One-step nucleic acid amplification (OSNA) fits better with lower cost in breast cancer axillary management

Introduction: One-Step Nucleic Acid Amplification (OSNA) has been already validated for Analysis of Sentinel Node (SLN) in breast cancer. We investigated benefits of OSNA beyond accuracy, with a focus on cost-effectiveness. Methods: 253 consecutive breast cancer patients were reviewed: SLN was analyzed by OSNA in 114 cases and by standard histopathology in 139 cases. Nodal involvement detection, reintervention rate, time between surgery and adjuvant therapy were assessed. A cost analysis of OSNA vs. standard histopathology was performed. Results: With OSNA the re-intervention rate significantly decreased (10.79% vs. 0%, p = 0.0003), and adjuvant therapy started earlier (38.5 days vs. 23.8 days, p < 0.0001). Total cost per patient was 5,990.8\u20ac for histopathology vs. 4,308\u20ac with OSNA (p < 0.0001) if positive SLN. In case of negative SLN costs were similar (2,419.6\u20ac vs. 2,425.2\u20ac, p = 0.947). Conclusions: OSNA reduces re-interventions, allows to start earlier adjuvant therapy and is more cost-effective than histopathology

Co-administration of H-ferritin-doxorubicin and Trastuzumab in neoadjuvant setting improves efficacy and prevents cardiotoxicity in HER2 + murine breast cancer model

Neoadjuvant chemotherapy has been established as the standard of care for HER2-positive breast cancer since it allows cancer down-staging, up to pathological complete response. The standard of care in the neoadjuvant setting for HER2-positive breast cancer is a combination of highly cytotoxic drugs such as anthracyclines and the anti-HER2 monoclonal antibody. Despite this cocktail allows a pathological complete response in up to 50%, their co-administration is strongly limited by intrinsic cardiotoxicity. Therefore, only a sequential administration of anthracyclines and the anti-HER2 treatment is allowed. Here, we propose the anthracycline formulation in H-Ferritin nanocages as promising candidate to solve this unmet clinical need, thanks to its capability to increase anthracyclines efficacy while reducing their cardiotoxicity. Treating a murine model of HER2-positive breast cancer with co-administration of Trastuzumab and H-Ferritin anthracycline nanoformulation, we demonstrate an improved tumor penetration of drugs, leading to increased anticancer efficacy and reduced of cardiotoxicity

Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells

Targeted therapies have profoundly changed the clinical prospect in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In particular, the anti-HER2 monoclonal antibody trastuzumab represents the gold standard for the treatment of HER2+ breast cancer patients. Its contribution in dampening cancer progression is mainly attributed to the antibody-dependent cellmediated cytotoxicity (ADCC) rather than HER2 blockade. Here, multiple half chains of trastuzumab were conjugated onto magnetic iron oxide nanoparticles (MNP-HC) to develop target-specifc and biologically active nanosystems to enhance anti-HER2 therapeutic potential. HER2 targeting was assessed in diferent human breast cancer cell lines, where nanoparticles triggered site-specifc phosphorylation in the catalytic domain of the receptor and cellular uptake by endocytosis. MNP-HC induced remarkable antiproliferative efect in HER2+ breast cancer cells, exhibiting enhanced activity compared to free drug. Accordingly, nanoparticles induced p27kip1 expression and cell cycle arrest in G1 phase, without loosing capability to prime ADCC. Finally, MNP-HC afected viability of trastuzumab-resistant cells, suggesting interference with the resistance machinery. Our fndings indicate that multiple arrangement of trastuzumab half chain on the nanoparticle surface enhances anticancer efcacy in HER2+ breast cancer cells. Powerful inhibition of HER2 signaling could promote responsiveness of resistant cells, thus suggesting ways for drug sensitization

Nano-targeting of mucosal addressin cell adhesion molecule-1 identifies bowel inflammation foci in murine model

Aim: We investigate MAdCAM-1 as a reliable target to detect active bowel inflammation for selective noninvasive nanodiagnostics. Materials & methods: We coupled anti-MAdCAM-1 antibodies to manganese oxide nanoparticles, and analyzed nanoconjugate biodistribution and safety in murine model of inflammatory bowel disease by imaging and histology. Results: Nanoparticles were stable and nontoxic. Upon administration in colitic mice, anti-MAdCAM-1 functionalized nanoparticles preferentially localized in the inflamed bowel, whereas untargeted nanoparticles were more rapidly washed out. Nanoparticles did not induce lesions in nontarget organs. Conclusion: Anti-MAdCAM-1 functionalized nanoparticles detected active bowel inflammation foci, accurately following MAdCAM-1 expression pattern. These nanoconjugates could be a promising noninvasive imaging system for an early and accurate follow-up in patients affected by acute colitis

Comparative analyses of the complete genome sequences of Pierce's disease and citrus variegated chlorosis strains of Xylella fastidiosa

