Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics.

Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child-Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0-∞]) to pralsetinib, with AUC0-∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)-Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study.

Background: Rearranged during transfection (RET) alterations are targetable oncogenic drivers in thyroid cancer. Primary data from the open-label, phase 1/2 ARROW study demonstrated clinical activity and manageable safety with pralsetinib, a selective RET inhibitor, in patients with advanced/metastatic RET-altered thyroid cancer. We present an updated analysis with more patients and longer follow-up. Methods: Adult patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC) or RET fusion-positive thyroid cancer who initiated oral pralsetinib at 400 mg once daily were included. Primary endpoints were overall response rate (ORR) by blinded independent central review (per RECIST v1.1) and safety. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival. Responses were assessed in three cohorts of patients with baseline measurable disease: patients with RET-mutant MTC who had received prior cabozantinib and/or vandetanib (C/V), treatment-naïve patients with RET-mutant MTC, and patients with previously treated RET fusion-positive thyroid cancer. Patient-reported outcomes (PROs) were an exploratory endpoint. Results: As of October 18, 2021, the measurable disease population comprised of 61 patients with RET-mutant MTC and prior C/V, 62 treatment-naïve patients with RET-mutant MTC, and 22 patients with RET fusion-positive thyroid cancer who had received prior systemic therapy, including radioactive iodine. The ORR was 55.7% [confidence interval; 95% CI: 42.4-68.5] in patients with RET-mutant MTC and prior C/V, 77.4% [95% CI: 65.0-87.1] in treatment-naïve patients with RET-mutant MTC, and 90.9% [95% CI: 70.8-98.9] in patients with previously treated RET fusion-positive thyroid cancer. Median DoR and median PFS were both 25.8 months in patients with RET-mutant MTC and prior C/V, not reached in treatment-naïve patients with RET-mutant MTC, and 23.6 and 25.4 months, respectively, in patients with previously treated RET fusion-positive thyroid cancer. In the RET-altered thyroid cancer safety population (N = 175), 97.1% of patients reported a treatment-related adverse event (TRAE); these led to discontinuation in 5.7% and dose reduction in 52.6% of patients. There was one death (0.6%) due to a TRAE. PROs improved or remained stable after pralsetinib treatment. Conclusions: In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer. Clinical Trial Registration: NCT03037385.

Factors that Influence Treatment Delay for Patients with Breast Cancer.

INTRODUCTION: The diagnosis or treatment of breast cancer is sometimes delayed. A lengthy delay may have a negative psychological impact on patients. The aim of our study was to evaluate the sociodemographic, clinical and pathological factors associated with delay in the provision of surgical treatment for localised breast cancer, in a prospective cohort of patients. METHODS: This observational, prospective, multicentre study was conducted in ten hospitals belonging to the Spanish national public health system, located in four Autonomous Communities (regions). The study included 1236 patients, diagnosed through a screening programme or found to be symptomatic, between April 2013 and May 2015. The study variables analysed included each patient's personal history, care situation, tumour history and data on the surgical intervention, pathological anatomy, hospital admission and follow-up. Treatment delay was defined as more than 30 days elapsed between biopsy and surgery. RESULTS: Over half of the study population experienced surgical treatment delay. This delay was greater for patients with no formal education and among widows, persons not requiring assistance for usual activities, those experiencing anxiety or depression, those who had a high BMI or an above-average number of comorbidities, those who were symptomatic, who did not receive NMR spectroscopy, who presented a histology other than infiltrating ductal carcinoma or who had poorly differentiated carcinomas. CONCLUSIONS: Certain sociodemographic and clinical variables are associated with surgical treatment delay. This study identifies factors that influence surgical delays, highlighting the importance of preventing these factors and of raising awareness among the population at risk and among health personnel.

Factors associated with readmissions in women participating in screening programs and treated for breast cancer: a retrospective cohort study.

