Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir or no Treatment for the Management of Influenza in the United States.

INTRODUCTION: This study sought to evaluate the cost-effectiveness of baloxavir marboxil compared with oseltamivir or no antiviral treatment from a US payer perspective using data from a real-world US administrative claims study. Given baloxavir's ability to rapidly stop viral shedding, the potential health economic implications of a baloxavir-induced population-level reduction in viral transmission was also explored. METHODS: A decision tree cost-effectiveness model was developed for seasonal influenza (2018-2020) using a lifetime time horizon with 3.0% discounting for costs and quality-adjusted life-years (QALYs). Patients aged ≥ 12 years could receive baloxavir, oseltamivir or no antiviral treatment. Patient characteristics, complications, and costs were derived from the Merative™ MarketScan® Research Databases including US commercial claims and Medicare and Medicaid Supplemental databases. A scenario analysis explored the impact of reduced viral transmission with baloxavir. RESULTS: In the base case analysis, baloxavir was cost-effective within a willingness-to-pay threshold of US$100,000/QALY compared with oseltamivir [incremental cost-effectiveness ratio (ICER), $6813/QALY gained] or no antiviral treatment (ICER, $669/QALY gained). The net monetary benefit (NMB) of baloxavir was $1180 and $6208 compared with oseltamivir and no treatment, respectively. The NMB of baloxavir increased linearly with reductions in viral transmission, where a 5% transmission reduction yielded an NMB of $2592 versus oseltamivir and $7621 versus no treatment. Baloxavir became dominant (more effective and less costly, with ICERs < 0) starting with a 12.0% reduction in viral transmission versus oseltamivir and 6.0% versus no antiviral treatment. CONCLUSION: Baloxavir was cost-effective compared with oseltamivir or no antiviral treatment. The potential of baloxavir to reduce viral transmission offers a substantial economic benefit from a US payer perspective.

Baloxavir is a prescription medicine that reduces the duration of flu symptoms and reduces the likelihood of complications from the flu, including serious complications that may require hospitalization. Baloxavir may reduce the spread of the flu to healthy people by reducing the amount and duration of virus shedding from infected people. We designed a model to estimate the cost benefits of using baloxavir versus another flu treatment, known as oseltamivir, or no flu treatment at all. Using baloxavir led to more cost savings than oseltamivir or no treatment for people in the US who have commercial health insurance. Baloxavir was even more cost-effective in the scenario where it reduced the number of flu cases (transmission benefit). This could ultimately have a meaningful benefit across a large health insurance population.

Anti-tumor effects of deubiquitinating enzyme inhibitor PR-619 in human chondrosarcoma through reduced cell proliferation and endoplasmic reticulum stress-related apoptosis.

Chondrosarcoma, a treatment-resistant cancer with limited therapeutic options, lacks significant advancements in treatment methods. However, PR-619, a novel inhibitor of deubiquitinating enzymes, has demonstrated anti-tumor effects in various malignancies. This study aimed to investigate the impact of PR-619 on chondrosarcoma both in vitro and in vivo. Two human chondrosarcoma cell lines, SW11353 and JJ012, were utilized. Cell viability was assessed using an MTT assay, while flow cytometry enabled the detection of apoptosis and cell cycle progression. Western blotting analyses were conducted to evaluate apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Furthermore, the in vivo anti-tumor effects of PR-619 were examined using a xenograft mouse model. The results revealed that PR-619 induced cytotoxicity, apoptosis, and cell cycle arrest at the G0/G1 stage by activating caspases, PARP cleavage, and p21. Moreover, PR-619 increased the accumulation of polyubiquitinated proteins and ER stress by activating IRE1, GRP78, caspase-4, CHOP, and other cellular stress responses, including JNK activation. In vivo analysis demonstrated that PR-619 effectively inhibited tumor growth with minimal toxicity in the xenograft mouse model. These findings provide evidence of the anti-tumor effects and induction of cellular and ER stress by PR-619 in human chondrosarcoma, suggesting its potential as a novel therapeutic strategy for in human chondrosarcoma.

PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study.

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.

The association between serum activin A levels and albuminuria among community-dwelling middle-aged and older adults in Taiwan.