Xylella fastidiosa is a xylem-dwelling, insect-transmitted, gamma-proteobacterium that causes diseases in many plants, including grapevine, citrus, periwinkle, almond, oleander, and coffee. X. fastidiosa has an unusually broad host range, has an extensive geographical distribution throughout the American continent, and induces diverse disease phenotypes. Previous molecular analyses indicated three distinct groups of X.fastidiosa isolates that were expected to be genetically divergent. Here we report the genome sequence of X. fastidiosa (Temecula strain), isolated from a naturally infected grapevine with Pierce's disease (PD) in a wine-grape-growing region of California. Comparative analyses with a previously sequenced X.fastidiosa strain responsible for citrus variegated chlorosis (CVC) revealed that 98% of the PD X.fastidiosa Temecula genes are shared with the CVC X. fastidiosa strain 9a5c genes. Furthermore, the average amino acid identity of the open reading frames in the strains is 95.7%. Genomic differences are limited to phage-associated chromosomal rearrangements and deletions that also account for the strain-specific genes present in each genome. Genomic islands, one in each genome, were identified, and their presence in other X.fastidiosa strains was analyzed. We conclude that these two organisms have identical metabolic functions and are likely to use a common set of genes in plant colonization and pathogenesis, permitting convergence of functional genomic strategies.18531018102

Metronomic nanocaged doxorubicin prevents chemoresistance and cardiotoxicity in breast cancer

Low-dose metronomic (LDM) chemotherapy is based on frequent administration of a lower dose of drugs, without the need of extensive interruptions [1]. LDM affects the vasculature growth and repair [1] and stimulates the host immune system against the tumor [2], while it has not activity against tumor cells. Nanotechnology could improve the effectiveness of LDM chemotherapy, by taking advantage of the unique targeting efficiency of engineered nanocarriers [3]. In the present work, we propose a new concept of low dose \u201cnanometronomic\u201d (LDNM) chemotherapy, using doxorubicin (DOX) as pilot drug. As an ideal DOX nanocarrier, we used H-Ferritin (HFn) nanocages, owing to its affinity for transferrin receptor 1 (TfR-1), which is constitutively overexpressed in cancer cells [4]. HFn-DOX complex was recently demonstrated to overcome chemoresistance by actively promoting DOX nuclear translocation in vitro [4]. 4T1-L tumor bearing mice were treated with placebo, DOX, liposomal-DOX (pl-DOX) or HFn-DOX under our LDNM setting. The progression of tumor volume was monitored in vivo demonstrating that HFn-DOX could decrease tumor growth, while DOX displayed a tumor progression similar to the control. An even better effect was achieved with pl-DOX, which was indeed able to arrest the tumor development. Moreover, we find that HFn-DOX antitumor effect is attributable to multiple nanodrug actions beyond cell killing, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Otherwise, although an even better reduction of tumor progression was achieved with pl-DOX a fivefold increase in MDR1positive cells has been displayed, suggesting that liposomal DOX is not suitable in view of a protracted metronomic treatment, due to the onset of chemoresistance. [5]. Multiparametric assessment of heart tissues, has been performed to investigate the cardiotoxicity of the metronomic HFn-DOX treatment [6]. Histological evaluations of cardiomyocyte cross- sections from mice treated with HFn-DOX, pl-DOX, DOX or non-treated was coupled with ultrastructural assessment of morphological alterations in mitochondria number, surface area and cristae depletion. Pathological alterations were detected in DOX and pl-DOX samples suggesting a strong cellular damage response compared to HFn-DOX samples. Therefore, the absence of obvious alterations in heart samples from mice treated with HFn-DOX strongly supports the lack of cardiotoxicity in LDNM HFn-DOX treatment, even compared to pl-DOX, which is currently considered the most safe anthracycline therapy in terms of cardiotoxicity. DOX and pl-DOX ultrastructural cardiac alterations were also associated to functional ones, such as the decrease in mitochodrial membrane potential and the reduction in the reactive oxygen species (ROS) quencher, GSH, confirming mitochondrial dysfunction induced by treatment with DOX and pl-DOX only. In summary, this study provides robust evidence that LDNM monotherapy with HFn-DOX is expected to remodel the therapeutic outcome of advanced metastatic BC compared to the drug alone and also to improve anthracycline therapies based on liposomal DOX, with a redefinition of the central role of DOX for solid malignancies under the new perspective of metronomic treatments. NDDTE 123-1 References [1] D. Loven, E. Hasnis, F. Bertolini, Y. Shaked, \u201cLow-dose metronomic chemotherapy: from past experience to new paradigms in the treatment of cancer,\u201d Drug Discov Today, vol. 18, pp. 193\u2013201, 2013. [2] I. Kareva, D. J. Waxman, G. L. Klement, \u201cMetronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance,\u201d Cancer Lett., vol. 358, pp. 100\u2013106, 2015. [3] S. S. W. Ng, A. Sparreboom, Y. Shaked, C. Lee, S. Man, N. Desai, P. Soon-Shiong, W. D. Figg, R. S. Kerbel, \u201cInfluence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel,\u201d Clin Cancer Res., vol. 12, pp. 4331\u20134338, 2006. [4] M. Bellini, S. Mazzucchelli, E. Galbiati, S. Sommaruga, L. Fiandra, M. Truff, M. A. Rizzuto, M. Colombo, P. Tortora, F. Corsi, D. Prosperi, \u201cProtein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in cancer cells,\u201d J Controlled Rel., vol. 196, pp. 184\u2013196, 2014. [5] L. Bao, A. Haque, K. Jackson, S. Hazari, K. Moroz, R. Jetly, S. Dash, \u201cIncreased expression of P-glycoprotein is associated with doxorubicin chemoresistance in the metastatic 4T1 breast cancer model,\u201d Am J Pathol., vol. 178, pp. 838\u2013852, 2011. [6] S. Khiati, I. Dalla Rosa, C. Sourbier, X. Ma, V. A. Rao, L. M. Neckers, H. Zhang, Y. Pommier, \u201cMitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity,\u201d Clin Cancer Res., vol. 20, pp. 4873\u2013 4881, 2014. NDDTE 123-

