Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 133
Filter
1.
J Pediatr ; : 114176, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38945446

ABSTRACT

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

2.
Eur J Pediatr ; 183(2): 929-938, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38054992

ABSTRACT

The identification of cystic fibrosis screening-positive, inconclusive diagnosis (CFSPID) in infants is a controversial outcome of newborn screening for cystic fibrosis (CF). Today, despite improvements in the knowledge of CFSPID and the description of several cohorts, little data are available on cohorts with a follow-up period of more than 6 years. In this study, we report the outcomes of an Italian cohort of CFSPID individuals with CFSPID or formerly CFTR-related disorders (CFTR-RD) (CFSPID > CFTR-RD) or diagnosed with CF (CFSPID > CF). This was an observational and multicentre Italian study collecting clinical data on CFSPID born between the period January 1, 2011, and December 13, 2019. A total of 268 participants were included: 243 with persistent CFSPID, 7 with CFSPID > CFTR-RD, and 18 with CFSPID > CF. The trend of sweat chloride (SC) values, percentage of definitive diagnoses, lung function in school-aged children, and development of CF-related complications were evaluated. At the end of the observation period, almost 80% of the individuals with CFSPID did not have a conclusive diagnosis. A total of 29 children (10.8%) transitioned to a diagnosis of CF for pathological SC values (≥ 60 mmol/L) or multi-organ involvement, and 18 (6.7%) to CFTR-RD. Children who were followed up for > 6 years (median age, 7.5 years; range, 6.04-10.5) had normal lung function and were pancreatic sufficient, and the evolution in CF was only present in two cases. CONCLUSION: Most Italian preschool and school-aged children with CFSPID did not have a conclusive diagnosis, and progression to CF was unlikely in children > 6 years of age. An annual follow-up could be indicated to identify early evolution in clinical features consistent with a CFTR-RD. WHAT IS KNOWN: • Cystic Fibrosis newborn screening identifies also subjects with an inconclusive diagnosis (CFSPID). • Over time a variable percentage of CFSPIDs will be diagnosed as CF. • Little data is available on CFSPIDs with a follow-up period of more than six years. WHAT IS NEW: • 80% of Italian preschool and school-age CFSPIDs not have a conclusive diagnosis. • Italian preschool and school-age CFSPIDs have normal lung function and are pancreatic sufficient. • Annual follow-up after 6 years is recommended in CFSPID with abnormal LCI2.5 or with a CF-causing variant in trans with a VVCC.


Subject(s)
Cystic Fibrosis , Infant , Infant, Newborn , Child , Humans , Child, Preschool , Cystic Fibrosis/diagnosis , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Neonatal Screening , Genetic Testing , Italy/epidemiology
3.
Ann Oncol ; 29(8): 1701-1709, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29905778

ABSTRACT

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Dosage , Humans , Lung/pathology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Randomized Controlled Trials as Topic , Treatment Outcome
4.
BMC Cancer ; 17(1): 141, 2017 02 16.
Article in English | MEDLINE | ID: mdl-28209123

