The cross-sectional study has been based on the implementation of the Obstetric Appropriateness Evaluation Protocol (OAEP) in seven hospitals to determine inappropriate hospital admissions and days ...of stay. The outcomes were: inappropriateness of admission and "percentage of inappropriateness" for one hospitalization. A total number of 2196 clinical records were reviewed. The mean percentage of inappropriateness for hospitalization was 22%. The percentage of inappropriateness for the first 10 d of hospitalization peaked in correspondence of the fourth (42%). The logistic regression model on inappropriated admission reported that emergency admission was a protective factor (OR = 0.4) and to be hospitalized in wards with ≥30 beds risk factor (OR = 5.12). The second linear model on "percentage of inappropriateness" showed that inappropriated admission and wards with ≥30 beds increased the percentage (p < 0.001); whereas the admission in Teaching Hospitals was inversely associated (p < 0.001). The present study suggests that the percentage of inappropriate admission depends especially on the inappropriate admission and the large number of beds in obstetric wards. This probably indicates that management of big hospitals, which is very complex, needs improving the processes of support and coordination of health professionals. The OAEP tool seems to be an useful instrument for the decision-makers to monitor and manage the obstetric wards.
to evaluate the efficacy of Selective Neck Dissections (SNDs) in different clinical settings examining a large series and verifying the prognosticators of regional recurrence.
from 1999 to 2011, 827 ...patients (pts) with squamous cell carcinoma of the oral cavity (39.9%), oropharynx (25.5%), hypopharynx (10.8%) and larynx (23.8%), had SND. Fifty-six point 6% of pts were class N0, 18.0% N1, 6.7% N2a, 11.8% N2b, 6.9% N2c or N3. The main characteristics are reported as regards class of T, grading, angiolymphatic and perineural invasion, type of SND, class of pN, number of examined nodes, previous or adjuvant treatments, complications, outcome.
Only 2.7% had recurrence in the neck side treated by SND (more often within the dissected levels). The main clinical and pathologic characteristics, significantly different in relationship with initial or salvage-planned-other T treatment and with elective or therapeutic treatment are reported. The main prognosticators for the regional recurrence of SND were the class of pN and the number on nodal metastases without Extra-Capsular Spread (ECS), the prognosticators for the recurrences elsewhere (T, contralateral neck, M) were the class of N and pN, angiolymphatic invasion, number of nodal metastases with ECS. The survival curves according to the main characteristics are reported.
the SNDs are reliable and allow for a low percentage of regional recurrences either as elective or therapeutic treatment, either in neck already treated by radiotherapy or not; the postoperative adjuvant treatments allow to compensate the unfavourable prognostic significance of the negative pathologic factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose to evaluate the efficacy of Selective Neck Dissections (SNDs) in different clinical settings examining a large series and verifying the prognosticators of regional recurrence. Patients and ...methods from 1999 to 2011, 827 patients (pts) with squamous cell carcinoma of the oral cavity (39.9%), oropharynx (25.5%), hypopharynx (10.8%) and larynx (23.8%), had SND. Fifty-six point 6% of pts were class N0, 18.0% N1, 6.7% N2a, 11.8% N2b, 6.9% N2c or N3. The main characteristics are reported as regards class of T, grading, angiolymphatic and perineural invasion, type of SND, class of pN, number of examined nodes, previous or adjuvant treatments, complications, outcome. Results Only 2.7% had recurrence in the neck side treated by SND (more often within the dissected levels). The main clinical and pathologic characteristics, significantly different in relationship with initial or salvage-planned-other T treatment and with elective or therapeutic treatment are reported. The main prognosticators for the regional recurrence of SND were the class of pN and the number on nodal metastases without Extra-Capsular Spread (ECS), the prognosticators for the recurrences elsewhere (T, contralateral neck, M) were the class of N and pN, angiolymphatic invasion, number of nodal metastases with ECS. The survival curves according to the main characteristics are reported. Conclusions the SNDs are reliable and allow for a low percentage of regional recurrences either as elective or therapeutic treatment, either in neck already treated by radiotherapy or not; the postoperative adjuvant treatments allow to compensate the unfavourable prognostic significance of the negative pathologic factors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Non-steroidal anti-inflammatory drugs (NSAIDs) have repeatedly shown to be effective in tumor prevention, but important side-effects limit their wide clinical use. Nitric oxide-releasing derivatives ...(NO-NSAIDs) are a promising class of compounds synthesized by combining a classic NSAID molecule with an NO-releasing moiety to counteract side-effects. These new chemical entities exhibit a significantly higher activity and much lower toxicity with respect to the parental drug. In the present paper, we report the results obtained from in
in vitro experimental systems aimed to evaluate the activity and mechanisms of action of the novel NO-releasing aspirin derivative, NCX 4040. The
in vitro studies were carried out on a panel of human colon (LoVo, LoVo Dx, WiDr, LRWZ), bladder (HT1376, MCR), and pancreatic (Capan-2, MIA PaCa-2, T3M4) cancer cell lines. With regard to colon cancer, NCX 4040 activity was also investigated
in vitro in combination with drugs currently used in clinical practice and was validated in
vivo on tumor-bearing mice xenografted with the aforementioned colon cancer cell lines. The
in vitro studies showed a high cytotoxic activity of NCX 4040 in all tumor histotypes and demonstrated the pivotal role of the NO component in drug activity. It was also observed that NCX 4040 exerts a pro-apoptotic activity via a mitochondria-dependent pathway. Moreover, the
in vivo studies on xenografted mice further confirmed the antitumor efficacy and low toxicity of NCX 4040 in colon cancer and highlighted its role as sensitizing agent of oxaliplatin cytotoxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Purpose: Alterations in tyrosine kinase (TK) expression or functionality have been linked to tumor growth, and the unraveling of TK pathways has led to the discovery of novel anticancer ...drugs. The aims of this study were to evaluate cytotoxic and multidrug resistance mechanisms, such as Ca2+ homeostasis and efflux pump activity, of three tyrosine kinase inhibitors (TKIs), lapatinib, sorafenib and gefitinib, in two breast cancer cell lines.
