Publications (14)97.44 Total impact
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Article: Functional Dissection of Pax3 in Paraxial Mesoderm Development and Myogenesis.
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ABSTRACT: The paired box transcription factor Pax3 is well-known as a major regulator of embryonic myogenesis. Before Pax3 expression becomes restricted to the dermomyotome, this transcription factor is also expressed in the developing somites. The role of Pax3 at this early stage is unclear, in particular because of the scarce frequency of Pax3-positive cells in the early mouse embryo. Inducible gene expression in embryonic stem (ES) cells represents an excellent tool to overcome this limitation, since it can provide large quantities of otherwise rare embryonic populations expressing a factor of interest. Here we used engineered mouse ES cells to perform a functional analysis of Pax3 with the aim to identify the molecular determinants involved in the early functions of this transcription factor. We find that Pax3 induction during embryoid body (EB) differentiation results in the up-regulation of genes expressed in the presomitic and somitic mesoderm. Moreover, we show that paraxial mesoderm induced by transient expression of Pax3 is not irreversibly committed to myogenesis, rather requires sustained Pax3 expression. Using a series of deletion mutants of Pax3, which differentially affect its transcriptional activity, we map protein domains necessary for induction of paraxial mesoderm and induction of the myogenic program. The paired, homeo- and transcriptional activation domains were each required for both processes, however the paired-c-terminal RED domain showed a paraxial mesoderm-specific activity that was dispensable for myogenesis. These findings demonstrate and provide mechanistic insight into an early role for Pax3 in the generation of paraxial mesoderm.Stem Cells 10/2012; · 7.78 Impact Factor -
Article: Effect of endoglin overexpression during embryoid body development.
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ABSTRACT: Increasing evidence points to endoglin (Eng), an accessory receptor for the transforming growth factor-β superfamily commonly associated with the endothelial lineage, as an important regulator of the hematopoietic lineage. We have shown that lack of Eng results in reduced numbers of primitive erythroid colonies as well as downregulation of key hematopoietic genes. To determine the effect of Eng overexpression in hematopoietic development, we generated a doxycycline-inducible embryonic stem cell line. Our results demonstrate that induction of Eng during embryoid body differentiation leads to a significant increase in the frequency of hematopoietic progenitors, in particular, the erythroid lineage, which correlated with upregulation of Scl, Gata1, Runx1, and embryonic globin. Interestingly, activation of the hematopoietic program happened at the expense of endothelial and cardiac cells, as differentiation into these mesoderm lineages was compromised. Eng-induced enhanced erythroid activity was accompanied by high levels of Smad1 phosphorylation. This effect was attenuated by addition of a bone morphogenetic protein (BMP) signaling inhibitor to these cultures. Among the BMPs, BMP4 is well known for its role in hematopoietic specification from mesoderm by promoting expression of several hematopoietic genes, including Scl. Because Scl is considered the master regulator of the hematopoietic program, we investigated whether Scl would be capable of rescuing the defective hematopoietic phenotype observed in Eng(-/-) embryonic stem cells. Scl expression in Eng-deficient embryonic stem cells resulted in increased erythroid colony-forming activity and upregulation of Gata1 and Gata2, positioning Eng upstream of Scl. Taken together, these findings support the premise that Eng modulates the hematopoietic transcriptional network, most likely through regulation of BMP4 signaling.Experimental hematology 06/2012; 40(10):837-46. · 3.11 Impact Factor -
Article: Modulation of TGF-β signaling by endoglin in murine hemangioblast development and primitive hematopoiesis.