BACKGROUND: We aimed to identify the risk factors associated with early, late and long-term readmissions in women diagnosed with breast cancer participating in screening programs. METHODS: We performed a multicenter cohort study of 1055 women aged 50-69 years participating in Spanish screening programs, diagnosed with breast cancer between 2000 and 2009, and followed up to 2014. Readmission was defined as a hospital admission related to the disease and/or treatment complications, and was classified as early (< 30 days), late (30 days-1 year), or long-term readmission (> 1 year). We used logistic regression to estimate the adjusted odds ratios (aOR), and 95% confidence intervals (95% CI) to explore the factors associated with early, late and long-term readmissions, adjusting by women's and tumor characteristics, detection mode, treatments received, and surgical and medical complications. RESULTS: Among the women included, early readmission occurred in 76 (7.2%), late readmission in 87 (8.2%), long-term readmission in 71 (6.7%), and no readmission in 821 (77.8%). Surgical complications were associated with an increased risk of early readmissions (aOR = 3.62; 95%CI: 1.27-10.29), and medical complications with late readmissions (aOR = 8.72; 95%CI: 2.83-26.86) and long-term readmissions (aOR = 4.79; 95%CI: 1.41-16.31). CONCLUSION: Our results suggest that the presence of surgical or medical complications increases readmission risk, taking into account the detection mode and treatments received. Identifying early complications related to an increased risk of readmission could be useful to adapt the management of patients and reduce further readmissions. TRIAL REGISTRATION: ClinicalTrials.govIdentifier: NCT03165006. Registration date: May 22, 2017 (Retrospectively registered).

Exploring the Role of Breast Density on Cancer Prognosis among Women Attending Population-Based Screening Programmes.

BACKGROUND: Our aim was to assess the role of breast density on breast cancer mortality and recurrences, considering patient and tumour characteristics and the treatments received among women attending population-based screening programmes. METHODS: We conducted a retrospective cohort study among women aged 50-69 years attending population-based screening programmes, diagnosed with invasive breast cancer between 2000 and 2009, and followed up to 2014. Breast density was categorised as low density (≤25% dense tissue), intermediate density (25-50%), and high density (≥50%). Cox proportional hazards regression models were fitted to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for death and recurrences, adjusting by patient characteristics, mode of detection (screen-detected vs. interval cancer), and tumour features. RESULTS: The percentage of deaths and recurrences was higher among women with intermediate- and high-density breasts than among women with low-density breasts (p=0.011 for death; p=0.037 for recurrences). Adjusted Cox proportional hazards regression models revealed that women with intermediate- and high-density breasts had a higher risk of death than women with low-density breasts, being statistically significant for intermediate densities (aHR = 2.19 [95% CI: 1.16-4.13], aHR = 1.44 [95% CI: 0.67-3.1], respectively). No association was found between breast density and recurrences. CONCLUSIONS: Breast density was associated with a higher risk of death, but not of recurrences, among women participating in breast cancer screening. These findings reinforce the need to improve screening sensitivity among women with dense breasts and to routinely assess breast density, not only for its role as a risk factor for breast cancer but also for its potential influence on cancer prognosis.

Variability of breast surgery in women participating in breast cancer screening programs. / Variabilidad en la práctica de la cirugía mamaria en mujeres participantes en el programa de cribado poblacional de cáncer de mama.

INTRODUCTION: Currently, variability in surgical practice is a problem to be solved. The aim of this study is to describe the variability in the surgical treatment of breast cancer and to analyze the factors associated with it. METHODS: The study population included 1057 women diagnosed with breast cancer and surgically treated. Our data were from the CaMISS retrospective cohort. RESULTS: The mean age at diagnosis was 59.3 ± 5 years. A total of 732 patients were diagnosed through screening mammograms and 325 patients as interval cancers. The mastectomy surgery was more frequent in the tumors detected between intervals (OR=2.5; [95%CI: 1.8-3.4]), although this effect disappeared when we adjusted for the rest of the variables. The most important factor associated with performing a mastectomy was TNM: tumors in stage III-IV had an OR of 7.4 [95%CI: 3.9-13.8], increasing in adjusted OR to 21.7 [95%CI: 11.4-41.8]. Histologically, infiltrating lobular carcinoma maintains significance in adjusted OR (OR=2.5; [95%CI: 1.4-4.7]). According to the screening program, there were significant differences in surgical treatment. Program 3 presented an OR of non-conservative surgery of 4.0 [95%CI: 1.8-8.9]. This program coincided with the highest percentage of reconstruction (58.3%). CONCLUSIONS: This study shows that, despite taking into account patient and tumor characteristics, there is great variability in the type of surgery depending on the place of diagnosis.

α-Galactosylceramide and peptide-based nano-vaccine synergistically induced a strong tumor suppressive effect in melanoma.

