Phase II study of dichloroacetate, an inhibitor of pyruvate dehydrogenase, in combination with chemoradiotherapy for unresected, locally advanced head and neck squamous cell carcinoma.

Chemoradiotherapy (CRT) for locally-advanced head and neck squamous cell carcinoma (LA-HSNCC) yields 5-year survival rates near 50% despite causing significant toxicity. Dichloroacetate (DCA), a pyruvate dehydrogenase kinase metabolic inhibitor, reduces tumor lactate production and has been used in cancer therapy previously. The safety of adding this agent to CRT is unknown. Our randomized, placebo-controlled, double-blind phase II study added DCA to cisplatin-based CRT in patients with LA-HNSCC. The primary endpoint was safety by adverse events (AEs). Secondary endpoints compared efficacy via 3-month end-of-treatment response, 5-year progression-free and overall survival. Translational research evaluated pharmacodynamics of serum metabolite response. 45 participants (21 DCA, 24 Placebo) were enrolled from May 2011-April 2014. Higher rates of all-grade drug related fevers (43% vs 8%, p = 0.01) and decreased platelet count (67% vs 33%, p = 0.02) were seen in DCA versus placebo. However, there were no significant differences in grade 3/4 AE rates. Treatment compliance to DCA/placebo, radiation therapy, and cisplatin showed no significant difference between groups. While end-of-treatment complete response rates were significantly higher in the DCA group compared to placebo (71.4% vs 37.5%, p = 0.0362), survival outcomes were not significantly different between groups. Treatment to baseline metabolites demonstrated a significant drop in pyruvate (0.47, p < 0.005) and lactate (0.61, p < 0.005) in the DCA group. Adding DCA to cisplatin-based CRT appears safe with no detrimental effect on survival and expected metabolite changes compared to placebo. This supports further investigation into combining metabolic agents to CRT. Trial registration number: NCT01386632, Date of Registration: July 1, 2011.

Epidemiology of substance-exposed pregnancies at one Great Lakes hospital that serves a large number of American Indians.

OBJECTIVE: The purpose of this research was to determine the prevalence of substance-exposed pregnancies at a hospital in the Great Lakes region of the U.S. METHOD: Data were collected via retrospective chart abstractions of patients who were seen for delivery at one Great Lakes region hospital during a 1-year period who were given at least one of the International Classification of Diseases codes related to substance use. RESULTS: A total of 342 medical records were included in the analysis, and, while much race/ethnicity data were missing, a large percentage of those in our analysis identified as American Indian. The prevalence of substance-exposed pregnancies at this hospital during a 1-year period was 34.5%. The majority (84.8%) were tobacco users, and many were found to have multiple substance exposures. Also, 48.5% were found to have a mental health diagnosis in addition to substance use. CONCLUSIONS: Data from this project can be used in prevention efforts, including preconception care for women at risk for substance use and mental health issues.

Infant birthweight and risk of childhood cancer: international population-based case control studies of 40 000 cases.

BACKGROUND: High birthweight is an established risk factor for childhood leukaemia. Its association with other childhood cancers is less clear, with studies hampered by low case numbers. METHODS: We used two large independent datasets to explore risk associations between birthweight and all subtypes of childhood cancer. Data for 16 554 cases and 53 716 controls were obtained by linkage of birth to cancer registration records across five US states, and 23 772 cases and 33 206 controls were obtained from the UK National Registry of Childhood Tumours. US, but not UK, data were adjusted for gestational age, birth order, plurality, and maternal age and race/ethnicity. RESULTS: Risk associations were found between birthweight and several childhood cancers, with strikingly similar results between datasets. Total cancer risk increased linearly with each 0.5 kg increase in birthweight in both the US [odds ratio 1.06 (95% confidence interval 1.04, 1.08)] and UK [1.06 (1.05, 1.08)] datasets. Risk was strongest for leukaemia [USA: 1.10 (1.06, 1.13), UK: 1.07 (1.04, 1.10)], tumours of the central nervous system [USA: 1.05 (1.01, 1.08), UK: 1.07 (1.04, 1.10)], renal tumours [USA: 1.17 (1.10, 1.24), UK: 1.12 (1.06, 1.19)] and soft tissue sarcomas [USA: 1.12 (1.05, 1.20), UK: 1.07 (1.00, 1.13)]. In contrast, increasing birthweight decreased the risk of hepatic tumours [USA: 0.77 (0.69, 0.85), UK: 0.79 (0.71, 0.89) per 0.5 kg increase]. Associations were also observed between high birthweight and risk of neuroblastoma, lymphomas, germ cell tumours and malignant melanomas. For some cancer subtypes, risk associations with birthweight were non-linear. We observed no association between birthweight and risk of retinoblastoma or bone tumours. CONCLUSIONS: Approximately half of all childhood cancers exhibit associations with birthweight. The apparent independence from other factors indicates the importance of intrauterine growth regulation in the aetiology of these diseases.

