Drug-induced Liver Injury in Latin America: 10-year Experience of the Latin American DILI (LATINDILI) Network.

BACKGROUND & AIMS: Latin America is a region of great interest for studying the clinical presentation of idiosyncratic drug-induced liver injury (DILI). A comprehensive analysis of patients enrolled into the LATINDILI Network over a decade is presented. METHODS: Demographics, clinical presentation, histological findings and outcome of prospectively recruited DILI cases in the LATINDILI Network were analyzed. Suspected culprit drugs were classified according to the Anatomical Therapeutic Chemical classification. Causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) scale. RESULTS: Overall, 468 idiosyncratic DILI cases were analyzed (62% women; mean age, 49 years). Hepatocellular injury predominated (62%); jaundice was present in 60% of patients, and 42% were hospitalized. Of the cases, 4.1% had a fatal outcome, and 24 patients (12%) developed chronic DILI. The most common drug classes were systemic anti-infectives (31%), musculoskeletal agents (12%), antineoplastic and immunomodulating agents (11%), and herbal and dietary supplements (9%). Notably, none of the patients with DILI due to antibacterials or immunosuppressants had a fatal outcome. In fact, Hy's law showed to have drug-specific predictive value, with anti-tuberculosis drugs, nimesulide, and herbal and dietary supplements associated with the worst outcome, whereas DILI caused by amoxicillin-clavulanate, nitrofurantoin, and diclofenac, which fulfilled Hy's law, did not have a fatal outcome. CONCLUSION: Features of DILI in Latin America are comparable to other prospective registries. However, the pattern of drugs responsible for DILI differs. An increasing incidence of herbal and dietary supplements, with high mortality rate, and likewise, nimesulide and nitrofurantoin, was noted. Thus, public health policies should raise awareness of the potential adverse effects of these compounds.

Characterisation of a Silicon Photomultiplier Based Oncological Brachytherapy Fibre Dosimeter.

Source localisation and real-time dose verification are at the forefront of medical research in brachytherapy, an oncological radiotherapy procedure based on radioactive sources implanted in the patient body. The ORIGIN project aims to respond to this medical community's need by targeting the development of a multi-point dose mapping system based on fibre sensors integrating a small volume of scintillating material into the tip and interfaced with silicon photomultipliers operated in counting mode. In this paper, a novel method for the selection of the optimal silicon photomultipliers to be used is presented, as well as a laboratory characterisation based on dosimetric figures of merit. More specifically, a technique exploiting the optical cross-talk to maintain the detector linearity in high-rate conditions is demonstrated. Lastly, it is shown that the ORIGIN system complies with the TG43-U1 protocol in high and low dose rate pre-clinical trials with actual brachytherapy sources, an essential requirement for assessing the proposed system as a dosimeter and comparing the performance of the system prototype against the ORIGIN project specifications.

IL28B gene polymorphism rs12979860, but not rs8099917, contributes to the occurrence of chronic HCV infection in Uruguayan patients.

BACKGROUND: Host single-nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) locus are associated with sustained virological response to antiviral therapy and with spontaneous Hepatitis C Virus (HCV) clearance. Prevalence of these SNPs varies depending on ethnicity. The impact of IL28B SNPs in HCV-infected patients is currently unknown in Uruguay. Therefore, the aim of this study was to evaluate and compare the distribution of polymorphisms in the IL28B gene (rs12979860 and rs8099917) among HCV-infected patients and healthy individuals in Uruguay and thus assess their possible association with the establishment of HCV infection. METHODS: DNA was recovered from 92 non-infected individuals and 78 HCV-infected patients and SNPs were determined by RFLP and allelic discrimination by real-time PCR. RESULTS: The distribution of rs12979860 genotypes for the infected population was 29.5%-CC, 47.4%-CT and 23.1%-TT and for the control group 45.7%, 42.4% and 11.9%, respectively. Prevalence in both infected and uninfected individuals is similar to that reported in other countries with admixed populations. The distribution of rs8099917 genotypes for the infected population was 57.7%-TT, 27.2%-TG and 14.1%-GG and for the control group 60.9%, 33.7% and 5.4%, respectively. The comparison of rs12979860 genotype distribution between the two populations evidenced a higher prevalence of the favourable genotype (CC) in the uninfected control group (p < 0.05). Additionally, results generated using logistic regression analysis show that individuals carrying rs12979860-TT or CT genotypes have a higher likelihood of developing chronic hepatitis upon infection with HCV, when compared to CC carriers, considering rs8099917 genotype as constant. CONCLUSION: Patients with HCV infection have a statistically significant lower prevalence of the favourable rs12979860 genotype when compared to uninfected individuals; therefore we can establish that only IL28B rs12979860-CT and TT genotypes seem to contribute to the occurrence of chronic HCV infection in the cohort of Uruguayan population studied. Considering that a trend towards a higher frequency of "good" response genotypes was observed in responder patients, we believe that IL28B rs12979860 genotyping could be a useful tool for predicting different therapies outcome, including in the DAA era.