α-Galactosylceramide (GalCer) is a glycolipid widely known as an activator of Natural killer T (NKT) cells, constituting a promising adjuvant against cancer, including melanoma. However, limited clinical outcomes have been obtained so far. This study evaluated the synergy between GalCer and major histocompatibility complex (MHC) class I and MHC class II melanoma-associated peptide antigens and the Toll-Like Receptor (TLR) ligands CpG and monophosphoryl lipid A (MPLA), which we intended to maximize following their co-delivery by a nanoparticle (NP). This is expected to improve GalCer capture by dendritic cells (DCs) and subsequent presentation to NKT cells, simultaneously inducing an anti-tumor specific T-cell mediated immunity. The combination of GalCer with melanoma peptides and TLR ligands successfully restrained tumor growth. The tumor volume in these animals was 5-fold lower than the ones presented by mice immunized with NPs not containing GalCer. However, tumor growth was controlled at similar levels by GalCer entrapped or in its soluble form, when mixed with antigens and TLR ligands. Those two groups showed an improved infiltration of T lymphocytes into the tumor, but only GalCer-loaded nano-vaccine induced a prominent and enhanced infiltration of NKT and NK cells. In addition, splenocytes of these animals secreted levels of IFN-γ and IL-4 at least 1.5-fold and 2-fold higher, respectively, than those treated with the mixture of antigens and adjuvants in solution. Overall, the combined delivery of the NKT agonist with TLR ligands and melanoma antigens via this multivalent nano-vaccine displayed a synergistic anti-tumor immune-mediated efficacy in B16F10 melanoma mouse model. STATEMENT OF SIGNIFICANCE: Combination of α-galactosylceramide (GalCer), a Natural Killer T (NKT) cell agonist, with melanoma-associated antigens presented by MHC class I (Melan-A:26) and MHC class II (gp100:44) molecules, and Toll-like Receptor (TLR) ligands (MPLA and CpG), within nanoparticle matrix induced a prominent anti-tumor immune response able to restrict melanoma growth. An enhanced infiltration of NKT and NK cells into tumor site was only achieved when the combination GalCer, antigens and TLR ligands were co-delivered by the nanovaccine.

Survival and Disease-Free Survival by Breast Density and Phenotype in Interval Breast Cancers.

Background: We aimed to evaluate survival and disease-free survival in different subtypes of interval cancers by breast density, taking into account clinical and biological characteristics.Methods: We included 374 invasive breast tumors (195 screen-detected cancers; 179 interval cancers, classified into true interval, false-negatives, occult tumors and minimal-sign cancers) diagnosed in women ages 50-69 years undergoing biennial screening from 2000-2009, followed up to 2014. Breast density was categorized into non-dense (<25% dense tissue) and mixed dense breasts (≥25%). Survival curves were generated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazard regression models were computed to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for death and recurrences by comparing women with interval and true interval cancers versus women with screen-detected cancers, controlling for tumor and patient characteristics. All analyses were stratified by breast density.Results: Interval cancers were detected in younger women, at more advanced stages, in denser breasts and showed a higher proportion of triple-negative cancers, especially among true interval cancers. Women with interval cancer and non-dense breasts had an aHR for death of 3.40 (95% CI, 0.92-12.62). Women with true interval cancers detected in non-dense breasts had the highest adjusted risk of death (aHR, 6.55; 95% CI, 1.37-31.39).Conclusions: Women with true interval cancer in non-dense breasts had a higher risk of death than women with screen-detected cancers.Impact: These results support the advisability of routinely collecting information on breast density, both for further tailoring of screening strategies and as a prognostic factor for diagnosed breast cancers. Cancer Epidemiol Biomarkers Prev; 27(8); 908-16. ©2018 AACR.

Prevalence of persistent pain after breast cancer treatment by detection mode among participants in population-based screening programs.

BACKGROUND: To date, the study of the risks and benefits of breast cancer screening has not included the onset of persistent pain after breast cancer treatment within the context of population-based screening programs. Our purpose was to investigate the prevalence of persistent pain and associated factors in women diagnosed with breast cancer (screening or interval) in the context of a population-based breast cancer screening program in Spain. METHODS: A total of 1,057 women participating in a population-based breast cancer screening program were diagnosed with breast cancer between 2000 and 2008. The women were treated surgically and followed-up to 2013. The risk of developing persistent pain was estimated through multivariate logistic regression analysis. RESULTS: Breast cancer was detected during routine screening in 732 women (69.3 %) and emerged as an interval cancer between two screening rounds in 325 (30.7 %). Persistent pain was present in 118 women (11.3 %). Women diagnosed through routine screening reported a higher prevalence of persistent pain (12.9 %) than those with interval cancers (7.8 %)(P < 0.05). Multivariate logistic regression analysis identified two other variables associated with persistent pain: having a Charlson index > =2 (Odds Ratio [OR]: 4.5 95 % Confidence Interval [CI]: 2.1-9.5) versus no comorbidities, and having undergone an axillary lymph node dissection (OR: 2.0 95 % CI: 1.0-4.0) versus sentinel lymph node biopsy. CONCLUSIONS: The prevalence of persistent pain was relatively low. The detection mode was not related to the onset of persistent pain. The factors associated with persistent pain were a Charlson index > =2 and the performance of axillary lymph node dissection. Women treated for breast cancer are at risk for developing persistent pain regardless of the detection mode, especially those with comorbidities and those who have undergone axillary lymph node dissection.

