ABSTRACT
Networks consist of interconnected units, known as nodes, and allow to formally describe interactions within a system. Specifically, bipartite networks depict relationships between two distinct sets of nodes, designated as sending and receiving nodes. An integral aspect of bipartite network analysis often involves identifying clusters of nodes with similar behaviors. The computational complexity of models for large bipartite networks poses a challenge. To mitigate this challenge, we employ a Mixture of Latent Trait Analyzers (MLTA) for node clustering. Our approach extends the MLTA to include covariates and introduces a double EM algorithm for estimation. Applying our method to COVID-19 data, with sending nodes representing patients and receiving nodes representing preventive measures, enables dimensionality reduction and the identification of meaningful groups. We present simulation results demonstrating the accuracy of the proposed method.
Subject(s)
Algorithms , COVID-19 , Models, Statistical , Humans , Computer Simulation , Cluster Analysis , SARS-CoV-2ABSTRACT
Ovarian cancer (OC) is the most lethal of all gynecological cancers. Due to vague symptoms, OC is mostly detected at advanced stages, with a 5-year survival rate (SR) of only 30%; diagnosis at stage I increases the 5-year SR to 90%, suggesting that early diagnosis is essential to cure OC. Currently, the clinical need for an early, reliable diagnostic test for OC screening remains unmet; indeed, screening is not even recommended for healthy women with no familial history of OC for fear of post-screening adverse events. Salivary diagnostics is considered a major resource for diagnostics of the future. In this work, we searched for OC biomarkers (BMs) by comparing saliva samples of patients with various stages of OC, breast cancer (BC) patients, and healthy subjects using an unbiased, high-throughput proteomics approach. We analyzed the results using both logistic regression (LR) and machine learning (ML) for pattern analysis and variable selection to highlight molecular signatures for OC and BC diagnosis and possibly re-classification. Here, we show that saliva is an informative test fluid for an unbiased proteomic search of candidate BMs for identifying OC patients. Although we were not able to fully exploit the potential of ML methods due to the small sample size of our study, LR and ML provided patterns of candidate BMs that are now available for further validation analysis in the relevant population and for biochemical identification.
Subject(s)
Ovarian Neoplasms , Saliva , Humans , Female , Proteomics/methods , Logistic Models , Ovarian Neoplasms/diagnosis , Biomarkers, Tumor , Machine LearningABSTRACT
Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.
Subject(s)
Antineoplastic Agents/adverse effects , Ovarian Neoplasms/drug therapy , Phthalazines/adverse effects , Piperazines/adverse effects , Poly(ADP-ribose) Polymerase Inhibitors/adverse effects , Anemia/chemically induced , Antineoplastic Agents/therapeutic use , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Fatigue/chemically induced , Female , Humans , Italy , Mutation , Nausea/chemically induced , Nausea/therapy , Neoplasm Recurrence, Local/drug therapy , Ovarian Neoplasms/genetics , Phthalazines/therapeutic use , Piperazines/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Vomiting/chemically inducedABSTRACT
OBJECTIVE: Fear of recurrence is a crucial issue in cancer care. On the one hand, the increase of cancer-survival rates and complexity of care is exposing patients to this type of fear. On the other hand, it is a distressing and recurrent psychosocial risk that affects quality of life and adherence to follow-up. Patients should have access to targeted psychological interventions aimed at reducing or preventing fear of recurrence. This mixed-methods pilot study reports the preliminary results of a novel mindfulness- and metacognition-based intervention specifically targeting fear of recurrence. METHODS: The study was composed of an individual (n = 76) and a group (n = 38) intervention, both lasting 8 weeks, that were evaluated through a preassessment and postassessment and a 1-month follow-up. We enrolled women recovering from breast cancer (n = 114) in follow-up care, with significant psychosocial distress. Patients with more severe psychopathology were assigned to the individual treatment, whereas the less severe ones were assigned to the group treatment. We explored the distress and the fear of recurrence through standardized measures and in-depth qualitative interviews. RESULTS: Results showed that depressive, anxious, and post-traumatic symptoms were reduced significantly in the entire sample. Patients reported a significant reduction of fear of recurrence, which was described in terms of loss of control, increase of uncertainty, and decrease of metacognitive and interpersonal skills. CONCLUSIONS: Although further studies are needed, these findings provide preliminary proof-of-concept results for the potential of integrated mindfulness- and metacognition-based interventions to reduce fear of recurrence in cancer patients.
