Currently used methods to detect and enumerate circulating tumor cells (CTCs) rely on the expression of the epithelial cell adhesion molecule (EpCAM) and cytokeratins. This selection may exclude ...cells that have undergone intrinsic modifications of their phenotype, as epithelial-mesenchymal transition (EMT). Aim of the study was to investigate the expression of EMT and stemness markers in CTCs from breast cancer patients in all stages of disease. 92 female breast cancer patients were enrolled. CTCs were isolated by CELLection™ Dynabeads® coated with the monoclonal antibody toward EpCam. Samples found positive for CTCs presence (CD45−/CK+) were evaluated for the expression of ER alpha, HER2, ALDH1, vimentin, and fibronectin. Samples negative for CTCs presence (CD45−/CK−) were also evaluated for the expression of vimentin and fibronectin, used as markers of EMT. CTCs were found in 66% of patients. The distribution of CTCs presence according to stage and grade of disease was found statistically significant. The expression of ALDH1 on CTCs was found to correlate to stage of disease and to the expression of vimentin and fibronectin. In 34% of patients, we detected cells with negative CK/CD45 expression but positive expression of vimentin and fibronectin. There is an urgent need for optimizing CTCs detection methods through the inclusion of EMT markers. The detection of cells in mesenchymal transition, retaining EMT and stemness features, may contribute to discover additional therapeutic targets useful to eradicate micrometastatic disease in breast cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Antiangiogenic agents (AAs) have reported grater efficacy compared to interferon. Despite these advances, radiological complete response to therapy is rare. We meta-analyzed the incidence of ...complete response in patients treated with AAs and in controls in main randomized clinical trials for first-line therapy in metastatic renal cell carcinoma. PubMed was reviewed for phase II–III randomized clinical trials with AAs vs. non-AAs in patients with good or intermediate prognosis. We calculated the relative risk of events in patients assigned to AAs compared to control. Five RCTs were found; four were phase III and one was phase II. A total of 2747 patients was valuable for final analysis and randomized to receive AAs or control. Patients in the control-group had interferon (85%) or placebo (15%); patients in the AAs-group received bevacizumab (48%), sunitinib (26%), pazopanib (20%) or sorafenib (6%). The incidence of complete response in patients treated with AAs was 2.0% (95% CI, 1.2–2.8) compared to 1.4% (95% CI, 0.7–2.1) in the control arm. Comparing the different type of AAs, the incidence of complete response was 2.5% (95% CI, 1.2–3.8) in the bevacizumab group and 1.6% (95% CI, 0.1–2.5) in the TKIs group. The relative risk to have a complete response was 1.52 (95% CI, 0.85–2.73; p = 0.16) in patients treated with AAs compared to controls; this was found higher in patients treated with TKIs compared to bevacizumab. The complete response is a rare event in metastatic kidney tumor, even if AAs reported greater efficacy in terms of progression-free survival and of overall response rate, they did not increase the curative rate of metastatic disease. Probably, some biologic factors other than angiogenesis may influence the complete response in this disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Unilateral or bilateral metastases to extraocular muscles are very rare in breast cancer.
We describe a case of inferior rectus extraocular muscle involved by ductal luminal B/Her-2 neu negative ...breast cancer, observed in a cohort of 580 patients. Our patient had received chemotherapy and hormonal therapy (tamoxifen for 3 years and letrozole in the following 3 years) for her primary cancer and developed an orbital metastasis while she was under aromatase inhibitor-based therapy. Diagnosis was confirmed by MRI and biopsy. Orbital radiotherapy, combined with fulvestrant, resulted in shrinking of the secondary mass. A third line hormonal therapy using palbociclib was then started. Twelve-months later, MRI showed no residual tumor mass. Currently, the patient is alive and in good general conditions after 20 months.
Literature review yielded 57 patients with extraocular muscle metastases from breast cancer, mostly due to the invasive lobular subtype of carcinoma. In addition to the present case, only 4 other extraocular muscles metastases from invasive ductal carcinoma has been reported, pointing out to the rarity of ductal type spread to the orbit in the natural history of breast cancer. Surgery may be used as a single treatment, despite no improvement of symptoms. Radiotherapy alone or combined with chemotherapy, or with chemotherapy plus hormonal therapy are available options. Results are, however, missing or poor. The present case is the first one with complete and stable response after 20 months to radiotherapy, antiestrogen drug fulvestrant and selective inhibitor of CDK4 /CDK6 palbociclib. In this subset of patients, with unusual metastatic sites and frequent multi-organ metastatic impairment, a multidisciplinary approach is indicated in order to achieve the best therapeutic management and long-term surveillance.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The peak roof drift ratio is one of the most important engineering parameters to describe the expected seismic damage in a building. A predictive model of the drift ratio was developed using a ...machine learning approach (Gaussian process regression model) on a dataset of approximately 11,800 records from 34 monitored buildings in Japan. Four predictors for ground motion and three predictors for building vulnerability are used in the machine-learning modelling. The residual analysis shows a reduction of 50% compared to the state of the art. The Gaussian process regression model is applied in a second analysis on an original dataset of approximately 4,500 records for 127 monitored buildings in Italy. A satisfactory comparison emerges by comparing the drift ratio prediction map with the observed damage pattern produced by satellite imagery for a test site in central Italy after the 2009 earthquake. The drift ratio map plays an important role in the simulation of an earthquake scenario at regional scale, which is needed by Civil Protection for emergency planning and management activities.
