29 research outputs found
Evaluation of six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon therapy in the He13A/98 multicenter trial
<p>ABSTRACT</p> <p>Purpose</p> <p>Interferon is approved for adjuvant treatment of patients with stage IIb/III melanoma. The toxicity and uncertainty regarding survival benefits of interferon have qualified its acceptance, despite significant durable relapse prevention in a fraction of patients. Predictive biomarkers that would enable selection of patients for therapy would have a large impact upon clinical practice. Specific CTLA-4 polymorphisms have previously shown an association with response to CTLA-4 blockade in patients with metastatic melanoma and the development of autoimmunity.</p> <p>Experimental design</p> <p>286 melanoma patients and 288 healthy controls were genotyped for six CTLA-4 polymorphisms previously suggested to be important (AG 49, CT 318, CT 60, JO 27, JO30 and JO 31). Specific allele frequencies were compared between the healthy and patient populations, as well as presence or absence of these in relation to recurrence. Alleles related to autoimmune disease were also investigated.</p> <p>Results</p> <p>No significant differences were found between the distributions of CTLA-4 polymorphisms in the melanoma population compared with healthy controls. Relapse free survival (RFS) and overall survival (OS) did not differ significantly between patients with the alleles represented by these polymorphisms. No correlation between autoimmunity and specific alleles was shown. The six polymorphisms evaluated where strongly associated (Fisher's exact p-values < 0.001 for all associations) and significant linkage disequilibrium among these was indicated.</p> <p>Conclusion</p> <p>No polymorphisms of CTLA-4 defined by the SNPs studied were correlated with improved RFS, OS, or autoimmunity in this high-risk group of melanoma patients.</p
Immunotherapy for advanced melanoma: Fulfilling the promise
The incidence of melanoma is increasing worldwide and despite early
detection and intervention, the number of patients dying from metastatic
disease continues to rise. The prognosis of advanced melanoma remains
poor, with median survival between 6 and 9 months. Over the past thirty
years and despite extensive clinical research, the treatment options for
metastatic disease were limited and melanoma is still considered as one
of the most therapy-resistant malignancies. Single-agent and combination
chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted
agent therapy and combination regimes failed to show significant
improvement in overall survival.
Recent advances and in-depth understanding of the biology of melanoma,
have contributed in the development of new agents. Based on the
molecular and immunological background of the disease, the new drugs
have shown benefit in overall and progression free survival. As the
picture of the disease begins to change, oncologists need to alter their
approach to melanoma treatment and consider disease biology together
with targeted individualized treatment. In this review the authors
attempt to offer an insight in present and past melanoma treatment
options, with a focus on the recently approved immunotherapeutic agents
and the clinical perspectives of these new weapons against metastatic
melanoma. (C) 2013 Elsevier Ltd. All rights reserved
Comparative effects of sibutramine and orlistat on weight loss, glucose metabolism and leptin levels in non-diabetic obese patients: A prospective study
Docetaxel-ifosfamide combination in patients with HER2-non-overexpressing advanced breast cancer failing prior anthracyclines
The feasibility of the docetaxel-ifosfamide combination, as well as the
definition of maximum tolerated doses (MTD) in a previous phase I study,
led us to continue evaluating the regimen in an extended phase II study
in patients with HER2-non-overexpressing, anthracycline pre-treated
advanced breast cancer. Patients with histologically confirmed
metastatic breast cancer failing prior anthracycline-based chemotherapy
were treated with docetaxel 100 mg/m(2) over 1 h on day 1 followed by
ifosfamide 5 g/m(2) divided over days 1 and 2 (2.5 g/m(2)/day over 1 h),
and recycled every 21 days with prophylactic granulocyte-colony
stimulating factor (G-CSF) administration from day 3-until a neutrophil
count > 10,000/mu l. Between March 1999 and June 2002, 71 patients with
a median age of 55 years (range, 28-72) and performance status (World
Health Organization; WHO) of 1 (range, 0-2) were treated; all were
assessable for toxicity and 70 patients for response. Clinical response
rates (RRs), on an intention-to-treat basis were: 41/71 [58%; 95%
CI, 46.5-69.5%]; 7 complete remissions (CRs), 34 partial remissions
(PRs), 15 stable disease (SD) and 15 progressive disease (PD). The
median response duration was 7.5 months (2-28 months), median
time-to-progression (TTP) 6 months (0.1-30 months), and median overall
survival (OS) 12 months (0.1-36 months). Grade 3/4 toxicities included;
neutropenia in 63% of patients-with 52% developing grade 4 neutropenia
(>= 7 days) and in 11% of these febrile neutropenia (FN), while no
grade 3/4 thrombocytopenia was observed. Other toxicities included;
peripheral neuropathy grade 2 only in 7%, grade 1/2 reversible central
nervous system (CNS) toxicity in 11%, no renal toxicity, grade 2
myalgias in 7%, grade 3 diarrhea in 4%, skin/nail toxicity in 11%,
and grade 1/2 fluid retention in 28% of patients. The present report
has demonstrated encouraging activity of the docetaxel-ifosfamide
combination in anthracycline-pretreated, HER2-negative advanced breast
cancer. Therefore, future randomized phase III studies versus
single-agent docetaxel or currently established combinations of the
latter with other agents in this setting with established clinical
activity, such as capecitabine or gemcitabine, will be warranted
Elevated Serum Leptin Levels: A Risk Factor for Non-Small-Cell Lung Cancer?