Activin A, a cytokine belonging to the transforming growth factor-ß family, has been shown to play pivotal roles in tissue remodeling after renal injury and is present in elevated levels in diabetic patients. However, the association between activin A and albuminuria remains unclear. We aimed to evaluate their association by using cross-sectional data from community-dwelling middle-aged and older adults in Taiwan. We assessed 466 participants (67% male; mean age 71 ± 13 years) from the I-Lan Longitudinal Aging study for whom data pertaining to serum activin A level and urine albumin-to-creatinine ratio (UACR) were available. Of these, 323 (69%) had normal albuminuria, 123 (26%) had microalbuminuria, and 20 (4%) had overt albuminuria. Patients with overt albuminuria and microalbuminuria had significantly higher activin A concentrations than those in the normal albuminuria group (p < 0.001). Circulating activin A was significantly correlated with multiple risk factors, including higher systolic blood pressure and higher UACR. Univariate and multivariate results indicated that activin A level was an independent variable for albuminuria. The cutoff value of 602 pg/mL of activin A demonstrated a sensitivity of 70.6% and specificity of 75.7% (AUC 0.774) in diagnosing overt albuminuria. In conclusion, middle-aged and older adults with elevated activin A levels were associated with a higher incidence of albuminuria.

Rectal Dose Is the Other Dosimetric Factor in Addition to Small Bowel for Prediction of Acute Diarrhea during Postoperative Whole-Pelvic Intensity-Modulated Radiotherapy in Gynecologic Patients.

We studied the association of rectal dose with acute diarrhea in patients with gynecologic malignancies undergoing whole-pelvic (WP) intensity-modulated radiotherapy (IMRT). From June 2006 to April 2019, 108 patients with previous hysterectomy who underwent WP IMRT were enrolled in this cohort study. WP irradiation of 39.6-45 Gy/22-25 fractions was initially delivered to the patients. Common Terminology Criteria for Adverse Events (CTCAE) version 3 was used to evaluate acute diarrhea during radiotherapy. Small bowel volume at different levels of isodose curves (Vn%) and mean rectal dose (MRD) were measured for statistical analysis. The multivariate analysis showed that the MRD ≥ 32.75 Gy (p = 0.005) and small bowel volume of 100% prescribed (V100%) ≥ 60 mL (p = 0.008) were independent factors of Grade 2 or higher diarrhea. The cumulative incidence of Grade 2 or higher diarrhea at 39.6 Gy were 70.5%, 42.2%, and 15.0% (p < 0.001) in patients with both high (V100% ≥ 60 mL and MRD ≥ 32.75 Gy), either high, and both low volume-dose factors, respectively. Strict constraints for the rectum/small bowel or image-guided radiotherapy to reduce these doses are suggested.

Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis.

BACKGROUND: To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. METHODS: Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). RESULTS: Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0-1.8) for peptic ulcer to 78.0 (95% CI, 74.8-81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05-2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. CONCLUSION: Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone-related complications among adult asthma patients.

MLN4924, a novel protein neddylation inhibitor, suppresses proliferation and migration of human urothelial carcinoma: In vitro and in vivo studies.

MLN4924, a small molecule inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit an anti-tumor effect on various malignancies. In this study, we investigated the anti-tumor effect of MLN4924 in human urothelial carcinoma (UC) in vitro and in vivo by using three human UC cell lines of various grading (T24, NTUB1 and RT4). The impact of MLN4924 on UC cells was determined by measuring viability (MTT), proliferation (BrdU incorporation), cell cycle progression (flow cytometry with propidium iodide staining) and apoptosis (flow cytometry with annexin V-FITC labeling). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration and invasion was analyzed by Transwell and wound healing assays. We also evaluated the effects of MLN4924 on tumor growth by a SCID xenograft mouse model. The data show that MLN4924 induced dose-dependent cytotoxicity, anti-proliferation, anti-migration, anti-invasion and apoptosis in human UC cells, accompanied by activations of Bad, phospho-histone H2A.X, caspase-3, 7 and PARP, decreased level of phospho-Bcl2, and caused cell cycle retardation at the G2M phase. Moreover, MLN4924 activated endoplasmic reticulum stress-related molecules (caspase-4, phospho-eIF2α, ATF-4 and CHOP) and other stress responses (JNK and c-Jun activations). Finally, we confirmed MLN4924 inhibited tumor growth in a UC xenograft mouse model with minimal general toxicity. We concluded that MLN4924 induces apoptosis and cell cycle arrest, as well as activation of cell stress responses in human UC. These findings imply MLN4924 provides a novel strategy for the treatment of UC.

