Impact of pre-treatment variables on the completion of 223radium-dichloride therapy in mCRPC patients with bone metastases.

INTRODUCTION: Radium-223 dichloride (223Ra) is an alpha-particle-emitter radiopharmaceutical, approved for metastatic castration-resistant prostate cancer (mCRPC) patients with symptomatic bone metastases and no visceral involvement. Its administration is based on a schedule of intravenous injection (55kBq/kg) every four weeks for up to six cycles. Because the biological effectiveness of 223Ra-therapy is dose-dependent, the main goal is to complete the entire treatment to achieve a better patient outcome. This study aims to identify potential pre-treatment variables that could impact on 223Ra-treatment completion and then be used to improve the clinical and supportive management of mCRPC patients. MATERIALS AND METHODS: 30 consecutive mCRPC patients (mean age 77 years old), who were admitted for Ra223-therapy at our Department from February 2016 to October 2018, were enrolled for the analysis. The population was grouped as patients who completed 223Ra-therapy (group Ra223-C) and patients who do not (group 223Ra-U). For each group, we analyzed the effects of potential pre-treatment variables (age, Gleason Score, tumor burden, "Time From Diagnosis To 223Ra therapy", type and number of previous treatments, hemoglobin level, Alkaline Phosphatase, Prostate Specific Antigen and pain) on the Ra223-therapy completion. Statistical analysis was performed to evaluate the association between the completion of 223Ra therapy and the variables examined. RESULTS: 16/30 (53%) patients were 223Ra-C, conversely 14/30 (47%) patients were 223Ra-U because of an early interrupted treatment. A statistically significant association was found only with tumor burden: 68.7% of patients who completed 223-therapy had less than 20 bone metastases (χ2=4.821, p=0.028). CONCLUSION: Our preliminary analysis demonstrates that the high tumor burden represents the most important pre-treatment factor that could affect treatment completion and that needs to be considered before starting 223Ra-therapy to achieve a better outcome in mCRPC patients.

Pelvic floor function following ventral rectopexy versus STARR in the treatment of obstructed defecation.

BACKGROUND: Obstructed defecation syndrome (ODS), most commonly found in females, can be treated by a transanal or abdominal approach with good success rate. Nevertheless, patients may experience de novo or persisting pelvic floor dysfunctions after surgery. The aim of this study was to compare the functional outcome of stapled transanal rectal resection (STARR) and ventral rectopexy (VRP) in a series of ODS patients. METHODS: Forty-nine female patients who had surgery for ODS between 2006 and 2016 were retrospectively evaluated: 28 (median age 60 years, IQR 54-69 years) had VRP and 21 (median age 58 years, IQR 51-66 years) had STARR. ODS was scored with the ODS score while the overall pelvic floor function was assessed with the three axial perineal evaluation (TAPE) score. Quality-of-life was evaluated by the patient assessment of constipation quality-of-life (PAC-Qol) questionnaire administered preoperatively and after 1 year of follow-up. RESULTS: The preoperative median ODS score and TAPE score were comparable in both groups. After a median follow-up of 12 months (range 12-18 months), the median ODS score was 12 (range 10-20) in the STARR group and 9 (range 3-15) in the VRP one (p = 0.02), while the median TAPE score was 70.5 (IQR 60.6-77.3) in the former and 76.8 (IQR 70.2-89.7) in the latter (p = 0.01). Postoperatively the physical domain of the PAC-QoL score had a median value of 2.74 (IQR 1.7-3.75) in the STARR group compared to 1.5 (IQR 1-2.5) in the VRP group (p = 0.03). No major complications were recorded in either group. CONCLUSIONS: VRP and STARR can improve defecation in patients with ODS with minimal complications, but the overall pelvic wellness evaluated by the TAPE score improves significantly only after VRP, suggesting a better performance of VRP than STARR when overall pelvic floor function is concerned.

The emerging trend of non-operative treatment in paediatric type I open forearm fractures.

PURPOSE: Open fractures are considered an orthopaedic emergency and are generally an indication for operative debridement. Recent studies have questioned this approach for the management of Gustilo-Anderson Type I open fractures in the paediatric population. This meta-analysis studies the non-operative management of Type I open paediatric forearm fractures. METHODS: An Ovid MEDLINE and PubMed database literature search was performed for studies that involved a quantified number of Gustilo-Anderson Type I open forearm fractures in the paediatric population, which were treated without operative intervention. A fixed-effect meta-analysis, weighting each study based on the number of patients, and a pooled estimate of infection risk (with 95% confidence interval (CI)) was performed. RESULTS: The search results yielded five studies that were eligible for inclusion. No included patients had operative debridement and all were treated with antibiotics. The number of patients in each study ranged from 3 to 45, with a total of 127 paediatric patients in the meta-analysis. The infection rate was 0% for all patients included. The meta-analysis estimated a pooled infection risk of 0% (95% CI 0 to 2.9). CONCLUSIONS: The five included studies had a total of 127 patients with no cases of infection after non-operative management of Type I open paediatric forearm fractures. The infection rate of Type I fractures among operatively managed patients is 1.9%. The trend in literature towards non-operative treatment of paediatric Type I open fractures holds true in this meta-analysis.

