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The elaboration of conservation strategies at regional scale, dealing with the potential effects of climate change on the abundance and distribution of tree species, should be supported by models produced at the appropriate scale. We used a bioclimatic model aimed at analysing the large-scale effects of climate change on the abundance and distribution of tree species with respect to their chorological and ecological characteristics. Abundance data for 16 species, sampled in 912 plots, distributed on a 3x3 km grid were used. A climatic model provided high resolution current climatic surfaces and a climatic scenario for 2080 was obtained using the A1FI emission scenario of HadCM3 GCM. A deterministic Regression Tree Analysis (RTA) and Multiple Linear Regression (MLR) were applied in order to define the realised niche of the species in relation to the chosen environmental variables. The comparison between RMSE values showed that RTA always outperforms MLR, in terms of predicting species distribution. Zonal species were better predicted than rare species (extrazonal or with specific habitat requirements). Climate change is expected to determine a general increase of the average potential altitude. Only the Mediterranean species are likely to be favoured by the predicted climate change, while for the two other chorological types (Sub-Mediterranean and Eurosiberian) the response seems to be species-specific, depending on the ecological characteristic of each species: the more thermophilous and xerophilous species should benefit from the predicted drought in terms of area and mean abundance, while mesophilous species should suffer a strong reduction.

Background: Accurate estimation of Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) incidence is crucial for assessing breast-implant-associated risk. However, the size of the implanted population worldwide is unknown, making it challenging to appropriately estimate this figure. This study aims to provide a new reliable and reproducible method to estimate the breast-implanted-population (BIP), reporting a reliable annual BIA-ALCL incidence estimate. Moreover, we discuss all activities performed over the past decade in collecting complete histories, managing, and monitoring outcomes of each Italian case., Methods: Data from the National Breast Implant Registry and from manufacturers have been used to define a new formula to estimate the BIP at risk of developing a breast-implant-related event. From the BIA-ALCL registry, complete information on Italian cases has been collected and analysed. Overall survival is estimated by the Kaplan-Meier curve., Results: From 2010 to June 2024, 111 BIA-ALCL cases were recorded in Italy. The estimated incidence rate showed an upward trend, ranging from 2.68 to 6.35 cases per 100,000 patient-years. Thanks to newly promoted disease awareness, most patients had a complete response to treatment, resulting in a three-year overall survival rate estimate of 98.2%., Conclusions: The BIP formula showed to be an innovative, effective and reproducible tool to make a reliable estimation of the implanted population, confirming that BIA-ALCL is a rare disease with an incidence rate estimate varying from 2.7 to 6.3 cases/100.000 patient-years in the last five years. Eleven-year experience in this field also confirmed that this disease has a favorable prognosis if properly treated., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Context: The utility of thyroglobulin (Tg) in the follow-up of differentiated thyroid cancer (DTC) patients has been well-documented. Although third-generation immunoassays have improved accuracy, limitations persist (interfering anti-Tg antibodies and measurement variability). Evolving treatment strategies require a reevaluation of Tg thresholds for optimal patient management., Objective: To assess the performance of serum Tg testing in two populations: patients receiving total thyroidectomy and radioiodine remnant ablation (RRA), or treated with thyroidectomy alone., Design: Prospective observational study. Setting. Centers contributing to the Italian Thyroid Cancer Observatory (ITCO) database., Patients: We included 540 patients with 5 years of follow-up and negative anti-Tg antibodies., Interventions: Serum Tg levels assessed