MLN4924, a Novel NEDD8-activating enzyme inhibitor, exhibits antitumor activity and enhances cisplatin-induced cytotoxicity in human cervical carcinoma: in vitro and in vivo study.

MLN4924, an inhibitor of NEDD8 activating enzyme (NAE), has been reported to have activity against various malignancies. Here, we investigated the antitumor properties of MLN4924 and MLN4924 in combination with cisplatin on human cervical carcinoma (CC) in vitro and in vivo. Two human CC cell lines, ME-180 and HeLa, were used in this study. The cytotoxic effects of MLN4924 and/or cisplatin were measured by cell viability (MTT), proliferation (BrdU incorporation), apoptosis (flow cytometry with annexin V-FITC labeling), and the expression of cell apoptosis-related proteins (Western blotting). In vivo efficacy was determined in Nu/Nu nude mice with ME-180 and HeLa xenografts. The results showed that MLN4924 elicited viability inhibition, anti-proliferation and apoptosis in human CC cells, accompanied by activations of apoptosis-related molecules and Bid, Bcl-2 phosphorylation interruption, and interference with cell cycle regulators. Moreover, MLN4924 caused an endoplasmic reticulum stress response (caspase-4, ATF-4 and CHOP activations) and expression of other cellular stress molecules (JNK and c-Jun activations). Additionally, MLN4924 suppressed growth of CC xenografts in nude mice. Furthermore, we demonstrated that MLN4924 potentiated cisplatin-induced cytotoxicity in CC cells with activation of caspases. Consistently with this, MLN4924 significantly enhanced cisplatin-induced growth inhibition of CC xenografts. Together, these findings suggest that MLN4924 alone or in combination with cisplatin is of value in treating human CCs.

Celecoxib-induced cytotoxic effect is potentiated by inhibition of autophagy in human urothelial carcinoma cells.

Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, can elicit anti-tumor effects in various malignancies. Here, we sought to clarify the role of autophagy in celecoxib-induced cytotoxicity in human urothelial carcinoma (UC) cells. The results shows celecoxib induced cellular stress response such as endoplasmic reticulum (ER) stress, phosopho-SAPK/JNK, and phosopho-c-Jun as well as autophagosome formation in UC cells. Inhibition of autophagy by 3-methyladenine (3-MA), bafilomycin A1 or ATG7 knockdown potentiated celecoxib-induced apoptosis. Up-regulation of autophagy by rapamycin or GFP-LC3B-transfection alleviated celecoxib-induced cytotoxicity in UC cells. Taken together, the inhibition of autophagy enhances therapeutic efficacy of celecoxib in UC cells, suggesting a novel therapeutic strategy against UC.

Clinicopathologic analysis of coxsackievirus a6 new variant induced widespread mucocutaneous bullous reactions mimicking severe cutaneous adverse reactions.

BACKGROUND: The cutaneous manifestations of human enterovirus (HEV) infection are usually limited, such as hand-foot-mouth disease. By comparison, Stevens-Johnson syndrome (SJS) is a life-threatening severe cutaneous adverse reaction (SCAR), mainly caused by drugs. During the HEV outbreaks in 2010-2012 in Taiwan, we identified 21 patients who developed widespread blistering mucocutaneous reactions without any suspected drug causality. METHODS: We screened possible pathogen(s) for detecting human herpes virus (HHV1-HHV7), HEV, or Mycoplasma pneumoniae infections using throat swab virus cultures, real-time PCR, DNA sequencing, immunochemistry and electron microscopy analyses. RESULTS: Coxsackievirus A6 (CVA6) DNA was identified in the blistering skin lesions in 6 of 21 patients. Cytotoxic T lymphocytes and natural killer cells expressing granulysin predominantly infiltrated into the skin lesions, sharing the histopathological features with SJS. Intact CVA6 viral particles were identified in the blister fluids and skin lesions by electron microscopy. The phylogenetic analysis of the viral genome showed the CVA6 DNA sequence sharing higher similarity (97.6%-98.1%) to CVA6 strains reported from Finland at 2008. CONCLUSIONS: This study identifies a new variant of CVA6 as the causative agent for severe mucocutaneous blistering reactions mimicking SCAR. An awareness of this unusual presentation of HEV infection is needed in the epidemic area.