Hypothyroidism reduces mammary tumor progression via Β-catenin-activated intrinsic apoptotic pathway in rats.

Experimental hypothyroidism retards mammary carcinogenesis promoting apoptosis of tumor cells. ß-catenin plays a critical role in cell adhesion and intracellular signaling pathways conditioning the prognosis of breast cancer. However, the mechanistic connections associated with the expression of ß-catenin in thyroid status and breast cancer are not known. Therefore, we studied the relationship between the expression and localization of ß-catenin and apoptosis in mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) in hypothyroid (Hypot) and euthyroid (EUT) rats. Female Sprague Dawley rats were treated with a dose of DMBA (15 mg/rat) at 55 days of age and were then divided into two groups: HypoT (0.01% 6-N-propyl-2-thiouracil in drinking water, n = 54) and EUT (untreated control, n = 43). Latency, incidence and progression of tumors were determined. At sacrifice, tumors were obtained for immunohistological studies and Western Blot. The latency was longer (p < 0.05), the incidence was lower (p < 0.0001) and tumor growth was slower (p < 0.01) in HypoT rats compared to EUT. The expression of Bax, cleaved caspase-9 and caspase-3 was significantly higher in tumors of HypoT than in EUT (p < 0.05) indicating the activation of the intrinsic pathway. In this group, ß-catenin was expressed in the plasma membrane and with less intensity, while its expression was nuclear and with greater intensity in the EUT (p < 0.05). Moreover, the expression of survivin was reduced in tumors of HypoT rats (p < 0.05). In conclusion, decreased expression of ß-catenin and its normal location in membrane of mammary tumors are associated with augmented apoptosis via activation of the intrinsic pathway in HypoT rats.

Movilización aséptica, simultánea y bilateral por rotura de la copa acetabular en una paciente de 43 años / Aseptic, simultaneous and bilateral mobilisation due to an acetabular shell fracture in a 43 year-old patient

La movilización del componente acetabular en una prótesis total de cadera (PTC) es la principal complicación en este tipo de cirugía. Además, los casos de rotura del cótilo llevan casi siempre a su movilización. Presentamos el caso de una mujer de 43 años con movilización aséptica por separación de la malla reticular bilateral del cotilo después de 13 y 14 años de la intervención (AU)

The acetabular shell mobilization is the main long-term complication in total hip replacement. Metal-back fracture has also to be considered among the possible causes of shell mobilization. A case is presented of bilateral acetabular shell mobilization due to the trabecular covering de-soldering from the metal-back in a 43 year-old patient, 13-14 years after the first surgery (AU)

[Aseptic, simultaneous and bilateral mobilisation due to an acetabular shell fracture in a 43 year-old patient]. / Movilización aséptica, simultánea y bilateral por rotura de la copa acetabular en una paciente de 43 años.

The acetabular shell mobilization is the main long-term complication in total hip replacement. Metal-back fracture has also to be considered among the possible causes of shell mobilization. A case is presented of bilateral acetabular shell mobilization due to the trabecular covering de-soldering from the metal-back in a 43 year-old patient, 13-14 years after the first surgery.

Can FDG-PET/CT predict early response to neoadjuvant chemotherapy in breast cancer?

