantrine exhibits erratic pharmacokinetics. Intersubject variability might be attributed, in part, to differences in gut microbiome-mediated drug metabolism. We assessed lumefantrine disposition in healthy mice stratified by enterotype to explore associations between the gut microbiota and lumefantrine pharmacokinetics. Gut microbiota enterotypes were classified according to abundance and diversity indices from 16S rRNA sequencing. Pharmacokinetic parameters were computed using noncompartmental analysis. Two distinct enterotypes were identified. Maximal concentration (C max) and total drug exposure measured as the area under the drug concentration-time curve (AUC0-24) differed significantly between the groups. The mean and standard deviation of C max were 660 ± 220 ng/mL versus 390 ± 59 ng/mL (P = 0.02), and AUC0-24 was 9,600 ± 2,800 versus 5,800 ± 810 ng × h/mL (P = 0.01). In healthy mice intragastrically dosed with the antimalarial drug lumefantrine in combination with artemether, lumefantrine exposure was associated with gut bacterial community structure. Studies of xenobiotic-microbiota interactions can inform drug posology and elucidate mechanisms of drug disposition.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 1.2020.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates in immunotherapy. For the 2020 update, all of the systemic therapy regimens have been categorized using a new preference stratification system; certain regimens are now recommended as "preferred interventions," whereas others are categorized as either "other recommended interventions" or "useful under certain circumstances."

Kinetic Driver of Antibacterial Drugs against Plasmodium falciparum and Implications for Clinical Dosing.

Antibacterial drugs are an important component of malaria therapy. We studied the interactions of clindamycin, tetracycline, chloramphenicol, and ciprofloxacin against Plasmodium falciparum under static and dynamic conditions. In microtiter plate assays (static conditions), and as expected, parasites displayed the delayed death response characteristic for apicoplast-targeting drugs. However, rescue by isopentenyl pyrophosphate was variable, ranging from 2,700-fold for clindamycin to just 1.7-fold for ciprofloxacin, suggesting that ciprofloxacin has targets other than the apicoplast. We also examined the pharmacokinetic-pharmacodynamic relationships of these antibacterials in an in vitro glass hollow-fiber system that exposes parasites to dynamically changing drug concentrations. The same total dose and area under the concentration-time curve (AUC) of the drug was deployed either as a single short-lived high peak (bolus) or as a constant low concentration (infusion). All four antibacterials were unambiguously time-driven against malaria parasites: infusions had twice the efficacy of bolus regimens, for the same AUC. The time-dependent efficacy of ciprofloxacin against malaria is in contrast to its concentration-driven action against bacteria. In silico simulations of clinical dosing regimens and resulting pharmacokinetics revealed that current regimens do not maximize time above the MICs of these drugs. Our findings suggest that simple and rational changes to dosing may improve the efficacy of antibacterials against falciparum malaria.

Optimal kinetic exposures for classic and candidate antitrypanosomals.

OBJECTIVES: Efficacy is determined not only by size, but also by shape, of drug exposure. Here the critical importance of the temporal pattern of drug concentrations (pharmacokinetic profile) is examined for antitrypanosomals in vitro. METHODS: An in vitro hollow-fibre cartridge system was used to study contrasting drug profiles with four clinically used agents and two experimental candidates against the deadly parasite Trypanosoma brucei. Artificial kinetics were employed intentionally to favour either high peak concentration or sustained duration of drug. RESULTS: Changing the shape of drug exposure significantly impacted drug efficacy. Suramin, melarsoprol and pentamidine were concentration-driven and therefore more efficacious when applied as short-lived high peaks. In contrast, difluoromethylornithine (DFMO) was time-driven, and therefore maximally effective as a constant infusion. Kinetic preference was robust over a wide range of drug exposures. Promising clinical candidates SCYX-7158 (acoziborole) and fexinidazole (parent and sulfone) were concentration-driven, suggesting optimal clinical regimens would involve relatively high but intermittent dosing. CONCLUSIONS: Antitrypanosomals have an intrinsic pharmacokinetic driver for optimal efficacy, with important implications for clinical management and future candidate development.

Activity of Aromathecins against African Trypanosomes.

African sleeping sickness is responsible for thousands of deaths annually, and new therapeutics are needed. This study evaluated aromathecins, experimental inhibitors of mammalian topoisomerase IB, against Trypanosoma brucei African trypanosomes. The compounds had selectively toxic antiparasitic potency, in situ poisoning activity against the phylogenetically unique topoisomerase in these parasites, and a representative compound intercalated into DNA with micromolar affinity. DNA intercalation and topoisomerase poisoning may contribute to the antitrypanosomal activity of aromathecins.