Ground motion modification over large areas is generally evaluated by focusing on source effects disregarding local lithostratigraphic site conditions. Hence, amplification maps of peak ground ...acceleration and peak ground velocity are proposed to improve the forecast of ground motion on a national scale. Topological information about litho-type successions and soil mechanical behaviour were retrieved from the Italian database of seismic microzonation and more than 30 million of seismic site response analyses were performed to quantify the amplification factors (i.e. the ratio between expected ground motion at the site of interest and that at the outcropping engineering bedrock). The maximum value of the amplified peak ground acceleration on the Italian territory results in about twice as much as the value expected at the outcropping of the engineering bedrock. Finally, damage scenario maps based on the amplified ground motion could be produced as a supporting tool for urban planning and emergency system management.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The effects induced by the choice of numerical base conditions for evaluating local seismic response are investigated in this technical note, aiming to provide guidelines for professional ...applications. A numerical modelling of the seismic site response is presented, assuming a one-dimensional scheme. At first, with reference to the case of a homogeneous soil layer overlying a half-space, two different types of numerical base conditions, named rigid and elastic, were adopted to analyse the seismic site response. Then, geological setting, physical and mechanical properties were selected from Italian case studies. In detail, the following stratigraphic successions were considered: shallow layer 1 (shear wave velocity, VS, equal to 400 m/s), layer 2 (VS equal to 600 m/s) and layer 3 (VS equal to 800 m/s). In addition, real signals were retrieved from the web site of the Italian accelerometric strong motion network. Rigid and elastic base conditions were adopted to estimate the ground motion modifications of the reference signals. The results are presented in terms of amplification factors (i.e., ratio of integral quantities referred to free-field and reference response spectra) and are compared between the adopted numerical models.
Most patients with early HR+ and HER2- breast cancer receive a hormone therapy; the clinical question still open is how to identify patients who can really benefit from adjuvant chemotherapy. The ...accurate identification of these patients is essential to avoid an over-treatment, increasing the risk of an unnecessary toxicity; on the contrary, the omission of chemotherapy can deprive high risk patients of a potential life-saving treatment (under-treatment). Several multigene assays (MGAs), assessing the risk of relapse according to the biological characteristics of the tumor, have been developed. To date, the 21-gene assay (Oncotype DX Breast Recurrence Score
) is the only test developed and validated to be actionable, i.e., able to predict the benefit of adjuvant chemotherapy. The different available tests can be classified according to their clinical utility based on their prognostic and predictive value. A prognostic test gives information about the outcome of the disease, regardless of the administered therapy. When the aim of the test is to drive the treatment decisions, the predictive component, and therefore the ability to accurately identify which patients could benefit from chemotherapy, is essential. This review summarizes the clinical evidences of the Oncotype DX
test supporting its clinical utility.
Clinicopathological prognostic features have limited value to identify with precision newly diagnosed patients with hormone receptor (HR)-positive, HER2-negative breast cancer (BC), who would benefit ...from chemotherapy (CT) in addition to adjuvant hormonal therapy (HT). The 21-gene Oncotype DX Breast Recurrence Score
(RS) assay has been demonstrated to predict CT benefit, hence supporting personalized decisions on adjuvant CT. The multicenter, prospective, observational study PONDx investigated the real-life use of RS
results in Italy and its impact on treatment decisions. Physicians' treatment recommendations (HT ± CT) were documented before and after availability of RS results, and changes in recommendations were determined. In the HR+ HER2- early BC population studied (N = 1738), physicians recommended CT + HT in 49% of patients pre-RS. RS-guided treatment decisions resulted in 36% reduction of CT recommendations. PONDx confirms that RS results provide clinically relevant information for CT recommendation in early-stage BC, resulting in a reduction of more than a third of CT use.
Everolimus is an oral inhibitor of mammalian target of rapamycin (mTOR-I) and is currently approved for the treatment of metastatic renal cell carcinoma (mRCC) after failure of first-line vascular ...endothelial growth factor receptor tyrosine kinase inhibitor (TKI).
In this narrative review, we aim to report the available evidence about the use of everolimus as second-line therapy for mRCC. A literature search was performed using PubMed/MEDLINE and abstracts from major conferences on clinical oncology as sources. We report data from prospective as well as retrospective and real world data studies and we analyze the safety and efficacy profile of everolimus as second-line therapy for mRCC.
Although different drugs are currently available for the second-line treatment of mRCC, everolimus represents a feasible and safe option in this setting, especially for patients who have experienced high-grade toxicity or are still carrying TKI-related toxicities from first-line treatment.
The clinical utility of liquid biopsy in cancer treatment will increase as circulating tumor cells （CTCs） analysis move from the enumeration to the real-time measurement of tumor characteristics. ...Intratumor heterogeneity is becoming increasingly recognized as a major drawback to the shift to personalized medicine. Spatial and temporal heterogeneity might be reflected by the serial assessment of CTCs. Indeed, the developing technologies for CTCs analysis now allow digital genomic and next- generation sequencing approaches, able to differentiate molecular subtypes of the disease and to monitor genetic variation over time. The liquid biopsy of cancer might offer a real-time assessment of tumor biology, providing the opportunity to serially evaluate patients most likely to benefit from targeted drugs based on a dynamic characterization of the disease at the molecular level. Mthough hurdles remain before liquid biopsy is seen in routine clinical practice, the information derived from CTCs may facilitate the real-time identification of actionable mutations in cancer leading the way toward personalized medicine.
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