[Effectiveness of pegylated interferon alfa 2a and ribavirin for chronic hepatitis C in clinical practice]. / Efectividad del interferón peguilado alfa 2a más ribavirina para la hepatitis crónica C en la práctica.

BACKGROUND: Nowadays, combination therapy with peginteferon plus ribavirin is the standard treatment for chronic hepatitis C. This scheme achieves, according to randomized and controlled trials, viral eradication in 54% to 56% of treated patients (42% to 46% of patients infected with genotype 1 and 76% to 82% of those with genotypes 2 or 3). OBJECTIVE: To evaluate the effectiveness of combined treatment with peginteferon alpha 2a and ribavirin for chronic hepatitis C, in daily clinical practice. PATIENTS AND METHODS: All patients with chronic hepatitis C who were treated by the authors with combined treatment (peginteeferon alpha 2a plus ribavirin), from January 2001 to July 2008, were included. Patients who completed the treatment as well as those that ended it earlier were included in the analysis. RESULTS: In this retrospective and multicentric study 75 patients with chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were enrolled (male gender represented 60%, average age was 42.3 years, genotype 1 meant 58.6% and 31.5% of patients had cirrhosis). The global sustained virological response, according to intention-to-treat analysis, was observed in 37 patients (49%). CONCLUSIONS: The global results in daily clinical practice showed a viral eradication rate close to that published by controlled and randomized studies.

Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: preliminary results of a multicenter prospective study.

PURPOSE: To assess the predictors of late rectal toxicity in a prospectively investigated group of patients treated at 70-80 Gy for prostate cancer (1.8-2 Gy fractions) with three-dimensional conformal radiotherapy. METHODS AND MATERIALS: A total of 1,132 patients were entered into the study between 2002 and 2004. Three types of rectal toxicity, evaluated by a self-administered questionnaire, mainly based on the subjective objective management, analytic late effects of normal tissue system, were considered: stool frequency/tenesmus/pain, fecal incontinence, and bleeding. The data from 506 patients with a follow-up of 24 months were analyzed. The correlation between a number of clinical and dosimetric parameters and Grade 2 or greater toxicity was investigated by univariate and multivariate (MVA) logistic analyses. RESULTS: Of the 1,132 patients, 21, 15, and 30 developed stool frequency/tenesmus/pain, fecal incontinence, and bleeding, respectively. Stool frequency/tenesmus/pain correlated with previous abdominal/pelvic surgery (MVA, p=0.05, odds ratio [OR], 3.3). With regard to incontinence, MVA showed the volume receiving>or=40 Gy (V40) (p=0.035, OR, 1.037) and surgery (p=0.02, OR, 4.4) to be the strongest predictors. V40 to V70 were highly predictive of bleeding; V70 showed the strongest impact on MVA (p=0.03), together with surgery (p=0.06, OR, 2.5), which was also the main predictor of Grade 3 bleeding (p=0.02, OR, 4.2). CONCLUSIONS: The predictive value of the dose-volume histogram was confirmed for bleeding, consistent with previously suggested constraints (V50<55%, V60<40%, V70<25%, and V75<5%). A dose-volume histogram constraint for incontinence can be suggested (V40<65-70%). Previous abdominal/pelvic surgery correlated with all toxicity types; thus, a modified constraint for bleeding (V70<15%) can be suggested for patients with a history of abdominal/pelvis surgery, although further validation on a larger population with longer follow-up is needed.

Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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). CONCLUSIONS: 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.

Predictors for rectal and intestinal acute toxicities during prostate cancer high-dose 3D-CRT: results of a prospective multicenter study.

