Results of a Phase II Double-Blinded Randomized Clinical Trial of Difluoromethylornithine for Cervical Intraepithelial Neoplasia Grades 2 to 3

ABSTRACT Purpose: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m 2 , versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels. Experimental Design: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix. Results: There were no statistically significant differences among the arms in histopathologic response. This could not be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology. Conclusions: DFMO is not active at 0.125 and 0.5 gm/m 2 for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noted in trials of actinic keratoses

Accuracy of optical spectroscopy for the detection of cervical intraepithelial neoplasia without colposcopic tissue information; a step toward automation for low resource settings

Optical spectroscopy has been proposed as an accurate and low-cost alternative for detection of cervical intraepithelial neoplasia. We previously published an algorithm using optical spectroscopy as an adjunct to colposcopy and found good accuracy (sensitivity ¼ 1.00 [95% confidence interval ðCIÞ ¼ 0.92 to 1.00], specificity ¼ 0.71 [95% CI ¼ 0.62 to 0.79]). Those results used measurements taken by expert colposcopists as well as the colposcopy diagnosis. In this study, we trained and tested an algorithm for the detection of cervical intraepithelial neoplasia (i.e., identifying those patients who had histology reading CIN 2 or worse) that did not include the colposcopic diagnosis. Furthermore, we explored the interaction between spectroscopy and colposcopy, examining the importance of probe placement expertise. The colposcopic diagnosis-independent spectroscopy algorithm had a sensitivity of 0.98 (95% CI ¼ 0.89 to 1.00) and a specificity of 0.62 (95% CI ¼ 0.52 to 0.71). The difference in the partial area under the ROC curves between spectroscopy with and without the colposcopic diagnosis was statistically significant at the patient level (p ¼ 0.05) but not the site level (p ¼ 0.13). The results suggest that the device has high accuracy over a wide range of provider accuracy and hence could plausibly be implemented by providers with limited training

Grambank reveals the importance of genealogical constraints on linguistic diversity and highlights the impact of language loss

While global patterns of human genetic diversity are increasingly well characterized, the diversity of human languages remains less systematically described. Here we outline the Grambank database. With over 400,000 data points and 2,400 languages, Grambank is the largest comparative grammatical database available. The comprehensiveness of Grambank allows us to quantify the relative effects of genealogical inheritance and geographic proximity on the structural diversity of the world's languages, evaluate constraints on linguistic diversity, and identify the world's most unusual languages. An analysis of the consequences of language loss reveals that the reduction in diversity will be strikingly uneven across the major linguistic regions of the world. Without sustained efforts to document and revitalize endangered languages, our linguistic window into human history, cognition and culture will be seriously fragmented.Genealogy versus geography Constraints on grammar Unusual languages Language loss Conclusio

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Prediction using hierarchical data: Applications for automated detection of cervical cancer

Although the Papanicolaou smear has been successful in decreasing cervical cancer incidence in the developed world, there exist many challenges for implementation in the developing world. Quantitative cytology, a semi-automated method that quantifies cellular image features, is a promising screening test candidate. The nested structure of its data (measurements of multiple cells within a patient) provides challenges to the usual classification problem. Here we perform a comparative study of three main approaches for problems with this general data structure: (i) extract patient-level features from the cell-level data, (ii) use a statistical model that accounts for the hierarchical data structure, and (iii) classify at the cellular level and use an ad hoc approach to classify at the patient level. We apply these methods to a dataset of 1728 patients, with an average of 2600 cells collected per patient and 133 features measured per cell, predicting whether a patient had a positive biopsy result. The best approach we found was to classify at the cellular level and count the number of cells that had a posterior probability greater than a threshold value, with estimated 61% sensitivity and 89% specificity on independent data. Recent statistical learning developments allowed us to achieve high accuracy

Managing the tension between performance measurement and strategy : coping strategies

Purpose - The aim of this paper is to explore an important but relatively uncharted territory: the actual functioning of performance measurement systems (PMS) in their organisational context. The objective of the paper is to document the ways in which managers go about aligning operational measures with their organisation's strategy in practice. Design/methodology/approach - This research adopts an interpretive multiple-case approach in order to gather rich data on the strategies used in managing operational PMS. Data were collected from detailed interviews with managers and supervisors in four government agencies. Findings - The expectations were that the operations managers would adjust their performance measures to support the changes in strategy. This was not the case. All the interviewees employed one or more tactics to cope with the tensions between strategy and performance measures. The ten tactics identified are collected into three strategies; do-nothing strategy, pseudo-realigning strategy, and distracting strategy. Research limitations/implications - This paper casts some doubt on the practice, rather than the principle, of strategy-aligned performance management. More work needs to be carried out to ascertain how other, both for profit and public sector, organisations deal with these tensions in practice. Practical implications - From a practitioner point of view it raises the question as to whether senior managers are exerting sufficient control over the alignment issue or providing suitable tools, methods or indeed incentives to bring alignment about. Originality/value - The paper highlights a gap between theory and practice and suggests that the way to ensure implementation of "modern management methods," might be to deal firstly with the issues of relevance, timeliness, structure, integration, and symmetry

Why phase II trials in cervical chemoprevention are negative: what have we learned?

Cervical cancer is an important cause of mortality in women worldwide, and the cervix is a well-established clinical, cytologic, and histopathologic model of carcinogenesis. The cervix is easily accessible for examination and biopsy, and colposcopy improves visualization. Identifying chemopreventives in cervical cancer requires rigorous study design: dose de-escalating phase I, IIa trials; placebo-controlled phase IIb trials; and multicenter phase III trials. Reduction in disease incidence and surrogate endpoint biomarkers (SEB) may be trial endpoints. The goal of chemoprevention studies is to prevent or delay the development of cancer. Each agent requires a phase I or IIa trial for each organ site. Phase I, IIa studies of micronutrients, retinoids, alpha-difluoromethylornithine, and indole-3-carbinol have demonstrated response rates of up to 70%, but results of placebo-controlled phase IIb studies have been disappointing and their findings confounded by the high regression rates in placebo-treated patients. Enhancement of research methods, including sufficient enrollment guided by power calculations, uniform biopsy at study entry and exit, and strict progression through trial design phases would ensure valid and reliable results. Because human papillomavirus (HPV) is the major etiologic agent, pretrial laboratory and animal studies should have demonstrated the efficacy of the chemopreventive agent to decrease HPV viral protein expression or HPV tumor induction. SEB modulation must be characterized in any trial's earliest phases before use in phases IIb and III. Lessons learned in chemoprevention will serve as a basis for immunoprevention and vaccine trials