at 1-year follow-up visit., Main Outcome Measure: Detection of structural disease within 5 years of follow-up., Results: After excluding 26 patients with structural disease detected at any time point, the median Tg did not differ between patients treated with or without radioiodine. Data-driven Tg thresholds were established based on the 97th percentile of Tg levels in disease-free individuals: 1.97 ng/mL for patients undergoing thyroidectomy alone (lower than proposed by the MSKCC protocol and ESMO Guidelines, yet demonstrating good predictive ability, with a negative predictive value (NPV) of 98%) and 0.84 ng/mL for patients receiving post-surgical RRA. High sensitivity and NPV supported the potential of these thresholds in excluding structural disease., Conclusions: This real-world study provides evidence for the continued reliability of 1-year serum Tg levels. The data-driven Tg thresholds proposed offer valuable insights for clinical decision-making in patients undergoing total thyroidectomy with or without RRA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The handling of data on food contamination frequently represents a challenge because these are often left-censored, being composed of both positive and non-detected values. The latter observations are not quantified and provide only the information that they are below a laboratory-specific threshold value. Besides deterministic approaches, which simplify the treatment through the substitution of non-detected values with fixed threshold or null values, a growing interest has been shown in the application of stochastic approaches to the treatment of unquantified values. In this study, a multiple imputation procedure was applied in order to analyze contamination data on deoxynivalenol, a mycotoxin that may be present in pasta and pasta substitute products. An application of the proposed technique to censored deoxynivalenol occurrence data is presented. The results were compared to those attained using deterministic techniques (substitution methods). In this context, the stochastic approach seemed to provide a more accurate, unbiased and realistic solution to the problem of left-censored occurrence data. The complete sample of values could then be used to estimate the exposure of the general population to deoxynivalenol based on consumption data.

Purpose: To examine quality of life (QOL) and sexual functioning in a series of patients with intermediate- and high-intermediate risk endometrial cancer, treated with exclusive adjuvant one week high-dose-rate (HDR) vaginal brachytherapy (VBT) schedule., Material and Methods: Between July 2008 and October 2013, 55 patients with diagnosis of endometrial cancer were treated with adjuvant exclusive VBT. All patients had undergone surgical treatment with a laparotomy approach before VBT. Post-operative VBT was administered 6-8 weeks after surgery. Treatment was delivered to vaginal vault using Nucletron HDR unit with iridium-192 source at a dose of 21 Gy/3 fractions of 7 Gy each, three times a week, every other day, prescribed at 0.5 cm depth of vaginal wall, and 3 cm in length from the apex. QOL was assessed using European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire Core-30 (QLQ-C30), and EORTC cancer-specific quality of life questionnaire (QLQ-CX24)., Results: Median follow-up time was 92 months (range, 42-162 months). Questionnaires were carried out respectively at 1, 3, 6, 12, 24, 36, 48, and 60 months after the end of BT. Response rate to questionnaires was 100% ( n = 55). Nineteen patients (35%) answered all the questions of surveys, while 36 patients (65%) completed the surveys, except for questions on sex activity, vaginal function, and sex enjoyment. Longitudinal analysis during 5-year follow-up period showed a statistically significant trend towards worsening of fatigue, constipation, and diarrhea. Overall physical functioning and role functioning was not impaired after VBT. Over the time, sex enjoyment improved, except for elderly patients. For emotional functioning, sex worry and social functioning presented no significant time-related effect., Conclusions: One week brachytherapy schedule to vaginal cuff is generally well-tolerated. QOL does not worsen after applying vaginal brachytherapy., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Termedia.)