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 5.2018.

The NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the targeted therapy and immunotherapy sections in the NCCN Guidelines. For the 2018 update, a new section on biomarkers was added.

Model System Identifies Kinetic Driver of Hsp90 Inhibitor Activity against African Trypanosomes and Plasmodium falciparum.

Hsp90 inhibitors, well studied in the laboratory and clinic for antitumor indications, have promising activity against protozoan pathogens, including Trypanosoma brucei which causes African sleeping sickness, and the malaria parasite, Plasmodium falciparum To progress these experimental drugs toward clinical use, we adapted an in vitro dynamic hollow-fiber system and deployed artificial pharmacokinetics to discover the driver of their activity: either concentration or time. The activities of compounds from three major classes of Hsp90 inhibitors in development were evaluated against trypanosomes. In all circumstances, the activities of the tested Hsp90 inhibitors were concentration driven. By optimally deploying the drug to match its kinetic driver, the efficacy of a given dose was improved up to 5-fold, and maximal efficacy was achieved with a significantly lower drug exposure. The superiority of concentration-driven regimens was evident in vitro over several logs of drug exposure and was predictive of efficacy in a mouse model of African trypanosomiasis. In studies with P. falciparum, antimalarial activity was similarly concentration driven. This experimental strategy offers an expedient and versatile translational tool to assess the impact of pharmacokinetics on antiprotozoal activity. Knowing kinetic governance early in drug development provides an additional metric for judging lead compounds and allows the incisive design of animal efficacy studies.

Effect of Antiretroviral Therapy on Plasma Concentrations of Chloroquine and Desethyl-chloroquine.

The effect of antiretroviral therapy (ART) on chloroquine and desethyl-chloroquine plasma concentrations was evaluated in clinical trial participants. Concentrations did not differ among participants receiving protease inhibitor-based ART (n = 9), efavirenz-based ART (n = 15), or other ART (n = 8) and those not receiving ART (n = 31). Efavirenz seemed to inhibit chloroquine desethylation.

Semi-quantitative measurement of the antimalarial lumefantrine from untreated dried blood spots using LC-MS/MS.

Study of the clinical effects of combination therapy for malaria is aided by the ability to measure concentrations of individual partner drugs. Existing methods for measurement of the antimalarial drug lumefantrine (LF) in dried blood spots (DBS) on filter paper rely on chemical pretreatment of the paper to facilitate drug elution. However, in the absence of pretreatment, DBS may still offer some utility for semi-quantitative measurements and pharmacokinetic-pharmacodynamic (PK-PD) analyses. We present a method for semi-quantitation of LF in DBS on untreated filter paper using liquid chromatography tandem mass spectrometry. Optimal recovery was achieved by extraction with acetone-water-formic acid (90:5:5). The range of quantitation was 100-20,000ng/ml. Mean intra- and inter-day accuracy values were 86.6% (coefficient of variation [CV]: 10.1%) and 91.8% (CV: 16.1%), therefore we propose the assay as semi-quantitative. Clinical application was demonstrated in exploratory PK-PD analyses of a drug efficacy trial of artemether-lumefantrine in children with uncomplicated falciparum malaria using post-treatment day 7 samples, parasite clearance times estimated from serial blood smears, and recurrence of malaria out to 35days. The median day 7 concentration among children (n=71) was 111ng/ml (interquartile range: 100-194ng/ml). We used a truncated calibration curve of 100-5000ng/ml for calculations due to low observed concentrations. Calculations using the full calibration curve yielded similar values (+1% avg. deviation). Controlling for participant age, sex, and parasite burden, each log increase in LF day 7 concentration corresponded to a decrease of 7.1h in mean parasite clearance time (95% confidence interval: 0.1-14.3h, P=0.05). A nested case-control study of participants (n=18) with and without recurrent malaria showed mean post-treatment day 7 concentrations of 181ng/ml and 235ng/ml, respectively, but the difference was not significant (P=0.64). A method for semi-quantitation of LF from post-treatment day 7 collections of DBS on untreated filter paper demonstrated clinical application in exploratory PK-PD analyses of parasite clearance and reinfection. Use of DBS will endure in certain study settings by virtue of their ease of collection and resilience. Their utility should continue to be explored as our instruments gain in sensitivity and as clinical pharmacology inquiries are pursued to the field.