Safety and preliminary efficacy data of a novel Casein Kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies

<p>Abstract</p> <p>Background</p> <p>Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL), the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV) has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2) phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies.</p> <p>Methods</p> <p>Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 – 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated.</p> <p>Results</p> <p>No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression. HPV DNA was negative in 48% of the previously positive patients. Long term follow-up did not reveal recurrences or adverse events.</p> <p>Conclusion</p> <p>CIGB 300 was safe and well tolerated. This is the first clinical trial where a drug has been used to target the CK2 phosphoaceptor domain providing an early proof-of-principle of a possible clinical benefit.</p

A methodological framework to distinguish spectrum effects from spectrum biases and to assess diagnostic and screening test accuracy for patient populations: Application to the Papanicolaou cervical cancer smear test

<p>Abstract</p> <p>Background</p> <p>A spectrum effect was defined as differences in the sensitivity or specificity of a diagnostic test according to the patient's characteristics or disease features. A spectrum effect can lead to a spectrum bias when subgroup variations in sensitivity or specificity also affect the likelihood ratios and thus post-test probabilities. We propose and illustrate a methodological framework to distinguish spectrum effects from spectrum biases.</p> <p>Methods</p> <p>Data were collected for 1781 women having had a cervical smear test and colposcopy followed by biopsy if abnormalities were detected (the reference standard). Logistic models were constructed to evaluate both the sensitivity and specificity, and the likelihood ratios, of the test and to identify factors independently affecting the test's characteristics.</p> <p>Results</p> <p>For both tests, human papillomavirus test, study setting and age affected sensitivity or specificity of the smear test (spectrum effect), but only human papillomavirus test and study setting modified the likelihood ratios (spectrum bias) for clinical reading, whereas only human papillomavirus test and age modified the likelihood ratios (spectrum bias) for "optimized" interpretation.</p> <p>Conclusion</p> <p>Fitting sensitivity, specificity and likelihood ratios simultaneously allows the identification of covariates that independently affect diagnostic or screening test results and distinguishes spectrum effect from spectrum bias. We recommend this approach for the development of new tests, and for reporting test accuracy for different patient populations.</p

Characterizing the Ectomycorrhizal Fungal Community of Whitebark Pine in Interior British Columbia: Mature Trees, Natural Regeneration and Planted Seedlings

Whitebark pine (Pinus albicaulis Engelm.; WBP) is an endangered subalpine tree species and requires associations with ectomycorrhizal fungi (ECMF) for survival and growth. Despite this obligate dependence, there are gaps in the identification of ECMF that associate with WBP. In addition, ECMF rarely feature in assessments of recovery actions and little is known about the relationship between ECMF and the insects and pathogens affecting WBP. We used next-generation sequencing to characterize ECMF occurring in soil and mycorrhizal root tip samples from naturally occurring mature WBP trees and seedlings as well as planted WBP seedlings in the Columbia Mountains of Interior British Columbia, Canada. ECMF data was paired with data on tree age, tree health and soil conditions. Thirty-three species and twenty-one genera of ECMF were identified with medium or high confidence from mycorrhizal root tip samples. Major groups were: generalist ascomycetes [Cenococcum, Meliniomyces (=Hyaloscypha)], Atheliales (Piloderma, Amphinema, Tylospora), non-ascomycetous generalists (e.g., Amphinema), associates of high-elevation conifers (species of Cortinarius, Russula) and Suilloids (Suillus, Rhizopogon). Differences in WBP ECMF with other, drier and southerly regions that have been studied previously, were consistent with a distinct forest type and an endemism hypothesis. Soil at the planting site and planted seedlings hosted a reduced ECMF community or were non-ectomycorrhizal, which can be explained by site factors and is expected to affect seedling survival. ECMF composition on mature trees was correlated with tree health, which may have implications for WBPs resistance to pathogens and signals that ECMF are affected by the decline of their host. Understanding the ecology of WBP ECMF and their relationship with tree performance is essential for WBP recovery efforts.</jats:p