Outcomes of early vs late treatment initiation in solid organ transplantation from hepatitis C virus nucleic acid test-positive donors to hepatitis C virus-uninfected recipients: Results from the HCV-TARGET study.

Curative hepatitis C virus (HCV) therapy has increased transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients (D+/R-). We evaluated outcomes of early and late HCV treatment among D+/R- nonliver organ transplants. Patients received HCV regimens per local standard (n = 10 sites). Outcomes were compared between early and late treatments. Early treatment regimens (ETR) (n = 56) were initiated pretransplantation to day 7 posttransplant. Late treatment regimens (LTRs) (n = 102) began median 31 (range, 8-114) days posttransplant. There were 79 kidney, 50 lung, 23 heart, and 6 mixed transplants, similar between groups. HCV RNA was quantifiable in 98% of LTR versus 44.6% of ETR recipients (P < .001). Mean (range) days on treatment were 28 (7-93) ETR and 81 (51-111) LTR (P < .0001). There were no virological failures with ETR, but relapse (n = 3) and nonresponse (n = 2) in LTR (P = .16), including fibrosing cholestatic hepatitis postrelapse (n = 1). Sustained virological response was 100% (95% confidence interval, 93.4-100.0) in ETR (n = 54) and 94.9% (95% confidence interval, 88.5-98.3) in LTR (n = 98). Acute rejection occurred in 11 (19.6%) ETR and 25 (24.5%) LTR. In total, 11 HCV-unrelated deaths occurred: 8 ETR and 3 LTR. Organ transplantation from HCV-infected nucleic acid test-positive donors to HCV-uninfected recipients was safe. ETR led to fewer virological failures with shorter treatment duration, supporting recommendations to initiate treatment promptly posttransplant.

DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: Real-world experience from HCV-TARGET cohort.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy is used in patients with HCV-related decompensated cirrhosis with the expectation of improving hepatic function. However, little is known about the long-term hepatic benefit of successful antiviral treatment. METHODS: Patients with advanced/decompensated cirrhosis (model for end-stage liver disease [MELD] ≥10), in whom NS5A-containing DAA therapy was initiated prior to September 2018, were included (from the HCV-TARGET cohort). Treatment outcomes and the impact of treatment on short-term and long-term hepatic function were examined. RESULTS: A total of 642 patients were analyzed. The mean age was 60 years, 68% were male. The median baseline MELD was 12 (range 10-39) and 64% had prior decompensation. Among patients with available virologic outcomes, 90.5% achieved a sustained virologic response at 12 weeks (SVR12). Eighty (24%) patients achieved a clinically significant decrease in MELD by ≥3 points during short-term follow-up (9-26 weeks after the end of treatment). However, in long-term follow-up (median of 4 years after treatment), mean changes in MELD (-0.30 points), total bilirubin (+0.23 mg/dl) and albumin (+0.36 g/dl) were marginal. Fifty-one patients died and 22 underwent liver transplant. In long-term follow-up, a clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%. CONCLUSION: In a large real-world experience of patients with advanced/decompensated HCV-related cirrhosis treated with DAAs, there were only marginal improvements in MELD, total bilirubin, or albumin at long-term follow-up (after achieving SVR12). These patients may remain at high risk of decompensation and must continue to be closely monitored. CLINICALTRIALS.GOV: NCT01474811. LAY SUMMARY: Hepatitis C virus infection can now be cured with medications, even in patients who have advanced scarring of the liver (cirrhosis). In this study, we evaluated whether liver function improves or deteriorates in the long-term, following successful treatment of hepatitis C in patients with cirrhosis. We found that overall liver function was relatively stable with only 29% of patients achieving a clinically meaningful improvement in liver function, and we therefore believe that these patients require ongoing monitoring.

Treatment Status of Hepatocellular Carcinoma Does Not Influence Rates of Sustained Virologic Response: An HCV-TARGET Analysis.