Effect of different treatment plans on irradiated small-bowel volume in gynecologic patients undergoing whole-pelvic irradiation.

To evaluate the effect of different treatment plans for whole-pelvic irradiation on small-bowel volumes (SBVs) in patients with gynecologic malignancies, 40 patients were enrolled in this study. Computed tomography (CT) simulations were performed, and the small bowel of each patient was outlined manually. Treatment plans with equal-weighted (EW) and non-equal-weighted (NEW) (70% in bilateral directions) techniques of four-field and intensity-modulated radiation therapy (IMRT) were performed. The V10-V100 represented the volume (cm³) at different levels of the prescribed doses (10-100%). The V10-V100 was compared among the different treatment planning techniques, and patients who were suitable for IMRT or NEW were identified. IMRT and NEW significantly reduced the V50-V100 and V40-V60 levels compared with EW, respectively. NEW caused a significant reduction in the V30-V60 levels in patients with a BMI ≥26 kg/m². Patients with IMRT demonstrated lower V70-V100 levels compared with those with NEW. In patients with a BMI ≥26 kg/m² or an age ≥55 years, lower V20-V50 levels were noted using NEW compared with IMRT. Treatment planning with larger weighting in the bilateral directions in four-field radiotherapy reduces the low-dose SBV in patients with gynecologic malignancies, especially in those with a high BMI or the elderly. IMRT effectively reduces high-dose SBV, especially in patients with a low BMI.

Sunlight, polymorphisms of vitamin D-related genes and risk of breast cancer.

BACKGROUND/AIM: Geographic gradients in breast cancer incidence and mortality suggest that vitamin D may reduce risk. The enzyme 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), which degrades the active form of vitamin D, and the vitamin D receptor (VDR) are both found in breast tissue. We investigated six polymorphisms in CYP24A1 and two in the VDR gene in association with breast cancer risk. MATERIALS AND METHODS: We conducted a case-control study within the nationwide U.S. Radiologic Technologists cohort, including 845 controls and 484 incident breast cancer cases. Associations of polymorphic variants and ecologic and personal measures of sun exposure with breast cancer risk were assessed using unconditional logistic regression. RESULTS: Two polymorphisms in CYP24A1 were associated with increased breast cancer risk (rs34043203, P(trend)=0.03; rs2762934, P(trend)=0.005) and one with reduced breast cancer risk (rs1570669, P(trend)=0.048). Risk was inversely associated with minor alleles for the VDR Bsm1 polymorphism (rs1544410, P(trend)=0.05) but not Fok1 (rs2228570). Sunlight measures were not associated with breast cancer risk, however significant interactions between time outdoors in the teen years and three unlinked genotypes were found for VDR (rs1544410, rs2228570) and CYP24A1 (rs1570669). CONCLUSION: In this nation-wide breast cancer case-control study, we found that the vitamin D pathway was involved in disease etiology and our results further suggest that reduced cancer risk, in association with sunlight, may depend on timing of exposure and genetic background. These findings merit further investigation.

Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009.

OBJECTIVES: Studies from the 1990s through mid-2000s report variable decreases in upper gastrointestinal (UGI) complications and differ regarding changes in lower gastrointestinal (LGI) complications. We determined incidence and case fatality of hospitalizations for GI complications in the United States over the past decade. METHODS: We used a national inpatient database to calculate yearly projections from 2001-2009 for incidence and case fatality of hospitalizations with primary discharge diagnoses of UGI and LGI complications (bleeding, perforation, and obstruction) and of undefined GI bleeding. RESULTS: Age/sex-adjusted incidence of GI complications decreased non-significantly from 236.1 to 223.7/100,000 population from 2001-2009. Components were UGI complications (85.0 to 66.0/100,000), LGI complications (100.3 to 104.4/100,000), and undefined bleeding (50.8 to 53.3/100,000). Decreases were seen in UGI bleeding (78.4 to 60.6/100,000), peptic ulcer bleeding (48.7 to 32.1/100,000), LGI bleeding (41.8 to 35.7/100,000), and colonic diverticular bleeding (30.4 to 23.9/100,000), whereas LGI obstruction increased (55.0 to 66.0/100,000). Age/sex-adjusted case fatality decreased from 3.78 to 2.70%. 2009 case fatality rates were 2.45% for UGI bleeding, 3.00% for undefined bleeding, 1.47% for LGI bleeding, 2.30% for LGI obstruction, 10.7% for UGI perforation, and 16.0% for LGI perforation. Case fatality increased with age, but was 3.54% in patients >75 years with bleeding or obstruction. CONCLUSIONS: Hospitalizations for UGI complications are decreasing in the United States owing to a decrease in UGI bleeding. LGI complications are relatively stable, with a decrease in LGI bleeding and a larger increase in LGI obstruction. Case fatality owing to bleeding or obstruction is low, increasing with age but remaining <5% even in the elderly.

