First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

BACKGROUND: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. PATIENTS AND METHODS: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. RESULTS: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. CONCLUSIONS: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Impact of Parkinson's disease on the efficiency of masticatory cycles: Electromyographic analysis.

BACKGROUND: This study evaluated the efficiency of masticatory cycles by means of the linear envelope of the electromyographic signal of the masseter and temporalis muscles in individuals with Parkinson's disease. MATERIAL AND METHODS: Twenty-four individuals were assigned into two groups: with Parkinson's disease, average ± SD 66.1 ± 3.3 years (n = 12) and without the disease, average ± SD: 65.8 ± 3.0 years (n = 12). The MyoSystem-I P84 electromyograph was used to analyze the activity of masticatory cycles through the linear envelope integral in habitual mastication of peanuts and raisins and non-habitual mastication of Parafilm M®. RESULTS: There was statistically significant difference (P ≤ 0.05) between individuals with Parkinson's disease and without the disease in non-habitual mastication of Parafilm M®, in the right temporal muscle (P = 0.01); habitual mastication of peanuts, in the right temporal muscle (P = 0.02), left temporal muscle (P = 0.03), and right masseter muscle (P = 0.01); and habitual mastication of raisins in the right temporal muscle (P = 0.001), left temporal muscle (P= 0.001), right masseter muscle (P= 0.001) and left masseter muscle (P= 0.03). CONCLUSIONS: These results suggest that Parkinson's disease interferes in the electromyographic activity of the masticatory cycles by reducing muscular efficiency.

Does Parkinson's disease interfere with electromyographic fatigue of masticatory muscles?

Parkinson's disease is a neurodegenerative disease with manifestations related to oxidative stress and damage to the skeletal striated musculature. This study evaluated the electromyographic fatigue of the masseter and temporal muscles in individuals with Parkinson's disease. The median frequency of the normotensive electromyographic signal was analyzed in 16 individuals, aged between 50 and 70 years, with Parkinson's disease in stages I and III of the Hoehn and Yahr disability scale (n=8) or without the disease (n=8). The data were tabulated and analyzed statistically (t-test, p .05). Compared with the group without Parkinson's disease, the group with the disease showed an increase in the median frequency, with significant differences for the right masseter (p=.05) and the right temporal (p=.03) muscles. The results suggest that there is a link between Parkinson's disease and functional alterations of the masticatory system, especially when electromyographic fatigue is assessed.

Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial.

BACKGROUND: Platinum-based chemoradiation (CCRT) is the standard treatment for Locally Advanced Head and Neck Squamous-Cell Carcinoma (LAHNSCC). Cetuximab/RT (CET/RT) is an alternative treatment option to CCRT. The efficacy of induction chemotherapy (IC) followed by chemoradiation compared to chemoradiation alone has not been demonstrated in randomized clinical trials. The goals of this phase II-III trial were to assess: (i) the overall survival (OS) of IC versus no-induction (no-IC) and (ii) the Grade 3-4 in-field mucosal toxicity of CCRT versus CET/RT. The present paper focuses on the analysis of efficacy. MATERIALS AND METHODS: Patients with LAHNSCC were randomized to receive concomitant treatment alone [CCRT (Arm A1) or CET/RT (Arm A2)], or three cycles of induction docetaxel/cisplatin/5 fluorouracil (TPF) followed by CCRT (Arm B1) or followed by CET/RT (Arm B2). The superiority hypothesis of OS comparison of IC versus no-IC (Arms B1 + B2 versus A1 + A2) required 204 deaths to detect an absolute 3-year OS difference of 12% (HR 0.675, with 80% power at two-sided 5% significance level). RESULTS: 414 out of 421 patients were finally analyzed: 206 in the IC and 208 in the no-IC arm. Six patients were excluded because of major violation and one because of metastatic disease at diagnosis. With a median follow-up of 44.8 months, OS was significantly higher in the IC arm (HR 0.74; 95% CI 0.56-0.97; P = 0.031). Complete Responses (P = 0.0028), Progression Free Survival (P = 0.013) and the Loco-regional Control (P = 0.036) were also significantly higher in the IC arm. Compliance to concomitant treatments was not affected by induction TPF. CONCLUSIONS: IC followed by concomitant treatment improved the outcome of patients with LAHNSCC without compromising compliance to the concomitant treatments. The degree of the benefit of IC could be different according to the type of the subsequent concomitant strategy. CLINICAL TRIAL NUMBER: NCT01086826, www.clinicaltrials.gov.