Objective: Leptin is intimately intertwined in the molecular
pathophysiology of several cancer types; with regard to lung cancer,
however, limited research has been conducted, with overall conflicting
results. Methods: The present case-control study comprises 66
non-small-cell lung cancer (NSCLC) cases and 132 healthy controls
matched for gender and age. Lifestyle, sociodemographic and medical
history information has been obtained in addition to body mass index
(BMI) measurements and weight change during the last 2 months. Serum
leptin and adiponectin levels were determined following a standard
protocol. Results: In multiple logistic regression analyses, elevated
serum leptin emerged as a risk factor for NSCLC independent of central
obesity, more pronounced after controlling for BMI and recent weight
loss (odds ratio = 4.58, 95% confidence interval: 1.94-10.82).
Additionally, smoking and animal foods consumption were strongly
associated with the disease, whereas plant foods consumption showed a
protective association. Conclusions: The observed higher serum leptin
levels in NSCLC cases might be attributed to direct or indirect effects
mediated by cancer-or cachexia-related cytokines. In line with the
growth-promoting properties of leptin in the lung tissue documented
elsewhere, increased serum leptin concentration may represent a
tumor-promoting event during non-small-cell lung carcinogenesis.
Copyright (C) 2008 S. Karger AG, Base
Salvage treatment with irinotecan/cisplatin versus pemetrexed/cisplatin in patients with non-small cell lung cancer pretreated with a non-platinum-based regimen in the first-line setting: A randomized phase II study of the Hellenic Oncology Research Group (HORG).
Circulating adiponectin levels and expression of adiponectin receptors in relation to lung cancer: Two case-control studies
Background: Decreased circulating levels of adiponectin, an
adipocyte-secreted hormone and endogenous insulin sensitizer, have been
associated with several obesity-related malignancies. Thiazolidinedione
administration, which increases adiponectin levels, decreases risk for
lung cancer. Whether circulating adiponectin levels are associated with
lung cancer and/or whether adiponectin receptors are expressed in lung
cancer remains unknown. Methods: We conducted a case-control study of 85
patients with incidental, histologically confirmed lung cancer and 170
healthy controls matched by gender and age. In a separate study,
archival lung specimens from 134 cancerous and 8 noncancerous tissues
were examined for relative expression of adiponectin receptors AdipoR1
and AdipoR2 using immunohistochemistry. Results: Tobacco smoking, heavy
alcohol intake and education were all associated with lung cancer risk,
whereas serum adiponectin levels were not significantly different
between cases and controls (multiple logistic regression, odds ratio per
SD of adiponectin among controls: 1.13, 95% confidence interval:
0.64-2.02). Adiponectin levels were significantly lower (odds ratio:
0.25, 95% confidence interval: 0.10-0.78) among patients with advanced
compared to those with limited disease stage. Expression of adiponectin
receptors was apparent only in the cancerous lung tissue (64.2% AdipoR1
and 61.9% AdipoR2 in cancerous vs. 0% among non-cancerous tissue).
Specifically, AdipoR1 was expressed in all disease types, but no
difference was noted with disease stage, whereas AdipoR2 was mainly
expressed in the non-small cell carcinomas and more prominently in the
advanced disease stage (80%). Conclusions: Circulating adiponectin
levels are not different in cases of this malignancy - which seems to be
unrelated to obesity and insulin resistance compared to their healthy
controls, though hormonal levels were significantly lower in advanced
versus limited lung cancer. Both adiponectin receptors were expressed in
cancerous lung tissue, but not in normal control tissue and there was a
differential expression by disease stage. These findings should be
further explored, especially in the context of the recently reported
protective effect of thiazolidinediones in diabetic patients with lung
cancer. Copyright (C) 2008 S. Karger AG, Basel
Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma
Purpose
A high-dose interferon alfa (IFN-alpha) regimen as reported in E1684 was
unique for the incorporation of an induction phase of maximally
tolerated dosages of intravenous (IV) therapy for the initial 4 weeks.
This is the only trial that has shown prolongation of overall survival
and relapse-free survival (RFS) in comparison with observation. Analysis
of the hazard curves for RFS and overall survival (OS) in E1684 revealed
separation of the high-dose and observation arms, suggesting that the
induction phase may represent a critical component of this regimen,
although this has not been tested prospectively.
Patients and Methods
We conducted a prospective randomized study of IV induction therapy
versus a full year of high-dose IFN, with primary end points of RFS and
OS for patients with stage IIB, IIC, and III melanoma, within 56 days of
curative surgery. Patients were randomly assigned to receive
IFN-alpha-2b 15 x 10(6) U/m(2) IV x 5/7 days weekly x 4 weeks (arm A)
versus the same regimen followed by IFN-alpha-2b 10 x 10(6) U (flat
dose) administered subcutaneously three times a week for 48 weeks (arm
B).
Results
Between 1998 and 2004, 364 patients were enrolled (353 eligible: arm A,
n = 177; arm B, n = 176). At a median follow-up of 63 months (95% CI,
58.1 to 67.7), the median RFS was 24.1 months versus 27.9 months (P =
.9) and the median OS was 64.4 months versus 65.3 months (P = .49).
Patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting,
alopecia, and neurologic toxicity.
Conclusion
There were no significant differences in OS and RFS between the regimens
of 1 month and 1 year of treatment