The migraine signature study: Methods and baseline results.

OBJECTIVE: To characterize patients who utilize services for migraine in a large integrated health care network, and describe patterns of care and utilization. BACKGROUND: Within health care systems, migraine is a common reason for seeking primary and neurology care, but relatively little is documented about who seeks care and the factors that explain variation in utilization. METHODS: We conducted a retrospective cohort study using electronic health record (EHR) data from Sutter Health primary care (PC) patients who had at least one office visit to a PC clinic between 2013 and 2017. Migraine status was ascertained from diagnosis codes and medication orders. Control status was assigned to those with no evidence of care for any type of headache. We divided the primary care migraine cohort into two groups: those who received all their care for migraine from PC (denoted PC-M) and those who had ≥1 encounter with a neurologist for migraine (denoted N-M). Migraine cases were also designated as having preexisting migraine if they had an encounter with a migraine diagnosis within (±) 6 months of their first study period PC visit and, otherwise, designated as first migraine consult. Two levels of contrasts included: patients with migraine and controls; and within the group of patients with migraine, PC-M and N-M groups. Comorbid conditions were determined from EHR encounter diagnosis codes. RESULTS: We identified 94,149 patients with migraine (including 21,525 N-M and 72,624 PC-M) and 1,248,763 controls. Comorbidities: Proportions of psychiatric [29.8% (n = 28,054) vs. 11.8% (n = 147,043)], autoimmune [(4.4% (n = 4162) vs. 2.6% (n = 31,981)], pain [13.2% (n = 12,439) vs. 5.8% (n = 72,049)], respiratory [24.6% (n = 23,186) vs. 12.3% (n = 153,692)], neurologic [2.9% (n = 2688) vs. 0.9% (n = 11,321)], and cerebrovascular [1.0% (n = 945) vs. 0.6% (n = 7500)] conditions were higher in the migraine group compared to controls, all p < 0.001. Among patients with migraine, the N-M group was similar to the PC-M group in sex, age, ethnicity, and marital status, but were more likely to have preexisting migraine (49.9% (n = 10,734) vs. 36.2% (n = 26,317), p < 0.001). Proportions of comorbid conditions were higher among the N-M group than the PC-M group {psychiatric [38.5% (n = 8291) vs. 27.2% (n = 19,763)], autoimmune [6.3% (n = 1365) vs. 3.9% (n = 2797)], pain [19.6% (n = 4218) vs. 11.3% (n = 8211)], respiratory [30.3% (n = 6516) vs. 23.0% (n = 16,670)], neurologic [6.0% (n = 1288) vs. 1.9% (n = 1400)], cardiovascular [9.7% (n = 2091) vs. 7.0% (n = 5076)], and cerebrovascular [2.3% (n = 500) vs. 0.6% (n = 445)], all p < 0.001}. Medications: During the study period, 82.6% (n = 77,762) of patients with migraine received ≥1 prescription order for an acute migraine medication [89.4% (n = 19,250) of N-M vs. 80.6% (n = 58,512) of PC]. Opioids were prescribed to 52.9% (n = 49,837) of patients with migraine [63.5% (n = 13,669) for N-M and 49.8% (n = 36,168) for PC-M patients). During the study period, 61.4% (n = 57,810) of patients received ≥1 prescription for a migraine preventive medication [81.4% (n = 17,521) of N-M and 55.5% (n = 40,289) of PC-M patients]. The most commonly prescribed classes of preventive medications were antidepressants. CONCLUSIONS: Among patients with migraine in a large health system, those who were also cared for in neurology were more likely to receive both acute and preventive medication migraine orders than those patients who did not see a neurologist, with triptans and antidepressants the most commonly prescribed classes of acute and preventive pharmacotherapies, respectively. Opioids were prescribed to approximately half of the total sample and more common in the N-M group. Adjusting for demographics, patients with migraine had higher rates of nearly every comorbidity we assessed and were more likely to utilize services compared to those without migraine. Overall, patients with migraine also cared for in neurology practices used more of all health care resource types under consideration and had more medical issues, which may be due in some part to a more severe, frequent and disabling disease state compared to those who sought care exclusively from PC practices.

Rates of Vascular Events in Patients With Migraine: A MarketScan® Database Retrospective Cohort Study.