Recent studies have suggested a negative impact of hepatocellular carcinoma (HCC) on sustained virologic response (SVR) to hepatitis C virus (HCV) direct acting antivirals (DAAs). We compared the effectiveness of DAAs in patients with cirrhosis, with and without HCC, and in those with HCC partially treated or untreated (PT/UT-HCC) versus completely treated (CT-HCC). HCC status was based on imaging 6 months before or 2 months after start of DAA therapy. Absence and presence of enhancing lesions after HCC treatment defined CT-HCC and PT/UT-HCC, respectively. Using minimally adjusted logistic regression, the association between the presence of HCC and SVR rates was estimated. Among the 1,457 patients with cirrhosis from HCV-TARGET with complete virologic data (per-protocol population) who did not undergo liver transplantation during treatment and followup, 1,300 were without HCC, 91 with CT-HCC, and 66 with PT/UT-HCC. Most patients were genotype 1 (81%) and treatment-experienced (56%), 41% had history of prior decompensation, and the median pretreatment Model for End-Stage Liver Disease was 9 (range 6-39). The SVR rates were 91% for patients without HCC, 84% for CT-HCC, and 80% for PT/UT-HCC. The presence of HCC (versus not having HCC) was associated with significantly lower odds of achieving SVR (odds ratio [OR] = 0.51, 95% confidence interval [CI]: 0.33-0.81; P = 0.003). However, among those with HCC, HCC treatment status (PT/UT-HCC versus CT-HCC) did not show association with SVR (OR = 0.79, 95% CI: 0.35-1.79, P = 0.569). Conclusions: The presence of HCC reduces the likelihood of SVR by 50%, but with no evident difference in those with completely treated HCC versus partially treated/untreated HCC.

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients With Genotype 1 Hepatitis C Virus Infection and Cirrhosis.

BACKGROUND & AIMS: We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET). METHODS: We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow-up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per-protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS: The per-protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16-5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46-6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59-7.00) were associated with SVR12. CONCLUSIONS: In an analysis of safety and effectiveness data from the HCV-TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment-experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.

Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV-TARGET study.

Data outside of clinical trials with direct-acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct-acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. CONCLUSION: In a large prospective observational cohort study, direct-acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090-1101).

Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study.

OBJECTIVE: Due to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants. DESIGN: HCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigator's choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12). RESULTS: Between December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%. CONCLUSIONS: In this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection. TRIAL REGISTRATION NUMBER: NCT01474811.

Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response.

BACKGROUND & AIMS: The combination of ledipasvir and sofosbuvir has been approved for treatment of genotype 1 hepatitis C virus (HCV) infection, including an 8-week regimen for treatment-naïve patients without cirrhosis and a baseline level of HCV RNA <6 million IU/mL. We analyzed data from a multicenter, prospective, observational study to determine real-world sustained virologic responses 12 weeks after treatment (SVR12) with regimens containing ledipasvir and sofosbuvir and identify factors associated with treatment failure. METHODS: We collected data from 2099 participants in the HCV-TARGET study with complete virologic data (per-protocol population). We analyzed data from 1788 patients receiving ledipasvir-sofosbuvir (282 for 8 weeks, 910 for 12 weeks, 510 for 24 weeks, and 86 for a different duration) and 311 receiving ledipasvir-sofosbuvir plus ribavirin (212 for 12 weeks and 81 for 24 weeks, 18 for other duration) to estimate SVR12 (with 95% confidence interval [CI]), and logistic regression methods to identify factors that predicted an SVR12. RESULTS: The overall study population was 25% black, 66% with HCV genotype 1A infection, 41% with cirrhosis, 50% treatment-experienced, and 30% receiving proton pump inhibitors at start of treatment. In the per-protocol population, SVR12s were achieved by 96% of patients receiving ledipasvir-sofosbuvir for 8 weeks (95% CI, 93%-98%), 97% receiving the drugs for 12 weeks (95% CI, 96%-98%), and 95% receiving the drugs for 24 weeks (95% CI, 93%-97%). Among patients also receiving ribavirin, SVR12 was achieved by 97% of the patients receiving the drugs for 12 weeks (95% CI, 94%-99%) and 95% receiving the drugs for 24 weeks (95% CI, 88%-99%). Of the 586 patients who qualified for 8 weeks of treatment, only 255 (44%) received the drugs for 8 weeks. The rate of SVR12 among those who qualified for and received 8 weeks of therapy was similar in those who qualified for 8 weeks but received 12 weeks therapy (96%; 95% CI, 92%-99% vs 98%; 95% CI, 95%-99%). Factors that predicted SVR12 were higher albumin (≥3.5 g/dL), lower total bilirubin (≤1.2 g/dL), absence of cirrhosis, and absence of proton pump inhibitor use. CONCLUSIONS: Regimens containing ledipasvir and sofosbuvir are highly effective for a broad spectrum of patients with HCV genotype 1 infection treated in different clinical practice settings. Expanded use of 8-week treatment regimens for eligible patients is supported by these real-world results. Modification of proton pump inhibitor use may increase rates of SVR. ClinicalTrials.gov no. NCT01474811.

