The ambitious role of anti angiogenesis molecules: Turning a cold tumor into a hot one

In renal cancer emerging treatment options are becoming available and there is a strong need to combine therapies to reformulate and adjourn clinical practice. We here highlight and discuss the need to take advantage of the common immune targets to design combined strategies to increase clinical responses

The applicability of frame imaging from a spinning spacecraft. Volume 1: Summary report

A detailed study was made of frame-type imaging systems for use on board a spin stabilized spacecraft for outer planets applications. All types of frame imagers capable of performing this mission were considered, regardless of the current state of the art. Detailed sensor models of these systems were developed at the component level and used in the subsequent analyses. An overall assessment was then made of the various systems based upon results of a worst-case performance analysis, foreseeable technology problems, and the relative reliability and radiation tolerance of the systems. Special attention was directed at restraints imposed by image motion and the limited data transmission and storage capability of the spacecraft. Based upon this overall assessment, the most promising systems were selected and then examined in detail for a specified Jupiter orbiter mission. The relative merits of each selected system were then analyzed, and the system design characteristics were demonstrated using preliminary configurations, block diagrams, and tables of estimated weights, volumes and power consumption

5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine

Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1–37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3–4 adverse events (OR = 10.40 [95% IC: 1.48–7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3–4 toxicity occurrence (OR = 10.9 [95% IC 1.2–96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity

Liver injury by experimental portal bacteremia: histogenetic recovery study in the rat

Abstract - To study the histogenetic recovery of hepatic lesions due to portal bacteremia, a complication of some clinical conditions, an experimental animal model had developed. Portal bacteremia was performed in 8-week rats and the morphological recovery of liver was histologically checked 1 to 6 days after bacteria inoculation. The major injuries, such as acute inflammatory exudate of the portobiliary spaces, piecemeal necrosis of muralium, micro-abscesses and areas of hepatocyte necrosis of the liver parenchyma, and thrombosis in the centrolobular vein were recorded 1 day after inoculation. Minimal signs of vacuolar degeneration, steatosis, necrosis areas, vessel congestion and focal hemosiderosis together with a small hepatocyte proliferative activity was instead appreciable with longer time. The results seem to suggest a role of vascular structures and Kupffer cells in the morphological repair. This experimental model could serve to understand better similar clinical hepatology conditions, such as portal bacteremia.Informazioni util

The use of ESEM-EDX as an innovative tool to analyze the mineral structure of peri-implant human bone

This study aimed to investigate the mineralization and chemical composition of the bone-implant interface and peri-implant tissues on human histological samples using an environmental scanning electron microscope as well as energy-dispersive x-ray spectroscopy (ESEM-EDX) as an innovative method. Eight unloaded implants with marginal bone tissue were retrieved after four months from eight patients and were histologically processed and analyzed. Histological samples were observed under optical microscopy (OM) to identify the microarchitecture of the sample and bone morphology. Then, all samples were observed under ESEM-EDX from the coronal to the most apical portion of the implant at 500x magnification. A region of interest with bone tissue of size 750 7 500 microns was selected to correspond to the first coronal and the last apical thread (ROI). EDX microanalysis was used to assess the elemental composition of the bone tissue along the thread interface and the ROI. Atomic percentages of Ca, P, N, and Ti, and the Ca/N, P/N and Ca/P ratios were measured in the ROI. Four major bone mineralization areas were identified based on the different chemical composition and ratios of the ROI. Area 1: A well-defined area with low Ca/N, P/N, and Ca/P was identified as low-density bone. Area 2: A defined area with higher Ca/N, P/N, and Ca/P, identified as new bone tissue, or bone remodeling areas. Area 3: A well-defined area with high Ca/N, /P/N, and Ca/P ratios, identified as bone tissue or bone chips. Area 4: An area with high Ca/N, P/N, and Ca/P ratios, which was identified as mature old cortical bone. Bone Area 2 was the most represented area along the bone-implant interface, while Bone Area 4 was identified only at sites approximately 1.5 mm from the interface. All areas were identified around implant biopsies, creating a mosaic-shaped distribution with well-defined borders. ESEM-EDX in combination with OM allowed to perform a microchemical analysis and offered new important information on the organic and inorganic content of the bone tissue around implants

Crizotinib plus radiotherapy in brain oligoprogressive NSCLC ROS1 rearranged and PD-L1 strong

ROS1+ patients represent a unique molecular subset of non-small cell lung cancer (NSCLC). Early phase clinical trials have shown a high response rate to crizotinib in these patients. We describe a case of an 18 years old woman, never smoker, with NSCLC ROS1+ and miliary brain metastases treated with crizotinib and radiotherapy. From October 2014 to June 2015 the Patient was treated with crizotinib. The first intracranial time to progression (IT-TTP) occurred after 7 months; the patient underwent stereotactic radiosurgery (SRS) and continued TKI treatment. The second IT-TTP appeared after 16 months. A continued response in the chest was observed for all the 23 months of crizotinib treatment. At the progression, we assessed programmed death ligand 1 (PD-L1) expression by immunohistochemistry, that resulted highly expressed. Our report indicates that the integration of crizotinib with local treatments should be considered in ROS1 NSCLC patients experiencing oligometastatic progression. Moreover, this case is an example of PD-L1 strong in oncogene addicted patients