OBJECTIVE: To estimate the baseline rates of vascular events among people with migraine. BACKGROUND: Several novel medications that target the calcitonin gene-related peptide (CGRP) pathway are approved to treat people with migraine. Given that the CGRP pathway also plays a role in maintaining cardiovascular homeostasis, determining the baseline rates of vascular events among people with migraine will help inform the safety of these novel medications. METHODS: In this retrospective cohort study, patients 18- to 64-year-old patients with migraine were identified from the MarketScan® database (January 2013-December 2017) and were categorized into 4 vascular risk categories: migraine with aura; and high, medium, and low vascular risk. Event rates (per 1000 person-years [PY]) for 19 vascular events were estimated overall, by risk category, and by baseline characteristics. RESULTS: Among 1,195,696 patients with migraine, 4.8% (57,853/1,195,696) had migraine with aura, and 2.8% (33,949/1,195,696), 15.5% (184,782/1,195,696), and 77.9% (931,059/1,195,696) were at high, medium, and low risk of vascular events, respectively. Rates of ischemic stroke (per 1000 PY) were 5.1 (95% confidence interval [CI]: 5.0, 5.2) overall, 8.6 (95% CI: 8.1, 9.1) for patients with migraine aura, 47.2 (95% CI: 45.3, 49.0) in the high-risk group, 9.4 (95% CI: 9.1, 9.7) in the medium-risk group, and 2.9 (95% CI: 2.9, 3.0) in the low-risk group. Rates of acute myocardial infarction (per 1000 PY) were 1.8 (95% CI: 1.8, 1.9) overall, 1.9 (95% CI: 1.7, 2.2) for patients with migraine aura, 14.0 (95% CI: 13.0, 14.9) in the high-risk group, 3.9 (95% CI: 3.7, 4.1) in the medium-risk group, and 1.1 (95% CI: 1.0, 1.1) in the low-risk group. High-risk patients had the highest rates of each of 19 evaluated vascular events, and rates were higher for men, older age groups, and those with higher comorbidity scores, medication usage, and medical utilization. CONCLUSION: Our findings provide recent rates of vascular disease in patients with migraine. In the future, this information will be useful to help inform clinical risk:benefit decision making when assessing the use of therapies such as CGRP antagonists for migraine.

Patient characteristics, treatment patterns, and mortality in elderly patients newly diagnosed with ALL.

To describe patient characteristics and treatment patterns among elderly patients (≥66 years) newly diagnosed with acute lymphoblastic leukemia (ALL), we analyzed 100% Medicare ALL data from 2007 to 2015. Only 764 out of 1428 (53.5%) elderly patients received treatment within 90 d of diagnosis with ≥30-d follow-up; 32.4% received chemotherapy without tyrosine kinase inhibitors (TKIs), 8.8% received both chemotherapy and TKIs, 9.8% received steroids only and 2.6% received TKIs only. Among 717 patients receiving chemotherapy any time during follow-up, 65.8% received only one course of treatment. Patients treated with chemotherapy or TKIs compared to untreated patients were younger (<75 years: 51.5 vs. 21.7%) and had a lower comorbidity burden (Charlson Comorbidity index ≤ 2: 90.9 vs. 71.4%). Overall, 67.5% of patients died within 3 years of diagnosis. Our findings demonstrate that many elderly ALL patients are not treated in the real-world setting and highlight the need for tolerable therapies for these patients.

Benefit-Risk Assessment of Blinatumomab in the Treatment of Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia.

Blinatumomab is the first-and-only Food and Drug Administration (FDA)-approved cluster of differentiation (CD) 19-directed CD3 bispecific T-cell engager (BiTE®) immunotherapy. It is currently FDA approved for the treatment of adults and children with Philadelphia chromosome-positive (Ph+) and Philadelphia chromosome-negative (Ph-) relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL) and B-cell precursor ALL with minimal residual disease. Similarly, initial marketing authorization for blinatumomab in the European Union was granted for the treatment of adults with Ph- R/R B-cell precursor ALL. The benefits of treating R/R B-cell precursor ALL patients with blinatumomab include increased overall survival, more favorable hematologic remission and molecular response rates, and a lower incidence rate of selected adverse events when compared with standard-of-care chemotherapy. The key risks associated with blinatumomab treatment include cytokine release syndrome, neurotoxicity, and medication errors. Here, we review the benefits and risks of blinatumomab treatment and describe how these risks can be mitigated.