ABSTRACT

BACKGROUND: There is emerging evidence showing a significant relationship between overall survival (OS) in non-small cell lung cancer NSCLC patients and weight change during chemotherapy or chemoradiation. A high neutrophil/lymphocyte ratio (NLR) at baseline and at follow-up is associated with shorter survival in cancer patients and may be a surrogate for ongoing inflammation, implicated in cancer cachexia and tumor progression. The objective of this study is to explore potential relationships between OS, serial weights, and serial NLRs in advanced NSCLC patients receiving chemotherapy. METHODS: One hundred thirty-nine patients with chemotherapy-naïve NSCLC, predominantly with stage III/IV disease, were treated with first-line platinum doublets from June, 2011 to August, 2012. NLR, tumor response, and body weight were recorded at baseline, 6, and 12 weeks from initiation of therapy and correlated with OS. The association between NLR and OS was assessed using Cox PH (proportional hazards) analysis, the association between NLR and weight change was assessed using a simple regression analysis, and the association between NLR and tumor response was assessed using the Fisher's exact test. RESULTS: One hundred thirty-nine patients with median age 68, PS 0-1/2 = 83/17%, male/female = 58%/42%. Median NLR at baseline was 3.6 (range 0.1898 to 30.910), at 6 weeks 3.11 (range 0.2703 to 42.11), and at 12 weeks 3.52 (range 0.2147 to 42.93). A Higher NLR at baseline, 6, and 12 weeks was associated with decreased OS (baseline: HR 1.06, p < 0.001; 6 weeks: HR 1.07, p = 0.001; 12 weeks: HR 1.05, p < 0.001), and longitudinal NLR, as a time-dependent covariate, was also associated with decreased OS (HR = 1.06, p < 0.001). Baseline weight and NLR were inversely related (cor = -0.267, p = 0.001), and weight change and NLR were inversely related at 12 weeks (cor = -0.371, p < 0.001). Longitudinal measurements of weight and NLR were also negatively associated (slope = -0.06, p < 0.001). Using a cutoff of NLR > 5, there was a significant association between progressive disease and NLR > 5 at 6 weeks (p = 0.02) and 12 weeks (p = 0.03). CONCLUSIONS: High baseline and progressive increases in NLRs are associated with progressive disease, inferior OS and weight loss in NSCLC patients. In addition to having prognostic significance, these observations suggest that studying molecular mediators of cachexia/inflammation and their relationships to tumor progression may identify new therapeutic targets in the large subset of NSCLC patients who have cancer cachexia.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Aged , Body Weight/physiology , Carcinoma, Non-Small-Cell Lung/epidemiology , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/physiopathology , Female , Humans , Kaplan-Meier Estimate , Leukocyte Count , Lung Neoplasms/epidemiology , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Lung Neoplasms/physiopathology , Lymphocytes/cytology , Male , Neutrophils/cytology , Retrospective Studies
5.
Ann Oncol ; 27(8): 1612-9, 2016 08.
Article in English | MEDLINE | ID: mdl-27217544

ABSTRACT

BACKGROUND: Unintentional weight loss occurs among advanced non-small-cell lung cancer (NSCLC) patients and is associated with worse survival. Small studies have suggested that weight gain during treatment is associated with superior survival. PATIENTS AND METHODS: A retrospective analysis analyzed data from three international phase III studies comprising 2301 advanced, non-squamous NSCLC patients who received a platinum-based, first-line doublet, with or without bevacizumab and maintenance therapy. Body weight was recorded before and after treatment by each study's schedule. The relationship between weight gain and overall survival (OS) and progression-free survival (PFS) was assessed using log-rank test and adjusted Cox modeling. Logistic regression assessed the association between baseline covariates and post-baseline weight gain. RESULTS: Four hundred and twenty-one (18.3%) patients had >5% weight gain after baseline. More than half of the weight gain cohort exhibited initial weight gain by 3 weeks. The median OS was 16.7 months versus 10.7 months for the >5% versus ≤5% weight gain subgroup (n = 1880) (P < 0.001). PFS was 6.9 versus 4.8 months, respectively (P < 0.001). Differences in overall tumor response rate (50.8% versus 25.4%, respectively) and disease control rate (tumor response or stable disease) (91.5% versus 63.6%, respectively) were also significant (P < 0.001). The Cox modeling revealed the >5% subgroup had longer survival [hazard ratio (HR) = 0.54, 95% confidence interval (CI) 0.47-0.62; P < 0.001] than the ≤5% subgroup after adjusting for baseline factors. Similar significant results were found for PFS (HR = 0.59, 95% CI 0.52-0.67; P < 0.001). Unadjusted logistic regression indicated a significant association between weight gain (>5% versus ≤5%) and age, and BMI. CONCLUSIONS: Weight gain during treatment may be an early indicator of clinical benefit. If confirmed in prospective studies, monitoring weight change may provide important information regarding survival outcomes in NSCLC and may provide ideas for new therapeutic strategies.