Mammographic and clinical characteristics of different phenotypes of screen-detected and interval breast cancers in a nationwide screening program.

In the context of a population-based screening program, we aimed to evaluate the major mammographic features and clinicopathological characteristics of breast tumors at diagnosis and the associations between them, focusing on tumors with the worst prognosis. We analyzed cancers diagnosed in a cohort of 645,764 women aged 45-69 years participating in seven population-based screening programs in Spain, between January 1, 2000 and December 31, 2006 and followed up until June 2009. We included all interval cancers and a sample of screen-detected cancers, whether invasive or in situ. We compared tumor-related information and breast density for different phenotypes (Triple-negative (TN), HER2+, Luminal B and Luminal A) in screen-detected and interval cancers. We used Chi-square or Fisher's exact test to compare major mammographic features of invasive versus in situ tumors, of screen-detected versus interval cancers, and of different types of interval cancers. We included 2582 tumors (1570 screen-detected and 1012 interval cancers). There were significant differences in the distribution of most clinicopathological variables between screen-detected and interval cancers. Invasive TN interval tumors were more common than other phenotypes in breasts with low mammographic density; three-quarters of these tumors presented as masses without associated calcifications. HER2+ tumors were more common in denser breasts and were associated with calcifications and multifocality. Architectural distortion was more common in Luminal A and Luminal B tumors. Certain radiologic findings are associated with pre-invasive lesions; these differ among invasive tumor phenotypes. We corroborate that TN and HER2+ cancers have distinctive appearances also in the context of population-based screening programs. This information can be useful for establishing protocols for diagnostic strategies in screening units.

Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking.

Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.

Impact of risk factors on different interval cancer subtypes in a population-based breast cancer screening programme.

BACKGROUND: Interval cancers are primary breast cancers diagnosed in women after a negative screening test and before the next screening invitation. Our aim was to evaluate risk factors for interval cancer and their subtypes and to compare the risk factors identified with those associated with incident screen-detected cancers. METHODS: We analyzed data from 645,764 women participating in the Spanish breast cancer screening program from 2000-2006 and followed-up until 2009. A total of 5,309 screen-detected and 1,653 interval cancers were diagnosed. Among the latter, 1,012 could be classified on the basis of findings in screening and diagnostic mammograms, consisting of 489 true interval cancers (48.2%), 235 false-negatives (23.2%), 172 minimal-signs (17.2%) and 114 occult tumors (11.3%). Information on the screening protocol and women's characteristics were obtained from the screening program registry. Cause-specific Cox regression models were used to estimate the hazard ratios (HR) of risks factors for interval cancer and incident screen-detected cancer. A multinomial regression model, using screen-detected tumors as a reference group, was used to assess the effect of breast density and other factors on the occurrence of interval cancer subtypes. RESULTS: A previous false-positive was the main risk factor for interval cancer (HR = 2.71, 95%CI: 2.28-3.23); this risk was higher for false-negatives (HR = 8.79, 95%CI: 6.24-12.40) than for true interval cancer (HR = 2.26, 95%CI: 1.59-3.21). A family history of breast cancer was associated with true intervals (HR = 2.11, 95%CI: 1.60-2.78), previous benign biopsy with a false-negatives (HR = 1.83, 95%CI: 1.23-2.71). High breast density was mainly associated with occult tumors (RRR = 4.92, 95%CI: 2.58-9.38), followed by true intervals (RRR = 1.67, 95%CI: 1.18-2.36) and false-negatives (RRR = 1.58, 95%CI: 1.00-2.49). CONCLUSION: The role of women's characteristics differs among interval cancer subtypes. This information could be useful to improve effectiveness of breast cancer screening programmes and to better classify subgroups of women with different risks of developing cancer.

The MAGEC system for spinal lengthening in children with scoliosis: A NICE Medical Technology Guidance.