Acute lymphoblastic leukemia: an assessment of international incidence, survival, and disease burden.

PURPOSE: Acute lymphoblastic leukemia (ALL) is a rare hematological malignancy. With the recent introduction of a classification system for hematopoietic and lymphoid neoplasms, more comprehensive assessment of ALL epidemiology is now possible. In this study, we describe recent international incidence of ALL and project the annual number of diagnoses to 2025. We also estimate relative survival and average potential years of life lost (AYLL) to assess the societal burden of ALL. METHODS: Age-specific incidence data for ALL from select cancer registries in different geographies were obtained from the International Agency for Research on Cancer's Cancer Incidence in Five Continents Database. Country-specific age-standardized rates were calculated to allow for direct comparisons between countries. ALL-specific mortality and relative survival data were only available from the United States (US) National Cancer Institute's Surveillance, Epidemiology, and End Results program; mortality rates were estimated for other countries. RESULTS: The age-standardized incidence rate of ALL during 2003-2007 ranged from 1.08 to 2.12 per 100,000 person-years in selected countries. Incidence was generally higher in the Americas and Oceania and lower in Asia and Eastern Europe. In most countries, the incidence rate of ALL in children was approximately four times that in adults. Survival was particularly poor among adults. In selected countries, the estimated AYLL ranged from 30 to 48 years for all ages and from 23 to 39 years for adults. CONCLUSIONS: Although a rare disease, ALL presents a significant public health burden given poor survival outcomes among adults, AYLL, and its importance as the most common pediatric cancer.

History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in patients with non-Hodgkin lymphoma not receiving granulocyte colony-stimulating factor prophylaxis.

We conducted a cohort study to examine the association between a wide variety of chronic comorbidities and risk of febrile neutropenia (FN) in patients with non-Hodgkin lymphoma (NHL) from 2000 to 2009 treated with chemotherapy at Kaiser Permanente Southern California. History of comorbidities and FN events were identified using electronic medical records. Cox model adjusting for propensity score was used to determine the association between a comorbid condition and FN. Models that additionally adjusted for cancer stage, baseline absolute neutrophil count, chemotherapy regimen and dose reduction were also evaluated. A total of 2480 patients with NHL were included, and 60% received CHOP/R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, with or without rituximab). In total, 236 (9.5%) patients developed FN in the first chemotherapy cycle. Anemia (adjusted hazard ratio [HR] = 1.6, 95% confidence interval [1.2-2.2]), HIV infection (HR = 3.8 [2.0-6.7]) and rheumatoid diseases (HR = 2.4 [1.3-4.0]) were associated with significantly increased risk of FN. These results provide evidence that chronic comorbidity increases the risk of FN.

Use of pegfilgrastim primary prophylaxis and risk of infection, by chemotherapy cycle and regimen, among patients with breast cancer or non-Hodgkin's lymphoma.

PURPOSE: This study aims to examine granulocyte colony-stimulating factor (G-CSF) prophylaxis by cancer type, chemotherapy regimen, and cycle in a real-world setting to assess if practice conforms to clinical guidelines, which recommend G-CSF prophylaxis every cycle when a patient's risk of febrile neutropenia (FN) is 20% or greater, and to describe the incidence of FN among patients who discontinue pegfilgrastim (peg) prophylaxis. METHODS: The cohort was selected from administrative claims data and includes adults diagnosed with non-Hodgkin's lymphoma (NHL) or breast cancer (BC) who began chemotherapy 2005-2010. RESULTS: About 83.2% of the 4,470 patients with BC treated with dose-dense doxorubicin, cyclophosphamide (ddAC), 83.6% of 2,197 patients with BC treated with docetaxel, doxorubicin, cyclophosphamide (TAC), and about 55.6% of the 2,722 patients with NHL treated with cyclophosphamide, doxorubicin, vincristine, with or without prednisone for 3-week cycles (CHOP-R Q3W) received peg prophylaxis in cycle 1. Among patients on these regimens who received peg prophylaxis in cycle 1 and were still on the regimen in cycle 4, about 90% received peg prophylaxis in that cycle. Among patients with BC or NHL who discontinued G-CSF, the incidence proportion of infection or FN varied by regimen and cycle, with a range from 0 to 14%. CONCLUSIONS: Despite clinical guidelines recommending G-CSF prophylaxis with chemotherapy regimens with a high risk of FN, many NHL and BC patients do not receive FN prophylaxis in cycle 1. However, among patients who receive G-CSF in cycle 1 and remain on the regimen, the majority appear to continue prophylaxis as indicated.