Subject(s)
Bevacizumab/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Pemetrexed/administration & dosage , Weight Gain/drug effects , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab/adverse effects , Body Mass Index , Cachexia/complications , Cachexia/drug therapy , Cachexia/physiopathology , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/physiopathology , Clinical Trials, Phase III as Topic , Disease-Free Survival , Female , Humans , Male , Middle Aged , Pemetrexed/adverse effects , Retrospective Studies , Treatment Outcome
6.
Br J Cancer ; 105(12): 1920-6, 2011 Dec 06.
Article in English | MEDLINE | ID: mdl-22095222

ABSTRACT

METHODS: Fluorescent in situ hybridisation analyses of PTEN, PIK3CA, EGFR and CEN7 were performed on tumour specimens from patients treated on the expanded access gefitinib trial. Progression-free survival (PFS) and overall survival (OS) were correlated with outcomes in all patients and EGFR wild-type patients. RESULTS: Progression-free survival (hazard ratio=2.54, P<0.001) and OS (hazard ratio=4.04, P<0.001) were significantly shorter in patients whose tumours had all of the following molecular patterns: CEN7 <4 copies per cell, PTEN loss (<2 copies in at least 20% of cells), and PIK3CA gain (>2 copies in at least 40% of cells) both in all and EGFR wild-type only patients. CONCLUSION: The combination of low CEN7 copy number, PTEN loss, and PI3KCA gain may be useful for identifying NSCLC patients unlikely to benefit from treatment with EGFR (TKIs), specifically in wild-type EGFR cases.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Gene Dosage , Lung Neoplasms/genetics , PTEN Phosphohydrolase/genetics , Phosphatidylinositol 3-Kinases/genetics , Quinazolines/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Class I Phosphatidylinositol 3-Kinases , ErbB Receptors/genetics , Female , Gefitinib , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Retrospective Studies , Survival Analysis , Treatment Outcome
7.
Br J Cancer ; 103(8): 1221-8, 2010 Oct 12.
Article in English | MEDLINE | ID: mdl-20859284

ABSTRACT

BACKGROUND: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. METHODS: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. RESULTS: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. CONCLUSIONS: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various 'high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions.


Subject(s)
Blood Chemical Analysis/methods , Carcinoma, Non-Small-Cell Lung/diagnosis , Early Detection of Cancer/methods , Lung Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Algorithms , Biomarkers, Tumor/analysis , Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/blood , Case-Control Studies , Cohort Studies , Female , Humans , Lung Neoplasms/blood , Male , Middle Aged , Serum/chemistry
8.
Med Lav ; 100(3): 211-27, 2009.
Article in Italian | MEDLINE | ID: mdl-19601405

ABSTRACT

BACKGROUND: Teachers are one of the so-called helping professions which are strongly exposed to the "Burnout syndrome". Nonetheless, public opinion is still convinced teachers enjoy a privileged status and physicians most often ignore psychiatric disorders following burnout due to teaching-related stress. Indeed, although France recently issued a suicide warning among teachers, and psychiatric diagnosis among this profession almost doubled in Japan in ten years, only few studies have been published on the subject in peer-reviewed journals. OBJECTIVE AND METHODS: The present study was carried out by administering a questionnaire to 1295 teachers from ten different Italian regions aimed at evaluating teachers' conditions as well as their perception of work-related health risks. RESULTS AND CONCLUSIONS: The outcome showed that teachers are mostly unaware of work-related health risks, they are discouraged by their employers, perceive union support as highly insufficient and feel under attack by the mass media as well as by the public. Further, any attempt by the head teacher to protect teacher's health--mandatory according to recent Italian legislation--is frequently misinterpreted as mobbing, due to the lack of appropriate legal knowledge. Interestingly, the study population believed that investigating the link between menopause and depressive disorders among teachers was extremely useful. In fact, over 82% of teachers are women with a median age of approximately 50. Social stress among women has in fact increased greatly given the triple role played by fifty-year-old teachers (mother of adolescents, care-giver for elderly parents and teacher). Lastly, general practitioners and psychiatrists need to be educated on psychiatric disorders due to teaching-related stress in order to achieve a correct diagnosis and treatment.