PURPOSE: Neoadjuvant chemotherapy (NAC) in breast cancer is currently used not only for locally advanced tumors, but also for large operable tumors when breast preservation is considered. It also provides the opportunity to evaluate chemotherapy tumor response. Our aim was to correlate the relative change in the standardized uptake value (SUV) of (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET/CT) with pathologic response after NAC. METHODS: We prospectively evaluated 40 patients with invasive ductal breast carcinomas from February 2010 to December 2011. FDG-PET/CT was performed at baseline and after the second cycle of NAC. All patients underwent surgery after NAC. Pathologic response was evaluated according to Residual Cancer Burden (RCB) index. RESULTS: The mean age was 41.9 years. Median primary tumor size was 6 cm. Pathologic complete response (pCR) was obtained in 12 (30%) patients. The tumor baseline mean maximum SUV (SUV(max)), and after second cycle were: 8.97 (sd.4.3) and 4.07 (sd.3.2), respectively. The relative change (ΔSUV) after the second course of NAC was significantly higher for patients with pCR (-81.58%) when compared to the non-pCR patients (-40.18%) (p = 0.001). The optimal ΔSUV threshold that discriminates between pCR and non-pCR was -71.8% (83.3% sensitivity; 78.5% specificity). Moreover, the optimal ΔSUV threshold to discriminate between NAC responders and non-responders was -59.1% (68% sensitivity; 75.0% specificity). CONCLUSIONS: Our data suggest that the FDG-PET/CT ΔSUV after the second course of NAC can predict pathological response in ductal breast carcinomas, and potentially identify a subgroup of non-responding patients for whom ineffective chemotherapy should be avoided. SYNOPSIS: Breast cancer is the most frequently diagnosed cancer in women. The indications for neoadjuvant chemotherapy are increasing. Early information on chemotherapy response is crucial and methods that predict the therapeutic effectiveness might avoid potentially ineffective chemotherapies in non-responding patients.

Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma.

BACKGROUND: Aurora kinases are key regulators of cell cycle and represent new promising therapeutic targets in several human tumours. METHODS: Biological relevance of Aurora kinase-A and -B was assessed on osteosarcoma clinical samples and by silencing these genes with specific siRNA in three human osteosarcoma cell lines. In vitro efficacy of two Aurora kinases-targeting drugs (VX-680 and ZM447439) was evaluated on a panel of four drug-sensitive and six drug-resistant human osteosarcoma cell lines. RESULTS: Human osteosarcoma cell lines proved to be highly sensitive to both drugs. A decreased drug sensitivity was observed in doxorubicin-resistant cell lines, most probably related to ABCB1/MDR1 overexpression. Both drugs variably induced hyperploidy and apoptosis in the majority of cell lines. VX-680 also reduced in vitro cell motility and soft-agar cloning efficiency. Drug association experiments showed that VX-680 positively interacts with all conventional drugs used in osteosarcoma chemotherapy, overcoming the cross-resistance observed in the single-drug treatments. CONCLUSION: Aurora kinase-A and -B represent new candidate therapeutic targets for osteosarcoma. In vitro analysis of the Aurora kinases inhibitors VX-680 and ZM447439 indicated in VX-680 a new promising drug of potential clinical usefulness in association with conventional osteosarcoma chemotherapeutic agents.

Physical exercise and environment exploration affect synaptogenesis in adult-generated neurons in the rat dentate gyrus: possible role of BDNF.

A brief training in a pool maze, with or without cognitive tasks, modifies the synaptogenesis and maturation of newborn neurons in adult rat dentate gyrus. These types of trainings have many aspects, including physical activity and exploration. Therefore, to evaluate whether physical exercise and environment exploration are able to affect synapse formation and the maturation of adult-generated neurons, GFP-retrovirus infusion was performed on rats which, on the fourth day after injection, were housed under running conditions or allowed to explore an enriched environment briefly in the absence of exercise for the following three days. Afterward, at the end of the trainings, electrophysiological and morphological studies were conducted. Considering that neurotrophic factors increase after exercise or environment exploration, hippocampal BDNF levels and TrkB receptor activation were evaluated. In this study, we show that both spontaneous physical activity and enriched environment exploration induced synaptogenesis and T-type voltage-dependent Ca(2+) currents in very immature neurons. Hippocampal BDNF levels and TrkB receptor activation were determined to be increasing following physical activity and exploration. A possible contribution of BDNF signaling in mediating the observed effects was supported by the use of 7-8-dihydroxyflavone, a selective TrkB agonist, and of ANA-12, an inhibitor of TrkB receptors.

An unconventional indication of the Sauve' - Kapandji procedure in a radial shaft pseudoarthrosis and chronic DRUJ dislocation: a case report.

We present a 42-years-old male who developed a radial shaft pseudoartrosis and a chronic DRUJ dislocation/instability, following a Galeazzi fracture. He presented to our Office with a severe inability of wrist and forearm motion. A Sauve'-Kapandji procedure was adopted, performing a lateral approach to the ulna and grafting the excised ulnar block to retrieve radial length at the pseudoarthrosis level. Cancellous bone grafts from the iliac crest were also applied and mixed with autologous platelet rich plasma to promote callus formation. The goal was to create an intentional pseudoarthrosis of the distal ulna combined with a DRUJ arthrodesis, in order to resolve instability and regain forearm pronation/supination. We obtained bone healing, an excellent clinical recovery, and the patient returned to all his previous activities six months after surgery. To our knowledge, this is the first reported case of a radial shaft psudoarthrosis treated with the Sauve'-Kapandji technique.

Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma.

The drug-dependent induction of premature senescence in neoplastic cells is considered per se an important tumor suppressive mechanism. DNA demethylating agents recently introduced in clinical trials, such as 5-aza-cytidine (Decitabine) and its derivatives, have been extensively characterized in recent years as antiproliferative compounds that act through multiple mechanisms, which have not yet been fully clarified. We recently analyzed the introduction of Decitabine in therapy for malignant pleural mesothelioma (MPM) observing that, despite the ability to induce profound biological effects in MPM cells, the drug failed to generate a massive apoptotic response. Since one of the most intriguing aspects of DNA demethylating agents is the possibility to accelerate the senescent response of tumor cells, we investigated the hypothesis of Decitabine inducing, in vitro, the premature aging of MPM cells.

Malten, a new synthetic molecule showing in vitro antiproliferative activity against tumour cells and induction of complex DNA structural alterations.

BACKGROUND: Hydroxypyrones represent several classes of molecules known for their high synthetic versatility. This family of molecules shows several interesting pharmaceutical activities and is considered as a promising source of new antineoplastic compounds. METHODS: In the quest to identify new potential anticancer agents, a new maltol (3-hydroxy-2-methyl-4-pyrone)-derived molecule, named malten (N,N'-bis((3-hydroxy-4-pyron-2-yl)methyl)-N,N'-dimethylethylendiamine), has been synthesised and analysed at both biological and molecular levels for its antiproliferative activity in eight tumour cell lines. RESULTS: Malten exposure led to a dose-dependent reduction in cell survival in all the neoplastic models studied. Sublethal concentrations of malten induce profound cell cycle changes, particularly affecting the S and/or G2-M phases, whereas exposure to lethal doses causes the induction of programmed cell death. The molecular response to malten was also investigated in JURKAT and U937 cells. It showed the modulation of genes having key roles in cell cycle progression and apoptosis. Finally, as part of the effort to clarify the action mechanism, we showed that malten is able to impair DNA electrophoretic mobility and drastically reduce both PCR amplificability and fragmentation susceptibility of DNA. CONCLUSION: Taken together, these results show that malten may exert its antiproliferative activity through the induction of complex DNA structural modifications. This evidence, together with the high synthetic versatility of maltol-derived compounds, makes malten an interesting molecular scaffold for the future design of new potential anticancer agents.

Dexamethasone affects Fas- and serum deprivation-induced cell death of human osteoblastic cells through survivin regulation.

Glucocorticoid-induced bone loss is the most prevalent form of secondary osteoporosis. Such loss could be due to the alteration of osteoclast and osteoblast lifespan through regulated apoptosis. The current study investigated the effect of dexamethasone on Fas- and starvation-induced apoptosis of mature osteoblasts and their precursors. Using the human osteoblastic hFOB1.19 and the MG63 osteosarcoma cell lines, we found that sub-lethal doses of dexamethasone act on pre-osteoblasts but not on mature cells by increasing their susceptibility to apoptosis. Apoptosis occurs in a caspase-dependent manner as both DNA fragmentation and mitochondrial transmembrane potential dissipation (ΔΨm) are inhibited by the pan-caspase inhibitor zVAD. The increased susceptibility of osteoblast precursors to apoptosis could be due to dexamethasonemediated down-regulation of survivin expression. Dexamethasone can up-regulate survivin, and to a lesser extent Bcl-2, in mature cells but not in pre-osteoblasts. In addition, it can induce FLIP over-expression in osteosarcoma cells. All these effects are inhibited by the glucocorticoid antagonist RU486, indicating that dexamethasone action is specific and, furthermore, that it depends on glucocorticoid receptor. Finally, we have found that survivin and Bcl-2 are essential for pre- and mature osteoblast survival as their silencing is sufficient to induce spontaneous apoptosis in both cell types. In conclusion, our data outline a new molecular mechanism of glucocorticoid-mediated bone loss due to the enhanced apoptosis of precursors compared to mature osteoblasts. Furthermore, the data suggest a mechanism of dexamethasone-induced resistance of osteosarcoma cells to Fas- and stress-induced apoptosis.

Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells.