Granulocyte colony-stimulating factor (G-CSF) patterns of use in cancer patients receiving myelosuppressive chemotherapy.

PURPOSE: Febrile neutropenia (FN) is a common and serious complication of myelosuppressive chemotherapy. Guidelines recommend primary granulocyte colony-stimulating factors (G-CSF) prophylaxis (PPG) in patients with a high risk (HR, >20 %) of developing FN. We performed a retrospective analysis using a subset of the Medicare 5 % database to assess patterns of G-CSF use and FN occurrence among elderly cancer patients receiving myelosuppressive chemotherapy. METHODS: Chemotherapy courses for patients aged 65+ years were identified; only the first course was used for this analysis. Using clinical guidelines, chemotherapy regimens were classified as HR or intermediate risk (IR) for FN. The first administration of G-CSF was classified as either PPG (within the first 5 days of the first cycle), secondary prophylaxis, or reactive. RESULTS: Twelve thousand seven hundred seven courses across five tumor types were classified as having a HR or IR regimen. G-CSF was used in 24.5-73.8 % of patients receiving a HR FN regimen, with the highest use in breast cancer or NHL. Except for breast cancer (where PPG was used in 52.1 %), PPG was given in less than half of patients receiving a HR regimen. Depending on the tumor type, 4.8-22.6 % of patients with a HR regimen had a neutropenia-related hospitalization. CONCLUSIONS: Guidelines recommend PPG with HR FN regimens and older age (>65 years), an important risk factor for developing severe neutropenic complications. However, our results show that in this elderly population, PPG was not routinely used (range 4.8-52.1 %) in patients receiving HR FN regimens. Careful attention to FN risk factors, including chemotherapy regimen and patient age, is needed when planning treatment strategies.

Innate immunity gene polymorphisms and the risk of colorectal neoplasia.

Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case-control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P < 0.01, but after adjustment for multiple testing, only rs2838732 (ITGB2) remained suggestively associated with colorectal neoplasia (OR(per T allele) = 0.68, 95% CI: 0.57-0.83, P = 7.7 × 10(-5), adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (OR(per T allele) = 0.41, 95% CI: 0.30-0.55, P = 2.4 × 10(-) (9)) than for adenoma (OR(per T allele) = 0.84, 95%CI: 0.69-1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status (P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (OR(per T allele) = 0.5, 95% CI: 0.37-0.69 and OR(per T allele) = 0.72, 95% CI: 0.54-0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88. Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia.

An international assessment of ovarian cancer incidence and mortality.

OBJECTIVE: To assess and characterize the temporal variation in ovarian cancer incidence and mortality by age within countries in the Americas, Europe, Asia, and Oceania. METHODS/MATERIALS: Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program in the United States (U.S.) were used to assess ovarian cancer incidence rates (1998-2008) and mortality rates, (1988-2007 for 12-month survival, 1988-2006 for 24-month survival, and 1988-2003 for 60-month survival), stratified by age at diagnosis. Data from GLOBOCAN were used to calculate country-specific incidence rates for 2010 and 2020 and case-fatality rates for 2010. RESULTS: A statistically significant decrease in Annual Percent Change (APC) of ovarian cancer incidence was observed in the U.S. for all women (-1.03%), among women who were diagnosed at <65 years of age (-1.09%) and among women who were diagnosed at ≥65 years of age (-0.95%). There was a statistically significant increase in the observed APC for survival at 12-months (0.19%), 24-months (0.58%), and 60-months (0.72%) for all women; however, 5-year survival for advanced stage (III or IV) disease was low at less than 50% for women <65 years and less than 30% for women ≥65 years. Global results showed a wide range in ovarian cancer incidence rates, with China exhibiting the lowest rates and the Russian Federation and the United Kingdom exhibiting the highest rates. CONCLUSIONS: Ovarian cancer survival has shown modest improvement from a statistical perspective in the U.S. However, it is difficult to ascertain how clinically relevant these improvements are at the population or patient level.

Hospital visits among women with skeletal-related events secondary to breast cancer and bone metastases: a nationwide population-based cohort study in Denmark.