Subject(s)
Breast Neoplasms/psychology , Fear/psychology , Metacognition , Mindfulness/methods , Neoplasm Recurrence, Local/psychology , Quality of Life/psychology , Adult , Anxiety/psychology , Female , Humans , Middle Aged , Pilot Projects , Stress, Psychological/psychologyABSTRACT
One of the most relevant problems in principal component analysis and factor analysis is the interpretation of the components/factors. In this paper, disjoint principal component analysis model is extended in a maximum-likelihood framework to allow for inference on the model parameters. A coordinate ascent algorithm is proposed to estimate the model parameters. The performance of the methodology is evaluated on simulated and real data sets.
Subject(s)
Principal Component Analysis , Probability , Algorithms , Computer Simulation , Data Interpretation, Statistical , Humans , Intelligence Tests , Likelihood FunctionsSubject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immune Tolerance/immunology , Neoplasms/radiotherapy , 2019-nCoV Vaccine mRNA-1273 , Adult , Adverse Drug Reaction Reporting Systems , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/adverse effects , Female , Humans , Immune Tolerance/genetics , Male , Middle Aged , Neoplasms/complications , Neoplasms/immunology , Neoplasms/virology , Radiation Oncology/trends , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicityABSTRACT
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.
Subject(s)
Algorithms , Alternative Splicing/genetics , Insulin-Like Growth Factor I/genetics , RNA, Messenger/genetics , Cluster Analysis , Female , Gene Expression Profiling , Humans , Male , Normal Distribution , Protein Isoforms , RNA Isoforms , Real-Time Polymerase Chain ReactionABSTRACT
The European Medicines Agency strongly recommends administration of trabectedin through a central venous catheter (CVC) to minimize the risk of extravasation. However, CVCs place patients at risk of catheter-related complications and have a significant budgetary impact for oncology departments. The most frequently used CVCs are subcutaneously implanted PORT-chamber catheters (PORTs); peripherally inserted central venous catheters (PICCs) are relatively new. We reviewed data of trabectedin-treated patients to evaluate the relative cost-effectiveness of the use of PORTs and PICCs in six Italian centres. Data on 102 trabectedin-treated patients (20 with sarcoma, 80 with ovarian cancer and two with cervical cancer) were evaluated. Forty-five patients received trabectedin by a PICC, inserted by trained nurses using an ultrasound-guided technique at the bedside, whereas 57 patients received trabectedin infusion by a PORT, requiring a day surgery procedure in the hospital by a surgeon. Device dislocation and infections were reported in four patients, equally distributed between PORT or PICC users. Thrombosis occurred in a single patient with a PORT. Complications requiring devices removal were not reported during any of the 509 cycles of therapy (median 5; range 1-20). PICC misplacement or early malfunctions were not reported during trabectedin infusion. The cost-efficiency ratio favours PORT over PICC only when the device is used for more than 1 year. Our data suggest that trabectedin infusion by PICC is safe and well accepted, with a preferable cost-efficiency ratio compared with PORT in patients requiring short-term use of the device (≤1 year).