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ABSTRACT: Endoglin (Eng), an accessory receptor for the transforming growth factor β (TGF-β) superfamily, is required for proper hemangioblast and primitive hematopoietic development. However the mechanism by which endoglin functions at this early developmental stage is currently unknown. Transcriptional analyses of differentiating eng(-/-) and eng(+/+) ES cells revealed that lack of endoglin leads to profound reductions in the levels of key hematopoietic regulators, including Scl, Lmo2, and Gata2. We also detected lower levels of phosphorylated Smad1 (pSmad1), a downstream target signaling molecule associated with the TGF-β pathway. Using doxycycline-inducible ES cell lines, we interrogated the TGF-β signaling pathway by expressing activated forms of ALK-1 and ALK-5, type I receptors for TGF-β. Our results indicate that ALK-1 signaling promotes hemangioblast development and hematopoiesis, as evidenced by colony assays, gene expression and FACS analyses, whereas signaling by ALK-5 leads to the opposite effect, inhibition of hemangioblast and hematopoietic development. In Eng(-/-) ES cells, ALK-1 rescued both the defective hemangioblast development, and primitive erythropoiesis, indicating that ALK-1 signaling can compensate for the absence of endoglin. We propose that endoglin regulates primitive hematopoiesis by modulating the activity of the Smad1/5 signaling pathway in early stages of development.Blood 05/2011; 118(1):88-97. · 9.90 Impact Factor -
Article: Proline isomerase Pin1 represses terminal differentiation and myocyte enhancer factor 2C function in skeletal muscle cells.
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ABSTRACT: Reversible proline-directed phosphorylation at Ser/Thr-Pro motifs has an essential role in myogenesis, a multistep process strictly regulated by several signaling pathways that impinge on two families of myogenic effectors, the basic helix-loop-helix myogenic transcription factors and the MEF2 (myocyte enhancer factor 2) proteins. The question of how these signals are deciphered by the myogenic effectors remains largely unaddressed. In this study, we show that the peptidyl-prolyl isomerase Pin1, which catalyzes the isomerization of phosphorylated Ser/Thr-Pro peptide bonds to induce conformational changes of its target proteins, acts as an inhibitor of muscle differentiation because its knockdown in myoblasts promotes myotube formation. With the aim of clarifying the mechanism of Pin1 function in skeletal myogenesis, we investigated whether MEF2C, a critical regulator of the myogenic program that is the end point of several signaling pathways, might serve as a/the target for the inhibitory effects of Pin1 on muscle differentiation. We show that Pin1 interacts selectively with phosphorylated MEF2C in skeletal muscle cells, both in vitro and in vivo. The interaction with Pin1 requires two novel critical phospho-Ser/Thr-Pro motifs in MEF2C, Ser(98) and Ser(110), which are phosphorylated in vivo. Overexpression of Pin1 decreases MEF2C stability and activity and its ability to cooperate with MyoD to activate myogenic conversion. Collectively, these findings reveal a novel role for Pin1 as a regulator of muscle terminal differentiation and suggest that Pin1-mediated repression of MEF2C function could contribute to this function.Journal of Biological Chemistry 11/2010; 285(45):34518-27. · 4.77 Impact Factor -
Article: Proline Isomerase Pin1 Represses Terminal Differentiation and Myocyte Enhancer Factor 2C Function in Skeletal Muscle Cells
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ABSTRACT: Reversible proline-directed phosphorylation at Ser/Thr-Pro motifs has an essential role in myogenesis, a multistep process strictly regulated by several signaling pathways that impinge on two families of myogenic effectors, the basic helix-loop-helix myogenic transcription factors and the MEF2 (myocyte enhancer factor 2) proteins. The question of how these signals are deciphered by the myogenic effectors remains largely unaddressed. In this study, we show that the peptidyl-prolyl isomerase Pin1, which catalyzes the isomerization of phosphorylated Ser/Thr-Pro peptide bonds to induce conformational changes of its target proteins, acts as an inhibitor of muscle differentiation because its knockdown in myoblasts promotes myotube formation. With the aim of clarifying the mechanism of Pin1 function in skeletal myogenesis, we investigated whether MEF2C, a critical regulator of the myogenic program that is the end point of several signaling pathways, might serve as a/the target for the inhibitory effects of Pin1 on muscle differentiation. We show that Pin1 interacts selectively with phosphorylated MEF2C in skeletal muscle cells, both in vitro and in vivo. The interaction with Pin1 requires two novel critical phospho-Ser/Thr-Pro motifs in MEF2C, Ser98 and Ser110, which are phosphorylated in vivo. Overexpression of Pin1 decreases MEF2C stability and activity and its ability to cooperate with MyoD to activate myogenic conversion. Collectively, these findings reveal a novel role for Pin1 as a regulator of muscle terminal differentiation and suggest that Pin1-mediated repression of MEF2C function could contribute to this function.Journal of Biological Chemistry 11/2010; 285(45):34518-34527. · 4.77 Impact Factor -
Article: Nuclear localization of cationic solid lipid nanoparticles containing Protamine as transfection promoter.