Scoliosis-structural lateral curvature of the spine-affects around four children per 1,000. The MAGEC system comprises a magnetically distractible spinal rod implant and an external remote controller, which lengthens the rod; this system avoids repeated surgical lengthening. Rod implants brace the spine internally and are lengthened as the child grows, preventing worsening of scoliosis and delaying the need for spinal fusion. The Medical Technologies Advisory Committee at the National Institute for Health and Care Excellence (NICE) selected the MAGEC system for evaluation in a NICE medical technologies guidance. Six studies were identified by the sponsor (Ellipse Technologies Inc.) as being relevant to the decision problem. Meta-analysis was used to compare the clinical evidence results with those of one conventional growth rod study, and equal efficacy of the two devices was concluded. The key weakness was selection of a single comparator study. The External Assessment Centre (EAC) identified 16 conventional growth rod studies and undertook meta-analyses of relevant outcomes. Its critique highlighted limitations around study heterogeneity and variations in baseline characteristics and follow-up duration, precluding the ability to draw firm conclusions. The sponsor constructed a de novo costing model showing that MAGEC rods generated cost savings of £9,946 per patient after 6 years, compared with conventional rods. The EAC critiqued and updated the model structure and inputs, calculating robust cost savings of £12,077 per patient with MAGEC rods compared with conventional rods over 6 years. The year of valuation was 2012. NICE issued a positive recommendation as supported by the evidence (Medical Technologies Guidance 18).

Epithelium-off photochemical corneal collagen cross-linkage using riboflavin and ultraviolet a for keratoconus and keratectasia: a systematic review and meta-analysis.

This report presents the results of a systematic review and meta-analyses of studies on epithelium-off photochemical corneal collagen cross-linkage for the management of keratoconus and secondary ectasia. The literature search identified 3,400 records of which 49 were considered for inclusion in the meta-analyses. Eight papers reported 4 unique randomized controlled trials, 29 studies were prospective, and 12 were retrospective studies. The majority of the studies (39/49) were graded as very low quality evidence. Twenty-six studies described adverse events and were included in the safety analysis. Meta-analyses are presented for changes in four outcomes: visual acuity, topography, refraction and astigmatism, and central corneal thickness. Statistically significant improvements were found in all efficacy outcomes at 12 months after the operation. Common side effects were pain, corneal edema, and corneal haze, which resolved usually within a few days after the procedure. The remaining uncertainty is duration of benefit to establish the procedure's potential benefit in avoiding or delaying disease progression and possibly reducing the need for corneal transplantation.

Tumor phenotype and breast density in distinct categories of interval cancer: results of population-based mammography screening in Spain.

INTRODUCTION: Interval cancers are tumors arising after a negative screening episode and before the next screening invitation. They can be classified into true interval cancers, false-negatives, minimal-sign cancers, and occult tumors based on mammographic findings in screening and diagnostic mammograms. This study aimed to describe tumor-related characteristics and the association of breast density and tumor phenotype within four interval cancer categories. METHODS: We included 2,245 invasive tumors (1,297 screening-detected and 948 interval cancers) diagnosed from 2000 to 2009 among 645,764 women aged 45 to 69 who underwent biennial screening in Spain. Interval cancers were classified by a semi-informed retrospective review into true interval cancers (n = 455), false-negatives (n = 224), minimal-sign (n = 166), and occult tumors (n = 103). Breast density was evaluated using Boyd's scale and was conflated into: <25%; 25 to 50%; 50 to 75%; >75%. Tumor-related information was obtained from cancer registries and clinical records. Tumor phenotype was defined as follows: luminal A: ER+/HER2- or PR+/HER2-; luminal B: ER+/HER2+ or PR+/HER2+; HER2: ER-/PR-/HER2+; triple-negative: ER-/PR-/HER2-. The association of tumor phenotype and breast density was assessed using a multinomial logistic regression model. Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. All statistical tests were two-sided. RESULTS: Forty-eight percent of interval cancers were true interval cancers and 23.6% false-negatives. True interval cancers were associated with HER2 and triple-negative phenotypes (OR = 1.91 (95% CI:1.22-2.96), OR = 2.07 (95% CI:1.42-3.01), respectively) and extremely dense breasts (>75%) (OR = 1.67 (95% CI:1.08-2.56)). However, among true interval cancers a higher proportion of triple-negative tumors was observed in predominantly fatty breasts (<25%) than in denser breasts (28.7%, 21.4%, 11.3% and 14.3%, respectively; <0.001). False-negatives and occult tumors had similar phenotypic characteristics to screening-detected cancers, extreme breast density being strongly associated with occult tumors (OR = 6.23 (95% CI:2.65-14.66)). Minimal-sign cancers were biologically close to true interval cancers but showed no association with breast density. CONCLUSIONS: Our findings revealed that both the distribution of tumor phenotype and breast density play specific and independent roles in each category of interval cancer. Further research is needed to understand the biological basis of the overrepresentation of triple-negative phenotype among predominantly fatty breasts in true interval cancers.