Malignant pleural mesothelioma (MPM) is a locally aggressive neoplasm, principally linked to asbestos fibres exposure. Strong evidences associate this pollutant with induction of DNA breaks, aberrant chromosomes segregation and important chromosomal rearrangements, considered crucial events in malignant transformation. A considerable contribution to cellular transformation in MPM is also given by the presence of high genomic instability, as well as by the increased DNA methylation, and consequent decreased expression, of tumor-suppressor genes. In this study we first demonstrated that MPM cells are characterized by a decreased methylation level of pericentromeric DNA sequences which can justify, at least in part, the genomic instability observed in this neoplasia. Concomitantly, we found a paradoxical increased expression of DNMT1, the most expressed DNA methyltransferases in MPM cells, DNMT3a and all five isoforms of DNMT3b. Thus, we compared two experimental strategies, DNMT1 silencing and usage of a demethylating agent (5-aza-2'-deoxycytidine or Decitabine), both theoretically able to revert the locally hypermethylated phenotype and considered potential future therapeutic approaches for MPM. Interestingly, both strategies substantially decrease cell survival of MPM cells but the antitumor activity of Decitabine, differently from DNMT1 silencing, is mediated, at least in part, by a p53-independent p21 upregulation, and is characterized by the arrest of MPM cells at the G2/M phase of the cell cycle. These results indicate that the two approaches act probably through different mechanisms and, thus, that DNMT1 silencing can be considered an effective alternative to Decitabine for cancer treatment.

Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1.

Heat shock factor 1 (HSF1), the transcriptional activator of the heat shock genes, is increasingly implicated in cancer. We have shown that HSF1 binds to the corepressor metastasis-associated protein 1 (MTA1) in vitro and in human breast carcinoma samples. HSF1-MTA1 complex formation was strongly induced by the transforming ligand heregulin and complexes incorporated a number of additional proteins including histone deacetylases (HDAC1 and 2) and Mi2alpha, all components of the NuRD corepressor complex. These complexes were induced to assemble on the chromatin of MCF7 breast carcinoma cells and associated with the promoters of estrogen-responsive genes. Such HSF1 complexes participate in repression of estrogen-dependent transcription in breast carcinoma cells treated with heregulin and this effect was inhibited by MTA1 knockdown. Repression of estrogen-dependent transcription may contribute to the role of HSF1 in cancer.

Mapping the intake of different elements in vegetal tissues by dual-energy X-ray imaging at DaPhine synchrotron light source.

This article reports on the first utilization of the soft X-ray beamline at the DaPhine synchrotron light source for mapping the intake of different elements in plant tissues. As a test, the method of dual-energy X-ray microradiography was applied to the investigation of the natural sulfur content in dried leaf and root samples. Our ultimate goal was to monitor the pollutant lead and its intake, which was added in controlled doses to the hydroponic medium of laboratory-controlled samples of vegetal species. The results obtained by the nondestructive X-ray radiographic analysis are compared to the values of concentrations determined by a standard chemical analysis utilizing atomic absorption spectroscopy. From this comparison the validity of the X-ray detection of heavy metals in biological samples has been confirmed. The superposition of the dual energy results on the simple planar radiography shows the representation of the pollutant intake directly on the sample structures. It should be pointed out that this method, developed here for plant root and leaves could be applied to any biological sample of interest, but the preparation and observation conditions necessitate different strategies according to the type of sample under analysis.

Loss of pericentromeric DNA methylation pattern in human glioblastoma is associated with altered DNA methyltransferases expression and involves the stem cell compartment.

Cancer is generally characterized by loss of CG dinucleotides methylation resulting in a global hypomethylation and the consequent genomic instability. The major contribution to the general decreased methylation levels seems to be due to demethylation of heterochromatin repetitive DNA sequences. In human immunodeficiency, centromeric instability and facial anomalies syndrome, demethylation of pericentromeric satellite 2 DNA sequences has been correlated to functional mutations of the de novo DNA methyltransferase 3b (DNMT3b), but the mechanism responsible for the hypomethylated status in tumors is poorly known. Here, we report that human glioblastoma is affected by strong hypomethylation of satellite 2 pericentromeric sequences that involves the stem cell compartment. Concomitantly with the integrity of the DNMTs coding sequences, we report aberrations in DNA methyltrasferases expression showing upregulation of the DNA methyltransferase 1 (DNMT1) and downregulation of the de novo DNA methyltransferase 3a (DNMT3a). Moreover, we show that DNMT3a is the major de novo methyltransferase expressed in normal neural progenitor cells (NPCs) and its forced re-expression is sufficient to partially recover the methylation levels of satellite 2 repeats in glioblastoma cell lines. Thus, we speculate that DNMT3a decreased expression may be involved in the early post-natal inheritance of an epigenetically altered NPC population that could be responsible for glioblastoma development later in adult life.