Effectiveness and Safety of Sofosbuvir-Based Regimens for Chronic HCV Genotype 3 Infection: Results of the HCV-TARGET Study.

BACKGROUND: Sofosbuvir (SOF) is active against all hepatitis C virus (HCV) genotypes, and SOF-based therapies lead to high rates of sustained virologic response (SVR). However, genotype 3 (GT3) HCV remains a challenge with lower SVR rates reported, particularly in patients with cirrhosis. This study reports the effectiveness and safety of SOF-based therapy in patients with GT3 HCV treated in clinical practice. METHODS: Hepatitis C Virus Therapeutic Registry and Research Network is an international, prospective observational study evaluating patients treated in usual clinical practice. Patients with GT3 HCV were analyzed to assess predictors of treatment response and adverse events using descriptive statistics and multivariable logistic regression. RESULTS: Treatment outcomes were available for 197 patients treated with SOF and ribavirin (RBV), with or without peginterferon, including 54% with cirrhosis and 49% who failed prior therapy. Of 178 patients treated with SOF/RBV, 60% achieved SVR at 12 weeks (SVR12), compared with 84% of 19 patients treated with SOF/peginterferon/RBV. For patients treated with SOF/RBV, the SVR12 rate was 58% in treatment-naive patients with cirrhosis, and 42% in those with cirrhosis who failed prior therapy. In noncirrhotic patients, SVR12 rates were 89% in treatment-naive and 88% in treatment-experienced patients. After controlling for age and sex, absence of cirrhosis (odds ratio [OR], 6.4; 95% confidence interval [CI], 2.78-14.74), albumin levels ≥3.2 g/dL (OR, 12.48; 95% CI, 3.86-40.33), and platelet count >10(5) cells/µL (OR, 7.44; 95% CI, 3.51-15.78) were associated with greater odds of SVR12 CONCLUSIONS: SVR rates were acceptable in patients with GT3 HCV without cirrhosis; however, in those with cirrhosis, treatment with SOF/RBV was suboptimal, highlighting the need for new therapies for this population.

The Association Between Body Mass Index and Presenting Symptoms in African American Women with Ovarian Cancer.

BACKGROUND: Ovarian cancer, the most lethal gynecologic malignancy, typically comes to clinical attention due to nonspecific gastrointestinal or pelvic symptoms. African Americans with ovarian cancer have a greater mortality burden than whites and are also much more likely to be obese. The objective of this study is to explore whether the presentation and duration of symptoms differ by body mass index (BMI) in African Americans with ovarian cancer. METHODS: We conducted a case-only analysis using data from a multicenter population-based study of invasive epithelial ovarian cancer in African American women. Information on risk factors and symptoms leading to diagnosis was obtained in a telephone interview. Frequency and duration of symptoms by BMI categories were compared using logistic regression and linear regression analyses. RESULTS: Of the 326 women, ∼60% was obese (BMI ≥30), with 30.8% having a BMI ≥35 kg/m(2). Ninety-four percent of women reported ≥1 symptom during the year before diagnosis. We observed differences in frequency of symptoms by BMI categories, with most being reported more frequently by the heaviest women. The reported duration of symptoms was longer in women with higher BMI, with statistically significant trend tests for 6 of the 10 symptoms evaluated. CONCLUSION: BMI appears to impact ovarian cancer symptomatology. Women with higher BMI report having symptoms for a longer period of time before diagnosis of ovarian cancer. Healthcare providers should be vigilant and consider ovarian cancer in the differential diagnosis for obese women presenting with abdominal and pelvic symptoms.