Evaluation of Vitek-2 and MicroScan ASTs directly from positive blood culture: A cost-effective 24-h reduction for Enterobacterales and staphylococci.

The reduction of antimicrobial susceptibility testing (AST) time-to-result is a central need, especially in sepsis treatment. The current automated rapid ASTs are still too expensive for many laboratories. We aimed to evaluate three pre-treatment methods for a same-day inoculation on both automated AST platforms available in our laboratory. We tested 100 Enterobacterales or staphylococci positive bottles. We obtained good results with the different methods and instruments. In particular, Vitek-2 showed good performances with Enterobacterales AST when inoculated with bacterial pellet (96.6% categorical agreement - CA-, 93.3% essential agreement - EA). Also short-term incubation colonies for staphylococci AST had acceptable CA (94.2%), even if with 77.5% EA. MicroScan system for staphylococci AST with both short-term incubation and direct blood inoculation reached >95% CA, but 92.5% and 83.6% EA, respectively. On the other hand, Enterobacterales AST showed optimal performances only with bacterial pellet inoculation (97.6% CA). In fact, direct blood inoculation showed not acceptable parameters for several molecules. Both systems allow a 24-h reduction in time-to-result, by using the same instruments of routine activity after rapid and cheap pre-treatments.

Oligo metastatic renal cell carcinoma: stereotactic body radiation therapy, if, when and how?

BACKGROUND AND PURPOSE: Renal cell carcinoma (RCC) has traditionally been considered radioresistant with a limited role for conventional fractionation as a local approach. Nevertheless, since the appearance of stereotactic body radiation therapy (SBRT), radiotherapy (RT) has been increasingly employed in the management of metastatic RCC (mRCC). The aim of this study was to evaluate the role of SBRT for synchronous and metachronous oligo metastatic RCC patients in terms of local control, delay of systemic treatment, overall survival and toxicity. PATIENTS AND METHODS: A Monocentric single institution retrospective data collection was performed. Inclusion criteria were: (1) oligo-recurrent or oligo-progressive disease (less than 5 metastases) in mRCC patients after radical/partial nephrectomy or during systemic therapy, (2) metastasectomy or other metastasis-directed, rather than SBRT not feasible, (3) any contraindication to receive systemic therapy (such as comorbidities), (4) all the histologies were included, (5) available signed informed consent form for treatment. Tumor response and toxicity were evaluated using the response evaluation criteria in solid tumors and the Common Terminology Criteria for Adverse Events version 4.03, respectively. Progression-free survival in-field and out-field (in-field and out-field PFS) and overall survival (OS) were calculated via the Kaplan-Meier method. The drug treatment-free interval was calculated from the start of SBRT to the beginning of any systemic therapy. RESULTS: From 2010 to December 2018, 61 patients with extracranial and intracranial metastatic RCC underwent SBRT on 83 lesions. Intracranial and extracranial lesions were included. Forty-five (74%) patients were treated for a solitary metastatic lesion. Median RT dose was 25 Gy (range 10-52) in 5-10 fractions. With a median follow-up of 2.3 years (range 0-7.15), 1-year in-field PFS was 70%, 2-year in-field PFS was 55%. One year out-field PFS was 39% and 1-year OS was 78%. Concomitant systemic therapy was employed for only 11 (18%) patients, for the others 50 (82%) the drug treatment-free rate was 70% and 50% at 1 and 2 years, respectively. No > G1 acute and late toxicities were reported. CONCLUSION: The pattern of failure was pre-dominantly out-of-field, even if the population was negatively selected and the used RT dose could be considered palliative. Therefore, SBRT appears to be a well-tolerated, feasible and safe approach in oligo metastatic RCC patients with an excellent in-field PFS. SBRT might play a role in the management of selected RCC patients allowing for a delay systemic therapy begin (one out of two patients were free from new systemic therapy at 2 years after SBRT). Further research on SBRT dose escalation is warranted.