Epigenetics in pediatrics.

Epigenetic mechanisms are external modifications of DNA that cause changes in gene function and are involved in many diseases. Specific examples of pediatric diseases with a known or suspected epigenetic component include Beckwith-Wiedemann syndrome, childhood leukemia, allergies, asthma, fetal alcohol spectrum disorders, childhood obesity, and type 2 diabetes mellitus. Currently, epigenetically active treatments are being used to treat childhood leukemia. Potential epigenetically active treatments and preventive regimens are under study for other diseases. Pediatricians need to be aware of the epigenetic basis of disease to help inform clinical decision making in the future.

Functions and regulation of MUC13 mucin in colon cancer cells.

BACKGROUND: MUC13 is overexpressed and aberrantly localized in colon cancer tissue; however, the specific functions and regulation of MUC13 expression are unknown. METHODS: Stable cell lines with either overexpressed or suppressed MUC13 levels were analyzed to determine cell growth, colony formation, cell migration, and cell invasion assays. The molecular mechanisms involved in MUC13 regulation were elucidated via chromatin immunoprecipitation (ChIP) and analysis of interleukin 6 (IL6) treatments. Colon cancer tissues were analyzed by immunohistochemistry (IHC) for the protein levels of MUC13 and P-STAT5 in colon cancer cells. RESULTS: Overexpression of MUC13 increased cell growth, colony formation, cell migration, and invasion. In concordance, MUC13 silencing decreased these tumorigenic features. Overexpression of MUC13 also modulated various cancer-associated proteins, including telomerase reverse transcriptase, sonic hedgehog, B cell lymphoma murine like site 1, and GATA like transcription factor 1. Additionally, MUC13-overexpressing cells showed increased HER2 and P-ERK expression. ChIP analysis revealed binding of STAT5 to the predicted MUC13 promoter. IL6 treatment of colon cancer cells increased the expression of MUC13 via activation of the JAK2/STAT5 signaling pathway. Suppression of JAK2 and STAT5 signaling by chemical inhibitors abolished IL6-induced MUC13 expression. IHC analysis showed increased expression of both P-STAT5 and MUC13 in colon cancer as compared to adjacent normal tissue. CONCLUSIONS: The results of this study, for the first time, suggest functional roles of MUC13 in colon cancer progression and provide information regarding the regulation of MUC13 expression via JAK2/STAT5 which may reveal promising therapeutic approaches for colon cancer treatment.

Novel curcumin-loaded magnetic nanoparticles for pancreatic cancer treatment.

Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has showed potent anticancer and cancer prevention activity in a variety of cancers. However, the clinical translation of CUR has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics, and poor bioavailability. To address these clinically relevant issues, we have developed a novel CUR-loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAF-II and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose-dependent manner. As a result, the MNP-CUR formulation effectively inhibited growth of HPAF-II and Panc-1 cells in cell proliferation and colony formation assays. The MNP-CUR formulation suppressed pancreatic tumor growth in an HPAF-II xenograft mouse model and improved the survival of mice by delaying tumor growth. The growth-inhibitory effect of MNP-CUR formulation correlated with the suppression of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-extra large (Bcl-xL), induced myeloid leukemia cell differentiation protein (Mcl-1), cell surface-associated Mucin 1 (MUC1), collagen I, and enhanced membrane ß-catenin expression. MNP-CUR formulation did not show any sign of hemotoxicity and was stable after incubation with human serum proteins. In addition, the MNP-CUR formulation improved serum bioavailability of CUR in mice up to 2.5-fold as compared with free CUR. Biodistribution studies show that a significant amount of MNP-CUR formulation was able to reach the pancreatic xenograft tumor(s), which suggests its clinical translational potential. In conclusion, this study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer.