A multi-center population-based case-control study of ovarian cancer in African-American women: the African American Cancer Epidemiology Study (AACES).

BACKGROUND: Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population. METHODS: The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case-control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained. RESULTS: Current accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women. CONCLUSIONS: AACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women.

Molecular signatures of epithelial ovarian cancer: analysis of associations with tumor characteristics and epidemiologic risk factors.

BACKGROUND: Six gene expression subtypes of invasive epithelial ovarian cancer were recently defined using microarrays by Tothill and colleagues. The Cancer Genome Atlas (TCGA) project subsequently replicated these subtypes and identified a signature predictive of survival in high-grade serous (HGS) cancers. We previously validated these signatures for use in formalin-fixed paraffin-embedded tissues. The aim of the present study was to determine whether these signatures are associated with specific ovarian cancer risk factors, which would add to the evidence that they reflect the heterogeneous etiology of this disease. METHODS: We modeled signature-specific tumor characteristics and epidemiologic risk factor relationships using multiple regression and multivariate response multiple regression models in 193 patients from a case-control study of epithelial ovarian cancer. RESULTS: We observed associations between the Tothill gene expression subtype signatures and both age at diagnosis (P = 0.0008) and race (P = 0.008). Although most established epidemiologic risk factors were not associated with molecular signatures, there was an association between breast feeding (P = 0.024) and first-degree family history of breast or ovarian cancer (P = 0.034) among the 106 HGS cases. Some of the above associations were validated using gene expression microarray data from the TCGA project. Weak associations were seen with age at menarche and duration of oral contraceptive use and the TCGA survival signature. CONCLUSIONS: These data support the potential for genomic characterization to elucidate the etiologic heterogeneity of epithelial ovarian cancer. IMPACT: This study suggests that molecular signatures may augment the ability to define etiologic subtypes of epithelial ovarian cancer.

Genital powder use and risk of ovarian cancer: a pooled analysis of 8,525 cases and 9,859 controls.

Genital powder use has been associated with risk of epithelial ovarian cancer in some, but not all, epidemiologic investigations, possibly reflecting the carcinogenic effects of talc particles found in most of these products. Whether risk increases with number of genital powder applications and for all histologic types of ovarian cancer also remains uncertain. Therefore, we estimated the association between self-reported genital powder use and epithelial ovarian cancer risk in eight population-based case-control studies. Individual data from each study were collected and harmonized. Lifetime number of genital powder applications was estimated from duration and frequency of use. Pooled ORs were calculated using conditional logistic regression matched on study and age and adjusted for potential confounders. Subtype-specific risks were estimated according to tumor behavior and histology. 8,525 cases and 9,859 controls were included in the analyses. Genital powder use was associated with a modest increased risk of epithelial ovarian cancer [OR, 1.24; 95% confidence interval (CI), 1.15-1.33] relative to women who never used powder. Risk was elevated for invasive serous (OR, 1.20; 95% CI, 1.09-1.32), endometrioid (OR, 1.22; 95% CI, 1.04-1.43), and clear cell (OR, 1.24; 95% CI, 1.01-1.52) tumors, and for borderline serous tumors (OR, 1.46; 95% CI, 1.24-1.72). Among genital powder users, we observed no significant trend (P = 0.17) in risk with increasing number of lifetime applications (assessed in quartiles). We noted no increase in risk among women who only reported nongenital powder use. In summary, genital powder use is a modifiable exposure associated with small-to-moderate increases in risk of most histologic subtypes of epithelial ovarian cancer.

Vitamin D receptor (VDR) polymorphisms and risk of ovarian cancer in Caucasian and African American women.