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Catheterization, Peripheral , Central Venous Catheters , Dioxoles/administration & dosage , Tetrahydroisoquinolines/administration & dosage , Adult , Aged , Catheterization, Peripheral/economics , Central Venous Catheters/economics , Cost-Benefit Analysis , Female , Humans , Infusions, Intravenous , Italy , Male , Middle Aged , Retrospective Studies , TrabectedinABSTRACT
AIM: EMA licensed eribulin mesylate in 2011 for women with advanced breast cancer already treated with at least two lines of chemotherapy, including anthracyclines and taxanes. Azienda Sanitaria Firenze experience is reported to assess the efficacy and safety of eribulin in the real-life setting. PATIENTS & METHODS: Eribulin was infused as per indication. All women treated in the last 2 years were reviewed. RESULTS: A total of 27 women received eribulin. All but one was pretreated with anthracyclines, 97% with taxanes and 87% with capecitabine. Median age was 63 years (range: 27-80). A median of four cycles of eribulin were infused (range: 2-10). Overall response rate was 30% with a 45% of clinical benefit (response plus stable disease for at least 24 weeks). Toxicities have been as expected. Severe toxicities were rare, with one patient experiencing sepsis and 18% developing grade 3 asthenia. CONCLUSION: Eribulin maintains its activity out of clinical trials, without unexpected toxicities.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Furans/therapeutic use , Ketones/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/mortality , Female , Furans/administration & dosage , Furans/adverse effects , Humans , Ketones/administration & dosage , Ketones/adverse effects , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Retrospective Studies , Treatment Outcome , Young AdultSubject(s)
Papillomavirus Vaccines/immunology , Uterine Cervical Dysplasia/therapy , Uterine Cervical Neoplasms/therapy , Vaccination , Adult , Female , Humans , Middle Aged , Papillomaviridae/isolation & purification , Prospective Studies , Uterine Cervical Neoplasms/virology , Uterine Cervical Dysplasia/virologyABSTRACT
BACKGROUND AND PURPOSE: Data on immunoresponse after SARS-CoV-2 vaccines for patients treated with exclusive radiotherapy (RT) are scarce. Since RT may affect the immune system, we conducted the MORA trial (Antibody response and cell-mediated immunity of MOderna mRNA-1273 vaccine in patients treated with RAdiotherapy). MATERIALS AND METHODS: Data regarding humoral and cellular immune response of patients treated with RT were prospectively collected after the second and third dose of mRNA vaccines. RESULTS: Ninety-two patients were enrolled. With a median of 147 days after the second dose, the median SARS-CoV-2 IgG titer was 300 BAU/mL: six patients were seronegative (Spike IgG titer ≤ 40 BAU/mL), whereas 24, 46 and 16 were poor responders (Spike IgG titer:41-200 BAU/mL), responders (Spike IgG titer:201-800 BAU/mL) and ultraresponders (Spike IgG titer > 800 BAU/mL), respectively. Among seronegative patients, two patients were negative also for cell mediated response, as tested with IFN-γ release Assay (IGRA) test. With a median of 85 days after the third dose, the median SARS-CoV-2 IgG titer was 1632 BAU/mL in 81 patients: only two patients were seronegative, whereas 16 and 63 patients were responders and ultraresponders, respectively. Among the 2 persistently seronegative patients, IGRA test was negative in one who had previously received anti-CD20 therapy. Documented paucisymptomatic (n = 3) or asymptomatic (n = 4) infection occurred after the third dose, during the Omicron wave. CONCLUSION: In patients treated with exclusive RT, even during the Omicron breakthrough, robust humoral response and clinical protection from severe SARS-CoV-2 disease were achievable with three doses of mRNA vaccine.