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ABSTRACT: Protamine has attracted much attention as DNA condenser and nuclear transfer enhancer although the excess of hydrophilicity and the strong DNA pack restrain its potentialities. In order to overcome this limitation, we added Protamine in the composition of solid lipid nanoparticles (SLN-Protamine) and we compared this carrier with the same kind of SLN containing Esterquat 1 instead of Protamine (SLN-EQ1). Carriers cytotoxicity was assessed on COS-I cells evaluating the cell cycle by propidium iodide test, while the transfection efficiency was studied using pEGFP as plasmid model. The cell penetrating activity of Protamine inside the lipid vectors was evaluated studying cell internalization by confocal microscopy using Red Nile-labeled carriers. SLN-Protamine:pDNA showed a mean diameter five-times smaller than the size of SLN-EQ1:pDNA and a remarkably lesser cytotoxicity. Transfection by SLN-Protamine:pDNA was seven-times more effective compared with the Protamine:pDNA polyplexes while no transfection capacity was observed for SLN-EQ1:pDNA complexes due to their inability to be internalized owing to their larger dimension. Red Nile-SLN-Protamine were localized in endocytic-like vesicles into the nuclear membrane suggesting the inclusion of Protamine in nano-lipophilic systems may enhance the reduction in the complex dimensions, the nuclear pDNA translocation and the pDNA release in the cells.European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 11/2010; 76(3):384-93. · 3.15 Impact Factor -
Article: Nfix regulates fetal-specific transcription in developing skeletal muscle.
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ABSTRACT: Skeletal myogenesis, like hematopoiesis, occurs in successive developmental stages that involve different cell populations and expression of different genes. We show here that the transcription factor nuclear factor one X (Nfix), whose expression is activated by Pax7 in fetal muscle, in turn activates the transcription of fetal specific genes such as MCK and beta-enolase while repressing embryonic genes such as slow myosin. In the case of the MCK promoter, Nfix forms a complex with PKC theta that binds, phosphorylates, and activates MEF2A. Premature expression of Nfix activates fetal and suppresses embryonic genes in embryonic muscle, whereas muscle-specific ablation of Nfix prevents fetal and maintains embryonic gene expression in the fetus. Therefore, Nfix acts as a transcriptional switch from embryonic to fetal myogenesis.Cell 02/2010; 140(4):554-66. · 32.40 Impact Factor -
Article: Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT.