New immunological potential markers for triple negative breast cancer: IL18R1, CD53, TRIM, Jaw1, LTB, PTPRCAP

Breast cancer (BC) is the second leading cause of cancer death in women worldwide, and settings of specific prognostic factors and efficacious therapies are made difficult by phenotypic heterogeneity of BC subtypes. Therefore, there is a current urgent need to define novel predictive genetic predictors that may be useful for stratifying patients with distinct prognostic outcomes. Here, we looked for novel molecular signatures for triple negative breast cancers (TNBCs). By a bioinformatic approach, we identified a panel of genes, whose expression was positively correlated with disease-free survival in TNBC patients, namely IL18R1, CD53, TRIM, Jaw1, LTB, and PTPRCAP, showing specific immune expression profiles linked to survival prediction; most of these genes are indeed expressed in immune cells and are required for productive lymphocyte activation. According to our hypothesis, these genes were not, or poorly, expressed in different TNBC cell lines, derived from either primary breast tumours or metastatic pleural effusions. This conclusion was further supported in vivo, as immuno-histochemical analysis on biopsies of TNBC invasive ductal carcinomas highlighted differential expression of these six genes in cancer cells, as well as in intra- and peri-tumoral infiltrating lymphocytes. Our data open to the possibility that inter-tumour heterogeneity of immune markers might have predictive value; further investigations are recommended in order to establish the real power of cancer-related immune profiles as prognostic factors

Standard of care and promising new agents for the treatment of mesenchymal triple-negative breast cancer

The pathologic definition of triple negative breast cancer (TNBC) relies on the absence of expression of estrogen, progesterone and HER2 receptors. However, this BC subgroup is distinguished by a wide biological, molecular and clinical heterogeneity. Among the intrinsic TNBC subtypes, the mesenchymal type is defined by the expression of genes involved in the epithelial to mesenchymal transition, stromal interaction and cell motility. Moreover, it shows a high expression of genes involved in proliferation and an immune-suppressive microenvironment. Several molecular alterations along different pathways activated during carcinogenesis and tumor progression have been outlined and could be involved in immune evasion mechanisms. Furthermore, reverting epithelial to mes-enchymal transition process could lead to the overcoming of immune-resistance. This paper reviews the current knowledge regarding the mesenchymal TNBC subtype and its response to conventional therapeutic strategies, as well as to some promising molecular target agents and immunotherapy. The final goal is a tailored combination of cytotoxic drugs, target agents and immunotherapy in order to restore immunocompetence in mesenchymal breast cancer patients

Immunotherapy in the Treatment of Metastatic Melanoma: Current Knowledge and Future Directions

Melanoma is one of the most immunologic malignancies based on its higher prevalence in immune-compromised patients, the evidence of brisk lymphocytic infiltrates in both primary tumors and metastases, the documented recognition of melanoma antigens by tumor-infiltrating T lymphocytes and, most important, evidence that melanoma responds to immunotherapy. The use of immunotherapy in the treatment of metastatic melanoma is a relatively late discovery for this malignancy. Recent studies have shown a significantly higher success rate with combination of immunotherapy and chemotherapy, radiotherapy, or targeted molecular therapy. Immunotherapy is associated to a panel of dysimmune toxicities called immune-related adverse events that can affect one or more organs and may limit its use. Future directions in the treatment of metastatic melanoma include immunotherapy with anti-PD1 antibodies or targeted therapy with BRAF and MEK inhibitors

Ultrasonographic evaluation of three approaches for botulinum toxin injection into tibialis posterior muscle in chronic stroke patients with equinovarus foot: An observational study

Spastic equinovarus (SEV) foot deformity is commonly observed in patients with post-stroke spasticity. Tibialis posterior (TP) is a common target for botulinum toxin type-A (BoNT-A) injection, as a first-line treatment in non-fixed SEV deformity. For this deep muscle, ultrasonographic guidance is crucial to achieving maximum accuracy for the BoNT-A injection. In current clinical practice, there are three approaches to target the TP: an anterior, a posteromedial, and a posterior. To date, previous studies have failed to identify the best approach for needle insertion into TP. To explore the ultrasonographic characteristics of these approaches, we investigated affected and unaffected legs of 25 stroke patients with SEV treated with BoNT-A. We evaluated the qualitative (echo intensity) and quantitative (muscle depth, muscle thickness, overlying muscle, subcutaneous tissue, cross-sectional area) ultrasound characteristics of the three approaches for TP injection. In our sample, we observed significant differences among almost all the parameters of the three approaches, except for the safety window. Moreover, our analysis showed significant differences in cross-sectional area between treated and untreated. Advantages and disadvantages of each approach were investigated. Our findings can thus provide a suitable reference for clinical settings, especially for novice operators