Subject(s)
COVID-19 , Neoplasms , Humans , 2019-nCoV Vaccine mRNA-1273 , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , SARS-CoV-2 , mRNA Vaccines , Neoplasms/radiotherapy , Antibodies, Viral , Immunoglobulin GABSTRACT
BACKGROUND: International and national oncology societies had released recommendations in favor of COVID-19 vaccination in cancer patients. In the context of the national vaccination campaign targeting the so called extremely vulnerable, we aimed to assess the safety and efficacy of the mRNA vaccines in a cohort of 623 patients. METHODS: Between March 26 and April 04, 2021, the Pfizer and BioNTech BNT162b2 mRNA and the Moderna mRNA-1273 vaccines were given as a two-dose prime-boost regimen. Starting on September 25th 2021 a third dose was offered to patients in whom a suboptimal immunogenicity with COVID-19 vaccination could be expected. Safety assessments were performed by phone call 7 days after each dose. Electronic health records were accessed to review demographic information, disease history, treatment detail, and outcome events of participants patients'. FINDINGS: No toxicities were reported in 63.7%, 54%, and in 48.7% patients with cancer after each dose. Mild-to-moderate pain at the injection site was the most commonly adverse event. After the second dose, 46% of the 610 patients reported toxicity, with more systemic side-effects observed. Fever was reported in 45% of patients, with a temperature ≥ 38 °C in 21.4% of them. Of the 335 patients receiving a third vaccine dose, 51% reported toxicity, with 13% of patients reporting more than one effect. Logistic regression analysis reported mixed results, with limited variables or categories reporting a significant odd ratio. The type of vaccine reported a significant value at first dose (OR = 0.12; CI 0.52, 0.26; p = 0.00). Thirty-four cases of COVID-19 infection were reported with only one patient requiring a short-term hospitalization for monitoring. INTERPRETATION: The safety profile of the mRNA vaccines does not raise any specific concerns and support prioritization of vaccination for cancer patients.
Subject(s)
COVID-19 , Neoplasms , Vaccines , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Immunization Programs , Medical Oncology , Neoplasms/chemically induced , Neoplasms/therapy , Vaccination/adverse effects , Vaccines/adverse effectsABSTRACT
IMPORTANCE: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. OBJECTIVE: To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. INTERVENTIONS: Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated. MAIN OUTCOMES AND MEASURES: The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). RESULTS: The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P < .001). The number of patients showing a reduction of 10% or greater in 3D-LVEF was 8 (19%) in the placebo arm, 5 (11.5%) in the ramipril arm, 5 (11.4%) in the bisoprolol, arm and 3 (6.8%) in the ramipril plus bisoprolol arm; 15 patients (35.7%) who received placebo showed a 10% or greater worsening of GLS compared with 7 (15.9; ramipril), 6 (13.6%; bisoprolol), and 6 (13.6%; ramipril plus bisoprolol) (P = .03). CONCLUSIONS AND RELEVANCE: The interim analysis of this randomized clinical trials suggested that cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodeling. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT2236806.
Subject(s)
Anthracyclines , Breast Neoplasms , Anthracyclines/adverse effects , Breast Neoplasms/pathology , Female , Humans , Middle Aged , Stroke Volume , Trastuzumab/adverse effects , Ventricular Function, LeftABSTRACT
AIMS AND BACKGROUND: Docetaxel is an active agent in metastatic cancers. The standard administration every 3 weeks frequently causes gastrointestinal toxicity and severe myelosuppression. These are rare with a weekly docetaxel regimen, which instead produces severe asthenia. To develop a new docetaxel schedule associated with mild myelosuppression and less fatigue, we conducted this pilot study to determine the feasibility and the maximum tolerated dose of a day one and eight every three weeks administration of docetaxel. PATIENTS AND METHODS: The first 3 patients were treated with a dose of 40 mg/m2 on day one and eight, which was then escalated by increments of 5 mg/m2 on both days up to determine the maximum tolerated dose, defined as the dose level associated with the same dose-limiting toxicity in at least 33% of patients. RESULTS: Twenty-one metastatic cancer patients entered the study, with a median age of 57 years and a median performance status of 1. The escalation of dose continued up to 55 mg/m2, where 2 of the 6 enrolled patients presented grade 3 diarrhea, which was our dose-limiting toxicity. Myelosuppression was mild, and no febrile neutropenia was observed. None of the patients showed grade 4 non-haematological toxicity. Only 9.5% of them presented grade 3 asthenia, whereas grade 3 diarrhea and mucositis were revealed in 19% and 9.5%, respectively. All grade 3 non-hematological toxicities were observed in heavily pretreated or elderly patients. CONCLUSIONS: The recommended dose of docetaxel was 50 mg/m2, but the regimen could not be recommended in heavily pretreated patients. However, it could become an option in an outpatient setting after a phase II study that better defines its toxicity profile and evaluate its antitumor activity.