Epidemiology of childhood acute myeloid leukemia.

Although leukemia is the most common childhood cancer diagnosis, the subtype, acute myeloid leukemia (AML), is less common and fewer etiologic studies exist. This review summarizes the major risk factors for AML. We searched the literature using PubMed for articles on childhood AML and reviewed 180 articles. While few risk factors are definitive, we identified several with consistent evidence of a possible effect. Thorough analysis of genetic and epigenetic factors is missing from this literature and methodological issues are unresolved. Future studies should more closely examine causal mechanisms, improve exposure measurement, and include analysis using genetic and epigenetic factors.

Increased expression and aberrant localization of mucin 13 in metastatic colon cancer.

MUC13 is a newly identified transmembrane mucin. Although MUC13 is known to be overexpressed in ovarian and gastric cancers, limited information is available regarding the expression of MUC13 in metastatic colon cancer. Herein, we investigated the expression profile of MUC13 in colon cancer using a novel anti-MUC13 monoclonal antibody (MAb, clone ppz0020) by immunohistochemical (IHC) analysis. A cohort of colon cancer samples and tissue microarrays containing adjacent normal, non-metastatic colon cancer, metastatic colon cancer, and liver metastasis tissues was used in this study to investigate the expression pattern of MUC13. IHC analysis revealed significantly higher (p<0.001) MUC13 expression in non-metastatic colon cancer samples compared with faint or very low expression in adjacent normal tissues. Interestingly, metastatic colon cancer and liver metastasis tissue samples demonstrated significantly (p<0.05) higher cytoplasmic and nuclear MUC13 expression compared with non-metastatic colon cancer and adjacent normal colon samples. Moreover, cytoplasmic and nuclear MUC13 expression correlated with larger and poorly differentiated tumors. Four of six tested colon cancer cell lines also expressed MUC13 at RNA and protein levels. These studies demonstrate a significant increase in MUC13 expression in metastatic colon cancer and suggest a correlation between aberrant MUC13 localization (cytoplasmic and nuclear expression) and metastatic colon cancer.

Parental infertility, infertility treatment and hepatoblastoma: a report from the Children's Oncology Group.

BACKGROUND: A recent study suggested a markedly increased risk of hepatoblastoma (HB) among children conceived with treatment for infertility. However, it is not clear whether this finding is confounded by the association between HB and low birthweight (LBW). METHODS: Associations between parental infertility and its treatment and HB were examined using data from a case-control study conducted through the Children's Oncology Group (COG). Telephone interviews were completed for 383 mothers of cases diagnosed with HB at US COG institutions between January 2000 and December 2008 and for 387 mothers of controls recruited through state birth registries. Logistic regression was used to examine possible associations. RESULTS: After adjusting for birthweight and other potential confounders, no significant association was found for any of the measures of parental infertility or its treatment. In HB cases conceived through assisted reproductive technology (ART), 4 of 16 also had Beckwith-Wiedemann syndrome (BWS) compared with 9 of 365 in HB cases without ART. CONCLUSIONS: Little evidence of an association between parental infertility or its treatment and HB was found. The relationship found in a previous study could be due to LBW and BWS which are risk factors for HB and also associated with parental infertility and its treatment.

Pediatric germ cell tumors and parental infertility and infertility treatment: a Children's Oncology Group report.