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p  = 0.65), tumor size >2 cm (OR 1.45, p  = 0.34), aggressive PTC histology (OR 0.55, p  = 0.15), and age at diagnosis (OR 0.90, p  = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p  = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients ( p  = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Context: Current guidelines recommend a selective use of radioiodine treatment (RAI) for papillary thyroid cancer (PTC)., Objective: This work aimed to determine how policy changes affect the use of RAI and the short-term outcomes of patients., Methods: A retrospective analysis of longitudinal data was conducted in an academic referral center of patients with nonaggressive PTC variants; no extrathyroidal invasion or limited to soft tissues, no distant metastases, and 5 or fewer central-compartment cervical lymph node metastases. In cohort 1, standard treatments were total thyroidectomy and RAI (May 2005-June 2011); in cohort 2 decisions on RAI were deferred for approximately 12 months after surgery (July 2011-December 2018). Propensity score matching was used to adjust for sex, age, tumor size, lymph node status, and extrathyroidal extension. Intervention included immediate RAI or deferred choice. Main outcome measures were responses to initial treatment during 3 or more years of follow-up., Results: In cohort 1, RAI was performed in 50 of 116 patients (51.7%), whereas in cohort 2, it was far less frequent: immediately in 10 of 156 (6.4%), and in 3 more patients after the first follow-up data. The frequencies of structural incomplete response were low (1%-3%), and there were no differences between the 2 cohorts at any follow-up visit. Cohort 2 patients had higher rates of "gray-zone responses" (biochemical incomplete or indeterminate response)., Conclusion: Selective use of RAI increases the rate of patients with "uncertain" status during early follow-up. The rate of structural incomplete responses remains low regardless of whether RAI is used immediately. Patients should be made aware of the advantages and drawbacks of omitting RAI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Capture-recapture studies have attracted a lot of attention over the past few decades, especially in applied disciplines where a direct estimate for the size of a population of interest is not available. Epidemiology, ecology, public health, and biodiversity are just a few examples. The estimation of the number of unseen units has been a challenge for theoretical statisticians, and considerable progress has been made in providing lower bound estimators for the population size. In fact, it is well known that consistent estimators for this cannot be provided in the very general case. Considering a case where capture-recapture studies are summarized by a frequency of frequencies distribution, we derive a simple upper bound of the population size based on the cumulative distribution function. We introduce two estimators of this bound, without any specific parametric assumption on the distribution of the observed frequency counts. The behavior of the proposed estimators is investigated using several benchmark datasets and a large-scale simulation experiment based on the scheme discussed by Pledger., (© 2020 The International Biometric Society.)

Lung cancer (LC) mortality remains a consistent part of the total deaths occurring worldwide. Its etiology is complex as it involves multifactorial components. This work aims in providing an epidemiological assessment on occupational and environmental factors associated to LC risk by means of an ecological study involving the 8092 Italian municipalities for the period 2006-2015. We consider mortality data from mesothelioma as proxy of asbestos exposure, as well as PM 2.5 and radon levels as a proxy of environmental origin. The compensated cases for occupational respiratory diseases, urbanization and deprivation were included as predictors. We used a negative binomial distribution for the response, with analysis stratified by gender. We estimated that asbestos is responsible for about 1.1% (95% CI: 0.8, 1.4) and 0.5% (95% CI: 0.2, 0.8) of LC mortality in males and females, respectively. The corresponding figures are 14.0% (95% CI: 12.5, 15.7) and 16.3% (95% CI: 16.2, 16.3) for PM 2.5 exposure, and 3.9% (95% CI: 3.5, 4.2) and 1.6% (95% CI: 1.4, 1.7) for radon exposure. The assessment of determinants contribution to observed LC deaths is crucial for improving awareness of its origin, leading to increase the equity of the welfare system.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Drop out is a typical issue in longitudinal studies. When the missingness is non-ignorable, inference based on the observed data only may be biased. This paper is motivated by the Leiden 85+ study, a longitudinal study conducted to analyze the dynamics of cognitive functioning in the elderly. We account for dependence between longitudinal responses from the same subject using time-varying random effects associated with a heterogeneous hidden Markov chain. As several participants in the study drop out prematurely, we introduce a further random effect model to describe the missing data mechanism. The potential dependence between the random effects in the two equations (and, therefore, between the two processes) is introduced through a joint distribution specified via a latent structure approach. The application of the proposal to data from the Leiden 85+ study shows its effectiveness in modeling heterogeneous longitudinal patterns, possibly influenced by the missing data process. Results from a sensitivity analysis show the robustness of the estimates with respect to misspecification of the missing data mechanism. A simulation study provides evidence for the reliability of the inferential conclusions drawn from the analysis of the Leiden 85+ data.

