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1.
Eur J Cancer ; 147: 120-127, 2021 04.
Article in English | MEDLINE | ID: mdl-33647547

ABSTRACT

INTRODUCTION: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer. MATERIALS AND METHODS: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause. RESULTS: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia. CONCLUSIONS: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection.


Subject(s)
COVID-19/diagnosis , COVID-19/epidemiology , Neoplasms/diagnosis , Neoplasms/epidemiology , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19/pathology , Community Networks , Disease Progression , Female , Hospital Mortality , Hospitalization/statistics & numerical data , Humans , Intensive Care Units/statistics & numerical data , Italy/epidemiology , Male , Middle Aged , Neoplasms/complications , Neoplasms/pathology , Pandemics , Prognosis , Registries , SARS-CoV-2/physiology , Severity of Illness Index
2.
Pharmacol Res Perspect ; 8(5): e00646, 2020 10.
Article in English | MEDLINE | ID: mdl-32813313

ABSTRACT

In previous studies, steady-state Z-endoxifen plasma concentrations (ENDOss) correlated with relapse-free survival in women on tamoxifen (TAM) treatment for breast cancer. ENDOss also correlated significantly with CYP2D6 genotype (activity score) and CYP2D6 phenotype (dextromethorphan test). Our aim was to ascertain which method for assessing CYP2D6 activity is more reliable in predicting ENDOss. The study concerned 203 Caucasian women on tamoxifen-adjuvant therapy (20 mg q.d.). Before starting treatment, CYP2D6 was genotyped (and activity scores computed), and the urinary log(dextromethorphan/dextrorphan) ratio [log(DM/DX)] was calculated after 15 mg of oral dextromethorphan. Plasma concentrations of TAM, N-desmethyl-tamoxifen (ND-TAM), Z-4OH-tamoxifen (4OH-TAM) and ENDO were assayed 1, 4, and 8 months after first administering TAM. Multivariable regression analysis was used to identify the clinical and laboratory variables predicting log-transformed ENDOss (log-ENDOss). Genotype-derived CYP2D6 phenotypes (PM, IM, NM, EM) and log(DM/DX) correlated independently with log-ENDOss. Genotype-phenotype concordance was almost complete only for poor metabolizers, whereas it emerged that 34% of intermediate, normal, and ultrarapid metabolizers were classified differently based on log(DM/DX). Multivariable regression analysis selected log(DM/DX) as the best predictor, with patients' age, weak inhibitor use, and CYP2D6 phenotype decreasingly important: log-ENDOss = 0.162 - log(DM/DX) × 0.170 + age × 0.0063 - weak inhibitor use × 0.250 + IM × 0.105 + (NM + UM) × 0.210; (R2  = 0.51). In conclusion, log(DM/DX) seems superior to genotype-derived CYP2D6 phenotype in predicting ENDOss.


Subject(s)
Breast Neoplasms/drug therapy , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6/metabolism , Dextromethorphan/administration & dosage , Tamoxifen/administration & dosage , Administration, Oral , Adult , Aged , Aged, 80 and over , Breast Neoplasms/blood , Breast Neoplasms/genetics , Breast Neoplasms/urine , Chemotherapy, Adjuvant , Dextromethorphan/blood , Dextromethorphan/urine , Female , Genotyping Techniques , Humans , Middle Aged , Tamoxifen/analogs & derivatives , Tamoxifen/blood , Tamoxifen/pharmacokinetics , Tamoxifen/urine
3.
Oncologist ; 24(6): e318-e326, 2019 06.
Article in English | MEDLINE | ID: mdl-30846513