Variation of circulating tumor cell levels during treatment of metastatic breast cancer: prognostic and therapeutic implications.

BACKGROUND: This study aimed to evaluate the prognostic significance of circulating tumor cells (CTCs) detection in advanced breast cancer patients. PATIENTS AND METHODS: We tested 80 patients for CTC levels before starting a new treatment and after 4, 8 weeks, at the first clinical evaluation and every 2 months thereafter. CTCs were detected using the CellSearch System. RESULTS: Forty-nine patients had >or=5 CTCs at baseline. At the multivariate analysis, baseline number of CTCs was significantly associated with progression-free survival [hazard ratio (HR) 2.5; 95% confidence interval (CI) 1.2-5.4]. The risk of progression for patients with CTCs >or=5 at last available blood draw was five times the risk of patients with 0-4 CTCs at the same time point (HR 5.3; 95% CI 2.8-10.4). Patients with rising or persistent >or=5 CTCs at last available blood draw showed a statistically significant higher risk of progression with respect to patients with <5 CTCs at both blood draws (HR 6.4; 95% CI 2.8-14.6). CONCLUSION: CTCs basal value is a predictive indicator of prognosis and changes in CTC levels during therapy may indicate a clinical response. Testing CTC levels during targeted treatments might substitute other measurement parameters for response evaluation.

Effect of congenital blindness on EMG activity of the facial muscles.

The aim of this work was to analyze electromyographically the facial muscles: orbicularis oris (upper and lower fascicles), orbicularis oculi (right and left lateral portions) and frontal, in blind and clinically normal (control) individuals, in various clinical conditions. Electromyographic averages of all data collected were normalized by maximal voluntary contraction of the studied muscles and statistical analysis was performed by Student's t test, using "Statistical Package for the Social Sciences" software--SPSS 12.0 (Chicago, IL). It was found that electromyographic alterations occur in the facial musculature that influences facial expressions of individuals. Results for the orbicularis oris muscle demonstrated that myoelectric activity among blind and control subjects was greater for the control group at muscular rest, blowing, and in labial projection. Electromyographic analysis of the orbicularis oculi among blind and control subjects in three clinical conditions studied demonstrated that activity was greater for the control group at muscular rest, blinking, and forced blinking. For the frontal muscles were demonstrated that electromyographic activity was greater for blind individuals. These data suggest the influence of congenital blindness on muscular development, including alterations in electromyographic activity of skin musculature in individuals with visual impairment.

Brain metastases in patients with advanced breast cancer.

BACKGROUND: The incidence of brain metastases (BM) is apparently rising in patients with advanced breast cancer (ABC). We performed a case control study to define current features of breast cancer related to central nervous system (CNS) metastases. PATIENTS AND METHODS: From March 1999 to May 2006, we identified 72 patients with symptomatic BM of breast cancer. A comparison group was randomly selected assigning to each case two patients with primary breast cancer and no BM, matched for year of diagnosis, age and tumour stage (pT status and nodal status). RESULTS: Cases had a significantly higher rate of negative estrogen receptors (ERs) (60% in cases vs. 29% in controls), negative progesterone receptors (PgRs) (79% vs. 43%), HER2/neu over expression (44% vs. 13%) and immunostaining for Ki-67 > or =20% (84% vs. 55%), with p-value <0.001 for all four parameters in univariate analyses. On multivariate analysis, HER2/neu over expression and Ki-67 -20% were independent predictive factors of brain relapse (Odds Ratio (OR) 2.55, 95% confidence intervals (CI) 1.10-5.94 and OR 2.97, 95% CI 1.01-8.73, respectively). Endocrine unresponsive tumours (both ER and PgR <10%) showed an increased risk of relapse with BM of borderline significance (OR 1.91, 95% CI 0.87-4.12). CONCLUSION: Patients with ER and PgR negative tumours either with or without HER-2/neu over expression should be considered at higher risk of BM.