PURPOSE: To find predictors for rectal and intestinal acute toxicity in patients with prostate cancer treated with > or =70 Gy conformal radiotherapy. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSION: 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.

Rectum contouring variability in patients treated for prostate cancer: impact on rectum dose-volume histograms and normal tissue complication probability.

BACKGROUND: Recent investigations showed some correlation between three-dimensional (3D) treatment planning dose-volume data (dose-volume histograms: DVH, dose statistics) and rectal toxicity for patients treated for prostate cancer. However, no data are available about the possible impact of inter-institute variability in contouring the rectum, so that the possibility of reliably using information from single-centre studies remains doubtful. PURPOSE: Within a retrospective three-institutes study on correlation between dose-volume treatment planning data and rectum bleeding in patients treated for prostate cancer, an investigation about the impact of inter- and intra-observer variability in contouring the rectum was performed. MATERIALS AND METHODS: Ten patients were considered for a dummy run exercise and three observers (one per Institute) contoured the rectum (including filling). An anatomically based definition of rectum extension was previously accepted by the three observers. Six of the ten patients were randomly chosen in the subgroup of patients (large spacing, LS) with a distance between computed tomography (CT) slices (outside the prostate region) equal to 10 mm; for the remaining four patients the distance between CT slices was 5 mm over the whole rectum volume (small spacing, SS). The original 3D treatment planning was recovered on the Cadplan treatment planning system for each patient and rectum dose statistics (mean, median and maximum rectum dose), volume, DVH and NTCP values were calculated for each observer. For DVH analysis, the values of V(50), V(55), V(60), V(65) and V(70) (defined as the % of rectum volume receiving at least 50, 55, 60, 65, 70 Gy) were considered. Normal tissue complication probabilities (NTCPs) were calculated for the original ICRU dose and for a 75.6 Gy ICRU dose (NTCP and NTCP(75.6), respectively). Intra-observer variability was investigated by asking the observers to redraw the same rectum contours 6 months later and comparing the two contouring sessions. RESULTS: In general, a good agreement was found for most patients and, in particular, for all SS patients. The impact of inter-observer variability was quite significant on dose statistics and DVH in two of six LS patients. Looking at the patient population, some systematic deviations, even if quite small, were demonstrated between institute B and institute C (volume, P = 0.02) and between institute A and institute B (mean/median dose, V(50)-V(65), NTCP(75.6); P < 0.05). Four of six LS patients (0/4 in the SS group) presented a maximum difference among observers at the cranial and/or caudal limit of the rectum equal to 1 cm. For these patients, inter-observer variability was significantly higher than for the others (P < 0.03). When inter-observer variability was expressed in terms of standard deviations (SD), values around 2-3 Gy and 0.5 Gy for LS and SS patients, respectively, were found for mean/median dose; values around 3-4% and 0.5-2% for LS and SS patients, respectively, were found for V(50)-V(70). The average SD for NTCP and NTCP(75.6) were 0.4 and 0.6%, respectively (0.5 and 0.9% for LS patients; 0.2 and 0.3% for SS patients). Intra-observer variability was found to be lower than inter-observer variability even if the impact on dose statistics and DVH was visible. CONCLUSIONS: Once a robust definition of rectum is assessed, inter- and intra-institute variability in contouring the rectum appear relatively modest. However, the results suggest that the number of LS patients in DVH correlation studies should be as low as possible; the low number of these patients in the multi-centric trial involving our institutions should not have significant impact on the results of the study.

Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions.

BACKGROUND: 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. 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. MATERIALS AND METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Long term rectal function after high-dose prostatecancer radiotherapy: results from a prospective cohort study.