Subject(s)
Mental Disorders/epidemiology , Occupational Diseases/epidemiology , Teaching , Adult , Female , Humans , Male , Middle Aged , Risk Factors , Stereotyping
9.
Br J Cancer ; 98(10): 1608-13, 2008 May 20.
Article in English | MEDLINE | ID: mdl-18475293

ABSTRACT

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Polyglutamic Acid/analogs & derivatives , Taxoids/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Non-Small-Cell Lung/pathology , Docetaxel , Drug Administration Schedule , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/therapeutic use , Patient Selection , Polyglutamic Acid/administration & dosage , Polyglutamic Acid/adverse effects , Polyglutamic Acid/therapeutic use , Quality of Life , Taxoids/administration & dosage , Taxoids/adverse effects , Treatment Outcome
10.
Eur J Cancer ; 40(8): 1193-8, 2004 May.
Article in English | MEDLINE | ID: mdl-15110883

ABSTRACT

Cancer patients, especially the elderly, present with a highly variable susceptibility to toxicity from chemotherapy. To estimate correctly a patient's risk for toxicity, both the average toxicity of a chemotherapy regimen and patient-related variables need to be assessed. However, treatment toxicities are typically reported item by item, not summarised per patient. We tested an index derived from a pilot study, the MAX2, on the ECOG database. Studies including 20 or more patients aged 70 years and older per arm were selected. Four studies were identified, representing 2526 patients, 410 (16%) being elderly. The association of the MAX2 index with the per patient incidence of grade 4 haematological and/or grade 3 or 4 non-haematological toxicity was highly significant, both for the overall group and for the elderly subgroup. The MAX2 index is a convenient and reproducible way of comparing the average per patient risk for toxicity from chemotherapy across several regimens.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Health Status Indicators , Neoplasms/drug therapy , Adult , Age Factors , Aged , Aged, 80 and over , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Humans , Middle Aged , Regression Analysis , Risk Factors , Sensitivity and Specificity
11.
Med Hypotheses ; 61(5-6): 583-5, 2003.
Article in English | MEDLINE | ID: mdl-14592791

ABSTRACT

UNLABELLED: We suggest two additional reasons why current, non-surgical therapies for most solid, epithelial-derived cancers can lack effectiveness. Studies with panc-1 human pancreatic cancer cells cultured with actinomycin D and/or MK 886 indicate firstly, that type 2 (intrinsic, autophagic, mitochondrial-dependent, MK 886-induced) programmed cell death is less effective than the type 1 (apoptotic, extrinsic, ligand-dependent, actinomycin D-induced) form in reducing the number of residual clonogenic cells, and secondly, that activation of cellular suicide during their combined culture results in a greater number of residual clonogenic cells compared with either agent alone. HYPOTHESIS: Based on results from the culture of panc-1 cells with MK 886 and/or actinomycin D, we suggest that in this system, and possibly in others: (a) type 2 programmed cell death is a less effective inhibitor of residual cells with clonogenic potential, and (b) activation together of both forms of PCD increases the number of residual clonogenic cells.


