Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function.

The Notch signaling pathway and the delta-like 4 ligand (DLL4) play key roles in embryonic vascular development. Many of the pathways involved in embryonic vascular development also play important roles in tumor angiogenesis. In this study, we assessed the expression of DLL4 in primary renal cancer and investigated the biological function of DLL4 in primary endothelial cells. Using real-time quantitative PCR and in situ hybridization, we showed that the expression of DLL4 was up-regulated within the vasculature of clear cell-renal cell carcinoma almost 9-fold more than normal kidney and was correlated with the expression of vascular endothelial growth factor (VEGF). The expression of DLL4 in endothelial cells was up-regulated by VEGF and basic fibroblast growth factor synergistically, and by hypoxia through hypoxia-inducible factor 1alpha. Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis. The inhibition of proliferation occurred via the induction of cell cycle arrest in G0-G1 by increased expression of p21 and decreased phosphorylation of retinoblastoma. We conclude that an optimal window of the DLL4 expression is essential for tumor angiogenesis and that selective modulation of the DLL4 expression within human tumors may represent a potential novel antiangiogenic therapy

Rééducation Posturale Globale in musculoskeletal diseases: scientific evidence and clinical practice

SUMMARY Several studies on the treatment of musculoskeletal diseases with physiotherapy and clinical experiences on the basis of a method called Rééducation Posturale Globale (RPG), have highlighted the usefulness of this treatment. Although such treatment technique is commonly used in physical therapy practice, only few studies support its therapeutic effectiveness. Objective: To search the literature for evidence of RPG effectiveness, in order to identify the most appropriate therapeutic contexts for its use. Methods: A review of the literature through the following databases: PubMed, Embase, Cinahl, Pedro, and Medscape. The keywords used for the search in the databases are: Rééducation Posturale Globale, Souchard, Posture, and Manual Therapy. The following clinical studies were selected: randomized controlled studies, non-randomized controlled studies, observation studies, and case reports, in English, Spanish, Portuguese, and Italian. Results: Out of 18 studies found, 9 were analyzed: 2 randomized controlled studies, 2 non-randomized controlled studies, 3 non-controlled studies, and 2 case reports. Conclusions: The RPG method has been shown to be an effective treatment technique for musculoskeletal diseases, in particular for ankylosing spondylitis, acute and chronic low back pain, and lumbar discherniation. Although the scarcity of rigorous experimental trials on a large scale does not allow the drawing of undisputable conclusions, the results gathered up to now are an encouragement to carry on research in the field of conservative treatment

Endocrine‐based treatments in clinically‐relevant subgroups of hormone receptor‐positive/her2‐negative metastatic breast cancer: Systematic review and meta‐analysis

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) +/- target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET +/- TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26-41% and 12-27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60-0.65 vs. HR range for single agent ET: 0.59-1.37; OS HR range for combinations: 0.74-0.87 vs. HR range for single agent ET: 0.68-0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making

Isolated Testicular Metastasis from Prostate Cancer

Prostatic adenocarcinoma is the most frequently diagnosed carcinoma in the male population; the most common sites of secondary lesions are nodes, bones, and lungs. We report the clinical case of a 58-year-old man presenting with a single metastasis in the left testis after a radical prostatectomy/lymphadenectomy for prostate cancer. CASE REPORT This clinical report focuses on a 58-year-old man with prostate cancer who developed an uncommon single metastasis in the left testis after radical surgery and adjuvant pelvic radiation therapy. CONCLUSIONS Prostate-specific antigen (PSA) levels are important in the follow-up of prostate cancer. At the same time, physical examination of all possible sites of metastasis and proper evaluation of all signs/symptoms are indispensable in the process of identifying recurrence and for the selection of patients undergoing adjuvant therapy

Neoadjuvant eribulin mesylate following anthracycline and taxane in triple negative breast cancer: Results from the HOPE study

Background Eribulin mesylate (E) is indicated for metastatic breast cancer patients previously treated with anthracycline and taxane. We argued that E could also benefit patients eligible for neoadjuvant chemotherapy. Methods Patients with primary triple negative breast cancer 2 cm received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 x 4 cycles (AT) followed by E 1.4 mg/m2 x 4 cycles. Primary endpoint was pathological complete response (pCR) rate; secondary and explorative endpoints included clinical/metabolic response rates and safety, and biomarker analysis, respectively. Using a two-stage Simon design, 43 patients were to be included provided that 4 of 13 patients had achieved pCR in the first stage of the study. Results In stage I of the study 13 women were enrolled, median age 43 years, tumor size 2–5 cm in 9/13 (69%), positive nodal status in 8/13 (61%). Main grade 3 adverse event was neutropenia (related to AT and E in 4 and 2 cases, respectively). AT followed by E induced clinical complete + partial responses in 11/13 patients (85%), pCR in 3/13 (23%). Median measurements of maximum standardized uptake value (SUVmax) resulted 13, 3, and 1.9 at baseline, after AT and E, respectively. Complete metabolic response (CMR) occurred after AT and after E in 2 and 3 cases, respectively. Notably, 2 of the 5 (40%) patients with CMR achieved pCR at surgery. Immunostaining of paired pre-/post-treatment tumor specimens showed a reduction of β-catenin, CyclinD1, Zeb-1, and c-myc expression, in the absence of N-cadherin modulation. The study was interrupted at stage I due to the lack of the required patients with pCR. Conclusions Despite the early study closure, preoperative E following AT showed clinical and biological activity in triple negative breast cancer patients. Furthermore, the modulation of β-catenin pathway core proteins, supposedly outside the domain of epithelial–mesenchymal transition, claims for further investigation. Trial registration EU Clinical Trial Register, EudraCT number 2012-004956-12