OBJECTIVE: Polymorphisms in the vitamin D receptor (VDR) gene have been shown in some studies to be associated with the risk of epithelial ovarian cancer (EOC) in Caucasian women. There are no published reports among African Americans. METHODS: Case-control data from the North Carolina Ovarian Cancer Study were analyzed using logistic regression to determine the association between seven VDR polymorphisms and EOC in both Caucasians (513 cases, 532 controls) and African Americans (74 cases, 79 controls). In a larger sample of African-Americans (125 cases, 155 controls), we assessed associations between six SNPs in proximity of rs7975232. RESULTS: African American women who carried at least one minor allele of rs7975232 were at higher risk for invasive EOC controlling for age and admixture with an odds ratio (OR) for association under the log-additive model of 2.08 (95% confidence interval (CI)=1.19, 3.63, p=0.010). No association was observed between any of the VDR variants and EOC among Caucasians. A larger sample of African Americans revealed a nearly two-fold increased risk of invasive EOC associated with rs7305032, a SNP in proximity to rs7975232 (R(2)=0.369) with a log-additive OR of 1.87 (95% CI=1.20, 2.93, p=0.006). CONCLUSIONS: This is the first report showing VDR variants associated with ovarian cancer risk in African American women. A larger study of African American women is needed to confirm these findings. These results imply that vitamin D exposure is a possible modifiable risk factor of ovarian cancer among African Americans.

Cancer Risk and Behavioral Factors, Comorbidities, and Functional Status in the US Elderly Population.

About 80% of all cancers are diagnosed in the elderly and up to 75% of cancers are associated with behavioral factors. An approach to estimate the contribution of various measurable factors, including behavior/lifestyle, to cancer risk in the US elderly population is presented. The nationally representative National Long-Term Care Survey (NLTCS) data were used for measuring functional status and behavioral factors in the US elderly population (65+), and Medicare Claims files linked to each person from the NLTCS were used for estimating cancer incidence. The associations (i.e., relative risks) of selected factors with risks of breast, prostate, lung and colon cancers were evaluated and discussed. Behavioral risk factors significantly affected cancer risks in the US elderly. The most influential of potentially preventable risk factors can be detected with this approach using NLTCS-Medicare linked dataset and for further deeper analyses employing other datasets with detailed risk factors description.

What can we learn from the age- and race/ethnicity- specific rates of inflammatory breast carcinoma?

Inflammatory Breast Carcinoma (IBC), the most aggressive type of breast tumor with unique clinicopathological presentation, is hypothesized to have distinct etiology with a socioeconomic status (SES) component. Using the Surveillance, Epidemiology and End Results (SEER) Program data for 2004-2007, we compare incidence rates of IBC to non-inflammatory locally advanced breast cancer (LABC) among racial/ethnic groups with different SES. The analysis includes women 20-84 years of age. To examine evidence for the distinct etiology of IBC, we analyzed age-distribution patterns of IBC and non-inflammatory LABC, using a mathematical carcinogenesis model. Based on the Collaborative Staging Extension codes, 2,942 incident IBC cases (codes 71 and 73) and 5,721 non-inflammatory LABC cases (codes 40-62) were identified during the four-year study period. Age-adjusted rates of IBC among non-Hispanic White and Hispanic women were similar (2.5/100,000 in both groups). Similar rates were also found in non-inflammatory LABC in these two groups (4.8/100,000 and 4.2/100,000, respectively). In African-American women, the IBC (3.91/100,000) and non-inflammatory LABC (8.47/100,000) rates were greater compared with other ethnic/racial sub-groups. However, the ratio of rates of IBC/non-inflammatory LABC was similar among all the racial/ethnic groups, suggesting that African-American women are susceptible to aggressive breast tumors in general but not specifically to IBC. The mathematical model successfully predicted the observed age-specific rates of both examined breast tumors and revealed distinct patterns. IBC rates increased until age 65 and then slightly decreased, whereas non-inflammatory LABC rates steadily increased throughout the entire age interval. The number of critical transition carcinogenesis stages (m-stages) predicted by the model were 6.3 and 8.5 for IBC and non-inflammatory LABC, respectively, supporting different etiologies of these breast tumors.