Feasibility of concurrent chemoradiotherapy with high-dose cisplatin after induction TPF chemotherapy in head and neck cancer: a critical review of the literature and the experience of the European Institute of Oncology.

Many concerns are related to the idea that the acute toxicity of induction chemotherapy (IC) performed with TPF (docetaxel, cisplatin, 5-fluorouracil) could reduce the ability to deliver the subsequent standard concurrent chemoradiotherapy (CRT) in head and neck cancer patients. We performed a critical review of the literature on the toxicity profile of the standard CRT administered after the IC with TPF. A total of 13 papers (including 950 patients) were selected. Results showed that most patients were treated with an adequate radiation total dose although a significant proportion of them (from 15 to 30%) completed the planned treatment with a delay of more than 5 days. A minority of patients were able to be treated with three cycles of concurrent cisplatin, but only few papers reported how many of patients reached the cumulative total dose of almost 200 mg/m2 cisplatin. The rate of deaths due to treatment-related toxicity varied from 0 to 9% (median and mean 2%). Two prospective trials stopped patient enrollment due to acute treatment-related toxicity and because a low number of patients were able to undergo the planned full schedule of cisplatin during the CRT, respectively. Retrospective analysis of 45 patients treated at our institute showed that this schedule was feasible with manageable side effects. In conclusion, the literature data did not provide homogeneous information on the feasibility of the standard CRT after induction TPF. A more uniform data collection of treatment-related toxicity will be helpful in better selecting the patients who might adequately tolerate this multimodality strategy.

Vinorelbine-based chemotherapy in hormone-refractory prostate cancer.

BACKGROUND: No consensus exists regarding further therapy for the management of hormone-refractory prostate cancer. In this phase II study, the combination of Vinorelbine with 5-Fluorouracil and folinic acid (FLN regimen) was evaluated in patients with progressive or resistant disease after hormone therapy. PATIENTS AND METHODS: Thirty-four patients were treated with Vinorelbine at a dose of 20 mg/m2 intravenously (i.v.) on days 1 and 3, folinic acid (FA), 100 mg/m2 i.v. and 5-Fluorouracil (5-FU), 350 mg/m2 i.v. as a short infusion on days 1 to 3. The therapy was given in an out-patient setting, every 3 weeks. RESULTS: All of the 34 eligible patients were evaluable for toxicity and 30 for activity. A total of 127 cycles was administered (91% at full dose). Among thelS5 patients with measurable disease, four had a partial response (26.6%; C.I. 95%, 28.3% to 65.7%) and four achieved stable disease. In 14 patients (47%) a clinical benefit was documented. Six out of 15 patients with bone-only involvement had stable disease (40%). The median duration of stabilization and partial response was 16 weeks (range 4-24 weeks). The most common toxicity was hematological: Grade 4 (NCI-CTC scale) in five patients at re-cycle. Other toxicities were of low incidence and easy to manage. CONCLUSION: The encouraging results obtained with the FLN regimen in terms of clinical benefit and its predictable and manageable toxicity support the palliative role of this chemotherapeutic strategy in hormone-refractory prostate patients.

Application of a combination of neutral red and amido black staining for rapid, reliable cytotoxicity testing of biomaterials.