Subject(s)
Apoptosis , Antibiotics, Antineoplastic/pharmacology , Cell Culture Techniques/methods , Cell Division , Cell Line, Tumor , Cell Survival , Dactinomycin/pharmacology , Enzyme Inhibitors/pharmacology , Humans , Indoles/pharmacology , Models, Theoretical , Neoplasms/therapy
12.
Article in English | MEDLINE | ID: mdl-12054916

ABSTRACT

MK 886, an arachidonic acid-related analog which inhibits the enzyme, 5-lipoxygenase by an indirect mechanism involving the 5-lipoxygenase activating protein, rapidly increased U937 cytosol Ca(2+), much of which localized around the cell nuclei. Five-lipoxygenase activity was not directly involved since the direct redox-dependent 5-LPOx inhibitor, SC-41661A did not increase Ca(2+). U937 cells subsequently undergo classic type 1 programmed cell death. At least initially the ionized calcium originates from internal stores. Coincident with the rise in U937 ionized calcium, MK 886 rapidly increased reactive oxygen species and reduced mitochondrial membrane potential, as judged by several fluorescent probes. The Ca(2+) response of myeloid leukemia-derived HL-60 cells to MK 886 was similar and both cell lines express Bcl-2 protein. Bcl-2-negative Panc-1 and PC-3 cells did not respond to MK 886 with a Ca(2+) signal but did develop oxidative stress and a decline in mitochondrial membrane potential; these events are thought to contribute to the inhibition of cell proliferation and induction of a type 2 PCD. In addition to its marked inhibition of Bcl-2 mRNA synthesis, an interesting hypothesis is that MK 886, serving as a low molecular weight ligand, either by direct or indirect inhibition of U937 Bcl-2 protein function, possibly related to an ion channel activity, alters the distribution of intracellular, possibly nuclear Ca(2+), thereby promoting the development of type 1 programmed cell death.


Subject(s)
Apoptosis/drug effects , Calcium Signaling/drug effects , Calcium/metabolism , Cytosol/drug effects , Indoles/pharmacology , Lipoxygenase Inhibitors/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Arachidonate 5-Lipoxygenase/metabolism , Cytosol/metabolism , Fluorescent Dyes , HL-60 Cells , Humans , Membrane Potentials/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Oxidative Stress , Proto-Oncogene Proteins c-bcl-2/analysis , Proto-Oncogene Proteins c-bcl-2/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , U937 Cells
13.
Eur J Cancer ; 38 Suppl 8: S13-8, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12645908

ABSTRACT

Three open-label, non-comparative, multicentre Phase II trials have examined the efficacy and tolerability of ZD0473 as first-and second-line therapy in non-small-cell lung cancer (NSCLC) patients and second-line therapy in small-cell lung cancer (SCLC) patients. Patients with second-line NSCLC or SCLC were evaluated as either platinum-sensitive or -resistant, based upon their time to relapse/progression after platinum-based therapy. First-line NSCLC patients (n = 18) received a total of 60 treatment cycles (median number per patient 2.5) whilst second-line NSCLC (n = 50) and SCLC (n = 48) patients both received a total of 127 treatment cycles (median number per patient 2.0). Grade 3/4 anaemia, neutropenia and thrombocytopenia was observed in: 38.8%, 22.2% and 27.7% of first-line NSCLC patients; 12.0%, 24.0% and 50% of second-line NSCLC patients; and 10.4%, 25.0% and 47.9% of second-line SCLC patients, respectively. The most common grade 3/4 non-haematological toxicities in all three trials were lethargy and dyspnoea. No clinically significant oto-, nephro- or neurotoxicity was observed. The first-line treatment of NSCLC produced an overall response rate (OR) of 6.3%. No OR was seen after second-line treatment of NSCLC, while ORs of 15.4% and 8.3% were seen in the platinum-resistant and -sensitive second-line SCLC patients, respectively.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Organoplatinum Compounds/therapeutic use , Adult , Aged , Aged, 80 and over , Clinical Trials, Phase II as Topic , Disease-Free Survival , Drug Resistance, Neoplasm , Dyspnea/chemically induced , Female , Hematologic Diseases/chemically induced , Humans , Male , Middle Aged , Multicenter Studies as Topic , Sleep Stages/drug effects , Treatment Outcome
14.
Semin Oncol ; 28(4 Suppl 14): 45-9, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11605183