A novel indocyanine green fluorescence-guided video-assisted technique for sentinel node biopsy in breast cancer

Background: The equipment to detect indocyanine green (ICG) fluorescence for sentinel lymph node (SLN) biopsy in breast cancer is not widely accessible nor optimal. The fluorescence appears as a poorly defined white shine on a black background, and dimmed lighting is required. The aim of this study was to assess the feasibility, accuracy and healthcare costs of a novel approach for SLN biopsy by a video-assisted ICG-guided technique. Methods: The technique for detecting SLN was radioisotope (RI) in 194 cases, video-assisted ICG-guided in 70 cases, and a combined method in 71 cases. In the video-assisted ICG group a full HD laparoscopic system equipped with Xenon lamps was used for a laser-free detection of ICG within a colored and magnified high-resolution image. Results: Detection of ICG fluorescence using a laparoscope with a near-infrared filter provided a highly-defined and coloured image during SLN biopsy. SLN was identified in 100% of patients in all groups. Multiple SLNs were identified in 0.5% of RI patients, in 12.9% of ICG patients and in 14.1% of ICG+RI patients (p<0.0001). In ICG + RI group, 95.1% of lymph nodes were radioactive and 92.7% were fluorescent. Operative times and healthcare costs were equivalent between groups. Conclusions: Video-assisted ICG-guided technique is a feasible and surgeon-friendly method for SLN biopsy, with equivalent efficacy compared to RI, providing an accurate staging of the axilla

Prediction of nodal staging in breast cancer patients with 1-2 sentinel nodes in the Z0011 era

The aim of this study was to provide an innovative nomogram to predict the risk of &gt;2 positive nodes in patients fulfilling the Z0011 criteria with 1-2 sentinel lymph nodes (SLNs) only retrieved.From 2007 to 2017, at the Breast Unit of ICS Maugeri Hospital 271 patients with 1-2 macrometastatic SLNs, fulfilling the Z0011 criteria, underwent axillary dissection and were retrospectively reviewed.A mean of 1.5 SLNs per patient were identified and retrieved. One hundred eighty-seven (69.0%) had 1-2 positive nodes, and 84 (31.0%) had &gt;2 metastatic nodes. Independent predictors of axillary status were: positive SLNs/retrieved SLNs ratio (odds ratio [OR] 10.95, P\u200a=\u200a.001), extranodal extension (OR 5.51, P\u200a=\u200a.0002), and multifocal disease (OR 2.9, P\u200a=\u200a.003). A nomogram based on these variables was constructed (area under curve after bootstrap\u200a=\u200a0.74).The proposed nomogram might select those patients fulfilling the Z0011 criteria, with 1-2 SLNs harvested, in whom a high axillary tumor burden is expected, aiding to guide adjuvant treatments

Localization of nonpalpable breast lesions with sonographically visible clip: optimizing tailored resection and clear margins

BACKGROUND: Achieving clear margins with adequate resection volumes is one of the principal goals of breast-conserving surgery. The aim of our study was to compare preoperative localization using 2 different clips, radiopaque or sonographically visible, to reach this goal. METHODS: We reviewed 209 consecutive nonpalpable breast cancers that were treated with lumpectomy: 59 with radiopaque and 150 with sonographically visible clip positioned during biopsy procedure. In the former case, preoperative localization was performed with mammography and in the latter by ultrasonography. RESULTS: Clear margins were achieved in 80.4% of patients: 57.6% in the first and 89.3% in the second group (P < .0001; odds ratio, 7.6; 95% confidence interval, 3.4 to 17.2). By using sonographically visible clips, the re-excision rate has decreased from 42.4% to 10.7%, (P < .0001), and resections resulted smaller with average calculated resection ratio of 3.54 vs 5.08 (P - .03). CONCLUSIONS: Preoperative localization using a sonographically visible clip allows a more tailored breast-conserving surgery and reduces the re-excision rate