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ABSTRACT: To predict acute Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer (EORTC) and Subjective Objective Signs Management and Analysis/Late Effect of Normal Tissue (SOMA/LENT) toxicities of the lower gastrointestinal (LGI) syndrome in patients with prostate cancer undergoing three-dimensional conformal radiotherapy using a tool (nomogram) that takes into account clinical and dosimetric variables that proved to be significant in the Italian Association for Radiation Oncology (AIRO) Group on Prostate Cancer (AIROPROS) 0102 trial. Acute rectal toxicity was scored in 1,132 patients by using both the RTOG/EORTC scoring system and a 10-item self-assessed questionnaire. Correlation between clinical variables/dose-volume histogram constraints and rectal toxicity was investigated by means of multivariate logistic analyses. Multivariate logistic analyses results were used to create nomograms predicting the symptoms of acute LGI syndrome. Mean rectal dose was a strong predictor of Grade 2-3 RTOG/EORTC acute LGI toxicity (p = 0.0004; odds ratio (OR) = 1.035), together with hemorrhoids (p = 0.02; OR = 1.51), use of anticoagulants/antiaggregants (p = 0.02; OR = 0.63), and androgen deprivation (AD) (p = 0.04; OR = 0.65). Diabetes (p = 0.34; OR = 1.28) and pelvic node irradiation (p = 0.11; OR = 1.56) were significant variables to adjust toxicity prediction. Bleeding was related to hemorrhoids (p = 0.02; OR = 173), AD (p = 0.17; OR = 0.67), and mean rectal dose (p = 0.009; OR = 1.024). Stool frequency was related to seminal vesicle irradiation (p = 0.07; OR = 6.46), AD administered for more than 3 months (p = 0.002; OR = 0.32), and the percent volume of rectum receiving more than 60 Gy (V60Gy) V60 (p = 0.02; OR = 1.02). Severe fecal incontinence depended on seminal vesicle irradiation (p = 0.14; OR = 4.5) and V70 (p = 0.033; OR = 1.029). To the best of our knowledge, this work presents the first set of nomograms available in the literature specific to symptoms of LGI syndrome and provides clinicians with a tailored probability of the specific outcome. Validation of the tool is in progress.International Journal of Radiation OncologyBiologyPhysics 08/2008; 71(4):1065-73. · 4.11 Impact Factor -
Article: Differentiation-dependent lysine 4 acetylation enhances MEF2C binding to DNA in skeletal muscle cells.
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ABSTRACT: Myocyte enhancer factor 2 (MEF2) proteins play a key role in promoting the expression of muscle-specific genes in differentiated muscle cells. MEF2 activity is regulated by the association with several transcriptional co-factors and by post-translational modifications. In the present report, we provide evidence for a novel regulatory mechanism of MEF2C activity, which occurs at the onset of skeletal muscle differentiation and is based on Lys4 acetylation. This covalent modification results in the enhancement of MEF2C binding to DNA and chromatin. In particular, we report that the kinetic parameters of MEF2/DNA association change substantially upon induction of differentiation to give a more stable complex and that this effect is mediated by Lys4 acetylation. We also show that Lys4 acetylation plays a prominent role in the p300-dependent activation of MEF2C.Nucleic Acids Research 03/2008; 36(3):915-28. · 8.03 Impact Factor -
Article: Predictors for rectal and intestinal acute toxicities during prostate cancer high-dose 3D-CRT: results of a prospective multicenter study.
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ABSTRACT: To find predictors for rectal and intestinal acute toxicity in patients with prostate cancer treated with > or =70 Gy conformal radiotherapy. Between July 2002 and March 2004, 1,132 patients were entered into a cooperative study (AIROPROS01-02). Toxicity was scored using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer scale and by considering the changes (before and after treatment) of the scores of a self-administered questionnaire on rectal/intestinal toxicity. The correlation with a number of parameters was assessed by univariate and multivariate analyses. Concerning the questionnaire, only moderate/severe complications were considered. Of 1,132 patients, 1,123 were evaluable. Of these patients, 375, 265, and 28 had Grade 1, 2, and 3 Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity, respectively. The mean rectal dose was the most predictive parameter (p = 0.0004; odds ratio, 1.035) for Grade 2 or worse toxicity, and the use of anticoagulants/antiaggregants (p = 0.02; odds ratio, 0.63) and hormonal therapy (p = 0.04, odds ratio, 0.65) were protective. The questionnaire-based scoring revealed that a greater mean rectal dose was associated with a greater risk of bleeding; larger irradiated volumes were associated with frequency, tenesmus, incontinence, and bleeding; hormonal therapy was protective against frequency and tenesmus; hemorrhoids were associated with a greater risk of tenesmus and bleeding; and diabetes associated highly with diarrhea. The mean rectal dose correlated with acute rectal/intestinal toxicity in three-dimensional conformal radiotherapy for prostate cancer, and hormonal therapy and the use of anticoagulants/antiaggregants were protective. According to the moderate/severe injury scores on the self-assessed questionnaire, several clinical and dose-volume parameters were independently predictive for particular symptoms.International Journal of Radiation OncologyBiologyPhysics 05/2007; 67(5):1401-10. · 4.11 Impact Factor -
Article: A multicenter study of the prognosis and treatment of adult brain ependymal tumors.