Methods: Two human breast cancer cell lines, Estrogen Receptor (ER) positive MCF-7 and ER negative BRC-230 were exposed to the investigated drugs for 20, 40, 60, 120 and 240 min. Cytotoxicity, cytosolic Ca2+ levels, extrusion pump activity and mitochondrial membrane depolarization were assessed by flow cytometry. Expression of drug efflux genes was determined by RT-PCR, and protein expression of drug targets by Western blot.
Results: MCF-7 cells did not express EGFR, p-EGFR, Her-2 or p-Her-2, while BRC-230 were positive for EGFR and p-EGFR only. ERK1/2 was equally expressed in both cell lines, but only BRC-230 were positive for p-ERK1/2. MEK and p-MEK were expressed in both cell lines, albeit more intensively in BRC-230. As expected, based on their drug target expression profiles, gefitinib and lapatinib were found to induce cytocidal effects and mitochondrial membrane depolarization in BRC-230 only, while sorafenib caused apoptosis and loss of mitochondrial potential in both cell lines. All three drugs triggered a rapid and biphasic increase in cytosolic Ca2+ (after a 20 min exposure), and a decline in xenobiotic extrusion pump activity that was independent of efflux gene downregulation. The thapsigargin-induced depletion of endoplasmic reticulum Ca2+ blocked the increase in cytosolic Ca2+, but had no effect on multidrug transporter activity or on mitochondrial membrane depolarization.
Conclusions: Gefitinib, lapatinib and sorafenib induced a rapid increase in cytosolic Ca2+ and mitochondrial membrane depolarization, in addition to blocking drug transporter activity, independently of the expression of specific drug targets and of drug-induced cytotoxicity. These data suggest that TKIs may elicit different molecular mechanisms to those previously reported in the literature. Further research of these pathways is warranted in order to identify new, more effective strategies for cancer treatment.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B262.
Despite the low efficacy of conventional antitumour drugs, chemotherapy remains an essential tool in controlling advanced gastric and oesophageal cancers. We aimed to provide a biological rationale ...based on the sorafenib–taxotere interaction for the clinical treatment of gastric cancer. In vitro experiments were performed on four human gastric cancer cell lines (GK2, AKG, KKP and NCI‐N87). Cytotoxicity was evaluated by sulforhodamine B (SRB) assay, cell cycle perturbations, apoptosis and mitotic catastrophe were assessed by flow cytometric and microscopic analyses, and protein expression was studied by Western blot. In the in vivo experiments, nude mice xenografted with the most resistant line were treated with sorafenib and docetaxel singly or in association. Sorafenib inhibited cell growth (IG50 values ranged from 3.4 to 8.1 μM) and caused down‐regulation of MAP‐K/ERK phosphorylation and of mcl‐1 and p‐bad expression after a 48‐hr exposure. Apoptosis induction was associated with caspase‐3 and ‐9 activation and mitochondrial membrane depolarization. The drug combination enhanced apoptosis (up to 80%) and produced a synergistic interaction when low doses of the taxane preceded administration of the antityrosine kinase. This synergism was probably due to the induction of an anomalous multidiploid G0‐G1 peak and to consequent mitotic catastrophe, which increased sensitivity to sorafenib. Consistent with in vitro results, the docetaxel–sorafenib sequence exhibited high therapeutic efficacy in NCI‐N87 mouse xenografts producing tumour weight inhibition (> 65%), tumour growth delay (up to 25 days) and increased mouse survival (30%). Our findings suggest the potential clinical usefulness of treatment with sorafenib and docetaxel for advanced gastric cancer.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The prognostic relevance of mitotic activity was analyzed in a series of 306 patients with node-negative breast cancer treated with locoregional therapy alone, until early relapse. Mitotic activity ...was evaluated as the number of mitotic figures per 10 high-power fields (mitotic activity index) or per 1000 tumor cells (mitotic index). Counting was carried out blindly by two observers. A high correlation was observed between the two determinations (rs = .96, P < .001). For clinical analysis, three mitotic activity index subgroups (mitotic figures/field ≤ 9, 10–19 and more than 19, according to grading criteria) and three mitotic index subgroups (percentage of mitotic figures less than 0.10, 0.11–0.50 and more than 0.50, according to tertile criteria) were considered. No relation was observed between mitotic variables and 6-year disease-free survival, whereas distant disease-free survival was strongly related to mitotic figures per 10 fields (85%, 89% and 70%, P = .012) and to the percentage of mitotic figures out of a total 1000 tumor cells (87%, 86% and 75%, P = .017). Similarly, both mitotic indices were significantly related to 6-year overall survival (99%, 95% and 77%, P < .001, for mitotic figures per 10 fields and 99%, 93% and 82%, P < .001, for the percentage of mitotic figures). These findings were particularly evident in patients with tumors of 1–2 cm. In conclusion, a high number of mitotic figures is associated with a higher probability of developing distant metastases and a shorter survival. The critical point remains the standardization of the preanalytical and analytical steps within quality control programs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Purpose: The current efficacy of HRPC therapy is disappointing and new agents and therapeutic modalities are urgently required. The aims of the present work were to examine the mechanisms of ...action and the in vitro activity of liposomal doxorubicin in HRPC cell lines.
