Evaluation of 39 cases of pediatric cutaneous head and neck melanoma.

BACKGROUND: Studies examining head and neck (H&N) melanoma in the pediatric population are scarce. OBJECTIVE: The goal of this study is to describe pediatric H&N melanoma with the intent of increasing understanding of the course of disease. METHODS: The Duke Melanoma Database and Duke Tumor Registry Database were searched for patients with a diagnosis of melanoma occurring on the H&N before age 18 years, with exclusion of ocular/mucosal/aerodigestive melanomas. RESULTS: Queries yielded 39 Caucasian pediatric patients, 24 (61.5%) of them male. The mean age at diagnosis was 14.2 years (15 years, median). The primary sites were represented as follows: cutaneous auricular (1/39, 2.6%), facial (15/39, 38.5%), and scalp/neck (23/39, 59%). The follow-up time ranged from 2 months to 23 years with a median of 9.9 years (95% confidence interval: 6.2-13 years). At the time of follow-up, there were 12 (12/39, 30.8%) melanoma-associated deaths. The anatomic distribution of primary melanoma for these 12 patients follows: 4 (33.3%) facial and 8 (66.7%) scalp/neck. Histologic data revealed 24 (61.5%) tumors classified as superficial spreading melanoma with nodular melanoma (12.8%) a distant second. The mean Breslow depth for patients with melanoma-related mortality was 2.4 mm, compared with 1.8 mm for those who were alive at last follow-up. LIMITATIONS: Small sample size limited this study. CONCLUSION: This study found that the majority (59%) of H&N melanomas presented as scalp or neck lesions with a predilection for adolescents and boys. Those who experienced melanoma-related mortality had thicker lesions. Superficial spreading melanoma was the most common subtype.

Association between body mass index and mortality in patients with glioblastoma mutliforme.

PURPOSE: To examine the association between obesity and survival in patients with glioblastoma mutliforme (GBM) METHODS: Using a prospective design, 1,259 patients with previously untreated GBM were recruited between 1991 and 2008. Height and weight were self-reported or abstracted from medical records at study entry and used to calculate body mass index (BMI) [weight (kg)/[height (m)](2). Cox proportional models were used to estimate the risk of death associated with BMI as a continuous variable or categorized using established criteria (normal weight, 18.5-24.9 kg/m(2); overweight, 25.0-29.9 kg/m(2); obese, ≥ 30.0 kg/m(2)). RESULTS: Median follow-up was 40 months, and 1,069 (85%) deaths were observed during this period. For all patients, minimal adjusted analyses indicated no significant association between BMI treated as a continuous variable and survival. Compared with patients with a BMI 18.5-24.9 kg/m(2), the minimally adjusted HR for overall survival was 1.08 (95% CI, 0.94-1.24) for a BMI 25-29.9 kg/m(2) and 1.08 (95% CI, 0.91-28) for a BMI ≥ 30.0 kg/m(2). After additional adjustment for adjuvant therapy, the HR for those with a BMI of 25.0-29.9 kg/m(2) was 1.14 (95% CI, 0.99-1.32) and 1.09 (95% CI, 0.91-1.30) for those with a BMI ≥ 30.0 kg/m(2). No significant interactions were revealed for BMI and any demographic variables. CONCLUSION: BMI was not associated with survival in newly diagnosed and previously untreated patients with GBM. Further research investigating the prognostic significance of alternative, quantitative measures of body habitus, and functional performance are required.

Treatment-related toxicity and supportive care in metastatic colorectal cancer.