OBJECTIVE: Skeletal-related events (SREs) among women with breast cancer may be associated with considerable use of health-care resources. We characterized inpatient and outpatient hospital visits in a national population-based cohort of Danish women with SREs secondary to breast cancer and bone metastases. METHODS: We identified first-time breast cancer patients with bone metastases from 2003 through 2009 who had a subsequent SRE (defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone). Hospital visits included the number of inpatient hospitalizations, length of stay, number of hospital outpatient clinic visits, and emergency room visits. The number of hospital visits was assessed for a pre-SRE period (90 days prior to the diagnostic period), a diagnostic period (14 days prior to the SRE), and a post-SRE period (90 days after the SRE). Patients who experienced more than one SRE during the 90-day post-SRE period were defined as having multiple SREs and were followed until 90 days after the last SRE. RESULTS: We identified 569 women with SREs secondary to breast cancer with bone metastases. The majority of women had multiple SREs (73.1%). A total of 20.9% and 33.4% of women with single and multiple SREs died in the post-SRE period, respectively. SREs were associated with a large number of hospital visits in the diagnostic period, irrespective of the number and type of SREs. Women with multiple SREs generally had a higher number of visits compared to those with a single SRE in the post-SRE period, eg, median length of hospitalization was 5 days (interquartile range 0-15) for women with a single SRE and 13 days (interquartile range 4-30) for women with multiple SREs. CONCLUSION: SREs secondary to breast cancer and bone metastases were associated with substantial use of hospital resources.

Chronic comorbid conditions associated with risk of febrile neutropenia in breast cancer patients treated with chemotherapy.

Chemotherapy-induced febrile neutropenia (FN) is associated with increased patient mortality and health care costs. Comorbid conditions such as liver and renal dysfunction have been linked to increased risk of FN. However, the effects of other chronic comorbid conditions on risk of FN have not been well studied. To examine the association between chronic comorbid conditions and FN in breast cancer patients, we identified incident breast cancer patients from 2000 to 2009 treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. Patients who received primary prophylactic granulocyte colony-stimulating factor (G-CSF) were excluded. We assessed history of comorbid conditions prior to cancer diagnosis using ICD-9 codes and disease registries. FN events were identified in the first chemotherapy cycle using a combination of ICD-9 codes and hospital discharge diagnoses. For each comorbid condition, propensity scores that included patient characteristics and other predisposing comorbid conditions were calculated and adjusted for in Cox models to determine associations between that comorbid condition and FN. We also evaluated secondary models that additionally adjusted for cancer stage, baseline absolute neutrophil count (ANC), chemotherapy regimen, and dose reductions. A total of 7,127 breast cancer patients were included; median age was 55 years, and the majority had localized (47 %) or regional (49 %) disease at diagnosis. In the first chemotherapy cycle, 335 (4.7 %) patients developed FN. Congestive heart failure (HR = 3.0; 95 % CI: 1.3-5.9), osteoarthritis (HR = 2.0; 95 % CI: 1.4-2.8), previous cancer (HR = 3.4; 95 % CI: 1.2-7.5), and thyroid disorder (HR = 1.6; 95 % CI: 1.1-2.3) were associated with increased risk of FN. These estimates were similar to those from secondary models that also adjusted for additional cancer and treatment-related covariates. Our findings suggest that several chronic comorbid conditions may be associated with risk of FN. This information, if confirmed by others, may aid clinical decision making with respect to use of prophylactic G-CSF during chemotherapy treatment.

Prevalence and incidence of comorbidities in elderly women with ovarian cancer.