PURPOSE: To prospectively evaluate long-term late rectal bleeding (lrb) and faecal incontinence (linc) after high-dose radiotherapy (RT) for prostate cancer in the AIROPROS 0102 population, and to assess clinical/dosimetric risk factors. MATERIALS AND METHODS: Questionnaires of 515 patients with G0 baseline incontinence and bleeding scores (follow-up ≥6 years) were analysed. Correlations between lrb/linc and many clinical and dosimetric parameters were investigated by univariate and multivariate logistic analyses. The correlation between lrb/linc and symptoms during the first 3 years after RT was also investigated. RESULTS: Of 515 patients lrb G1, G2 and G3 was found in 32 (6.1%), 2 (0.4%) and 3 (0.6%) patients while linc G1, G2 and G3 was detected in 50 (9.7%), 3 (0.6%) and 3 (0.6%), respectively. The prevalence of G2-G3 lrb events was significantly reduced compared to the first 3-years (1% vs 2.7%, p=0.016) ≥G1 lrb was significantly associated with V75 Gy (OR=1.07). In multivariate analysis, ≥G1 linc was associated with V40 Gy (OR=1.015), use of antihypertensive medication (OR=0.38), abdominal surgery before RT (OR=4.7), haemorrhoids (OR=2.6), and G2-G3 acute faecal incontinence (OR=4.4), a nomogram to predict the risk of long-term ≥G1 linc was proposed. Importantly, the prevalence of ≥G1 linc was significantly correlated with the mean incontinence score during the first 3 years after RT (OR=16.3). CONCLUSIONS: Long-term (median: 7 years) rectal symptoms are prevalently mild and strongly correlated with moderate/severe events occurring in the first 3 years after RT. Linc was associated with several risk factors.

Twenty years of radiobiology in clinical practice: the Italian contribution.

AIMS AND BACKGROUND: To present the Italian state-of-the-art contribution to radiobiology of external beam radiotherapy, brachytherapy, and radionuclide radiotherapy. METHODS AND STUDY DESIGN: A survey of the literature was carried out, using PubMed, by some independent researchers of the Italian group of radiobiology. Each paper was reviewed by researchers of centers not comprising its authors. The survey was limited to papers in English published over the last 20 years, written by Italian investigators or in Italian institutions, excluding review articles. RESULTS: A total of 135 papers have been published in journals with an impact factor, with an increase in the number of published papers over time, for external beam radiotherapy rather than radionuclide radiotherapy. The quantity and quality of the papers researched constitutes a proof of the enduring interest in clinical radiobiology among Italian investigators. CONCLUSIONS: The survey could be useful to individuate expert partners for an Italian network on clinical radiobiology, addressing future collaborative investigations.

Increasing the risk of late rectal bleeding after high-dose radiotherapy for prostate cancer: the case of previous abdominal surgery. Results from a prospective trial.

PURPOSE: To evaluate and discuss the role of specific types of abdominal surgery (SURG) before radical radiation therapy as a risk factor for late rectal toxicity in prostate cancer patients. METHODS: Results concerning questionnaire-based scored late bleeding and faecal incontinence in 718 patients with a complete follow-up of 36 months were analysed, focusing on the impact of specific pre-radiotherapy abdominal/pelvic surgery procedures. Patients were accrued in the prospective study AIROPROS 0102. Different types of surgery (rectum-sigma resection, kidney resection, cholecystectomy or appendectomy) were considered as covariates together with a number of different parameters previously found to be predictive of late toxicity and including clinical as well as dosimetric parameters. Univariate (UVA) and multivariate (MVA) logistic analyses were carried out. RESULTS: In total 69/718 patients were previously submitted to one or more surgical procedures, mostly cholecystectomy (n=21) and appendectomy (n=27). Actuarial incidences of G2-G3 and G3 bleeding were 52 (7.2%) and 24 (3.3%) respectively; 19 (2.6%) chronic incontinence events were registered. Cholecystectomy was found to be highly correlated with late rectal bleeding at UVA: OR=4.3 and p=0.006 for G2-G3 and OR=5.4 and p=0.01 for G3. Considering MVA (including dosimetric and clinical factors), G2-G3 bleeding was significantly correlated to cholecystectomy (OR=6.5, p=0.002), V75 Gy (OR=1.074, p=0.003) and secondarily with appendectomy (OR=2.7, p=0.10), presence of acute radioinduced rectal bleeding (OR=1.70, p=0.21) and androgen deprivation (OR=0.67, p=0.25). Appendectomy (OR=5.9, p=0.004) and cholecystectomy (OR=5.5, p=0.016) were very strong predictors of G3 bleeding with V75 Gy playing a less significant role (OR=1.037, p=0.26). Conversely, no specific surgery was correlated with actuarial or chronic incontinence. CONCLUSIONS: This analysis highlights previous SURG as the best predictor of late rectal bleeding. Among the different types of abdominal surgery, cholecystectomy and appendectomy play the major role, especially for severe late bleeding.

Is it time to tailor the prediction of radio-induced toxicity in prostate cancer patients? Building the first set of nomograms for late rectal syndrome.

