Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells.

MicroRNAs are often associated with the pathogenesis of many cancers, including head and neck squamous cell carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to have a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study, we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of i nhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 has a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC

The effect on survival of continuing chemotherapy to near death

<p>Abstract</p> <p>Background</p> <p>Overuse of anti-cancer therapy is an important quality-of-care issue. An aggressive approach to treatment can have negative effects on quality of life and cost, but its effect on survival is not well-defined.</p> <p>Methods</p> <p>Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified 7,879 Medicare-enrolled patients aged 65 or older who died after having survived at least 3 months after diagnosis of advanced non-small cell lung cancer (NSCLC) between 1991 and 1999. We used Cox proportional hazards regression analysis, propensity scores, and instrumental variable analysis (IVA) to compare survival among patients who never received chemotherapy (n = 4,345), those who received standard chemotherapy but not within two weeks prior to death (n = 3,235), and those who were still receiving chemotherapy within 14 days of death (n = 299). Geographic variation in the application of chemotherapy was used as the instrument for IVA.</p> <p>Results</p> <p>Receipt of chemotherapy was associated with a 2-month improvement in overall survival. However, based on three different statistical approaches, no additional survival benefit was evident from continuing chemotherapy within 14 days of death. Moreover, patients receiving chemotherapy near the end of life were much less likely to enter hospice (81% versus 51% with no chemotherapy and 52% with standard chemotherapy, P < 0.001), or were more likely to be admitted within only 3 days of death.</p> <p>Conclusions</p> <p>Continuing chemotherapy for advanced NSCLC until very near death is associated with a decreased likelihood of receiving hospice care but not prolonged survival. Oncologists should strive to discontinue chemotherapy as death approaches and encourage patients to enroll in hospice for better end-of-life palliative care.</p

Adaptation and validation of the Charlson Index for Read/OXMIS coded databases

BACKGROUND: The Charlson comorbidity index is widely used in ICD-9 administrative data, however, there is no translation for Read/OXMIS coded data despite increasing use of the General Practice Research Database (GPRD). Our main objective was to translate the Charlson index for use with Read/OXMIS coded data such as the GPRD and test its association with mortality. We also aimed to provide a version of the comorbidity index for other researchers using similar datasets. METHODS: Two clinicians translated the Charlson index into Read/OXMIS codes. We tested the association between comorbidity score and increased mortality in 146 441 patients from the GPRD using proportional hazards models. RESULTS: This Read/OXMIS translation of the Charlson index contains 3156 codes. Our validation showed a strong positive association between Charlson score and age. Cox proportional models show a positive increasing association with mortality and Charlson score. The discrimination of the logistic regression model for mortality was good (AUC = 0.853). CONCLUSION: We have translated a commonly used comorbidity index into Read/OXMIS for use in UK primary care databases. The translated index showed a good discrimination in our study population. This is the first study to develop a co-morbidity index for use with the Read/OXMIS coding system and the GPRD. A copy of the co-morbidity index is provided for other researchers using similar database

Health status, use of healthcare, and socio-economic implications of cancer survivorship in Portugal : results from the fourth national health survey

Health status, use of healthcare, and socio-economic implications of cancer survivorship in Portugal: results from the Fourth National Health SurveyUnderstanding the morbidity and socio-economic implications of cancer survivorship is essential for a comprehensive management of oncological diseases. We compared cancer survivors (CS) with the general population regarding health status, use of healthcare resources and socio-economic condition. We analyzed data from a representative sample of the Portuguese population aged a parts per thousand yen15 years (n = 35,229). We defined three groups of CS, according to the time since diagnosis and the latest cancer treatment: CS 1 diagnosis within 12 months of interview; CS 2 diagnosis more than 12 months before and treatment in the previous 12 months; CS 3 diagnosis and treatment more than 12 months before. These were compared with the general population, adjusting for differences in sex, age, and place of residence. The prevalence of CS was 2.2 % (CS 1: 0.2 %; CS 2: 0.9 %, CS 3: 1.1 %). Self-perceived health status was worse among CS and short-time incapacity more frequent among CS 1 and CS 2. Health expenses were higher in the early stages of survivorship. Lower household income and financial difficulties were more frequent in CS 1 and CS 3 men, respectively. This study confirmed the higher consumption of healthcare resources and worse financial situation among CS. Our study provides valuable information for understanding the global impact of cancer survivorship.The authors thank the National Health Systems Observatory (Observatorio Nacional de Saude), National Institute of Health Dr. Ricardo Jorge (INSA), Ministry of Health and the National Institute of Statistics (INE) for providing the data (Ministerio da Saude, Instituto Nacional de Saude Dr. Ricardo Jorge; IP, Departamento de Epidemiologia/Instituto Nacional de Estatistica: Inquerito Nacional de Saude 2005/2006). Luis Pacheco-Figueiredo received a grant from the Fundacao para a Ciencia e a Tecnologia (SFRH/SINTD/60124/2009)

Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab

We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival

Spirituality and end-of-life care in disadvantaged men dying of prostate cancer

Despite the positive influence of spiritual coping on the acceptance of a cancer diagnosis, higher spirituality is associated with receipt of more high intensity care at the end of life. The purpose of our study was to assess the association between spirituality and type of end-of-life care received by disadvantaged men with prostate cancer. We studied low-income, uninsured men in IMPACT, a state-funded public assistance program, who had died since its inception in 2001. Of the 60 men who died, we included the 35 who completed a spirituality questionnaire at program enrollment. We abstracted sociodemographic and clinical information as well as treatment within IMPACT, including zolendroic acid, chemotherapy, hospice use, and palliative radiation therapy. We measured spirituality with the Functional Assessment of Chronic Illness Therapy—Spiritual Well-Being questionnaire (FACIT-Sp) and compared end-of-life care received between subjects with low and high FACIT-Sp scores using chi-squared analyses. A higher proportion of men with high (33%) versus low (13%) spirituality scores enrolled in hospice, although our analysis was not adequately powered to demonstrate statistical significance. Likewise, we saw a trend toward increased receipt of palliative radiation among those with higher spirituality (37% vs. 25%, P = 0.69). The differences in end-of-life care received among those with low and high spirituality varied little by the FACIT-Sp peace and faith subscales. End-of-life care was similar between men with lower and higher spirituality. Men with higher spirituality trended toward greater hospice use, suggesting that they redirected the focus of their care from curative to palliative goals

Q-TWiST analysis of lapatinib combined with capecitabine for the treatment of metastatic breast cancer

The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients

Cancer screening and preventative care among long-term cancer survivors in the United Kingdom

BACKGROUND: Long-term cancer survivors in the United Kingdom are mostly followed up in a primary care setting by their general practitioner; however, there is little research on the use of services. This study examines whether cancer survivors receive adequate screening and preventative care in UK primary care. PATIENTS AND METHODS: We identified a cohort of long-term survivors of breast, colorectal and prostate cancer with at least a 5-year survival using the General Practice Research Database, with controls matched for age, gender and practice. We compared adherence with cancer screening and the use of preventative care between cancer survivors and controls. RESULTS: The cancer survivors' cohort consisted of 18 612 breast, 5764 colorectal and 4868 prostate cancer survivors. Most cancer survivors receive cancer screening at the same levels as controls, except for breast cancer survivors who were less likely to receive a mammogram than controls (OR=0.78, 95% CI: 0.66-0.92). Long-term cancer survivors received comparable levels of influenza vaccinations and cholesterol tests, but breast (OR 0.81, 95% CI: 0.74-0.87) and prostate cancer survivors (OR=0.70, 95% CI: 0.57-0.87) were less likely to receive a blood pressure test. All survivors were more likely to receive bone densitometry. CONCLUSION: The provision and uptake of preventive care in a primary care setting in the United Kingdom is comparable between the survivors of three common cancers and those who have not had cancer. However, long-term breast cancer survivors in this cohort were less likely to receive a mammogra

Trends in healthcare utilization among older Americans with colorectal cancer: A retrospective database analysis

<p>Abstract</p> <p>Background</p> <p>Analyses of utilization trends (cost drivers) allow us to understand changes in colorectal cancer (CRC) costs over time, better predict future costs, identify changes in the use of specific types of care (eg, hospice), and provide inputs for cost-effectiveness models. This retrospective cohort study evaluated healthcare resource use among US Medicare beneficiaries diagnosed with CRC between 1992 and 2002.</p> <p>Methods</p> <p>Cohorts included patients aged 66+ newly diagnosed with adenocarcinoma of the colon (n = 52,371) or rectum (n = 18,619) between 1992 and 2002 and matched patients from the general Medicare population, followed until death or December 31, 2005. Demographic and clinical characteristics were evaluated by cancer subsite. Resource use, including the percentage that used each type of resource, number of hospitalizations, and number of hospital and skilled nursing facility days, was evaluated by stage and subsite. The number of office, outpatient, and inpatient visits per person-year was calculated for each cohort, and was described by year of service, subsite, and treatment phase. Hospice use rates in the last year of life were calculated by year of service, stage, and subsite for CRC patients who died of CRC.</p> <p>Results</p> <p>CRC patients (mean age: 77.3 years; 44.9% male) used more resources than controls in every category (<it>P </it>< .001), with the largest differences seen in hospital days and home health use. Most resource use (except hospice) remained relatively steady over time. The initial phase was the most resource intense in terms of office and outpatient visits. Hospice use among patients who died of CRC increased from 20.0% in 1992 to 70.5% in 2004, and age-related differences appear to have evened out in later years.</p> <p>Conclusion</p> <p>Use of hospice care among CRC decedents increased substantially over the study period, while other resource use remained generally steady. Our findings may be useful for understanding CRC cost drivers, tracking trends, and forecasting resource needs for CRC patients in the future.</p