OBJECTIVE: Studies suggest comorbidity plays an important role in ovarian cancer. We characterized the epidemiology of comorbid conditions in elderly U.S. women with ovarian cancer. METHODS: Women with ovarian cancer age ≥66 years, and matched cancer-free women, were identified using the National Cancer Institute's Surveillance, Epidemiology, and End Results registry linked to Medicare claims. Prevalence before diagnosis/index date and 3- and 12-month incidence rates (per 1000 person-years) after diagnosis/index date were estimated for 34 chronic and acute conditions across a broad range of diagnostic categories. RESULTS: There were 5087 each of women with ovarian cancer and cancer-free women. The prevalence of most conditions was similar between cancer and cancer-free patients, but exceptions included hypertension (51.8% and 43.5%, respectively), osteoarthritis (13.4% and 17.3%, respectively), and cerebrovascular disease (8.0% and 9.8%, respectively). In contrast, 3- and 12-month incidence rates (per 1000 person years) of most conditions were significantly higher in cancer than in cancer-free patients: hypertension (177.3 and 47.4, respectively); thromboembolic event (145.3 and 5.5, respectively); congestive heart failure (113.3 and 28.6, respectively); infection (664.4 and 55.2, respectively); and anemia (408.3 and 33.1, respectively) at 12 months. CONCLUSIONS: Comorbidities were common among elderly women. After cancer diagnosis, women with ovarian cancer had a much higher incidence of comorbidities than cancer-free women. The high incidence of some of these comorbidities may be related to the cancer or its treatment, but others may have been prevalent but undiagnosed until the cancer diagnosis. The presence of comorbidities may affect treatment decisions.

Obesity-related hormones and endometrial cancer among postmenopausal women: a nested case-control study within the B~FIT cohort.

Endometrial cancer risk is strongly influenced by obesity, but the mechanisms of action remain unclear. Leptin and adiponectin, secreted from adipose tissue, reportedly play a role in such carcinogenic processes as cell proliferation, angiogenesis, and insulin regulation. In this case-control study, nested within the Breast and Bone Follow-up of the Fracture Intervention Trial (n=15,595), we assessed pre-diagnostic serum leptin, total adiponectin, and high-molecular-weight (HMW) adiponectin in relation to endometrial cancer among postmenopausal women. During the 10-year follow-up, 62 incident endometrial cases were identified and matched to 124 controls on age, geographical site, time of fasting blood draw at baseline (1992-1993), and trial participation status. Adipokines and C-peptide were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated via conditional logistic regression, with exposures categorized in tertiles (T). Multivariable models considered C-peptide, BMI (kg/m(2)), and estradiol (E2) as potential confounders. Endometrial cancer risk was significantly associated with higher leptin levels, adjusted for E2 and C-peptide (OR(T3 vs T1)=2.96; 95% CI, 1.21-7.25; P trend <0.01). After further adjustment for BMI, the estimates were attenuated and the positive trend was no longer statistically significant (OR(T3 vs T1)=2.11; 95% CI, 0.69-6.44; P trend=0.18). No significant associations were observed with adiponectin or HMW adiponectin and endometrial cancer. Our findings with leptin suggest that the leptin-BMI axis might increase endometrial cancer risk through mechanisms other than estrogen-driven proliferation. Continued exploration of these pathways in larger prospective studies may help elucidate mechanisms underlying observed obesity-endometrial cancer associations.

Estimated number of prevalent cases of metastatic bone disease in the US adult population.

BACKGROUND: The prevalence of metastatic bone disease in the US population is not well understood. We sought to estimate the current number of US adults with metastatic bone disease using two large administrative data sets. METHODS: Prevalence was estimated from a commercially insured cohort (ages 18-64 years, MarketScan database) and from a fee-for-service Medicare cohort (ages ≥65 years, Medicare 5% database) with coverage on December 31, 2008, representing approximately two-thirds of the US population in each age group. We searched for claims-based evidence of metastatic bone disease from January 1, 2004, using a combination of relevant diagnosis and treatment codes. The number of cases in the US adult population was extrapolated from age- and sex-specific prevalence estimated in these cohorts. Results are presented for all cancers combined and separately for primary breast, prostate, and lung cancer. RESULTS: In the commercially insured cohort (mean age = 42.3 years [SD = 13.1]), we identified 9505 patients (0.052%) with metastatic bone disease. Breast cancer was the most common primary tumor type (n = 4041). In the Medicare cohort (mean age = 75.6 years [SD = 7.8]), we identified 6427 (0.495%) patients with metastatic bone disease. Breast (n = 1798) and prostate (n = 1862) cancers were the most common primary tumor types. We estimate that 279,679 (95% confidence interval: 274,579-284,780) US adults alive on December 31, 2008, had evidence of metastatic bone disease in the previous 5 years. Breast, prostate, and lung cancers accounted for 68% of these cases. CONCLUSION: Our findings suggest that approximately 280,000 US adults were living with metastatic bone disease on December 31, 2008. This likely underestimates the true frequency; not all cases of metastatic bone disease are diagnosed, and some diagnosed cases might lack documentation in claims data.