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ABSTRACT: The current analysis of outcomes in a large series of adult patients with intracranial ependymal tumors contributes to the characterization of the primary prognostic factors and to the therapeutic management of this rare disease, for which limited information is available in the literature. The authors analyzed data on patient and tumor characteristics, treatment, and survival in a series of 70 patients age > 17 years with pathologic diagnoses of brain ependymal tumors from 4 institutions. The 5- and 10-year overall survival (OS) rates (+/- standard errors) were 67% +/- 6% and 50% +/- 8%, respectively. The 5- and 10-year failure-free survival (FFS) rates were 43% +/- 7% and 24% +/- 6%, respectively. Younger age and infratentorial tumor location were associated with longer survival. Among patients with Grade 2 ependymoma (n = 51), 21 (41%) received no postsurgical treatment. These 21 patients had a 5-year OS rate of 78% +/- 10% and a 10-year OS rate of 68% +/- 13%; the 5- and 10-year FFS rates for these patients were 47% +/- 12% and 12% +/- 11%, respectively. Twenty-six patients with Grade 2 ependymoma (51%) received postoperative radiotherapy (RT). These 26 patients had a 5-year OS rate of 71% +/- 9% and a 10-year OS rate of 59% +/- 11%; the 5- and 10-year FFS rates for these patients were 54% +/- 10% and 34% +/- 10%, respectively. Among patients with Grade 2 ependymoma, neither OS nor FFS differed significantly between those who did not receive postoperative RT and those who did; however, these two groups were heterogeneous with respect to prognostic factors. On multivariate analysis, RT use exhibited a trend toward improved OS and was significantly predictive of improved FFS. The current analysis does not rule out the possibility that deferral of RT at the time of recurrence could have a detrimental effect on FFS or OS in patients with Grade 2 ependymoma, regardless of the degree of ablation. The role of postoperative RT for patients who undergo imaging-based macroscopic total resection remains to be addressed.Cancer 03/2004; 100(6):1221-9. · 4.77 Impact Factor -
Article: Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.
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ABSTRACT: Accurate modeling of late rectal reactions needs the collection of individual 3D dose-volume data (i.e. DVH) as well as clinical information of large cohorts of patients. The possibility of collecting a large number of patients with many different dose-volume combinations is very suitable for this purpose. The purpose of the study is to search for significant correlation between dose-volume histograms/dose statistics of the rectum and late rectum bleeding. Data from three institutions for 402 patients previously treated for prostate cancer with three to four field techniques, were retrospectively pooled and were collected with a number of clinical and physical parameters, including DVHs of the rectum (including filling). Patients with large air/fecal content in the rectum during planning computerized tomography (CT) scan were excluded from the analysis (n = 74). Out of 328 patients, 229 patients received an ICRU dose between 70 and 76Gy and the current analysis is referred to this subgroup of patients (median follow up: 30 months, range: 12-85 months). Out of these 229 patients, 189 patients were treated with conformal techniques. Rectum was contoured from the anal verge up to the sigmoid flessure by one observer for each institution. Dosimetric and contouring consistencies between the three institutions were previously investigated and the impact on DVHs was found to be quite modest for the purposes of the study. Median/quartile values of all parameters were considered as cut-off values for statistical analysis. We considered as bleeders those patients who experienced grades II-III late bleeding (modified RTOG scoring scale). Twenty two of 229 patients experienced > or =grade II late bleeding (30 months actuarial incidence: 10.7%). Significant correlation between a number of parameters and late bleeding was found (log-rank test). With regard to DVH, all median and third quartile values for V50-V70 were found to be