Vitamin D insufficiency is prevalent among pregnant African American adolescents.

STUDY OBJECTIVE: Recent attention has focused on vitamin D insufficiency but few data exist on vitamin D status among pregnant minority youth. DESIGN: A screening study was undertaken in adolescents having prenatal blood samples drawn for other routine tests obtained during the second trimester (18+/-1.8 week gestation, n=44) or third trimester of pregnancy (28.4+/-2.1 week gestation, n=36). Serum 25- hydroxyvitamin D (25(OH)D) was measured and significant determinants of vitamin D insufficiency in this cohort were identified. SETTING: Urban prenatal clinic. PARTICIPANTS: Eighty pregnant African American adolescents (< or = 18 y of age). MAIN OUTCOME MEASURE(S): Vitamin D status, STDs, hemoglobin, season, birth weight RESULTS: Serum 25(OH)D in this group averaged 21.6+/-8 ng/mL (age 16.5+/-1.1 y, n=80), and did not significantly differ between the second (20.95+/-8.2 ng/mL, n=44) and third trimester cohorts (22.5+/-7.9 ng/mL, n=36). Vitamin D insufficiency (< 20 ng/mL) was evident in 46.25% and vitamin D deficiency (<15 ng/mL) was evident in 21.25% of those studied. Significant predictors of suboptimal vitamin D status included sampling during the winter months (P=0.004), lower hemoglobin concentration (P=0.019), and higher second trimester leptin levels (P=0.018). Inverse associations between 25(OH)D and bacterial vaginosis were evident when controlled for season of sampling (P=0.02, n=80). CONCLUSIONS: Vitamin D insufficiency was prevalent among urban pregnant minority adolescents. Further studies are needed to address the impact of this finding on maternal and neonatal calcium homeostasis and bone health.

Genetic determinants of serum lipid levels in Chinese subjects: a population-based study in Shanghai, China.

We examined the associations between 21 single nucleotide polymorphisms (SNPs) of eight lipid metabolism genes and lipid levels in a Chinese population. This study was conducted as part of a population-based study in China with 799 randomly selected healthy residents who provided fasting blood and an in-person interview. Associations between variants and mean lipid levels were examined using a test of trend and least squares mean test in a general linear model. Four SNPs were associated with lipid levels: LDLR rs1003723 was associated with total cholesterol (P-trend = 0.002) and LDL (P-trend = 0.01), LDLR rs6413503 was associated with total cholesterol (P-trend = 0.05), APOB rs1367117 was associated with apoB (P-trend = 0.02), and ABCB11 rs49550 was associated with total cholesterol (P-trend = 0.01), triglycerides (P-trend = 0.01), and apoA (P-trend = 0.01). We found statistically significant effects on lipid levels for LDLR rs6413503 among those with high dairy intake, LPL rs263 among those with high allium vegetable intake, and APOE rs440446 among those with high red meat intake. We identified new associations between SNPs and lipid levels in Chinese previously found in Caucasians. These findings provide insight into the role of lipid metabolism genes, as well as the mechanisms by which these genes may be linked with disease.

Energy intake and risk of postmenopausal breast cancer: an expanded analysis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.

Although animal experiments have consistently shown a positive relationship between breast cancer and energy intake, evidence from human studies remains inconclusive. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort, 29,170 women, ages 55 to 75 years, who successfully completed a food frequency questionnaire (FFQ) at entry (1993-2001), were followed through 2007, and 1,319 incident breast cancers were ascertained (median time from FFQ completion to diagnosis, 4.4 years). Women in the highest quartile of energy intake, relative to the lowest, had modestly, but significantly, increased breast cancer risk [multivariate relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.03-1.42; P(trend) = 0.03]. The inclusion of body mass index and physical activity in the model reduced risk slightly (RR, 1.18; 95% CI, 1.00-1.39; P(trend) = 0.07). However, in similar analyses using energy intake from a FFQ administered approximately five years after entry (27,428 women; 806 incident breast cancers; median time from FFQ completion to diagnosis, 2.7 years), women in the highest and lowest quartiles of energy intake had similar risk. When follow-up time after the first FFQ was divided into three 4-year periods, the multivariate RRs for high versus low energy intake increased from 1.21 to 1.37 to 1.55 with increasing time since dietary assessment. Although the divergent results for the two FFQs could be due to subtle questionnaire differences, our findings suggest a modest positive association between energy intake and postmenopausal breast cancer that strengthens with time since dietary assessment.