ABSTRACT

INTRODUCTION: Gefitinib, erlotinib, and afatinib represent the approved first-line options for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Because pivotal trials frequently lack external validity, real-world data may help to depict the diagnostic-therapeutic pathway and treatment outcome in clinical practice. METHODS: MOST is a multicenter observational study promoted by the Veneto Oncology Network, aiming at monitoring the diagnostic-therapeutic pathway of patients with nonsquamous EGFR-mutant NSCLC. We reported treatment outcome in terms of median time to treatment failure (mTTF) and assessed the impact of each agent on the expense of the regional health system, comparing it with a prediction based on the pivotal trials. RESULTS: An EGFR mutation test was performed in 447 enrolled patients, of whom 124 had EGFR mutation and who received gefitinib (n = 69, 55%), erlotinib (n = 33, 27%), or afatinib (n = 22, 18%) as first-line treatment. Because erlotinib was administered within a clinical trial to 15 patients, final analysis was limited to 109 patients. mTTF was 15.3 months, regardless of the type of tyrosine kinase inhibitor (TKI) used. In the MOST study, the budget impact analysis showed a total expense of €3,238,602.17, whereas the cost estimation according to median progression-free survival from pivotal phase III trials was €1,813,557.88. CONCLUSION: Good regional adherence and compliance to the diagnostic-therapeutic pathway defined for patients with nonsquamous NSCLC was shown. mTTF did not significantly differ among the three targeted TKIs. Our budget impact analysis suggests the potential application of real-world data in the process of drug price negotiation. IMPLICATIONS FOR PRACTICE: The MOST study is a real-world data collection reporting a multicenter adherence and compliance to diagnostic-therapeutic pathways defined for patients with epidermal growth factor receptor-mutant non-small cell lung cancer. This represents an essential element of evidence-based medicine, providing information on patients and situations that may be challenging to assess using only data from randomized controlled trials, e.g., turn-around time of diagnostic tests, treatment compliance and persistence, guideline adherence, challenging-to-treat populations, drug safety, comparative effectiveness, and cost effectiveness. This study may be of interest to various stakeholders (patients, clinicians, and payers), providing a meaningful picture of the value of a given therapy in routine clinical practice.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Critical Pathways/statistics & numerical data , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Afatinib/economics , Afatinib/therapeutic use , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/economics , Carcinoma, Non-Small-Cell Lung/genetics , Cost-Benefit Analysis , Critical Pathways/standards , DNA Mutational Analysis/standards , DNA Mutational Analysis/statistics & numerical data , Disease Progression , Disease-Free Survival , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Erlotinib Hydrochloride/economics , Erlotinib Hydrochloride/therapeutic use , Female , Follow-Up Studies , Gefitinib/economics , Gefitinib/therapeutic use , Guideline Adherence/standards , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/economics , Lung Neoplasms/genetics , Male , Medication Adherence/statistics & numerical data , Middle Aged , Mutation , Practice Guidelines as Topic , Progression-Free Survival , Prospective Studies , Protein Kinase Inhibitors/economics , Time Factors , Treatment Failure
4.
Anticancer Res ; 33(12): 5531-4, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24324093

ABSTRACT

Radiation-refractory and progressive Kaposi's sarcoma remains a challenge for the oncologist. Systemic chemotherapy has improved, but results are poor. Gemcitabine is largely employed in oncology for its high therapeutic rates. We report four cases of patients with radiation-refractory and progressive classic Kaposi's sarcoma, two of whom were pre-treated with chemotherapy and then underwent treatment with gemcitabine. All patients had an objective response with long progression-free survival. Gemcitabine seems to be very effective and safe in the treatment of classic Kaposi's sarcoma.