significantly associated with an increased risk of rectal bleeding, if excepting the median value of V70. Based on the results of univariate analysis, the patients were divided into two groups: 'high risk', with at least one value above quartiles in the range V50-V60 (V50: 70%, V55: 64%, V60: 55%); 'low risk', the remaining patients. The 30 months actuarial rates of bleeding were 19.2 and 5.9% for the 'high' and the 'low' risk group, respectively (P = 0.0003 log-rank test). A multivariate analysis (Cox regression model) including 'DVH grouping' and the main remaining variables (age, previous prostatectomy, diabetes, hypertension, adjuvant hormonal therapy, rectum volume and ICRU dose) showed that 'DVH grouping' is the most predictive parameter (P = 0.005) together with adjuvant hormonal therapy (P = 0.025) and ICRU dose (P = 0.06). Our data confirm the role of the rectal DVH in separating groups of patients having prostate radiotherapy in low and high risk of developing late bleeding. Based on these results, V50 below 60-65% and V60 below 50-55% seem to be the robust cut-off values to keep the risk of developing late rectal bleeding reasonably low. However, due to the 'heterogeneity' of the considered population, the results found should be applied with caution in 'more homogeneous' groups of patients. The association of adjuvant hormone deprivation seems to be associated with an increased risk of rectal toxicity; the mechanism for this effect should be a focus of further research.Radiotherapy and Oncology 08/2002; 64(1):1-12. · 5.58 Impact Factor -
Article: Practice patterns for prostate cancer in nine central and northern Italy radiation oncology centers: a survey including 1759 patients treated during two decades (1980-1998).
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ABSTRACT: Prostate cancer patients in Italy are offered the choice of the full spectrum of possible treatment options for their disease, but the diffusion of the more recent technological refinements among the Radiation Oncology centers is not homogeneous and there is a need to establish a reference "historical" data source. This retrospective study describes the changing patterns in prostate cancer patient practice and the therapeutic results obtained in nine Radiation Oncology centers of Northern and Central Italy (five in Northern Italy and four in Central Italy). A total of 1759 prostate cancer patients, radically treated in the nine radiotherapy (RT) centers between 1980 and 1998, made up the study population. Data collected for each patient included clinical, pathologic, therapeutic features, and toxicity. The overall survival, disease-specific survival (DSS), and clinical relapse-free survival (RFS) were calculated for the whole series and for the subsets of patients defined by different clinical, pathologic, and therapeutic features, according to three accrual periods (A, 1980-1990; B, 1991-1994; and C, 1995-1998). Univariate and multivariate analyses were performed to identify prognostic factors related to survival and late adverse effects (cystitis and proctitis) probability. Patient accrual increased markedly during the 2 decades considered, and the percentage of cases with Stage C or D disease dropped from 49% (period A) to 43% (period B) to 37% (period C) (p < 0.0001, chi-square). The baseline prostate-specific antigen value was available for 10%, 76%, and 95% of the cases treated in the three different periods. The major changes in the therapeutic options were an increase in dose to the prostate (>66 Gy in 44%, 84%, and 93% of the patients treated in period A, B, and C, respectively); a reduction in treated volumes, including pelvic lymphatic drainage (56-39% before 1995, 22% thereafter); and an increase in cases treated in association with hormonal therapy (50% before 1991, 80% thereafter). Lower energy (<10 MV) photon beams were progressively abandoned (12% before 1990 vs. 6-7% thereafter), along with an increase in the use of blocks (60% in the last 4 years of the study vs. about 30-40% before 1995) and "conformal" RT (applied in 41% of cases treated after 1994). The actuarial RFS, DSS, and overall survival rate at 5 years was, respectively, 60% +/- 2%, 75% +/- 2%, 66% +/- 