Colorectal cancer-screening program improves both short- and long-term outcomes: a single-center experience in Trieste

Screening programs (SC) have been proven to reduce both incidence and mortality of CRC. We retrospectively analyzed patients who underwent surgical treatment for CRC between 01/2011 and 01/2017. The current screening program in our region collects patients aged from 50 to 69. For this reason, out of a total of 600 patients, we compared 125 patients with CRC founded during the SC to 162 patients who presented with symptoms and were diagnosed between\ua050\u201369\ua0years old (NO-SC). 45% patients in the SC group were diagnosed as AJCC stage I vs 27% patients in the NO-SC group; 14% vs 20% were stage II, 14% vs 26% were stage III, and 3% vs 14% were stage IV (p 0.002). We found a significant difference in surgical approach: 89% SC vs 56% NO-SC patients had laparoscopic surgery (p 0.002). In the NO-SC group, 16% patients underwent resection in an emergency setting. Only 5% patients in the SC group had postoperative complications vs 14% patients in the NO-SC group (p 0.03). We had a 2-year OS of 86%, being 95% in the SC group and 80% in the NO-SC group (p 0.002). Likewise, the whole 2-year DFS was 77%, whereas it was 90% in the SC group and 66% in the NO-SC group (p 0.002). Screening significantly improves early diagnosis and accelerated surgical treatment. We obtained earlier stages at diagnosis, a less invasive surgical approach, and lower rates of complications and emergency surgery, all this leading to an improvement in both OS and DFS

Current Status of Fibroblast Growth Factor Receptor-Targeted Therapies in Breast Cancer

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC

Anthracyclines strike back: Rediscovering non‐pegylated liposomal doxorubicin in current therapeutic scenarios of breast cancer

Simple Summary Anthracyclines are among the most active chemotherapies in breast cancer (BC). However, they can cause structural and cumulative dose-related cardiac damage; hence, they require careful administration after preliminary functional cardiac assessment and subsequent monitoring, along with a limitation in the cumulative dose delivered. Non-pegylated liposomal doxorubicin (NPLD) has been precisely developed to optimize the doxorubicin toxicity profile, while retaining its therapeutic efficacy, thanks to a reduced diffusion in normal tissues with preserved drug penetrance into cancer sites. This has allowed administration of NPLD beyond a conventional doxorubicin maximum cumulative dose, as well as in patients with cardiac comorbilities or anthracycline pretreatment. At present, NPLD is approved in Europe and Canada in combination with cyclophosphamide as the first line of metastatic HER2-negative BC. However, given the increasing complexity of the therapeutic scenario in this setting, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms. Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450-480 mg/m(2). Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms

Comparative evaluation of the penetration depth into dentinal tubules of three endodontic irrigants

This study aimed to examine the penetration depth into dentinal tubules of some chelating agents. The 17% EDTA and two preparations containing surfactants (Smear Clear, Bioakt Endo) were tested. Surface tension and liquid viscosity were measured using a Dynamic Contact Angle Analyzer and a Haake rotational rheometer. To measure the penetration depth inside dentinal tubules, thirty maxillary central incisors were selected from a pool of extracted human permanent teeth and allocated to three experimental groups (10 samples each), as well as were mechanically shaped and cleansed with 5.25% NaOCl, followed by each of the chelators being labeled with 0.1 wt % Rhodamine B according to final irrigation protocol established. The samples were embedded in an epoxy resin, after which 200 μm thick transverse sections were obtained at 2, 5, and 8 mm from the apex with a saw microtome. The specimens were then observed using a confocal laser microscope (CLSM) and the penetration of the labeled solution was measured in every third of each sample. Statistical analysis was performed using ANOVA or Kruskal–Wallis tests according to the distribution of data, evaluated with the Shapiro–Wilk normality test. Viscosity and surface tension tests have shown that BioAKT Endo has the lowest values compared to EDTA and Smear Clear. The medium penetration depth did not significantly differ among the three irrigants, while it increased considerably from the apical to the coronal level in all groups. Additionally, the maximum penetration depth increased significantly from the apical to coronal level, while among groups, BioAKT Endo showed the highest values at the apical and middle level compared to the other irrigants. No significant differences were observed among the three groups in medium and maximum penetration depths when the entire root was considered. New irrigants containing surfactants show reduced surface tension and, in one case (BioAKT Endo), viscosity. The lowering of the surface tension allows for better penetration of liquids into dentinal tubules than EDTA alone, thus improving the cleaning of the root canal system