PURPOSE: Development of user-friendly tools for the prediction of single-patient probability of late rectal toxicity after conformal radiotherapy for prostate cancer. METHODS AND MATERIALS: This multicenter protocol was characterized by the prospective evaluation of rectal toxicity through self-assessed questionnaires (minimum follow-up, 36 months) by 718 adult men in the AIROPROS 0102 trial. Doses were between 70 and 80 Gy. Nomograms were created based on multivariable logistic regression analysis. Three endpoints were considered: G2 to G3 late rectal bleeding (52/718 events), G3 late rectal bleeding (24/718 events), and G2 to G3 late fecal incontinence (LINC, 19/718 events). RESULTS: Inputs for the nomogram for G2 to G3 late rectal bleeding estimation were as follows: presence of abdominal surgery before RT, percentage volume of rectum receiving >75 Gy (V75Gy), and nomogram-based estimation of the probability of G2 to G3 acute gastrointestinal toxicity (continuous variable, which was estimated using a previously published nomogram). G3 late rectal bleeding estimation was based on abdominal surgery before RT, V75Gy, and NOMACU. Prediction of G2 to G3 late fecal incontinence was based on abdominal surgery before RT, presence of hemorrhoids, use of antihypertensive medications (protective factor), and percentage volume of rectum receiving >40 Gy. CONCLUSIONS: We developed and internally validated the first set of nomograms available in the literature for the prediction of radio-induced toxicity in prostate cancer patients. Calculations included dosimetric as well as clinical variables to help radiation oncologists predict late rectal morbidity, thus introducing the possibility of RT plan corrections to better tailor treatment to the patient's characteristics, to avoid unnecessary worsening of quality of life, and to provide support to the patient in selecting the best therapeutic approach.

Clinical and dosimetric predictors of late rectal toxicity after conformal radiation for localized prostate cancer: results of a large multicenter observational study.

PURPOSE: Assessing the predictors of late rectal toxicity after high-dose conformal radiotherapy for prostate cancer. METHODS: One thousand one hundred thirty-two patients entered a prospective observational multicentric study; late rectal toxicity was evaluated by a self-reported questionnaire. Results concerning bleeding and faecal incontinence of 718/1132 patients with a complete follow-up at 36 months were analysed. The correlation between a number of clinical-dosimetric parameters and moderate/severe toxicity was investigated by univariate and multivariate logistic analyses. RESULTS: Fifty-two (7.2%) and 57/718 (7.9%) patients were scored as moderate/severe bleeders and faecal incontinents, respectively; 19/57 incontinent patients showed persistent incontinence at 36 months. Bleeding was mainly correlated with V75 Gy while severe bleeding was mainly correlated with the previous abdominal/pelvic surgery; a different rectal dose-volume relationship in the two groups of patients (with/without surgery) was found. Moderate/severe acute toxicity was weakly correlated to late bleeding. The best predictor of faecal incontinence was acute toxicity (OR=4 and 7 for chronic and actuarial incontinence, respectively). CONCLUSION: The application of rectal dose-volume constraints limited the incidence of rectal bleeding. The risk of bleeding may be further reduced by limiting V75 Gy<5% and, in the case of patients previously submitted to abdominal/pelvic surgery, V70 Gy<15-20%. Faecal incontinence seems to be mainly a consequential effect after acute toxicity.

Características clínicas de presentación y evolutivas de una cohorte de 48 pacientes con enfermedad de Crohn en Uruguay

Objetivo: describir las características clínicas y evolutivas de una cohorte de pacientes con enfermedad de Crohn (EC). Material y método: se analizó en forma retrospectiva y prospectiva una cohorte de 48 pacientes con EC, que iniciaron su enfermedad entre 1951 y 2003, procedentes de la asistencia pública y privada, de Montevideo y del interior, asistidos por los autores en al menos una oportunidad al 30 de juniode 2003. Con los datos de las historias clínicas se confeccionó un registro con las variables: sexo, edad de inicio, antecedentes familiares de enfermedad inflamatoria, resección intestinal y mortalidad. Resultados: 50 porciento fueron mujeres y 50 porciento hombres. La edad mínima fue de 4 años y la máxima de 89, con una mediana de 25; 43,7 porciento tuvo compromiso de colon, 23 porciento de ileon, 16,7 porciento de ileon-colon y 16,7 porciento proximal al ileon; 52,2 porciento presentó enfermedad perianal. Tenían antecedentes familiares de EII cinco pacientes (10,4 porciento), y presentaron manifetaciones extraintestinales siete (14,6 porciento), siendo más de 70 porciento articulares. La media de seguimiento fue de 12,3 años. Requirieron resección intestinal 31,2 porciento de los pacientes (20 prociento requirió más de una), con una mediana entre el inicio de EC y la cirugía de cuatro años, no habiendo diferencia estadísticamente significativa respecto a la topografía. Fallecieron tres pacientes. Conclusiones: en esta cohorte, la afectación de colon y perianal fue mayor a lo esperado, en cambio el requerimiento de resección intestinal y la morbimortalidad menor, aunque no despreciable considerando el grupo etario afectado