2% for period A; 74% +/- 2%, 90% +/- 1%, 83% +/- 2%, for period B; and 67% +/- 5%, 90% +/- 2%, 79% +/- 5% for period C. The actuarial overall survival, DSS, and RFS rate for the whole series of 1759 patients was 77% +/- 1%, 86% +/- 1%, and 68% +/- 1% at 5 years, respectively. Multivariate analysis showed that only American Urologic Association stage, grade, dose to the prostate, accrual period, association with hormonal treatment after (or both after and before) RT (only in terms of DSS and RFS), and baseline prostate-specific antigen value (only for RFS) retained prognostic significance in the final Cox model. The increase in the accrual of prostate cancer patients radically treated with RT has been accompanied by considerable changes in the clinical features at presentation, as well as in the staging and treatment procedures. Patients treated more recently had better survival results. An earlier stage and more favorable grade were linked with better overall, DSS, and RFS at multivariate analysis. Lower prostate-specific antigen baseline values were also related to better RFS. Better results were obtained with higher radiation doses, and the dose to tumor seemed the most important treatment-related prognostic factor. The toxicity (cystitis and proctitis, every Radiation Therapy Oncology Group grade) was substantially the same in the different accrual periods, but larger treated volumes and higher doses appeared to increase the incidence of late effects.International Journal of Radiation OncologyBiologyPhysics 05/2002; 52(5):1310-9. · 4.11 Impact Factor -
Article: Hyperfractionated radiotherapy for T2N0 glottic carcinoma: a retrospective analysis at 10 years follow-up in a series of 60 consecutive patients.
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ABSTRACT: To report results of hyperfractionated radiotherapy for T2N0 glottic carcinoma at a single institution after extended follow-up. Between 1980 and 1988 at Varese University Hospital, 60 consecutive patients with T2N0 glottic carcinoma received exclusive radiotherapy consisting of 1.5 Gy/fraction twice a day. Treatment gaps during the radiotherapy course were allowed according to individual tolerance. This policy resulted in a wide range of elapsed treatment time: median, 5.7 weeks; range, 3.7-8.9. Median follow-up is 9.8 years. As a result of dose/time distribution, 16, 20 and 24 patients received an average weekly dose rate of <10 Gy/week, equal to 10 Gy/week or >10 Gy/week, respectively. Mean total dose for each group was 62.8 Gy, 63.7 Gy and 63.8 Gy, respectively. Five-year local-regional control was 69 +/- 6% (95% CI); ultimate local-regional control, including salvage surgery, was 78 +/- 5%. All failures were at the primary site, and no patient developed neck recurrence as first site of failure. The actuarial incidence of grade 2-3 late reactions at 5 years was 42 +/- 6%. Most late toxicity events were grade 2: only 2 patients developed grade 3 reactions and none grade 4. None of the several clinical and treatment-related variables showed any statistically significant impact on local-regional control or late toxicity at univariate and multivariate analysis. In particular, 3-year local-regional control rates were 73 +/- 11%, 84 +/- 8% and 69 +/- 10% for an average weekly dose rate of <10 Gy/week, equal to 10 Gy/week and >10 Gy/week, respectively (not significantly different). At a very long follow-up, the hyperfractionated regimen tested in the study was shown to be effective and devoid of major complications, provided individual patient acute tolerance is carefully taken into account. Also, time factor did not affect outcome in this series.Tumori 90(3):317-23. · 0.86 Impact Factor
Top co-authors
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Institutions
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2011–2012
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University of Minnesota Twin Cities
- Department of Medicine
Minneapolis, MN, USA
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2008–2010
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Università degli Studi di Modena e Reggio Emilia
Modena, Emilia-Romagna, Italy
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