Cell viability and growth for cytotoxicity evaluation of materials for prosthetic devices has been tested using various methods. The aim of this study was to extend the choice of reliable methods to quantify cytotoxicity of materials in vitro. By measuring both viability and growth of cells exposed to biomaterials in vitro, two different parameters are analysed and quantified upon reading of the absorbance of coloured solutions in a spectrophotometer. Neutral red uptake and amido black staining of cells have been used for cell viability and cell number measurement, respectively: they have been found to be well correlated with the number of surviving cells. These methods have been adjusted to a 96-well microplate cell culture system and re-evaluated as simple and reliable methods for the quantitative assessment of biomaterial effect on cells.

In vitro assessment of phagocytosis of bovine collagen by human monocytes/macrophages using a spectrophotometric method.

The use of a wound dressing with covering and haemostatic properties significantly improves wound healing. In this study, a lyophilized bovine collagen sponge used for the treatment of wounds and ulcerae has been tested in a cell culture system. Phagocytosis of collagen fragments by human blood monocytes/macrophages has been investigated. For the assessment of collagen ingestion by mononuclear phagocytes, a picrosirius dye specific for collagen molecules has been used. By adapting this histochemical technique to microplate cell culture system, replicate monocyte cultures are assayed. Collagen content is determined by evaluating spectrophotometrically at 540 nm the absorbance of a sirius red/picric acid solution. Using this simple and sensitive method, the phagocytosis of bovine collagen by LPS-stimulated monocytes/macrophages has been ascertained.

Effects of chromium extract on cytokine release by mononuclear cells.

We have evaluated the effects of chromium extract on the release by peripheral blood mononuclear cells (PBMCs) of cytokines favouring bone resorption. Furthermore, we have evaluated whether the chromium effects could be correlated with the activation and proliferation of PBMCs. Cell cultures were maintained in serum-free medium (AIM-V), in order to avoid the interference of exogenous growth factors. Increasing concentrations of chromium extract, ranging between 3 and 100%, were added to culture medium. Cytokine release (IL-1beta, TNFalpha, IL-6, GM-CSF and IFNgamma) was assessed on both PBMCs cultured with AIM-V only (unstimulated PBMC) and PBMCs cultured with AIM-V plus phytohaemagglutinina (PHA-stimulated PBMC). The activation and proliferation of PBMCs were evaluated by assessing DNA synthesis and soluble IL-2 receptor release, in order to determine whether an IL-2-dependent immune response can be induced by chromium. Our results show that in unstimulated PBMCs chromium ions slightly increased the release of pro-inflammatory cytokines, such as TNFalpha and IL-6, even though the increase is not significant. On the contrary, the different concentrations of chromium extract significantly inhibited the response to PHA stimulation, as shown by the decrease in IL-6 and sIL-2r release, and by the influence on cell viability and DNA synthesis. Both these effects are undesirable and support hypotheses on the biological effects of chromium. The continuous release of chromium from the implant could induce in PBMCs the release of bone-resorbing cytokines, which in the long term could be responsible for irreversible tissue damage. Moreover, chromium seems to inhibit the IL-2-dependent response of PBMCs, so that they are not able to trigger an efficient cell-mediated immune response.

Cytokine production and adhesive protein expression by endothelial cells after contact with polyethylene terephthalate.

The authors have evaluated adhesive protein expression and cytokine production by human umbilical vein endothelial cells cultured in contact with polyethylene terephthalate (PET). ELAM-1, ICAM-1 and VCAM-1 expression was determined by flow cytometry; the concentration of interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) in the supernatant was determined by enzyme immunoassay. The contact with PET determined a significant increase in ELAM-1 expression and insignificant increase in cytokine production, demonstrating that PET had a limited capability to stimulate endothelial cells in a pro-inflammatory sense.

Adhesive protein expression on human endothelial cells after in vitro contact with woven Dacron.