ABSTRACT

Non-small cell lung cancer is a major worldwide health problem. Approximately 80% of non-small cell lung cancer patients present with advanced disease for which there is little or no chance of cure. Although survival in stage IV non-small cell lung cancer patients is prolonged by treatment with combination chemotherapy regimens, all of these patients develop disease that is refractory to currently available systemic therapy. Basic scientists have identified a number of new therapeutic targets that offer the potential for novel therapeutic interventions, which might control chemotherapy-refractory disease or potentiate the effectiveness of chemotherapy and radiation therapy. The new targets include tumor-associated angiogenesis, biochemical pathways that stimulate tumor proliferation, and programmed cell death (apoptosis). Each of these novel targets will be discussed briefly in this review.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Angiogenesis Inhibitors/therapeutic use , Animals , Apoptosis/drug effects , Cell Division/drug effects , Humans
15.
Cancer Lett ; 166(2): 223-31, 2001 May 26.
Article in English | MEDLINE | ID: mdl-11311496

ABSTRACT

The 5-lipoxygenase inhibitors SC41661A and MK886 with different mechanisms of action and the free radical spin trap, NTBN inhibit proliferation of the human bronchiolar lung cancer cell line NCI H-358 (5807 CRL). With continued culture, the agents induced a form of programmed cell death in which DNA laddering was not detected and ultrastructural changes were not characteristic of classic 'type 1' cellular suicide. The changes were more consistent with a type 2 cytosolic, autophagic form of PCD. MK886 induced strikingly abnormal mitochondrial morphology. Since the lipoxygenase inhibitors and NTBN induce classic type 1 PCD in U937 monoblastoid cells, these agents can activate either pathway, depending upon cell type. It is not certain whether activation of type 1 or 2 pathways depends entirely upon cell lineage and/or initiating agent, if all cells retain both pathways, and if type 1 PCD a more effective mediator of the process. These are all relevant questions for assessing the impact of PCD on malignant cell survival and considering ways in which it might be enhanced.


Subject(s)
Lipoxygenase Inhibitors , Lung Neoplasms/pathology , Amides/pharmacology , Cell Death , Cell Division/drug effects , Cyclic N-Oxides , Flow Cytometry , Humans , Indoles/pharmacology , Lipoxygenase Inhibitors/pharmacology , Lung Neoplasms/ultrastructure , Nitrogen Oxides/pharmacology , Pyridines/pharmacology , Spin Labels , Tumor Cells, Cultured
16.
Cancer Treat Res ; 105: 171-88, 2001.
Article in English | MEDLINE | ID: mdl-11224987
17.
Anticancer Res ; 20(4): 2433-9, 2000.
Article in English | MEDLINE | ID: mdl-10953307

ABSTRACT

Incomplete programmed cell death is one explanation for the escape of cancer cells from therapy. Inhibitors of the enzyme 5-lipoxygenase reduce proliferation and initiate programmed cell death in many different types of malignantly transformed cells. The 5-lipoxygenase inhibitor, MK 886. induces an atypical form of programmed cell death in H-358 bronchiolar lung cancer cells. A genomic response of H-358 cells after 24 hr of culture at a 40 uM concentration that inhibited proliferation was analyzed with a Clontech human cDNA array containing 588 cDNAs corresponding to identified genes. The data grouped into 3 major categories and initial conclusions regarding countervailing, cellular stress, programmed cell death, DNA damage and repair mRNA-responses as possible reasons for escape from the antiproliferative response are discussed. The use of cDNA arrays to estimate the extent to which malignantly transformed cells respond to therapy or why they do not and so infer prognosis and identify possible therapeutic modifications is indicated.