BACKGROUND: Few risk factors have been established for childhood germ cell tumors (GCT). Parental infertility and infertility treatment may be associated with GCT development but these risk factors have not been fully investigated. METHODS: A case-control study of childhood GCT was conducted through the Children's Oncology Group (COG). Cases, under the age of 15 years at diagnosis, were recruited through COG institutions from January 1993 to December 2002. Controls were obtained through random digit dialing. Information about infertility and infertility treatment along with demographic factors was collection through maternal interviews. Subgroups created by gender, age at diagnosis, and tumor location were examined separately. Statistical analysis was performed using multivariate logistic regression models. RESULTS: Overall, no association between GCT and infertility or its treatment was found. In subgroup analysis, females whose mothers had two or more fetal losses were found to be at increased risk for non-gonadal tumors (Odds ratio (OR)=3.32, 95% Confidence interval (CI)=1.12-9.88). Younger maternal age was associated with a lower risk of gonadal GCT in females (OR=0.52, 95% CI=0.28-0.96). There was an increased risk of all GCT and gonadal GCT in males born to older mothers (OR=2.88, 95% CI=1.13-7.37 and OR=3.70, 95% CI=1.12-12.24). CONCLUSION: While no association between parental infertility or its treatment and childhood GCT was found overall, possible associations with maternal age and history of recurrent fetal loss were found in subgroups defined by gender.

Birth order and risk of childhood cancer: a pooled analysis from five US States.

The causes of childhood cancers are largely unknown. Birth order has been used as a proxy for prenatal and postnatal exposures, such as frequency of infections and in utero hormone exposures. We investigated the association between birth order and childhood cancers in a pooled case-control dataset. The subjects were drawn from population-based registries of cancers and births in California, Minnesota, New York, Texas and Washington. We included 17,672 cases <15 years of age who were diagnosed from 1980 to 2004 and 57,966 randomly selected controls born 1970-2004, excluding children with Down syndrome. We calculated odds ratios and 95% confidence intervals using logistic regression, adjusted for sex, birth year, maternal race, maternal age, multiple birth, gestational age and birth weight. Overall, we found an inverse relationship between childhood cancer risk and birth order. For children in the fourth or higher birth order category compared to first-born children, the adjusted OR was 0.87 (95% CI: 0.81, 0.93) for all cancers combined. When we examined risks by cancer type, a decreasing risk with increasing birth order was seen in the central nervous system tumors, neuroblastoma, bilateral retinoblastoma, Wilms tumor and rhabdomyosarcoma. We observed increased risks with increasing birth order for acute myeloid leukemia but a slight decrease in risk for acute lymphoid leukemia. These risk estimates were based on a very large sample size, which allowed us to examine rare cancer types with greater statistical power than in most previous studies, however the biologic mechanisms remain to be elucidated.

Childhood cancer in relation to parental race and ethnicity: a 5-state pooled analysis.

BACKGROUND: Children of different racial/ethnic backgrounds have varying risks of cancer. However, to the authors' knowledge, few studies to date have examined cancer occurrence in children of mixed ancestry. METHODS: This population-based case-control study examined cancer among children aged <15 years using linked cancer and birth registry data from 5 US states from 1978 through 2004. Data were available for 13,249 cancer cases and 36,996 controls selected from birth records. Parental race/ethnicity was determined from birth records. Logistic regression analysis was used to examine the association of cancer with different racial/ethnic groups. RESULTS: Compared with whites, blacks had a 28% decreased risk of cancer (odds ratio [OR], 0.72; 95% confidence interval [95% CI], 0.65-0.80), whereas both Asians and Hispanics had an approximate 15% decrease. Children of mixed white/black ancestry also were found to be at decreased risk (OR, 0.71; 95% CI, 0.56-0.90), but estimates for mixed white/Asian and white/Hispanic children did not differ from those of whites. Compared with whites: 1) black and mixed white/black children had decreased ORs for acute lymphoblastic leukemia (OR, 0.39 [95% CI, 0.31-0.49] and OR, 0.58 [95% CI, 0.37-0.91], respectively); 2) Asian and mixed white/Asian children had decreased ORs for brain tumors (OR, 0.51 [95% CI, 0.39-0.68] and OR, 0.79 [95% CI, 0.54-1.16], respectively); and 3) Hispanic and mixed white/Hispanic children had decreased ORs for neuroblastoma (OR, 0.51 [95% CI, 0.42-0.61] and OR, 0.67 [95% CI, 0.50-0.90], respectively). CONCLUSIONS: Children of mixed ancestry tend to have disease risks that are more similar to those of racial/ethnic minority children than the white majority group. This tendency may help formulate etiologic studies designed to study possible genetic and environmental differences more directly.