In this research adhesive proteins are studied in order to evaluate the interference of woven Dacron in the endothelialization process and in the ability of endothelial cells to bind circulating leucocytes. Endothelial cells from human umbilical vein (HUVEC) were put in contact with woven Dacron for 24 h. PECAM-1, ELAM-1, ICAM-1 and VCAM-1 expression was then evaluated by flow cytometry, using indirect immunofluorescence reaction with monoclonal antibodies. The study of adhesive proteins was completed with the quantitative determination of surface antigens expressed as the antibody binding capacity (ABC). Antigenic density was calculated by the DAKO QFIT calibration system for indirect immunofluorescence. After contact with woven Dacron no significant change was observed in the percentage of positive cells or in the fluorescence intensity of the adhesins. No significant variation was also noted by calculating the surface antigen density by means of calibration fluorospheres. It can be concluded that the material examined does not significantly affect leucocyte adhesion to the endothelium.

Expression of adhesion molecules on endothelial cells after contact with knitted Dacron.

The aim of this study is to evaluate the expression of some adhesion molecules on the surface of endothelial cells cultured in contact with knitted Dacron. These molecules, as mediators of cell adhesion, could play a role in the modulation of adhesion on the biomaterials, therefore conditioning the response of tissues to implant. Twenty different cultures of human umbilical vein endothelial cells (HUVECs) were cultured in contact with knitted Dacron. Both HUVECs grown without the material and HUVECs incubated with endotoxin were used as control. After 24 h, the cell adhesion molecules PECAM-1, ELAM-1, ICAM-1 and VCAM-1 were evaluated on the cells by monoclonal antibodies and flow cytometry. After 24 h of contact with knitted Dacron, a significant decrease in the proportion of cells expressing PECAM-1 was observed, as well as a significant increase in the proportion of cells expressing ELAM-1. The contact with knitted Dacron did not induce significant variations of ICAM-1 and VACM-1. The incubation with endotoxin determined a significant increase in the proportion of ELAM-1-positive cells, a significant increase in ICAM-1 fluorescence intensity, and a significant increase both in fluorescence intensity and in the proportion of VCAM-1-positive cells. The results obtained with the endotoxin are in agreement with those reported in the literature. The ELAM-1 increase, observed after contact with knitted Dacron, could favour leucocyte adhesion, while the decrease in PECAM-1 expression could result from an inhibiting effect on the endothelial cell adhesion so as to hinder the mechanisms involved in the endothelialization of the material. The variations were interpreted as inhibiting endothelialization and favouring the leucocyte adhesion effect by knitted Dacron.

Bone-resorbing cytokines in serum of patients with aseptic loosening of hip prostheses.

Our aim was to determine if the serum levels of bone-resorbing cytokines (IL-1beta, TNF-alpha, IL-6, GM-CSF) are altered in patients with aseptic loosening of a total hip prosthesis, and if such levels are influenced by the type of implant. We determined cytokine levels in sera from 35 patients before revision for failed total hip arthroplasty and compared them with those in 25 healthy donors. We also assessed the soluble receptor of interleukin-2 (sIL-2r) in serum as an indication of a specific immune reaction against the implant. Our findings showed that the sIL-2r and TNF-alpha serum level did not change. The IL-6 level was not significantly altered, but was higher in patients with TiAIV prostheses than in those with a CrCoMo implant and in patients with cemented prostheses. The IL-1beta level was found to be higher in those with a TiAIV cemented prosthesis than in the control group (p=0.0001) and other groups of patients (p=0.003 v uncemented TiAIV, p=0.01 v cemented CrCoMo, p=0.001 v uncemented CrCoMo). The GM-CSF level significantly increased in patients compared with healthy subjects (p=0.008), and it was higher in those with cemented than with uncemented implants (p=0.01). Only patients with cementless CrCoMo prostheses had levels of GM-CSF similar to those of the control group. The highest GM-CSF concentrations were observed in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) in the last months before revision (p=0.04). In addition, when massive osteolysis was observed, the level of GM-CSF tended to decrease to that of the control group.