The Enigmatic Spelaeorhynchidae Oudemans, 1902 (Acari: Mesostigmata) Blood-Feeding Ectoparasites Infesting Neotropical Bats, with Catalog and Notes on a Collection from the Manú Biosphere Reserve in Peru

A survey of ectoparasites associated with bats collected along an elevational transect in the Manú Biosphere Reserve, Peru, includes specimens of two species of an unusual and rarely collected family of parasitic mites, the Spelaeorhynchidae Oudemans, and reveals information on the natural occurrence of these infections. In lowland rainforest (450–1,000 m) along the Rio Alto Madre de Dios, Spelaeorhynchus soaresi Peracchi was recorded exclusively infecting two species of frugivorous Carollia, C. brevicauda and C. perspicillata. At higher elevations in the mountains and cloud forests, Spelaeorhynchus praecursor Neumann exclusively infected two species of nectarivorous Anoura, A. cultrata and A. geoffroyi. The consistency of both altitudinal and host distributional limits between sampling periods suggests that the true focus of infection may be sustained in certain habituated, long-term roosting sites. This valuable spelaeorhynchid survey collection (slides and vials) is available for further study at the following repositories: the Harold W. Manter Laboratory of Parasitology, University of Nebraska–Lincoln, and the Field Museum of Natural History, Chicago

Current status of vandetanib (ZD6474) in the treatment of non-small cell lung cancer

Vandetanib (ZD6474) is an oral small molecule inhibitor of multiple intracellular receptor kinases, including the vascular endothelial growth factor receptor (VEGFR) -2 and epidermal growth factor receptor (EGFR). Both VEGFR and EGFR pathways have emerged as instrumental in the growth and metastasis of multiple malignancies, including non-small cell lung cancer (NSCLC). Indeed, inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC. As there is considerable cross talk between these pathways, dual inhibition with such agents has become an attractive strategy, with encouraging Phase II clinical trial data to date. The convenience of one oral agent targeting both pathways is clear, and clinical trials have established the maximum tolerated daily dose of vandetanib, with data from randomized Phase III trials emerging. This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib, and speculate on the future of this agent in NSCLC

The Enigmatic Spelaeorhynchidae Oudemans, 1902 (Acari: Mesostigmata) Blood-Feeding Ectoparasites Infesting Neotropical Bats, with Catalog and Notes on a Collection from the Manú Biosphere Reserve in Peru

A survey of ectoparasites associated with bats collected along an elevational transect in the Manú Biosphere Reserve, Peru, includes specimens of two species of an unusual and rarely collected family of parasitic mites, the Spelaeorhynchidae Oudemans, and reveals information on the natural occurrence of these infections. In lowland rainforest (450–1,000 m) along the Rio Alto Madre de Dios, Spelaeorhynchus soaresi Peracchi was recorded exclusively infecting two species of frugivorous Carollia, C. brevicauda and C. perspicillata. At higher elevations in the mountains and cloud forests, Spelaeorhynchus praecursor Neumann exclusively infected two species of nectarivorous Anoura, A. cultrata and A. geoffroyi. The consistency of both altitudinal and host distributional limits between sampling periods suggests that the true focus of infection may be sustained in certain habituated, long-term roosting sites. This valuable spelaeorhynchid survey collection (slides and vials) is available for further study at the following repositories: the Harold W. Manter Laboratory of Parasitology, University of Nebraska–Lincoln, and the Field Museum of Natural History, Chicago

Arthropods infesting small mammals (Insectivora and Rodentia) near Cedar Point Biological Station in southwestern Nebraska

Cedar Point Biological Station (CPBS) is located in the mixed grass prairie of the central Great Plains, at the transition between the subregions known as the “tall grass” and “short grass” prairies. Adding to the habitat diversity, there are wetlands and riparian habitats associated with the North Platte River and the edge of the Sandhills region of north central Nebraska. This concurrence of habitats supports a diverse small mammal community. The purpose of this paper is to assemble all published information on ectoparasites associated with small mammals (Insectivora, Rodentia) of southwestern Nebraska, and to report the results of an intensive survey carried out by students of the Parasitology field course during two summers at CPBS. In 2012 and 2013, 27 species of mammal-associated arthropods were collected, including five species of sucking lice (Anoplura), a chewing louse (Ischnocera), six species of fleas (Siphonaptera), thirteen species of mesostigmatic mites (Laelapidae, Macronyssidae, Macrochelidae), and two species of metastigmatic ticks (Ixodidae). These specimens were brushed from the pelage of 11 species of small mammals that were captured in a variety of habitats around CPBS. The arthropod list includes 17 new records for the State of Nebraska. This collection is housed in the Harold W. Manter Laboratory of Parasitology (HWML), University of Nebraska State Museum, at the University of Nebraska-Lincoln, and serves as a taxonomic base for our continued efforts to establish a long-term catalog of parasites associated with small mammals in southwestern Nebraska

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.

PurposeCabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.MethodsThis was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).ResultsSixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.ConclusionsDespite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib

Five-Year Outcomes From the Randomized, Phase III Trials CheckMate 017 and 057: Nivolumab Versus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer

Nivolumab; Docetaxel; Cáncer de pulmónNivolumab; Docetaxel; Lung cancerNivolumab; Docetaxel; Càncer de pulmóPURPOSE Immunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3–5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC

Treatment of stage IV non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American college of chest physicians evidence-based clinical practice guidelines

Stage IV non-small cell lung cancer (NSCLC) is a treatable, but not curable, clinical entity in patients given the diagnosis at a time when their performance status (PS) remains good

Brief Report: Safety and Antitumor Activity of Alectinib Plus Atezolizumab From a Phase 1b Study in Advanced ALK-Positive NSCLC

INTRODUCTION: Alectinib is a preferred first-line treatment option for advanced ALK-positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects. METHODS: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK-positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity. RESULTS: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1-39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64-97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo-NE), neither was median overall survival (95% CI: 33 mo-NE). CONCLUSIONS: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made

Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells

SummaryOncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis are not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting the DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression through active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in the majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas