Elia Mario Biganzoli - Academia.edu (original) (raw)
Papers by Elia Mario Biganzoli
Clinical Chemistry and Laboratory Medicine (CCLM), 2022
Clinical practice guidelines (CPGs) on screening, surveillance, and treatment of several diseases... more Clinical practice guidelines (CPGs) on screening, surveillance, and treatment of several diseases recommend the selective use of biomarkers with central role in clinical decision-making and move towards including patients in this process. To this aim we will clarify the multidisciplinary interactions required to properly measure the cost-effectiveness of biomarkers with regard to the risk-benefit of the patients and how Health Technology Assessment (HTA) approach may assess value of biomarkers integrated within the decision-making process. HTA through the interaction of different skills provides high-quality research information on the effectiveness, costs, and impact of health technologies, including biomarkers. The biostatistical methodology is relevant to HTA but only meta-analysis is covered in depth, whereas proper approaches are needed to estimate the benefit-risk balance ratio. Several biomarkers underwent HTA evaluation and the final reports have pragmatically addressed: 1) ...
BJU International, 2022
First, we should observe that tPSA and fPSA concentrations and their ratios have been measured by... more First, we should observe that tPSA and fPSA concentrations and their ratios have been measured by niche immunoassays restricted to few research centres: Hybritech Tandem-R (Beckman-Coulter) and Prostatus (Wallac), both calibrated against Hybritech International Standard (IS) [1,2]. The current generation of PSA immunoassays is re-calibrated to the WHO IS 96/670 resulting in ~20–25% lower PSA values and, accordingly, we expect an underestimation of the PSA-based risk of PCa death [3]. Furthermore considering that after the re-calibration to the WHO IS the inter-method bias has shifted from >22% to ~11%, we argue that the predictive ability of the suggested PSA thresholds to discontinue PSA-based screening, strictly depends on the methodology (i.e. although the antibodies may be those of current Beckman assay) and on the calibration used [3].
Clinical Chemistry and Laboratory Medicine (CCLM), 2022
reproduced without the permission of the copyright holder.
C l i n M e d International Library Citation: Orenti A, Biganzoli E, Boracchi P (2016) Estimating... more C l i n M e d International Library Citation: Orenti A, Biganzoli E, Boracchi P (2016) Estimating Relapse Free Survival as a Net Probability: Regression Models and Graphical Representation. An Application of a Large Breast Cancer Case Series. Int J Cancer Clin Res 3:063 Received: January 30, 2016: Accepted: August 10, 2016: Published: August 12, 2016 Copyright: © 2016 Orenti A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Orenti et al. Int J Cancer Clin Res 2016, 3:063
Clinical Nutrition, 2021
The characterization of folate status in subjects at risk of deficiency and with altered vitamin ... more The characterization of folate status in subjects at risk of deficiency and with altered vitamin homeostasis is crucial to endorse preventive intervention health policies, especially in developed countries. Several physiological changes (i.e. pregnancy), clinical situations and diseases have been associated to increased requirement, impaired intake and absorption of folate. However clinical practice guidelines (CPG) endorse folic acid supplementation generally discarding the use of its determination in serum to assess the risk of deficiency and/or its concentration at baseline. Poor confidence on the diagnostic accuracy of serum folate assays still persists in the current CPGs although recent standardization efforts have greatly improved inter-method variability and precision. In this review we critically appraise the methodological issues concerning laboratory folate determination and the evidence on the potential adverse effects of folic acid exposure. The final aim is to build a sound background to promote serum folate-based cost-effective health care policies by optimizing folic acid supplementation in subjects at risk of deficiency and with altered folate homeostasis. Our first result was to adjust in relation to current serum folate assays the thresholds reported by CPGs as index of folate status, defined on the association with metabolic and hematologic indicators. We identify a statistically significant difference between the estimated thresholds and accordingly show that the assessment of folate status actually changes in relation to the assay employed. The use of the method-dependent thresholds here reported may pragmatically endorse the stewardship of folic acid supplementation in clinical practice and increase the cost-effectiveness of health care policies.
Cancers, 2021
Simple Summary The initial treatment of early breast cancer has achieved important clinical resul... more Simple Summary The initial treatment of early breast cancer has achieved important clinical results over time. However, late recurrences after many years of disease-free survival remain an open question, which has recently attracted the attention of a few researchers. The authors of this commentary suggest that the approach emerging from scientific meetings regarding this subject is marred by the lack of attention to recent clinical and laboratory data. The role of tumor dormancy and the dynamics of disease recurrence are presented here and a more general reflection on therapeutic approaches to cancer is proposed. Abstract The problem of late recurrence in breast cancer has recently gained attention and was also addressed in an international workshop held in Toronto (ON, Canada), in which several aspects of the question were examined. This Commentary offers a few considerations, which may be useful for the ongoing investigations. A few premises are discussed: (a) clinical recurrence...
Children, 2021
Background: The prevalence of pediatric metabolic syndrome is usually closely linked to overweigh... more Background: The prevalence of pediatric metabolic syndrome is usually closely linked to overweight and obesity; however, this condition has also been described in children with disabilities. We performed a multivariate pattern analysis of metabolic profiles in neurologically impaired children and adolescents in order to reveal patterns and crucial biomarkers among highly interrelated variables. Patients and methods: We retrospectively reviewed 44 cases of patients (25M/19F, mean age 12.9 ± 8.0) with severe disabilities. Clinical and anthropometric parameters, body composition, blood pressure, and metabolic and endocrinological assessment (fasting blood glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, gamma-glutamyl transpeptidase) were recorded in all patients. As a control group, we evaluated 120 healthy children and adolescents (61M/59F, mean age 12.9 ± 2.7). Results: In th...
Journal of Infection, 2020
The Breast, 2020
Background: Dormant avascular micrometastases and single, or small groups of, non-proliferating c... more Background: Dormant avascular micrometastases and single, or small groups of, non-proliferating cells are currently assumed to explain the multipeak dynamics of distant metastases (DM) following primary breast cancer surgical removal. Methods: The hazard rate pattern for DM was analysed in 1518 premenopausal node-positive patients, enrolled in a series of randomized clinical trials on early breast cancer, which were carried out in Italy and Belgium. Patients underwent surgery alone (n ¼ 397) or surgery plus adjuvant chemotherapy (n ¼ 1121) and the minimal follow up was 15 years. Results: The DM hazard rate for patients undergoing surgery alone displayed two early sharp peaks at 9 and 33 months, a wide intermediate one spanning from about 50 to 90 months and a late peak at 115 e120 months. Adjuvant chemotherapy was associated with a prominent reduction of the two early peaks leaving a residual one at about 18 months and a reduction of the intermediate peak leaving two small peaks at about 50 and 80 months. The late peak remained unchanged. Conclusions: Present results reveal the ability of adjuvant chemotherapy to reduce not only the rate of early relapses, but also the rate of intermediate relapses at about the sixth year of follow up. Adjuvant chemotherapy is not impacting on the development of metastases underlying the late peak detected at the tenth year. These findings suggest the existence of a previously unknown dormancy state that, at the primary tumour surgical removal, results in evolving chemo-sensitive metastatic processes, and, moreover, of a later chemo-refractory dormancy state.
JNCI: Journal of the National Cancer Institute, 2018
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as... more Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI). Methods: We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n ¼ 529 with, n ¼ 298 without) or diclofenac (n ¼ 787 with, n ¼ 220 without). The BMI subgroups were defined as less than 25 kg/m 2 (lean) and 25 or more kg/m 2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided. Results: The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]¼ 0.59, 95% confidence interval [CI] ¼ 0.37 to 0.96, P ¼ .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR ¼ 0.55, 95% CI ¼ 0.31 to 0.96, P ¼ .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups. Conclusions: These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated over the last decades in several, mainly retrospective, consecutive or case-control studies for their potential role in preventing breast cancer development and progression (1,2). It should be noted that most of the studies so far, with some exceptions, have investigated the chronic use of NSAIDs globally, without accounting for the pharmacological properties specific to the different drugs. Additionally, NSAIDs, such as diclofenac and ketorolac, both COX-1 and-2 inhibitors, have been introduced over the past decades as effective pain
Journal of Clinical Oncology, 2001
PURPOSE: There is considerable interest in biologic markers able to predict the response of cance... more PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy...
International Journal of Molecular Sciences, 2016
In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients w... more In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease.
Clinical Lung Cancer, 2013
Event dynamics were evaluated in 1506 patients undergoing initial surgery for non-small-cell lung... more Event dynamics were evaluated in 1506 patients undergoing initial surgery for non-small-cell lung cancer. The hazard rate for distant metastases displayed a multipeak pattern with sex-dependent peak timing. Other patient and tumor characteristics did not modify peak position, whereas a factor-specific modulation of peak heights was also observed. The multipeak distant metastases dynamics may be an intrinsic feature of metastatic progression in non-small-cell lung cancer. Background: We studied event dynamics (probability of an event occurring over a specific time interval) in patients undergoing surgery for early-stage non-small-cell lung cancer (NSCLC) according to patient and tumor characteristics. Methods: By using a database of 1506 patients who underwent initial surgery for NSCLC, event dynamics, based on a time-specific hazard rate, were evaluated. The event of interest was the development of distant metastases, with or without a local recurrence. The effect of sex, tumor size, nodal involvement, histology, lymphovascular space invasion, pleural invasion, age, and race were studied. Results: The hazard rate for developing distant metastases was not constant over time but was characterized by specific peaks, the first being approximately 9 months after surgery and the second at 18 to 20 months for men and 24 to 26 months for women. For women, the hazard rate peaked considerably in the first year. For men, the hazard rate peaks were smaller but lasted for a longer duration. Pathologic factors associated with a higher risk of recurrence (eg, size, lymph node involvement, pleural invasion) all increased the sex-specific hazard rates. Conclusions: The probability of developing distant metastases after surgery for NSCLC peaks at specific and consistent time intervals after surgery, with specific differences between men and women. A factor-specific modulation of peak heights that ranged from no impact (eg, race) to relevant effects for primary tumor size, nodal involvement, and pleural invasion, possibly related to sex, was also observed. The bimodal distant metastases dynamics may be an intrinsic feature of metastatic progression in NSCLC.
Knowledge-Based Systems, 2011
Many algorithms have been proposed for the machine learning task of classification. One of the si... more Many algorithms have been proposed for the machine learning task of classification. One of the simplest methods, the naive Bayes classifier, has often been found to give good performance despite the fact that its underlying assumptions (of independence and a Normal distribution of the variables) are perhaps violated. In previous work, we applied naive Bayes and other standard algorithms to a breast cancer database from Nottingham City Hospital in which the variables are highly non-Normal and found that the algorithm performed well when predicting a class that had been derived from the same data. However, when we then applied naive Bayes to predict an alternative clinical variable, it performed much worse than other techniques. This motivated us to propose an alternative method, based on naive Bayes, which removes the requirement for the variables to be Normally distributed, but retains the essential structure and other underlying assumptions of the method. We tested our novel algorithm on our breast cancer data and on three UCI datasets which also exhibited strong violations of Normality. We found our algorithm outperformed naive Bayes in all four cases and outperformed multinomial logistic regression (MLR) in two cases. We conclude that our method offers a competitive alternative to MLR and naive Bayes when dealing with data sets in which non-Normal distributions are observed.
International Journal of Radiation Biology, 2010
To study whether ipsilateral breast tumour recurrence (IBTR) dynamics are modified by post-operat... more To study whether ipsilateral breast tumour recurrence (IBTR) dynamics are modified by post-operative radiotherapy (RT). Methods and materials: The hazard rate for IBTR was analysed in a database from patients undergoing breast conserving surgery with or without post-operative radiotherapy within randomised clinical trials from the Milan Cancer Institute. Results: The hazard rate for IBTR presents a bimodal pattern. Post-operative radiotherapy, in addition to reducing IBTR incidence from 24.5% to 5.8% at 10 years, causes more than a one year delay in its clinical manifestation. Distant metastasis dynamics are not modified by radiotherapy administration. Conclusions: In the light of a biology-based model of breast cancer metastasis development, IBTR peak delay most likely originates in a more prolonged dormancy time that, in turn, is related to local microenvironment conditions. Present clinical findings suggest that, besides a direct killing effect on residual tumour cells, microenvironmental modifications may play a major role in RT effectiveness.
BackgroundThe ability to identify the positive subjects is crucial for public health practice to ... more BackgroundThe ability to identify the positive subjects is crucial for public health practice to reduce transmission and supporting contact tracing and isolation. The reliability of the criteria of the test-based criteria as the required condition for the reintroduction of the asymptomatic and positive patients of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the community was evaluated assessing the time span from positive to negative for RNA detection by Real Time – Polymerase Chain Reaction (RT-PCR). Methods. We used information concerning negative conversion time and the respective times. Cumulative probabilities of negative conversion time during the follow-up were evaluated by Crude Cumulative Incidences (CCIs). Non-parametric estimates of CCIs and respective 95% C.I.s were obtained.Results. We report the results for 52,186 individuals. 33486 subjects resulted negative or potentially negative with a CCI of 75.2% at 70 days from the first swab (95% CI: 74.8% t...
Advances in Computational …, 2011
Abstract. This paper presents a new compensation mechanism to be used with a Partial Logistic Art... more Abstract. This paper presents a new compensation mechanism to be used with a Partial Logistic Artificial Neural Network for Competing Risks with Automatic Relevance Determination (PLANN-CR-ARD) and tested comprehensibly on a real breast cancer dataset with ...
International Journal of Environmental Research and Public Health
The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but ... more The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast and other solid cancers is compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.
Clinical Chemistry and Laboratory Medicine (CCLM), 2022
Clinical practice guidelines (CPGs) on screening, surveillance, and treatment of several diseases... more Clinical practice guidelines (CPGs) on screening, surveillance, and treatment of several diseases recommend the selective use of biomarkers with central role in clinical decision-making and move towards including patients in this process. To this aim we will clarify the multidisciplinary interactions required to properly measure the cost-effectiveness of biomarkers with regard to the risk-benefit of the patients and how Health Technology Assessment (HTA) approach may assess value of biomarkers integrated within the decision-making process. HTA through the interaction of different skills provides high-quality research information on the effectiveness, costs, and impact of health technologies, including biomarkers. The biostatistical methodology is relevant to HTA but only meta-analysis is covered in depth, whereas proper approaches are needed to estimate the benefit-risk balance ratio. Several biomarkers underwent HTA evaluation and the final reports have pragmatically addressed: 1) ...
BJU International, 2022
First, we should observe that tPSA and fPSA concentrations and their ratios have been measured by... more First, we should observe that tPSA and fPSA concentrations and their ratios have been measured by niche immunoassays restricted to few research centres: Hybritech Tandem-R (Beckman-Coulter) and Prostatus (Wallac), both calibrated against Hybritech International Standard (IS) [1,2]. The current generation of PSA immunoassays is re-calibrated to the WHO IS 96/670 resulting in ~20–25% lower PSA values and, accordingly, we expect an underestimation of the PSA-based risk of PCa death [3]. Furthermore considering that after the re-calibration to the WHO IS the inter-method bias has shifted from >22% to ~11%, we argue that the predictive ability of the suggested PSA thresholds to discontinue PSA-based screening, strictly depends on the methodology (i.e. although the antibodies may be those of current Beckman assay) and on the calibration used [3].
Clinical Chemistry and Laboratory Medicine (CCLM), 2022
reproduced without the permission of the copyright holder.
C l i n M e d International Library Citation: Orenti A, Biganzoli E, Boracchi P (2016) Estimating... more C l i n M e d International Library Citation: Orenti A, Biganzoli E, Boracchi P (2016) Estimating Relapse Free Survival as a Net Probability: Regression Models and Graphical Representation. An Application of a Large Breast Cancer Case Series. Int J Cancer Clin Res 3:063 Received: January 30, 2016: Accepted: August 10, 2016: Published: August 12, 2016 Copyright: © 2016 Orenti A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Orenti et al. Int J Cancer Clin Res 2016, 3:063
Clinical Nutrition, 2021
The characterization of folate status in subjects at risk of deficiency and with altered vitamin ... more The characterization of folate status in subjects at risk of deficiency and with altered vitamin homeostasis is crucial to endorse preventive intervention health policies, especially in developed countries. Several physiological changes (i.e. pregnancy), clinical situations and diseases have been associated to increased requirement, impaired intake and absorption of folate. However clinical practice guidelines (CPG) endorse folic acid supplementation generally discarding the use of its determination in serum to assess the risk of deficiency and/or its concentration at baseline. Poor confidence on the diagnostic accuracy of serum folate assays still persists in the current CPGs although recent standardization efforts have greatly improved inter-method variability and precision. In this review we critically appraise the methodological issues concerning laboratory folate determination and the evidence on the potential adverse effects of folic acid exposure. The final aim is to build a sound background to promote serum folate-based cost-effective health care policies by optimizing folic acid supplementation in subjects at risk of deficiency and with altered folate homeostasis. Our first result was to adjust in relation to current serum folate assays the thresholds reported by CPGs as index of folate status, defined on the association with metabolic and hematologic indicators. We identify a statistically significant difference between the estimated thresholds and accordingly show that the assessment of folate status actually changes in relation to the assay employed. The use of the method-dependent thresholds here reported may pragmatically endorse the stewardship of folic acid supplementation in clinical practice and increase the cost-effectiveness of health care policies.
Cancers, 2021
Simple Summary The initial treatment of early breast cancer has achieved important clinical resul... more Simple Summary The initial treatment of early breast cancer has achieved important clinical results over time. However, late recurrences after many years of disease-free survival remain an open question, which has recently attracted the attention of a few researchers. The authors of this commentary suggest that the approach emerging from scientific meetings regarding this subject is marred by the lack of attention to recent clinical and laboratory data. The role of tumor dormancy and the dynamics of disease recurrence are presented here and a more general reflection on therapeutic approaches to cancer is proposed. Abstract The problem of late recurrence in breast cancer has recently gained attention and was also addressed in an international workshop held in Toronto (ON, Canada), in which several aspects of the question were examined. This Commentary offers a few considerations, which may be useful for the ongoing investigations. A few premises are discussed: (a) clinical recurrence...
Children, 2021
Background: The prevalence of pediatric metabolic syndrome is usually closely linked to overweigh... more Background: The prevalence of pediatric metabolic syndrome is usually closely linked to overweight and obesity; however, this condition has also been described in children with disabilities. We performed a multivariate pattern analysis of metabolic profiles in neurologically impaired children and adolescents in order to reveal patterns and crucial biomarkers among highly interrelated variables. Patients and methods: We retrospectively reviewed 44 cases of patients (25M/19F, mean age 12.9 ± 8.0) with severe disabilities. Clinical and anthropometric parameters, body composition, blood pressure, and metabolic and endocrinological assessment (fasting blood glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, triglycerides, glutamic oxaloacetic transaminase, glutamate pyruvate transaminase, gamma-glutamyl transpeptidase) were recorded in all patients. As a control group, we evaluated 120 healthy children and adolescents (61M/59F, mean age 12.9 ± 2.7). Results: In th...
Journal of Infection, 2020
The Breast, 2020
Background: Dormant avascular micrometastases and single, or small groups of, non-proliferating c... more Background: Dormant avascular micrometastases and single, or small groups of, non-proliferating cells are currently assumed to explain the multipeak dynamics of distant metastases (DM) following primary breast cancer surgical removal. Methods: The hazard rate pattern for DM was analysed in 1518 premenopausal node-positive patients, enrolled in a series of randomized clinical trials on early breast cancer, which were carried out in Italy and Belgium. Patients underwent surgery alone (n ¼ 397) or surgery plus adjuvant chemotherapy (n ¼ 1121) and the minimal follow up was 15 years. Results: The DM hazard rate for patients undergoing surgery alone displayed two early sharp peaks at 9 and 33 months, a wide intermediate one spanning from about 50 to 90 months and a late peak at 115 e120 months. Adjuvant chemotherapy was associated with a prominent reduction of the two early peaks leaving a residual one at about 18 months and a reduction of the intermediate peak leaving two small peaks at about 50 and 80 months. The late peak remained unchanged. Conclusions: Present results reveal the ability of adjuvant chemotherapy to reduce not only the rate of early relapses, but also the rate of intermediate relapses at about the sixth year of follow up. Adjuvant chemotherapy is not impacting on the development of metastases underlying the late peak detected at the tenth year. These findings suggest the existence of a previously unknown dormancy state that, at the primary tumour surgical removal, results in evolving chemo-sensitive metastatic processes, and, moreover, of a later chemo-refractory dormancy state.
JNCI: Journal of the National Cancer Institute, 2018
Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as... more Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI). Methods: We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n ¼ 529 with, n ¼ 298 without) or diclofenac (n ¼ 787 with, n ¼ 220 without). The BMI subgroups were defined as less than 25 kg/m 2 (lean) and 25 or more kg/m 2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two-sided. Results: The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]¼ 0.59, 95% confidence interval [CI] ¼ 0.37 to 0.96, P ¼ .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR ¼ 0.55, 95% CI ¼ 0.31 to 0.96, P ¼ .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups. Conclusions: These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been evaluated over the last decades in several, mainly retrospective, consecutive or case-control studies for their potential role in preventing breast cancer development and progression (1,2). It should be noted that most of the studies so far, with some exceptions, have investigated the chronic use of NSAIDs globally, without accounting for the pharmacological properties specific to the different drugs. Additionally, NSAIDs, such as diclofenac and ketorolac, both COX-1 and-2 inhibitors, have been introduced over the past decades as effective pain
Journal of Clinical Oncology, 2001
PURPOSE: There is considerable interest in biologic markers able to predict the response of cance... more PURPOSE: There is considerable interest in biologic markers able to predict the response of cancer patients to therapy. HER2 overexpression is a potential indicator of responsiveness to doxorubicin and paclitaxel and of unresponsiveness to tamoxifen in breast carcinoma patients. However, the significance of HER2 overexpression in responsiveness to cyclophosphamide, methotrexate, and fluorouracil (CMF) has remained unclear. In this study, we investigated this issue in the 386 breast cancer patients in the first CMF controlled clinical trial with a 20-year follow-up. PATIENTS AND METHODS: Node-positive breast carcinoma patients were randomly assigned to receive either no further treatment after radical mastectomy (179 women) or 12 monthly cycles of adjuvant CMF chemotherapy (207 women). Overexpression of HER2 and the status of other tumor variables was assessed by immunohistochemistry in at least 324 (84%) of the 386 patients. Statistical analyses were performed to assess the efficacy...
International Journal of Molecular Sciences, 2016
In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients w... more In order to evaluate the serum anti-skin autoantibodies and cytokine concentrations in patients with different epidermolysis bullosa (EB) types and severity, 42 EB patients and 38 controls were enrolled. Serum anti-skin antibodies were significantly higher in the patients than in the controls (p = 0.008, p < 0.001, p < 0.001, p < 0.001 and p < 0.001 for desmoglein 1 (DSG1) desmoglein 3 (DSG3), bullous pemphigoid 180 (BP180), BP230 and type VII collagen (COL7), respectively). The same trend was observed for interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor-β, and interferon-γ (p < 0.001, p < 0.001, p < 0.001, p = 0.008, p < 0.001 and p = 0.002, respectively). Increases in anti-skin antibodies and cytokine concentrations were higher in patients with recessive dystrophic EB than in those with different types of EB, in generalized cases than in localized ones, and in patients with higher Birmingham Epidermolysis Bullosa Severity (BEBS) scores than in those with a lower score. The BEBS score was directly correlated with BP180, BP230, COL7 (p = 0.015, p = 0.008 and p < 0.001, respectively) and IL-6 (p = 0.03), whereas IL-6 appeared significantly associated with DSG1, DSG3, BP180, BP230 and COL7 (p = 0.015, p = 0.023, p = 0.023, p = 0.015 and p = 0.005, respectively). This study showed that autoimmunity and inflammatory responses are frequently activated in EB, mainly in severe forms, suggesting the use of immunosuppressive drugs or biologicals that are active against pro-inflammatory cytokines to reduce clinical signs and symptoms of disease.
Clinical Lung Cancer, 2013
Event dynamics were evaluated in 1506 patients undergoing initial surgery for non-small-cell lung... more Event dynamics were evaluated in 1506 patients undergoing initial surgery for non-small-cell lung cancer. The hazard rate for distant metastases displayed a multipeak pattern with sex-dependent peak timing. Other patient and tumor characteristics did not modify peak position, whereas a factor-specific modulation of peak heights was also observed. The multipeak distant metastases dynamics may be an intrinsic feature of metastatic progression in non-small-cell lung cancer. Background: We studied event dynamics (probability of an event occurring over a specific time interval) in patients undergoing surgery for early-stage non-small-cell lung cancer (NSCLC) according to patient and tumor characteristics. Methods: By using a database of 1506 patients who underwent initial surgery for NSCLC, event dynamics, based on a time-specific hazard rate, were evaluated. The event of interest was the development of distant metastases, with or without a local recurrence. The effect of sex, tumor size, nodal involvement, histology, lymphovascular space invasion, pleural invasion, age, and race were studied. Results: The hazard rate for developing distant metastases was not constant over time but was characterized by specific peaks, the first being approximately 9 months after surgery and the second at 18 to 20 months for men and 24 to 26 months for women. For women, the hazard rate peaked considerably in the first year. For men, the hazard rate peaks were smaller but lasted for a longer duration. Pathologic factors associated with a higher risk of recurrence (eg, size, lymph node involvement, pleural invasion) all increased the sex-specific hazard rates. Conclusions: The probability of developing distant metastases after surgery for NSCLC peaks at specific and consistent time intervals after surgery, with specific differences between men and women. A factor-specific modulation of peak heights that ranged from no impact (eg, race) to relevant effects for primary tumor size, nodal involvement, and pleural invasion, possibly related to sex, was also observed. The bimodal distant metastases dynamics may be an intrinsic feature of metastatic progression in NSCLC.
Knowledge-Based Systems, 2011
Many algorithms have been proposed for the machine learning task of classification. One of the si... more Many algorithms have been proposed for the machine learning task of classification. One of the simplest methods, the naive Bayes classifier, has often been found to give good performance despite the fact that its underlying assumptions (of independence and a Normal distribution of the variables) are perhaps violated. In previous work, we applied naive Bayes and other standard algorithms to a breast cancer database from Nottingham City Hospital in which the variables are highly non-Normal and found that the algorithm performed well when predicting a class that had been derived from the same data. However, when we then applied naive Bayes to predict an alternative clinical variable, it performed much worse than other techniques. This motivated us to propose an alternative method, based on naive Bayes, which removes the requirement for the variables to be Normally distributed, but retains the essential structure and other underlying assumptions of the method. We tested our novel algorithm on our breast cancer data and on three UCI datasets which also exhibited strong violations of Normality. We found our algorithm outperformed naive Bayes in all four cases and outperformed multinomial logistic regression (MLR) in two cases. We conclude that our method offers a competitive alternative to MLR and naive Bayes when dealing with data sets in which non-Normal distributions are observed.
International Journal of Radiation Biology, 2010
To study whether ipsilateral breast tumour recurrence (IBTR) dynamics are modified by post-operat... more To study whether ipsilateral breast tumour recurrence (IBTR) dynamics are modified by post-operative radiotherapy (RT). Methods and materials: The hazard rate for IBTR was analysed in a database from patients undergoing breast conserving surgery with or without post-operative radiotherapy within randomised clinical trials from the Milan Cancer Institute. Results: The hazard rate for IBTR presents a bimodal pattern. Post-operative radiotherapy, in addition to reducing IBTR incidence from 24.5% to 5.8% at 10 years, causes more than a one year delay in its clinical manifestation. Distant metastasis dynamics are not modified by radiotherapy administration. Conclusions: In the light of a biology-based model of breast cancer metastasis development, IBTR peak delay most likely originates in a more prolonged dormancy time that, in turn, is related to local microenvironment conditions. Present clinical findings suggest that, besides a direct killing effect on residual tumour cells, microenvironmental modifications may play a major role in RT effectiveness.
BackgroundThe ability to identify the positive subjects is crucial for public health practice to ... more BackgroundThe ability to identify the positive subjects is crucial for public health practice to reduce transmission and supporting contact tracing and isolation. The reliability of the criteria of the test-based criteria as the required condition for the reintroduction of the asymptomatic and positive patients of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the community was evaluated assessing the time span from positive to negative for RNA detection by Real Time – Polymerase Chain Reaction (RT-PCR). Methods. We used information concerning negative conversion time and the respective times. Cumulative probabilities of negative conversion time during the follow-up were evaluated by Crude Cumulative Incidences (CCIs). Non-parametric estimates of CCIs and respective 95% C.I.s were obtained.Results. We report the results for 52,186 individuals. 33486 subjects resulted negative or potentially negative with a CCI of 75.2% at 70 days from the first swab (95% CI: 74.8% t...
Advances in Computational …, 2011
Abstract. This paper presents a new compensation mechanism to be used with a Partial Logistic Art... more Abstract. This paper presents a new compensation mechanism to be used with a Partial Logistic Artificial Neural Network for Competing Risks with Automatic Relevance Determination (PLANN-CR-ARD) and tested comprehensibly on a real breast cancer dataset with ...
International Journal of Environmental Research and Public Health
The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but ... more The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast and other solid cancers is compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.