Aim: To evaluate the efficacy of residual site radiation therapy (RSRT) on local control (LC), progression-free (PFS) and overall (OS) survival in patients with primary mediastinal lymphoma (PMBCL), following rituximab and chemotherapy treatment (ICHT)., Patients and Methods: The study included 34 patients with PMBCL treated between 2006 and 2014 with ICHT with/without autologous stem cell transplantation and RSRT. Between the end of ICHT/stem cell transplantation and RSRT, patients were evaluated with 18 F-fluorodeoxyglucose positron-emission tomography. The gross tumor volume included morphological mediastinal residual disease after ICHT/SCT. The percentage of LC, PFS and OS were assessed., Results: All patients received RSRT with a median dose of 30 Gy. Median follow-up was 82 months. One patient out of 34 (3%) showed progressive disease 9 months from diagnosis. The 10-year PFS and OS were 97% and 97% respectively., Conclusion: RSRT in patients with PMBCL treated with ICHT did not impact unfavorably on LC and patient survival., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In longitudinal studies, subjects may be lost to follow up and, thus, present incomplete response sequences. When the mechanism underlying the dropout is nonignorable, we need to account for dependence between the longitudinal and the dropout process. We propose to model such a dependence through discrete latent effects, which are outcome-specific and account for heterogeneity in the univariate profiles. Dependence between profiles is introduced by using a probability matrix to describe the corresponding joint distribution. In this way, we separately model dependence within each outcome and dependence between outcomes. The major feature of this proposal, when compared with standard finite mixture models, is that it allows the nonignorable dropout model to properly nest its ignorable counterpart. We also discuss the use of an index of (local) sensitivity to nonignorability to investigate the effects that assumptions about the dropout process may have on model parameter estimates. The proposal is illustrated via the analysis of data from a longitudinal study on the dynamics of cognitive functioning in the elderly., (Copyright © 2018 John Wiley & Sons, Ltd.)

Quantile regression provides a detailed and robust picture of the distribution of a response variable, conditional on a set of observed covariates. Recently, it has be been extended to the analysis of longitudinal continuous outcomes using either time-constant or time-varying random parameters. However, in real-life data, we frequently observe both temporal shocks in the overall trend and individual-specific heterogeneity in model parameters. A benchmark dataset on HIV progression gives a clear example. Here, the evolution of the CD4 log counts exhibits both sudden temporal changes in the overall trend and heterogeneity in the effect of the time since seroconversion on the response dynamics. To accommodate such situations, we propose a quantile regression model, where time-varying and time-constant random coefficients are jointly considered. Since observed data may be incomplete due to early drop-out, we also extend the proposed model in a pattern mixture perspective. We assess the performance of the proposals via a large-scale simulation study and the analysis of the CD4 count data.

Lipin-1 is a Mg 2+ -dependent phosphatidic acid phosphatase (PAP) that in mice is necessary for normal glycerolipid biosynthesis, controlling adipocyte metabolism, and adipogenic differentiation. Mice carrying inactivating mutations in the Lpin1 gene display the characteristic features of human familial lipodystrophy. Very little is known about the roles of lipin-1 in human adipocyte physiology. Apparently, fat distribution and weight is normal in humans carrying LPIN1 inactivating mutations, but a detailed analysis of adipose tissue appearance and functions in these patients has not been available so far. In this study, we performed a systematic histopathological, biochemical, and gene expression analysis of adipose tissue biopsies from human patients harboring LPIN1 biallelic inactivating mutations and affected by recurrent episodes of severe rhabdomyolysis. We also explored the adipogenic differentiation potential of human mesenchymal cell populations derived from lipin-1 defective patients. White adipose tissue from human LPIN1 mutant patients displayed a dramatic decrease in lipin-1 protein levels and PAP activity, with a concomitant moderate reduction of adipocyte size. Nevertheless, the adipose tissue develops without obvious histological signs of lipodystrophy and with normal qualitative composition of storage lipids. The increased expression of key adipogenic determinants such as SREBP1 , PPARG , and PGC1A shows that specific compensatory phenomena can be activated in vivo in human adipocytes with deficiency of functional lipin-1., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Our aim is to assess the incidence of second cancer in long-time surviving primary mediastinal B-cell lymphoma (PMBCL) patients treated with combined radiochemoimmunotherapy (standard methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin with rituximab and mediastinal radiation therapy at a dose of 30 to 36 Gy). For this purpose, 92 points were evaluated. After a median overall survival of 137 months (range 76-212), we recorded second cancer in 3 of 80 long-surviving patients (3.75%) with cumulative incidence of 3.47% at 15 years and 11% at 17 years, with a 17-year second cancer-free survival of 82%. We observed 2 papillary thyroid cancers with a standardized incidence ratio (SIR) of 7.97 and an absolute excess risk (AER) of 17. 84 and 1 acute myeloid leukemia (AML) with an SIR of 66.53 and an AER of 10.05. No breast cancer occurred. Although we should take into account the limits of the proposed statistical analysis, combined modality treatment was related to a significant SIR and AER for thyroid cancer and acute myeloid leukemia., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Previous studies of serum total IgE (t-IgE) were not able to discriminate well-enough atopic from non-atopic subjects, that is, with or without serum-specific IgE antibodies to allergens., Objectives: To model growth curves of the total IgE levels in children without atopic sensitization (hereafter defined as "normal" t-IgE levels) and to test their usefulness in predicting atopic sensitization., Methods: The German Multicentre Allergy Study (MAS), a birth cohort with 1314 recruited newborns, began in 1990 and examined the participants until age 20 years. Total and specific IgE (t-IgE, s-IgE) were analyzed with a fluorescent enzyme immunoassay ImmunoCAP (TFS, Sweden) at ages 1, 2, 3, 5, 6, 7, 10, 13, and 20 years. Participants were classified as "never atopic" if all their available serum samples had negative response (cutoff: <0.35 kU A /L) for s-IgE to the nine common foodborne and airborne allergenic extracts (milk, egg, soy, wheat, house dust mite, cat, dog, birch, and grass) tested in the MAS birth cohort. By contrast, participants were defined as atopic if they had, for at least at one available serum sample, s-IgE≥0.35 kU A /L to at least one allergenic extract tested. The evolution of t-IgE levels in the "never atopic" children was described by growth curves, estimated by exploiting a quantile regression model. A "reference" percentile, based on the t-IgE value measured at age 5 years, was assigned to each child with no IgE sensitization at that age. Upward deviations from the own "reference" quantile of t-IgE in atopic and "never atopic" children were calculated and a ROC analysis was used to identify the best cutoff point for predicting atopic sensitization., Results: Overall, 1113 of 1314 children were included in this analysis. Of these, 469 were "never atopic" and 644 atopic. Quantile trajectories of t-IgE levels in "never atopic" subjects were stable from 5 years of age, increased to a plateau at age 10-13 years, and decreased slightly afterward. The onset of atopic s-IgE responses was characterized by an upward deviation of serum t-IgE levels from their "reference" trajectory. T-IgE quantiles predicted the onset of atopy with high efficiency (AUC>80%). ROC analysis showed that deviations from the t-IgE level "reference" quantile above 0.32, 0.41, 0.42, 0.30, and 0.58 kU/L (log-units) at 6, 7, 10, 13, and 20 years of age, respectively, predicted an atopic sensitization., Conclusion: The growth curves of "normal" serum t-IgE concentrations were estimated in "never atopic" children; for each individual who was non-atopic at 5 years of age a "reference" quantile was identified that represented the individual's "normal" level of