Medical cost trajectories and onsets of cancer and noncancer diseases in US elderly population.

Time trajectories of medical costs-associated with onset of twelve aging-related cancer and chronic noncancer diseases were analyzed using the National Long-Term Care Survey data linked to Medicare Service Use files. A special procedure for selecting individuals with onset of each disease was developed and used for identification of the date at disease onset. Medical cost trajectories were found to be represented by a parametric model with four easily interpretable parameters reflecting: (i) prediagnosis cost (associated with initial comorbidity), (ii) cost of the disease onset, (iii) population recovery representing reduction of the medical expenses associated with a disease since diagnosis was made, and (iv) acquired comorbidity representing the difference between post- and pre diagnosis medical cost levels. These parameters were evaluated for the entire US population as well as for the subpopulation conditional on age, disability and comorbidity states, and survival (2.5 years after the date of onset). The developed approach results in a family of new forecasting models with covariates.

Recreational physical activity and ovarian cancer risk and survival.

PURPOSE: Physical activity may influence ovarian cancer risk and outcomes through effects on ovulation, inflammatory markers, and other processes. We examined associations between self-reported physical activity and ovarian cancer risk and survival in a population-based, case-control study in North Carolina. METHODS: The analyses involved 638 epithelial ovarian cancer cases and 683 controls recruited between 1999-2008. Logistic regression analyses were used to assess ovarian cancer risk in relation to reported average physical activity at various time periods. Kaplan-Meier analyses and proportional hazards modeling were used to assess associations between physical activity and survival among ovarian cancer cases. RESULTS: Modestly reduced risks for ovarian cancer were observed in some categories of physical activity, but there were no consistent patterns of greater reductions in risk with higher activity levels. Physical activity before diagnosis was not significantly related to ovarian cancer survival overall, but survival was better for women who reported greater than 2 hours of activity/week as compared to those reporting less than 1 hour/week among women who were non-obese (multivariable Hazard ratio = 0.69, 95% confidence interval: 0.47-1.00). CONCLUSIONS: Our data provide weak evidence in support of beneficial effects of physical activity on ovarian cancer risk and survival, but results should be interpreted cautiously because of the lack of a clear dose response relation with higher levels of exercise and the likely misclassification of self-reported activity.

Age trajectories of physiological indices in relation to healthy life course.

We analysed relationship between the risk of onset of "unhealthy life" (defined as the onset of cancer, cardiovascular diseases, or diabetes) and longitudinal changes in body mass index, diastolic blood pressure, hematocrit, pulse pressure, pulse rate, and serum cholesterol in the Framingham Heart Study (Original Cohort) using the stochastic process model of human mortality and aging. The analyses demonstrate how decline in resistance to stresses and adaptive capacity accompanying human aging can be evaluated from longitudinal data. We showed how these components of the aging process, as well as deviation of the trajectories of physiological indices from those minimising the risk at respective ages, can lead to an increase in the risk of onset of unhealthy life with age. The results indicate the presence of substantial gender difference in aging related decline in stress resistance and adaptive capacity, which can contribute to differences in the shape of the sex-specific patterns of incidence rates of aging related diseases.

Dynamic determinants of longevity and exceptional health.

It is well known from epidemiology that values of indices describing physiological state in a given age may influence human morbidity and mortality risks. Studies of connection between aging and life span suggest a possibility that dynamic properties of age trajectories of the physiological indices could also be important contributors to morbidity and mortality risks. In this paper we use data on longitudinal changes in body mass index, diastolic blood pressure, pulse pressure, pulse rate, blood glucose, hematocrit, and serum cholesterol in the Framingham Heart Study participants, to investigate this possibility in depth. We found that some of the variables describing individual dynamics of the age-associated changes in physiological indices influence human longevity and exceptional health more substantially than the variables describing physiological state. These newly identified variables are promising targets for prevention aiming to postpone onsets of common elderly diseases and increase longevity.