Breast cancer epidemiology according to recognized breast cancer risk factors in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial Cohort.

BACKGROUND: Multidisciplinary attempts to understand the etiology of breast cancer are expanding to increasingly include new potential markers of disease risk. Those efforts may have maximal scientific and practical influence if new findings are placed in context of the well-understood lifestyle and reproductive risk factors or existing risk prediction models for breast cancer. We therefore evaluated known risk factors for breast cancer in a cancer screening trial that does not have breast cancer as a study endpoint but is large enough to provide numerous analytic opportunities for breast cancer. METHODS: We evaluated risk factors for breast cancer (N = 2085) among 70,575 women who were randomized in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Using Poisson regression, we calculated adjusted relative risks [RRs, with 95% confidence intervals (CIs)] for lifestyle and reproductive factors during an average of 5 years of follow-up from date of randomization. RESULTS: As expected, increasing age, nulliparity, positive family history of breast cancer, and use of menopausal hormone therapy were positively associated with breast cancer. Later age at menarche (16 years or older vs. < 12: RR = 0.81, 95% CI, 0.65-1.02) or menopause (55 years or older vs. < 45: RR = 1.29, 95% CI, 1.03-1.62) were less strongly associated with breast cancer than was expected. There were weak positive associations between taller height and heavier weight, and only severe obesity [body mass index (BMI; kg/m(2)) 35 or more vs. 18.5-24.9: RR = 1.21, 95% CI, 1.02-1.43] was statistically significantly associated with breast cancer. CONCLUSION: The ongoing PLCO trial offers continued opportunities for new breast cancer investigations, but these analyses suggest that the associations between breast cancer and age at menarche, age at menopause, and obesity might be changing as the underlying demographics of these factors change. CLINICAL TRIALS REGISTRATION: (http://www.clinicaltrials.gov), NCT00002540.

Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists.

Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1,083 controls within the US radiologic technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR = 0.3; 95% CI 0.1-0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR = 1.2; 95% CI 0.9-1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the dose-response relationship between personal diagnostic X-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (p (interaction) = 0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic X-ray exposure (p (interaction) = 0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.

Physical activity, sedentary behavior, and endometrial cancer risk in the NIH-AARP Diet and Health Study.

Consistent with a strong hormonal etiology, endometrial cancer is thought to be influenced by both obesity and physical activity. Although obesity has been consistently related to risk, associations with physical activity have been inconclusive. We examined relationships of activity patterns with endometrial cancer incidence in the NIH-AARP Diet and Health Study cohort, which included 109,621 women, ages 50-71, without cancer history, who in 1995-1996 completed a mailed baseline questionnaire capturing daily routine and vigorous (defined as any period of >or=20 min of activity at work or home causing increases in breathing, heart rate, or sweating) physical activity. A second questionnaire, completed by 70,351 women, in 1996-1997 collected additional physical activity information. State cancer registry linkage identified 1,052 primary incident endometrial cancers from baseline through December 31, 2003. In multivariate proportional hazards models, vigorous activity was inversely associated with endometrial cancer in a dose-response manner (p for trend = 0.02) (relative risk (RR) for >or=5 times/week vs. never/rarely = 0.77, 95% confidence interval (CI): 0.63-0.95); this association was more pronounced among overweight and obese women (body mass index >or=25; RR = 0.61, 95% CI: 0.47-0.79) than among lean women (body mass index <25; RR = 0.76, 95% CI: 0.52-1.10; p for interaction = 0.12). Although we observed no associations with light/moderate, daily routine or occupational physical activities, risk did increase with number of hours of daily sitting (p for trend = 0.02). Associations with vigorous activities, which may interact with body mass index, suggest directions for future research to clarify underlying biologic mechanisms, including those relating to hormonal alterations.