Subject(s)
Adenocarcinoma, Bronchiolo-Alveolar/drug therapy , Antineoplastic Agents/pharmacology , Arachidonate 5-Lipoxygenase/drug effects , DNA, Complementary/analysis , Indoles/pharmacology , Lipoxygenase Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Adenocarcinoma, Bronchiolo-Alveolar/genetics , Adenocarcinoma, Bronchiolo-Alveolar/pathology , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology
18.
Am J Clin Oncol ; 23(4): 371-5, 2000 Aug.
Article in English | MEDLINE | ID: mdl-10955866

ABSTRACT

Advanced non-small-cell lung cancer (NSCLC) remains an incurable disease despite significant progress in chemotherapy. We conducted a phase II clinical trial to investigate the efficacy and toxicity of a cisplatin, etoposide, and 5-fluorouracil (5-FU) combination in advanced metastatic and/or recurrent NSCLC. Forty patients with advanced, recurrent, or metastatic, measurable NSCLC were treated with cisplatin, 60 mg/m2 intravenously (i.v.) on day 1; etoposide, 120 mg/m2/day i.v. on days 1, 2, and 3; and 5-FU. 1,000 mg/m2/day i.v. continuous infusion on days 1 through 5. Treatment was administered in 4-week cycles. Thirty patients had distant metastases and were previously untreated, and 10 patients had recurrent disease after prior treatment with either surgery (1 patient), radiation therapy (5 patients), or both treatments (4 patients). Twenty-nine patients were evaluable for response. Seven (24%) patients achieved a partial remission (PR), 18 (62%) had stable disease (SD), and 8 (14%) had progressive disease (PD). Overall median survival was 7.9 months (range, 0.4-27.4 months). Patients who achieved a PR had a median survival of 23.5 months (9.3-27.4 months). In contrast, patients with SD had a median survival of 9.9 months (2.5-25.3 months), and patients with PD had a median survival of 2.1 months (1-9.3 months). Median duration of response of 27.1 weeks (4.9-76.5 weeks) for patients with PR, and time to progression was 13.4 weeks (3.7-54.5 weeks) for patients with SD. Toxicity was primarily hematologic and gastrointestinal, and there were three deaths due to infection. The combination of cisplatin, 5-FU, and etoposide as administered in this study appears to have considerable toxicity and does not appear to be superior to other cisplatin-containing regimens used for the treatment of advanced NSCLC.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/administration & dosage , Etoposide/administration & dosage , Fluorouracil/administration & dosage , Lung Neoplasms/drug therapy , Adult , Aged , Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/secondary , Cause of Death , Cisplatin/adverse effects , Diarrhea/chemically induced , Disease Progression , Etoposide/adverse effects , Female , Fluorouracil/adverse effects , Follow-Up Studies , Hematologic Diseases/chemically induced , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Pilot Projects , Remission Induction , Survival Rate
19.
Ann Oncol ; 11(6): 673-8, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10942054

ABSTRACT

PURPOSE: To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting > or = 7 days. RESULTS: There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%-63%) in 28 evaluable patients and 36% (95% CI: 20%-55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0-12.5 months). The median survival was 13.9 months (range 1-35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects. CONCLUSIONS: The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.


Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/analogs & derivatives , Taxoids , Aged , Aged, 80 and over , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin/adverse effects , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Dexamethasone/therapeutic use , Docetaxel , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Paclitaxel/adverse effects , Paclitaxel/therapeutic use , Survival Analysis , Treatment Outcome
20.
Med Hypotheses ; 54(6): 1000-2, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10867755

ABSTRACT

If chemotherapy or ionizing radiation induce widespread genomic responses tending to circumvent or antagonize their ability to kill malignant cells, an additional cause for therapeutic failure would be suggested. There is evidence that some agents evoke extensive countervailing genomic activity, the nature and extent of which can be assessed with the use of 'gene chips'.


Subject(s)
Antineoplastic Agents/adverse effects , Genome , Radiotherapy/adverse effects , Antineoplastic Agents/therapeutic use , Cell Division/drug effects , DNA Damage , DNA Repair , DNA Replication , Humans , Mutation , Pancreatic Neoplasms/pathology , Tumor Cells, Cultured
SELECTION OF CITATIONS
SEARCH DETAIL
...