Infant leukemia and parental infertility or its treatment: a Children's Oncology Group report.

BACKGROUND: Little is known about the potential risk factors for infant leukemia. With its very young age at diagnosis, exposures occurring in the perinatal period are suspected. Parental infertility and infertility treatment have been studied with regard to childhood cancer in general, but rarely in individual cancer subtypes. METHODS: A case-control study of infant leukemia was conducted through the Children's Oncology Group, including cases diagnosed from January 1996 to December 2006 and controls selected through random digit dialing and birth certificate tracing. Maternal phone interviews were conducted to obtain information about infertility, infertility treatment and demographic factors. All cases as well as subgroups defined by mixed lineage leukemia (MLL) translocation status and leukemia subtype were examined. Statistical analysis was performed using multivariate logistic regression models. RESULTS: No significant associations between infertility or its treatment and combined infant leukemia were found. In subgroup analyses, there was a significant increase in the risk of MLL--leukemia for children born to women not trying to conceive compared with those trying for <1 year for all types combined [odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.01-2.59] and for acute lymphoblastic leukemia (OR = 2.50, 95% CI = 1.36-4.61). CONCLUSIONS: There were no positive associations between parental infertility or infertility treatment and infant leukemia. While this is the largest study to date, both selection and recall bias may have impacted the results. However, for infant leukemia, we can potentially rule out large increases in risk associated with parental infertility or its treatment.

Cancer risk among children with very low birth weights.

OBJECTIVE: The risk of hepatoblastoma is strongly increased among children with very low birth weight (<1500 g). Because data on very low birth weight and other childhood cancers are sparse, we examined the risk of malignancy with very low birth weight in a large data set. METHODS: We combined case-control data sets created by linking the cancer and birth registries of California, Minnesota, New York, Texas, and Washington states, which included 17672 children diagnosed as having cancer at 0 to 14 years of age and 57966 randomly selected control subjects. Unconditional logistic regression analysis was used to examine the association of cancer with very low birth weight and moderately low birth weight (1500-1999 g and 2000-2499 g, respectively), compared with moderate/high birth weight (>or=2500 g), with adjustment for gender, gestational age, birth order, plurality, maternal age, maternal race, state, and year of birth. RESULTS: Most childhood cancers were not associated with low birth weights. However, retinoblastomas and gliomas other than astrocytomas and ependymomas were possibly associated with very low birth weight. The risk of other gliomas was also increased among children weighing 1500 to 1999 g at birth. CONCLUSIONS: These data suggested no association between most cancers and very low birth weight, with the exception of the known association of hepatoblastoma and possibly moderately increased risks of other gliomas and retinoblastoma, which may warrant confirmation.

Comparability and representativeness of control groups in a case-control study of infant leukemia: a report from the Children's Oncology Group.

Traditionally, controls in US pediatric cancer studies were selected through random digit dialing. With declining participation and lack of nonparticipant information, random digit dialing (RDD) controls may be substandard. Birth certificate (BC) controls are an alternative, because they are population based and include data from nonparticipants. The authors examined controls collected by random digit dialing and birth certificates for a Children's Oncology Group case-control study of infant leukemia in 1995-2006. Demographic variables were used to assess differences in RDD and BC controls and their representativeness. RDD and BC controls did not differ significantly with regard to maternal variables (age, race, education, marital status, alcohol during pregnancy) or child variables (sex, gestational age, birth weight), but they varied in smoking during pregnancy (22% RDD controls, 12% BC controls) (P = 0.05). The study's combined control group differed significantly from US births: Mothers of controls were more likely to be older (29.8 vs. 27.2 years), white (84% vs. 59%), and married (85% vs. 67%) and to have >16 years of education (37% vs. 25%). Control children were more often full term (88% vs. 81%) and heavier (3,436 vs. 3,317 g). Finally, participating BC mothers were likely to be older and to have more education than nonparticipants. Thus, the study's control groups were comparable but differed from the population of interest.

Parental age and risk of childhood cancer: a pooled analysis.