t-IgE production. Upward deviations of observed t-IgE levels from the own "reference" quantile, from 6 to 20 years of age, predicted at each year the occurrence of atopic sensitization., Clinical Implications: The trajectory of t-IgE levels can be elaborated since age 5 years in non-atopic children. A child whose t-IgE levels are consistently higher than those predicted by his/her growth curve may have developed atopic sensitization., (© 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: This study addresses a recurrent biological problem, that is to define a formal clustering structure for a set of tissues on the basis of the relative abundance of multiple alternatively spliced isoforms mRNAs generated by the same gene. To this aim, we have used a model-based clustering approach, based on a finite mixture of multivariate Gaussian densities. However, given we had more technical replicates from the same tissue for each quantitative measurement, we also employed a finite mixture of linear mixed models, with tissue-specific random effects., Results: A panel of human tissues was analysed through quantitative real-time PCR methods, to quantify the relative amount of mRNA encoding different IGF-1 alternative splicing variants. After an appropriate, preliminary, equalization of the quantitative data, we provided an estimate of the distribution of the observed concentrations for the different IGF-1 mRNA splice variants in the cohort of tissues by employing suitable kernel density estimators. We observed that the analysed IGF-1 mRNA splice variants were characterized by multimodal distributions, which could be interpreted as describing the presence of several sub-population, i.e. potential tissue clusters. In this context, a formal clustering approach based on a finite mixture model (FMM) with Gaussian components is proposed. Due to the presence of potential dependence between the technical replicates (originated by repeated quantitative measurements of the same mRNA splice isoform in the same tissue) we have also employed the finite mixture of linear mixed models (FMLMM), which allowed to take into account this kind of within-tissue dependence., Conclusions: The FMM and the FMLMM provided a convenient yet formal setting for a model-based clustering of the human tissues in sub-populations, characterized by homogeneous values of concentrations of the mRNAs for one or multiple IGF-1 alternative splicing isoforms. The proposed approaches can be applied to any cohort of tissues expressing several alternatively spliced mRNAs generated by the same gene, and can overcome the limitations of clustering methods based on simple comparisons between splice isoform expression levels.

Objective: To assess the risk of adverse pregnancy outcomes in patients with acquired and/or congenital thrombophilia factors., Patients and Methods: A cohort of 130 women with a history of pregnancy loss and no successful gestation were investigated for the presence of congenital and acquired thrombophilia factors, and then compared with a control group of 130 healthy women who had had at least one successful gestation and no pregnancy loss, and were screened for congenital and acquired thrombophilia factors., Results: Acquired and congenital thrombophilia factors were found in 30 (23%) patients and in 14 (10.8%) controls (p < 0.015). The presence of ≥1 congenital thrombophilia factor was associated with pregnancy loss with an odds ratio of 2.46 (p = 0.040). Moreover, women who had had >1 early fetal loss had a 2.85-fold risk of being carriers of congenital thrombophilia factors, compared to the controls., Conclusion: Our study showed the increased risk of miscarriage in patients with congenital thrombophilia factors and >1 early fetal loss., (© 2014 S. Karger AG, Basel.)

Objectives: The purpose of this study was to establish reference charts for fetal corpus callosum length in a convenience sample., Methods: A prospective cross-sectional study was conducted at the Artemisia Fetal-Maternal Medical Center between December 2008 and January 2012. Among 16,975 fetal biometric measurements between 19 weeks and 37 weeks 6 days' gestation, 3438 measurements of the corpus callosum (20.3%) were available. After excluding 488 measurements (14.2%), a total of 2950 fetuses (85.8%) were considered and analyzed only once. Parametric and nonparametric quantile regression models were used for the statistical analysis. To evaluate the robustness of the proposed reference charts with respect to various distributional assumptions on the sonographic measurements at hand, we compared the gestational age (GA)-specific reference curves produced by the statistical methods used., Results: The mean corpus callosum length was 26.18 mm (SD, 4.5 mm; 95% confidence interval, 26.01-26.34 mm). The linear regression equation expressing the length of the corpus callosum as a function of GA was length (mm) = -11.17 + 1.62 × GA. The correlation between the dimension and gestation was expressed by the coefficient r = 0.83. Normal mean lengths according the parametric and nonparametric methods were defined for each week of gestation., Conclusions: This work provides new quantile-based reference charts for corpus callosum length measurements that may be useful for diagnosis of congenital corpus callosum anomalies in fetal life., (© 2014 by the American Institute of Ultrasound in Medicine.)