Subject(s)
Antineoplastic Agents/therapeutic use , Deoxycytidine/analogs & derivatives , Sarcoma, Kaposi/drug therapy , Aged , Deoxycytidine/therapeutic use , Disease-Free Survival , Humans , Male , Middle Aged , Treatment Outcome , Gemcitabine
5.
Br J Clin Pharmacol ; 71(3): 437-44, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21284703

ABSTRACT

AIM: Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance. METHODS: Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA. RESULTS: Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,∞)) (r(2) = 0.77). CONCLUSIONS: Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Cytidine Deaminase/genetics , Equilibrative Nucleoside Transporter 1/genetics , Neoplasms/drug therapy , Age Factors , Aged , Aged, 80 and over , Cytidine Deaminase/metabolism , Deoxycytidine/analogs & derivatives , Equilibrative Nucleoside Transporter 1/metabolism , Female , Genotype , Humans , Male , Middle Aged , Multivariate Analysis , Neoplasms/genetics , Polymorphism, Genetic , White People , Gemcitabine
6.
Nutrition ; 19(6): 510-4, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12781850

ABSTRACT

OBJECTIVE: Bioelectrical impedance vector analysis allows non-invasive evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements. METHODS: Whole-body impedance measurements were made with a single frequency (50 kHz) analyzer (BIA-101, Akern/RJL Systems) in 148 adult, white, male subjects 45 to 85 y old: 56 healthy control subjects, 31 cancer patients after surgical procedure (without disease), and 61 patients with locally advanced (30 patients) or disseminated (31 patients) disease with the same body mass index and age. All patients were free from antineoplastic treatment and active nutritional intervention. RESULTS: Mean vectors of cancer groups without disease and locally advance disease versus the control group were characterized by a comparable normalized resistance component with a reduced reactance component (separate 95% confidence limits, P < 0.05), indicating a comparable ionic conduction (hydration) with loss of dielectric mass (cell membranes and tissue interfaces) of soft tissues. Overlapping 95% confidence limits of their mean vectors indicated comparable electrical tissue properties in less versus more advanced disease. CONCLUSION: Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients.


Subject(s)
Body Composition , Electric Impedance , Neoplasms/complications , Neoplasms/physiopathology , Aged , Aged, 80 and over , Body Mass Index , Cachexia/etiology , Cachexia/physiopathology , Esophageal Neoplasms/complications , Esophageal Neoplasms/physiopathology , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/physiopathology , Humans , Lung Neoplasms/complications , Lung Neoplasms/physiopathology , Middle Aged
7.
Proc Natl Acad Sci U S A ; 99(14): 9456-61, 2002 Jul 09.
Article in English | MEDLINE | ID: mdl-12077324

ABSTRACT

Deletions and point mutations in the dystrophin gene cause either the severe progressive myopathy Duchenne muscular dystrophy (DMD) or the milder Becker muscular dystrophy, depending on whether the translational reading frame is lost or maintained. Because internal in-frame deletions in the protein produce only mild myopathic symptoms, it should be possible, by preventing the inclusion of specific mutated exon(s) in the mature dystrophin mRNA, to restore a partially corrected phenotype. Such control has been previously accomplished by the use of synthetic oligonucleotides; nevertheless, a significant drawback to this approach is caused by the fact that oligonucleotides would require periodic administrations. To circumvent this problem, we have produced several constructs able to express in vivo, in a stable fashion, large amounts of chimeric RNAs containing antisense sequences. In this paper we show that antisense molecules against exon 51 splice junctions are able to direct skipping of this exon in the human DMD deletion 48-50 and to rescue dystrophin synthesis. We also show that the highest skipping activity was found when antisense constructs against the 5' and 3' splice sites are coexpressed in the same cell.


Subject(s)
Dystrophin/biosynthesis , Dystrophin/genetics , Muscular Dystrophy, Duchenne/genetics , Muscular Dystrophy, Duchenne/therapy , RNA, Small Nuclear/genetics , Animals , Exons , Female , Genetic Therapy , Humans , In Vitro Techniques , Male , Muscular Dystrophy, Duchenne/metabolism , Oocytes/metabolism , RNA/genetics , RNA/pharmacology , RNA Precursors/genetics , RNA Splicing , RNA, Antisense/genetics , RNA, Antisense/pharmacology , RNA, Small Nuclear/pharmacology , Sequence Deletion , Transduction, Genetic , Xenopus laevis
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