Características clínicas de presentación y seguimiento de una cohorte de 121 pacientes con colitis ulcerosa crónica en Uruguay

Objetivo: describir las caracteríticas clínicas y evolutivas de una cohorte de pacientes con colititis ulcerosa crónica (CUC). Material y método: se analizó en forma retrospectiva y prospectiva una cohorte de 121 pacientes con diagnóstico de CUC que iniciaron su enfermedad entre 1951 y 2003, procedentes de la asistencia pública y privada, de Montevideo y del interior, asistidos por los autores en al menos una oportunidad al 30 de junio de 2003. Con los datos de las historias clínicas se confeccionó un registro que incluyó: edad de inicio, topografía, severidad, manifestaciones extraintestinales, requerimiento de cirugía y mortalidad. Resultados: 53.7 porciento fueron mujeres y 46.3 porciento hombres. La edad mínima al inicio fue de 3 años y la máxima de 76, con una mediana de 32. El compromiso fue 18.8 porciento recto, 22,2 porciento rectosigmoide, 19,8 porciento colitis izquierda y 38,5 porciento pancolitis. El debut fue leve en 47,1 porciento moderado en 31,4 porciento y severo en 18,2 porciento (p=0,0001). Presentarn manifestaciones extraintestinales 7,4 porciento y antecedentes familiares de CUC 4,1 porciento. Requirieron cirugía diez pacientes (8,3 porciento) con una mediana entre el inicio de la enfermedad y ésta de 5,5 años, siendo en 70 porciento por severidad del empuje. El tiempo medio de seguimiento fue de 10,5 años. Desarrollaron cáncer de colon tres pacientes (2,5 porciento). Conclusiones: esta cohorte presentó bajo requerimiento de cirugía, la que se asoció a severidad del empuje y ocurrió fundamentalmente en el primer año de enfermedad, y baja ocurrencia de cáncer y mortalidad

Características clínicas de presentación y evolutivas de una cohorte de 48 pacientes con enfermedad de Crohn en Uruguay / Presentation and progression characteristics in a cohort of 48 patients with Crohn disease in Uruguay

Objetivo: describir las características clínicas y evolutivas de una cohorte de pacientes con enfermedad de Crohn (EC). Material y método: se analizó en forma retrospectiva y prospectiva una cohorte de 48 pacientes con EC, que iniciaron su enfermedad entre 1951 y 2003, procedentes de la asistencia pública y privada, de Montevideo y del interior, asistidos por los autores en al menos una oportunidad al 30 de junio de 2003. Con los datos de las historias clínicas se confeccionó un registro con las variables: sexo, edad de inicio, antecedentes familiares de enfermedad inflamatoria intestinal (EII), topografía, enfermedad perianal, manifestaciones extraintestinales, resección intestinal y mortalidad. Resultados: 50 por ciento fueron mujeres y 50 por ciento hombres. La edad mínima fue de 4 años y la máxima de 89, con una mediana de 25; 43,7 por ciento tuvo compromiso de colon, 23 por ciento de íleon, 16,7 por ciento de íleon-colon y 16,7 por ciento proximal al íleon; 52,2 por ciento presentó enfermedad perianal. Tenían antecedentes familiares de EII cinco pacientes (10,4 por ciento), y presentaron manifestaciones extraintestinales siete (14,6 por ciento), siendo más de 70 por ciento articulares. La media de seguimiento fue de 12,3 años. Requirieron resección intestinal 31,2 por ciento de los pacientes (20 por ciento requirió más de una), con una mediana entre el inicio de la EC y la cirugía de cuatro años, no habiendo diferencia estadísticamente significativa respecto a la topografía. Fallecieron tres pacientes. Conclusiones: en esta cohorte, la afectación de colon y perianal fue mayor a lo esperado, en cambio el requerimiento de resección intestinal y la morbimortalidad menor, aunque no despreciable considerando el grupo etario afectado. (AU)