We investigated the hypothesis that patients developing high-grade erythema of the breast skin during radiation treatment could be more likely to present increased levels of proinflammatory cytokines which may lead, in turn, to associated fatigue. Forty women with early stage breast cancer who received adjuvant radiotherapy were enrolled from 2007 to 2010. Fatigue symptoms, erythema, and cytokine levels (IL-1β, IL-2, IL6, IL-8, TNF-α, and MCP-1) were registered at baseline, during treatment, and after radiotherapy completion. Seven (17.5%) patients presented fatigue without associated depression/anxiety. Grade ≥2 erythema was observed in 5 of these 7 patients. IL-1β, IL-2, IL-6, and TNF-α were statistically increased 4 weeks after radiotherapy (P < 0.05). After the Heckman two-step analysis, a statistically significant influence of skin erythema on proinflammatory markers increase (P = 0.00001) was recorded; in the second step, these blood markers showed a significant impact on fatigue (P = 0.026). A seeming increase of fatigue, erythema, and proinflammatory markers was observed between the fourth and the fifth week of treatment followed by a decrease after RT. There were no significant effects of hormone therapy, breast volume, and anemia on fatigue. Our study seems to suggest that fatigue is related to high-grade breast skin erythema during radiotherapy through the increase of cytokines levels.

Purpose: The aim of this study was to evaluate the pregnancy outcomes in women with Hodgkin lymphoma (HL) diagnosis, treated between 1972 and 1999 at Department of Radiotherapy and Hematology of University "Sapienza" of Roma., Methods and Materials: We retrospectively studied 99 female patients that conceived after treatment for HL. Fifty-nine (59%) were treated with chemotherapy and radiotherapy, 32 (32%) with radiotherapy alone as supradiaphragmatic or as infradiaphragmatic and 8 (8%) patients with chemotherapy alone., Results: Ninety-nine patients reported 145 pregnancies. We observed 132 deliveries (2 of them twin births) after a median of 55 months (range, 14-278 months) from the end of therapy. Twelve women (12%) experienced 13 miscarriages after a median of 50 months (range, 13-120) from the end of therapy. We recorded 9/132 (7%) premature births and 3/134 babies (2%) were underweight at the time of birth. We recorded 2 cases of congenital malformations. No statistical differences were recorded when adverse pregnancy outcomes were analyzed with respect to chemotherapy alone, radiotherapy alone, or combined therapy., Conclusions: No significant associations between pregnancy outcomes and therapeutic approaches were found. In particular, the infradiaphragmatic radiotherapy showed no statistical association with miscarriages, premature birth, and low birth weight at term when compared with other therapeutic approaches., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To report the clinical findings and long-term results of front-line, third-generation MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) chemotherapy and mediastinal involved-field radiotherapy (IFRT) in 85 consecutive, previously untreated patients with primary mediastinal large B cell lymphoma (PMLBCL) diagnosed and managed at a single institution., Methods and Materials: Between 1991 and April 2004, 92 consecutive, untreated patients with PMLBCL were treated at our institution. The median age was 33 years (range, 15-61 years), 46 patients (50%) showed a mediastinal syndrome at onset; 52 patients (57%) showed a low/low-intermediate (0 to 1) and 40 patients (43%) an intermediate-high/high (2 to 3) International Prognostic Index (IPI) score. Eighty-five patients were treated with standard chemotherapy (MACOP-B), and 80 underwent mediastinal IFRT at a dose of 30-36 Gy., Results: After a MACOP-B regimen, the overall response rate was 87% and the partial response rate 9%. After chemotherapy, (67)Ga scintigraphy/positron emission tomography results were positive in 43 of 52 patients (83%), whereas after IFRT 11 of 52 patients (21%) remained positive (p < 0.0001). After a median follow-up of 81 months (range, 2-196 months), progression or relapse was observed in 15 of 84 patients (18%). The projected 5-year overall survival and progression-free survival rates were 87% and 81%, respectively. The 5-year overall survival and progression-free survival rates were better for patients with an IPI of 0 to 1 than for those with an IPI of 2 to 3 (96% vs. 73% [p = 0.002] and 90% vs. 67% [p = 0.007], respectively)., Conclusions: Combined-modality treatment with intensive chemotherapy plus mediastinal IFRT induces high response and lymphoma-free survival rates. Involved-field RT plays an important role in inducing negative results on (67)Ga scintigraphy/positron emission tomography in patients responsive to chemotherapy.