Preventing acute gut wall damage in infectious diarrhoeas with glycosylated dendrimers.

Intestinal pathogens use the host's excessive inflammatory cytokine response, designed to eliminate dangerous bacteria, to disrupt epithelial gut wall integrity and promote their tissue invasion. We sought to develop a non-antibiotic-based approach to prevent this injury. Molecular docking studies suggested that glycosylated dendrimers block the TLR4-MD-2-LPS complex, and a 13.6 kDa polyamidoamine (PAMAM) dendrimer glucosamine (DG) reduced the induction of human monocyte interleukin (IL)-6 by Gram-negative bacteria. In a rabbit model of shigellosis, PAMAM-DG prevented epithelial gut wall damage and intestinal villous destruction, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. Computational modelling studies identified a 3.3 kDa polypropyletherimine (PETIM)-DG as the smallest likely bioactive molecule. In human monocytes, high purity PETIM-DG potently inhibited Shigella Lipid A-induced IL-6 expression. In rabbits, PETIM-DG prevented Shigella-induced epithelial gut wall damage, reduced local IL-6 and IL-8 expression, and minimized bacterial invasion. There was no change in ß-defensin, IL-10, interferon-ß, transforming growth factor-ß, CD3 or FoxP3 expression. Small and orally delivered DG could be useful for preventing gut wall tissue damage in a wide spectrum of infectious diarrhoeal diseases.

Target fishing and docking studies of the novel derivatives of aryl-aminopyridines with potential anticancer activity.

A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines (human cervical cancer-HeLa; human chronic myeloid leukemia-K562; human melanoma-Fem-x) and two types of normal peripheral blood mononuclear cells, with and without phytohemaglutinin (PBMC-PHA; PBMC+PHA). Twelve of the studied compounds showed moderate cytotoxicity, with selectivity against K562 but not the remaining two cancer cell lines. Four compounds were not active in cytotoxicity assays, presumably due to high predicted lipophilicity and low solubility. To rationalize the observed cytotoxic effects, structure-based virtual screening was carried out against a pool of potential targets constructed using the inverse docking program Tarfisdock and bibliographical references. The putative targets were identified on the basis of the best correlation between docking scores and in vitro cytotoxicity. It is proposed that the mechanism of action of the studied aminopyridines involves the disruption of signaling pathways and cancer cell cycle through the inhibition of cyclin-dependent kinases and several tyrosine kinases, namely Bcr-Abl kinase and KIT receptor kinase. The obtained results can guide further structural modifications of the studied compounds aimed at developing selective agents targeting proteins involved in cancer cell survival and proliferation.

Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex.

The cell surface interaction between bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) and MD-2 is central to bacterial sepsis syndromes and wound healing. We have shown that a generation (G) 3.5 polyamidoamine (PAMAM) dendrimer that was partially glycosylated with glucosamine inhibits TLR4-MD-2-LPS induced inflammation in a rabbit model of tissue scaring. However, it was a mixture of closely related chemical species because of the polydispersity of the starting PAMAM dendrimer. Generation 2 triazine dendrimers with single chemical entity material status are available at low cost and at the kilogram scale. PAMAM dendrimer can be synthetically grafted onto this triazine core dendrimer to make new triazine-PAMAM hybrid dendrimers. This led us to examine whether molecular modelling methods could be used to identify the key structural design principles for a bioactive lead molecule that could be synthesized and biologically evaluated. We describe our computer aided molecular studies of several dendrimer based constructs and the key design principles identified. Our approach should be more broadly applicable to the biologically focused, rational and accelerated design of molecules for other TLR receptors. They could be useful for treating infectious, inflammatory and malignant diseases.

Partially glycosylated dendrimers block MD-2 and prevent TLR4-MD-2-LPS complex mediated cytokine responses.

The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4'phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design additional macromolecular dendrimer based antagonists for other Toll Like Receptors. They could be useful for treating a spectrum of infectious, inflammatory and malignant diseases.

Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents.

A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.