As survival of metastatic colorectal cancer (mCRC) increases, patients have more exposure to chemotherapy and related toxicity. The objective is to determine how toxicity patterns affect care. Via a population-based strategy, mCRC cases diagnosed between June 2003 and June 2006 were identified from one academic and nine community oncology practices in the southeastern United States. Demographic, disease, treatment, hospitalization, and toxicity data were abstracted by retrospective chart review, double-entered, and verified for accuracy. Of the 738 charts screened, 110 were eligible based upon preidentified inclusion criteria. As part of first-line chemotherapy, 87% received oxaliplatin, 12% received irinotecan, and 74% received bevacizumab. Gastrointestinal toxicity was the most common toxicity-related cause of drug discontinuation (16 of 61 events) and hospitalization (19 of 54 events). Both neurologic and hematologic toxicities were identified more frequently when oxaliplatin-containing regimens were administered (50% and 48%, respectively) than with irinotecan-containing regimens (10% and 24%, respectively). Dose reduction was most commonly associated with hematologic toxicity (22 of 55 events). Oxaliplatin and irinotecan required similar rates of antidiarrheal, antinausea, erythropoiesis-stimulating, and granulocyte-stimulating treatments. These data, obtained from a usual-practice setting, provide benchmarks to improve clinical practice.

Total dietary antioxidant index and survival in patients with glioblastoma multiforme.

OBJECTIVES: The role of antioxidants in survival of cancer patients is controversial. No data on the relationships between antioxidant intake and survival of glioma patients are available. Our objective was to examine such association in a large series of cases. METHODS: The study population includes 814 glioblastoma multiforme cases that were newly diagnosed, histologically confirmed, aged 20 or older, and residing in the San Francisco Bay Area at diagnosis. Cases were identified via the regional cancer registry's rapid case ascertainment system during 1991-1994 (series I), 1997-2000 (series II), and 2001-2004 (series III). Daily dietary antioxidant intake at diagnosis was assessed via food-frequency questionnaire and was expressed as total antioxidant index, calculated based on Trolox equivalent per gram of food. In addition, the study collected information on supplements/vitamin intake. RESULTS: Overall, our results indicated no consistent, significant association of survival with dietary antioxidant intake or its combination with vitamin supplements. However, in series III, we observed a significant association between higher antioxidant index and better survival: HR = 0.58 (95% CI: 0.46, 0.74) for each unit of antioxidant index on a log-scale. CONCLUSIONS: Although it is possible that this is a chance finding, the association between dietary antioxidants and survival in the most recently recruited patients warrants further investigations.

Longitudinal patterns of chemotherapy use in metastatic colorectal cancer.

Multiple agents and combination therapies available to patients with advanced colorectal cancer have significantly improved survival and provided an opportunity for individualization of care, allowing clinicians and patients to prioritize risks and benefits of comparable regimens.

Comorbidity, age, race and stage at diagnosis in colorectal cancer: a retrospective, parallel analysis of two health systems.

BACKGROUND: Stage at diagnosis plays a significant role in colorectal cancer (CRC) survival. Understanding which factors contribute to a more advanced stage at diagnosis is vital to improving overall survival. Comorbidity, race, and age are known to impact receipt of cancer therapy and survival, but the relationship of these factors to stage at diagnosis of CRC is less clear. The objective of this study is to investigate how comorbidity, race and age influence stage of CRC diagnosis. METHODS: Two distinct healthcare populations in the United States (US) were retrospectively studied. Using the Cancer Care Outcomes Research and Surveillance Consortium database, we identified CRC patients treated at 15 Veterans Administration (VA) hospitals from 2003-2007. We assessed metastatic CRC patients treated from 2003-2006 at 10 non-VA, fee-for-service (FFS) practices. Stage at diagnosis was dichotomized (non-metastatic, metastatic). Race was dichotomized (white, non-white). Charlson comorbidity index and age at diagnosis were calculated. Associations between stage, comorbidity, race, and age were determined by logistic regression. RESULTS: 342 VA and 340 FFS patients were included. Populations differed by the proportion of patients with metastatic CRC at diagnosis (VA 27% and FFS 77%) reflecting differences in eligibility criteria for inclusion. VA patients were mean (standard deviation; SD) age 67 (11), Charlson index 2.0 (1.0), and were 63% white. FFS patients were mean age 61 (13), Charlson index 1.6 (1.0), and were 73% white. In the VA cohort, higher comorbidity was associated with earlier stage at diagnosis after adjusting for age and race (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.58-1.00; p = 0.045); no such significant relationship was identified in the FFS cohort (OR 1.09, 95% CI 0.82-1.44; p = 0.57). In both cohorts, no association was found between stage at diagnosis and either age or race. CONCLUSION: Higher comorbidity may lead to earlier stage of CRC diagnosis. Multiple factors, perhaps including increased interactions with the healthcare system due to comorbidity, might contribute to this finding. Such increased interactions are seen among patients within a healthcare system like the VA system in the US versus sporadic interactions which may be seen with FFS healthcare.

Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.

PURPOSE: The combination of a vascular endothelial growth factor (VEGF) -neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy. PATIENTS AND METHODS: In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2alpha were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers. RESULTS: Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016). CONCLUSION: In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Retinoic acid inhibition of chromatin remodeling at the human immunodeficiency virus type 1 promoter. Uncoupling of histone acetylation and chromatin remodeling.

All-trans retinoic acid (RA) represses HIV-1 transcription and replication in cultured monocytic cells and in primary monocyte-derived macrophages. Here we examine the role of histone acetylation and chromatin remodeling in RA-mediated repression. RA pretreatment of latently infected U1 promonocytes inhibits HIV-1 expression in response to the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). TSA is thought to activate HIV-1 transcription by inducing histone hyperacetylation within a regulatory nucleosome, nuc-1, positioned immediately downstream from the transcription start site. Acetylation of nuc-1 is thought to be a critical step in activation that precedes nuc-1 remodeling and, subsequently, transcriptional initiation. Here we demonstrate that TSA treatment induces H3 and H4 hyperacetylation and nuc-1 remodeling. Although RA pretreatment inhibits nuc-1 remodeling and HIV-1 transcription, it has no effect on histone acetylation. This suggests that acetylation and remodeling are not obligatorily coupled. We also show that growth of U1 cells in retinoid-deficient medium induces nuc-1 remodeling and HIV-1 expression but does not induce histone hyperacetylation. These findings suggest that remodeling, not histone hyperacetylation, is the limiting step in transcriptional activation in these cells. Together, these data suggest that RA signaling maintains the chromatin structure of the HIV-1 promoter in a transcriptionally non-permissive state that may contribute to the establishment of latency in monocyte/macrophages.

Retinoid-dependent restriction of human immunodeficiency virus type 1 replication in monocytes/macrophages.

Vitamin A deficiency has been correlated with increased severity of human immunodeficiency virus type 1 (HIV-1)-associated disease. Moreover, vitamin A supplementation can reduce AIDS-associated morbidity and mortality. Our group and others have shown that retinoids, the bioactive metabolites of vitamin A, repress HIV-1 replication in monocytic cell lines and primary macrophages by blocking long-terminal-repeat (LTR)-directed transcription. Based on these studies, we hypothesize that retinoids are natural repressors of HIV-1 in vivo. We show here that all-trans-retinoic acid (RA)-mediated repression of HIV-1 activation requires pretreatment for at least 12 h and is blocked by the protein synthesis inhibitors cycloheximide and puromycin. Studies of the kinetics of RA-mediated repression in U1 cells and primary monocyte-derived macrophages (MDMs) reveal that the repressive effects of RA on HIV-1 expression are long-lasting but reversible. We demonstrate that HIV-1 expression is activated when U1 cells or MDMs are cultured in retinoid-free synthetic medium and show that physiological concentrations of RA repress this activation. In addition, the synthetic pan-retinoic acid receptor antagonist BMS-204 493 activates HIV-1 replication in U1 cells in a dose-dependent manner, suggesting that RA-induced transactivation of cellular gene expression is required for HIV-1 repression. Together, these data support the hypothesis that retinoids present in tissue culture media in vitro and serum in vivo maintain HIV-1 in a transcriptionally repressed state in monocytes/macrophages.