Subject(s)
Neoplasm Metastasis/drug therapy , Neoplasms/drug therapy , Taxoids/administration & dosage , Adult , Aged , Diarrhea/chemically induced , Docetaxel , Drug Administration Schedule , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Mucositis/chemically induced , Neoplasms/complications , Neoplasms/pathology , Pilot Projects , Taxoids/toxicityABSTRACT
Over the years, thanks to the addition of new generation systemic agents, as well as the use of more advanced and precise radiotherapy techniques, it was able to obtain a high curability rate for breast cancer. Anthracyclines play a key role in the treatment of breast disease, with a well-known benefit on disease-free survival of patients with positive nodal status. Trastuzumab have shown a significant outcome advantage after 1-year administration in case of HER2-positive disease. Unfortunately, significant increase in cardiotoxicity has been observed after anthracyclines and trastuzumab therapies. Even though the cardiology and oncology community strongly recommend a cardiotoxicity prevention strategy for this subset of patients, there is still no consensus on the optimal patient's approach. We aimed to review the published and ongoing researches on cardioprevention strategies and to present the SAFE trial (CT registry ID: NCT2236806; EudraCT number: 2015-000914-23). It is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effect of bisoprolol, ramipril or both drugs, compared to placebo, on subclinical heart damage evaluated by speckle tracking cardiac ultrasound in non-metastatic breast cancer patients.
Subject(s)
Anthracyclines/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Cardiotonic Agents/therapeutic use , Cardiotoxicity/prevention & control , Trastuzumab/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bisoprolol/therapeutic use , Clinical Trials, Phase III as Topic , Female , Humans , Ramipril/therapeutic use , Randomized Controlled Trials as Topic , Trastuzumab/administration & dosageABSTRACT
BACKGROUND: Ductal carcinoma in situ (DCIS) is a heterogeneous disease, for which the best adjuvant treatment is still uncertain. Many attempts of risk-groups stratification have been made over time, developing prognostic scores to predict risk of local recurrence (LR) on the basis of features such as age, final surgical margins (FSM) status, grade, and tumor size. The aim of our analysis was to evaluate the patterns of recurrence from a two large-institutional retrospective series. PATIENTS AND METHODS: We collected data on 457 patients treated with BCS and adjuvant RT between 1990 and 2012. Final analysis was performed on 278 patients, due to missing data about hormonal status (HS). Patients were treated at the Radiation Oncology Unit of the University of Florence (n = 195), and S. Maria Annunziata Hospital (n = 83) (Florence, Italy). RESULTS: At a median follow up time of 10.8 years (range 3-25), we observed 20 LR (7.2%). The 5-year and 10-year LR rates were 4.9% and 10.2%, respectively. At Cox regression univariate analysis, estrogen receptor (ER) positive status (p = 0.001), HS positive (p = 0.003), and FSM <1 mm (p = 0.0001) significantly impacted on LR. At Cox regression multivariate analysis positive ER status maintained a protective role (p = 0.003), and FSM status <1 mm its negative impact (p = 0.0001) on LR rate. CONCLUSIONS: Our experience confirmed the wide heterogeneity of DCIS. Inadequate FSM and negative ER status negatively influenced LR rates. Tumor biology should be integrated in adjuvant treatment decision-making process.