Características clínicas de presentación y seguimiento de una cohorte de 121 pacientes con colitis ulcerosa crónica en Uruguay / Presentation and follow up characteristics of 121 patients with chronic ulcerative colitis in Uruguay

Objetivo: describir las características clínicas y evolutivas de una cohorte de pacientes con colitis ulcerosa crónica (CUC). Material y método: se analizó en forma retrospectiva y prospectiva una cohorte de 121 pacientes con diagnóstico de CUC que iniciaron su enfermedad entre 1951 y 2003, procedentes de la asistencia pública y privada, de Montevideo y del interior, asistidos por los autores en al menos una oportunidad al 30 de junio de 2003. Con los datos de las historias clínicas se confeccionó un registro que incluyó: edad de inicio, topografía, severidad, manifestaciones extraintestinales, requerimiento de cirugía y mortalidad. Resultados: 53,7 por ciento fueron mujeres y 46,3 por ciento hombres. La edad mínima al inicio fue de 3 años y la máxima de 76, con una mediana de 32. El compromiso fue: 18,8 por ciento recto, 22,2 por ciento rectosigmoide, 19,8 por ciento colitis izquierda y 38,5 por ciento pancolitis. El debut fue leve en 47,1 por ciento, moderado en 31,4 por ciento y severo en 18,2 por ciento (p=0,0001). Presentaron manifestaciones extraintestinales 7,4 por ciento y antecedentes familiares de CUC 4,1 por ciento. Requirieron cirugía diez pacientes (8,3por ciento), con una mediana entre el inicio de la enfermedad y ésta de 5,5 años, siendo en 70 por ciento por severidad del empuje. El tiempo medio de seguimiento fue 10,5 años. Desarrollaron cáncer de colon tres pacientes (2,5 por ciento). Conclusiones: esta cohorte presentó bajo requerimiento de cirugía, la que se asoció a severidad del empuje y ocurrió fundamentalmente en el primer año de enfermedad, y baja ocurrencia de cáncer y mortalidad. (AU)

Características clínicas de presentación y seguimiento de una cohorte de 121 pacientes con colitis ulcerosa crónica en Uruguay / Presentation and follow up characteristics of 121 patients with chronic ulcerative colitis in Uruguay

Objetivo: describir las características clínicas y evolutivas de una cohorte de pacientes con colitis ulcerosa crónica (CUC). Material y método: se analizó en forma retrospectiva y prospectiva una cohorte de 121 pacientes con diagnóstico de CUC que iniciaron su enfermedad entre 1951 y 2003, procedentes de la asistencia pública y privada, de Montevideo y del interior, asistidos por los autores en al menos una oportunidad al 30 de junio de 2003. Con los datos de las historias clínicas se confeccionó un registro que incluyó: edad de inicio, topografía, severidad, manifestaciones extraintestinales, requerimiento de cirugía y mortalidad. Resultados: 53,7 por ciento fueron mujeres y 46,3 por ciento hombres. La edad mínima al inicio fue de 3 años y la máxima de 76, con una mediana de 32. El compromiso fue: 18,8 por ciento recto, 22,2 por ciento rectosigmoide, 19,8 por ciento colitis izquierda y 38,5 por ciento pancolitis. El debut fue leve en 47,1 por ciento, moderado en 31,4 por ciento y severo en 18,2 por ciento (p=0,0001). Presentaron manifestaciones extraintestinales 7,4 por ciento y antecedentes familiares de CUC 4,1 por ciento. Requirieron cirugía diez pacientes (8,3por ciento), con una mediana entre el inicio de la enfermedad y ésta de 5,5 años, siendo en 70 por ciento por severidad del empuje. El tiempo medio de seguimiento fue 10,5 años. Desarrollaron cáncer de colon tres pacientes (2,5 por ciento). Conclusiones: esta cohorte presentó bajo requerimiento de cirugía, la que se asoció a severidad del empuje y ocurrió fundamentalmente en el primer año de enfermedad, y baja ocurrencia de cáncer y mortalidad.