BACKGROUND: Few risk factors for childhood cancer are well-established. We investigated whether advancing parental age increases childhood cancer risk. METHODS: We assessed the relationship between parental age and childhood cancer in a case-control study using pooled population-based data. Our pooling was based on linked cancer and birth registry records from New York, Washington, Minnesota, Texas, and California. Subjects included 17,672 cancer cases diagnosed at ages 0-14 years during 1980-2004 and 57,966 controls born during 1970-2004. Individuals with Down syndrome were excluded. Odds ratios and 95% confidence intervals were calculated by logistic regression for the association between parental age and childhood cancer after adjustment for sex, birth weight, gestational age, birth order, plurality, maternal race, birth year, and state. RESULTS: Positive linear trends per 5-year maternal age increase were observed for childhood cancers overall (odds ratio = 1.08 [95% confidence interval = 1.06-1.10]) and 7 of the 10 most frequent diagnostic groups: leukemia (1.08 [1.05-1.11]), lymphoma (1.06 [1.01-1.12]), central nervous system tumors (1.07 [1.03-1.10]), neuroblastoma (1.09 [1.04-1.15]), Wilms' tumor (1.16 [1.09-1.22]), bone tumors (1.10 [1.00-1.20]), and soft tissue sarcomas (1.10 [1.04-1.17]). No maternal age effect was noted for retinoblastoma, germ cell tumors, or hepatoblastoma. Paternal age was not independently associated with most childhood cancers after adjustment for maternal age. CONCLUSIONS: Our results suggest that older maternal age increases risk for most common childhood cancers. Investigation into possible mechanisms for this association is warranted.

Childhood cancer among twins and higher order multiples.

Although several studies have found no change or a decreased risk of childhood cancer in twins, few have controlled for potential confounders such as birth weight. We examined the association of birth plurality and childhood cancer in pooled data from five U.S. states (California, Minnesota, New York, Texas, and Washington) using linked birth-cancer registry data. The data, excluding children with Down syndrome or who died before 28 days of life, included 17,672 cases diagnosed from 1980 to 2004 at ages 28 days to 14 years and 57,966 controls with all cases and controls born from 1970 to 2004. Analyses were restricted to children weighing

Breast and cervical cancer screening among low-income women in Nebraska: findings from the Every Woman Matters program, 1993-2004.

OBJECTIVE: To examine the likelihood of enrollees in the Nebraska Every Woman Matters program being screened for breast and cervical cancer. METHODS: We explored the relationship between sociodemographic characteristics and receiving cancer screening services. RESULTS: Older and Native American women were more likely than younger and White women to have mammograms ordered [adjusted odds ratio (OR)=1.41, 95% confidence interval (CI) 1.08, 1.85]. African American [OR=0.54, 95% CI 0.46, 0.64] and Native American women [OR=0.47, 95% CI 0.39, 0.55] were less likely than White women to have clinical breast exams performed. Native American [OR=0.19, 95% CI 0.16, 0.23] and African American women [OR=0.56, 95% CI 0.46, 0.68] were less likely than White women to have a Pap test performed. CONCLUSION: Receiving cancer screening services was related to race; thus, understanding barriers for screening for minority women is warranted.

Perinatal characteristics and risk of neuroblastoma.

Neuroblastoma (NB), a tumor of the sympathetic nervous system, is the most common infant malignancy. The etiology of NB is largely unknown. We explored the association between birth record variables and subsequent NB development in a population-based case-cohort study in Minnesota by linking the birth and cancer registries. NB cases included 155 children born during 1976-2004 who were diagnosed from 28 days through 14 years of age. The comparison group included 8,752 individuals randomly sampled from the birth cohort of cases. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Controlling for birth year and sex, maternal history of one fetal loss (HR = 1.7, 95% CI 1.2-2.5), maternal prenatal drug-use (recorded starting in 1992) (HR = 5.7, 95% CI 2.3-14) and child's small size for gestational age (HR = 2.1, 95% CI 1.1-4.0) were significantly associated with NB. Age group specific analyses indicated that maternal hypertension (HR = 3.0, 95% CI 1.3-7.2) and maternal age <20 years (HR = 2.6, 95% CI 1.1-6.1) increased risks for infant NB only. Our study provides evidence that a few perinatal exposures as recorded in birth records may play a role in NB etiology.