A challenge in microarray data analysis concerns discovering local structures composed by sets of genes that show homogeneous expression patterns across subsets of conditions. We present an extension of the mixture of factor analyzers model (MFA) allowing for simultaneous clustering of genes and conditions. The proposed model is rather flexible since it models the density of high-dimensional data assuming a mixture of Gaussian distributions with a particular omponent-specific covariance structure. Specifically, a binary and row stochastic matrix representing tissue membership is used to cluster tissues (experimental conditions), whereas the traditional mixture approach is used to define the gene clustering. An alternating expectation conditional maximization (AECM) algorithm is proposed for parameter estimation; experiments on simulated and real data show the efficiency of our method as a general approach to biclustering. The Matlab code of the algorithm is available upon request from authors.

Understanding the mechanisms that sustain the effects of disease modifying drugs in multiple sclerosis (MS) may help refine current therapies and improve our knowledge of disease pathogenesis. By using cDNA microarrays, we investigated gene expression in the peripheral blood mononuclear cells (PBMC) of 7 MS patients, at baseline (T0) as well as after 1 (T1) and 3 months (T3) of interferon beta-1a (IFN-beta-1a; Rebif 44 microg) therapy. Gene expression changes involved genes of both immunological and non-immunological significance. We validated IL-10 up-regulation, which is in accordance with previous reports, and other novel changes that underscore the capacity of IFN-beta to impair antigen presentation and migration of inflammatory elements into the central nervous system (up-regulation of filamin B and down-regulation of IL-16 and rab7). Overall, gene expression changes became less pronounced after 3 months of therapy, suggesting a homeostatic response to IFN-beta. This may be of use for the design of new treatment schedules.

Essential thrombocythaemia (ET) is usually considered an indolent disease, but it may progress during its natural course into acute leukaemia (AL); however, an influence of myelosuppressive agents in the blastic transformation of ET cannot be excluded. We performed a retrospective study to assess the incidence of AL in ET patients treated with pipobroman (PB) as first-line therapy. One hundred and sixty-four patients with ET were managed with PB at a dose of 1 mg/kg/d until a stable platelet count below 400 x 10(9)/l was achieved. Maintenance therapy was given at a planned dose ranging between 0.2 and 1 mg/kg/d according to platelet count, in all cases, with a median daily dose of 25 mg (range 7-75 mg/d). The median treatment time was 100 months (range 25-243 months). The patients were evaluated for the occurrence of AL and/or secondary malignancies and survival end-points. AL was observed in nine patients (5.5%) after a median treatment time of 153 months (range 79-227 months). The overall survival (OS) and the event-free survival (EFS) at 120 months were 95% and 97%, whereas at 180 months, they were 84% and 76% respectively. In conclusion, this retrospective analysis shows a low incidence of AL in a large group of patients consecutively treated with PB as first-line chemotherapy. Therefore, an investigation of the role of myelosuppressive agents in the blastic transformation of ET would be of interest.