Methods: Doxorubicin (Doxo) and liposomal Doxo (Myocet®) activity was assessed by SRB test, and apoptosis by TdT assay, in DU145 and DU145-R HRPC cell lines. Intracellular drug incorporation and localization was analyzed by fluorescence image microscopy, CD95 and GD3 expression by cytofluorimetry, and protein marker alterations by Western blot.
Results: Myocet® showed a higher cytotoxic activity than Doxo in both cell lines, particularly in docetaxel-resistant DU145-R cells after a 72-h exposure, with 70% of apoptotic cells at 1/10 of the plasma peak concentration. In addition, cytofluorimetry and fluorescence microscopy revealed that Myocet® achieved higher intracellular concentrations than Doxo. The liposomal anthracycline formulation was found to concentrate primarily in the Golgi apparatus and induced a significant increase in the expression of CD95 death receptor, GD3 ganglioside, and caspase-2 and -3 in both cell lines. Interestingly, Myocet® also induced a stronger Mcl-1 downregulation than Doxo, although this was more pronounced in the parental DU145 cell line.
Conclusions: Myocet® demonstrates a remarkable activity in HRPC cells, particularly in those previously resistant to Doxo, probably due to its high intracellular drug concentration and Golgi localization. Myocet® appears to have two mechanisms of action: a conventional anthracycline-induced DNA damage-dependent apoptosis, and a Golgi-dependent cell death pathway, confirmed by the increase in CD95, GD3 and caspase-2 and -3 expression. Our results strengthen the hypotheses that the Golgi apparatus may act as a stress sensor, and that organelles other than mitochondria may trigger cell death, further proof that combinatorial targeting of diverse cell death pathways may improve the efficacy of anti-cancer strategies. In conclusion, our data advocate further evaluations of Myocet® as a second line treatment for advanced HRPC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A83.
Recovery from hemiplegia is a complex phenomenon that depends on various adaptive processes involving both the affected and the unaffected hemisphere. Our aim in this study was to investigate changes ...in cerebral perfusion in hemiplegic stroke patients during passive movements and their correlation with the subsequent motor recovery. The study included 30 patients with single, subcortical ischemic cerebral lesions. Within 14 days (range 8 to 14 days) from stroke onset, all patients were examined for the effects of passive elbow movements on cerebral blood flow in the middle cerebral arteries (MCAs) by means of bilateral transcranial Doppler (TCD) ultrasonography. On the same day as TCD assessment, they were also evaluated clinically with the Canadian Neurological Scale (CNS) and with Medical Research Council (MRC) scale for motor deficit of the affected arm. A clinical evaluation using the same scales was repeated after two months of motor rehabilitation therapy. We investigated the relationship between changes of Mean Flow Velocity (MFV) during passive movements and degree of recovery after stroke. The logistic regression procedure indicated that out of all factors considered as possibly related to a good clinical motor deficit recovery of the affected arm, evaluated by means of MRC, only the MFV percentage increase played a predictive role. In particular, for each additional point of contralateral MFV percentage increase during passive movement of the affected arm, the relative probability of good clinical recovery increased 5.68 times (95% CI=1.76-18.40; p=0.004). Similar results were found when the clinical recovery was measured by means of the CNS (slope=0.40, p<0.001). Passive movements in hemiplegic stroke patients before clinical recovery elicit activation patterns that may be critical for the restoration of motor function.I n particular, early and consistent activation of the affected hemisphere, as detected with TCD, seems to predict the positive evolution of a motor deficit.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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