Subject(s)
Breast Neoplasms/chemistry , Carcinoma, Intraductal, Noninfiltrating/therapy , Mastectomy, Segmental/methods , Receptors, Estrogen/analysis , Adult , Aged , Breast Neoplasms/therapy , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Middle Aged , Proportional Hazards Models , Radiotherapy, Adjuvant/methods , Regression Analysis , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: It is not clear if progression-free survival (PFS) is a good surrogate end-point for overall survival (OS) for metastatic colorectal cancer if antiangiogenic therapies are used. MATERIALS AND METHODS: We investigated randomized controlled trials testing antiangiogenic agents against chemotherapy. Log hazard ratios (HR) for PFS and OS were used to construct linear regression models. The surrogate threshold effect (STE) was calculated. RESULTS: Thirteen studies and 24 comparison arms were available, including 7,179 patients. This model returned a significant correlation between PFS and OS (R(2)=0.68, p<0.001) with an STE of 0.83. Analysis restricted to first-line gave similar results (R(2)=0.68, p<0.001, STE=0.75). CONCLUSION: There is a significant correlation between the effect of treatment on PFS and OS. PFS remains a good surrogate end-point for OS even if anti-angiogenic agents are used.
Subject(s)
Bevacizumab/administration & dosage , Colorectal Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Angiogenesis Inhibitors/administration & dosage , Biomarkers , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/pathology , Disease-Free Survival , Humans , Neovascularization, Pathologic/epidemiology , Neovascularization, Pathologic/pathology , Randomized Controlled Trials as TopicSubject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Furans/administration & dosage , Ketones/administration & dosage , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Feasibility Studies , Female , Furans/adverse effects , Humans , Ketones/adverse effects , Retrospective StudiesABSTRACT
OBJECTIVES: Customized chemotherapy has several advantages: patients are more likely to be treated with the most effective agents and can be spared the toxicity of ineffective drugs. Based on the literature, excision repair cross complementation group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) genes represent predictive biomarkers of response to platinum compound and gemcitabine, in NSCLC. MATERIALS AND METHODS: We had planned a phase II trial (Simon design) to evaluate combination chemotherapy according to single nucleotide polymorphisms (SNPs) of ERCC1 (118T/C and 8092C/A) and RRM1 (-37C/A and -524T/C) in naïve patients affected by advanced NSCLC. ERCC1 and RRM1 SNPs assessment was performed in peripheral blood lymphocytes (PBLs). Combination chemotherapy was selected based on ERCC1 and RRM1 SNPs: we assume that patients with one or two C alleles at position 118 and with one or two A alleles at position 8092 in ERCC1 gene would correspond to Cisplatin non-responder and than with two A alleles at -37 and two C alleles at -524 in RRM1 gene to gemcitabine non-responder. Four schedules were provided: cisplatin+gemcitabine, cisplatin+docetaxel, gemcitabine+docetaxel; docetaxel+vinorelbine. Primary endpoint was overall response (ORR) in the intention-to-treat population. RESULTS: 42 patients were enrolled from January 2010 to November 2011; 40 patients received at least 1 cycle of chemotherapy; median age was 66 years (range: 47-72); 36(90%) had stage IV, 4(10%) IIIB; 23(58%) had adenocarcinoma, 14(35%) squamous carcinoma. Twenty-five (62%) patients received treatment A, 3(8%) treatment B, 11(28%) treatment C, 1(23%) treatment D. ORR was 55%, analysis in squamous patients subgroups showed 71.4% ORR. The median follow-up was 19.7 months, PFS was 23 weeks (95% CI = 15-26) and OS was 40.4 weeks (95% CI = 32-55). Treatment was well tolerated. CONCLUSION: We observed an increase of ORR in NSCLC patients when they were treated with chemotherapy according to ERCC1 and RRM1 SNPs status.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , DNA-Binding Proteins/genetics , Endonucleases/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Polymorphism, Single Nucleotide , Tumor Suppressor Proteins/genetics , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Follow-Up Studies , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Ribonucleoside Diphosphate Reductase , Treatment Outcome , GemcitabineABSTRACT
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.