Incidence rates of endometrial hyperplasia, endometrial cancer and hysterectomy from 1980 to 2003 within a large prepaid health plan.

Obesity strongly increases the risk of endometrial cancer and is projected to increase current and future endometrial cancer incidence. In order to fully understand endometrial cancer incidence, one should also examine both hysterectomy, which eliminates future risk of endometrial cancer, and endometrial hyperplasia (EH), a precursor that prompts treatment (including hysterectomy). Hysterectomy and EH are more common than endometrial cancer, but data on simultaneous temporal trends of EH, hysterectomy and endometrial cancer are lacking. We used linked pathology, tumor registry, surgery and administrative datasets at the Kaiser Permanente Northwest Health Plan to calculate age-adjusted and age-specific rates, 1980-2003, of EH only (N = 5,990), EH plus hysterectomy (N = 904), hysterectomy without a diagnosis of EH or cancer (N = 14,926) and endometrial cancer (N = 1,208). Joinpoint regression identified inflection points and quantified annual percentage changes (APCs). The EH APCs were -5.3% (95% confidence interval [CI] = -7.4% to -3.2%) for 1980-1990, -12.9% (95% CI = -15.6% to -10.1%) for 1990-1999 and 2.4% (95% CI = -6.6% to 12.2%) for 1999-2003. The EH-plus-hysterectomy APCs were -8.6% (95% CI = -10.6% to -6.5%) for 1980-2000 and 24.5% (95% CI = -16.5% to 85.7%) for 2000-2003. Hysterectomy rates did not significantly change over time. The endometrial cancer APCs were -6.5% (95% CI = -10.3% to -2.6%) for 1980-1988 and 1.4% (95% CI = -0.2% to 3.0%) for 1988-2003. Hysterectomy rates were unchanged, but increased endometrial cancer incidence after 1988 and the reversal, in 1999, of the longstanding decline in EH incidence could reflect the influence of obesity on endometrial neoplasia.

Granulocyte-colony stimulating factor use and medical costs after initial adjuvant chemotherapy in older patients with early-stage breast cancer.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) reduces the risk of severe neutropenia associated with chemotherapy, but its cost implications following chemotherapy are unknown. OBJECTIVE: Our objective was to examine associations between G-CSF use and medical costs after initial adjuvant chemotherapy in early-stage (stage I-III) breast cancer (ESBC). METHODS: Women diagnosed with ESBC from 1999 to 2005, who had an initial course of chemotherapy beginning within 180 days of diagnosis and including ≥1 highly myelosuppressive agent, were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Medicare claims were used to describe the initial chemotherapy regimen according to the classes of agents used: anthracycline ([A]: doxorubicin or epirubicin); cyclophosphamide (C); taxane ([T]: paclitaxel or docetaxel); and fluorouracil (F). Patients were classified into four study groups according to their G-CSF use: (i) primary prophylaxis, if the first G-CSF claim was within 5 days of the start of the first chemotherapy cycle; (ii) secondary prophylaxis, if the first claim was within 5 days of the start of the second or subsequent cycles; (iii) G-CSF treatment, if the first claim occurred outside of prophylactic use; and (iv) no G-CSF. Patients were described by age, race, year of diagnosis, stage, grade, estrogen (ER) and progesterone (PR) receptor status, National Cancer Institute (NCI) Co-morbidity Index, chemotherapy regimen and G-CSF use. Total direct medical costs ($US, year 2009 values) to Medicare were estimated from 4 weeks after the last chemotherapy administration up to 48 months. Medical costs included those for ESBC treatment and all other medical services received after chemotherapy. Least squares regression, using inverse probability weighting (IPW) to account for censoring within the cohort, was used to evaluate adjusted associations between G-CSF use and costs. RESULTS: A total of 7026 patients were identified, with an average age of 72 years, of which 63% had stage II disease, and 59% were ER and/or PR positive. Compared with no G-CSF, those receiving G-CSF primary prophylaxis were more likely to have stage III disease (30% vs. 16%; p < 0.0001), to be diagnosed in 2003-5 (87% vs. 26%; p < 0.0001), and to receive dose-dense AC-T (26% vs. 1%; p < 0.0001), while they were less likely to receive an F-based regimen (12% vs. 42%; p < 0.0001). Overall, the estimated average direct medical cost over 48 months after initial chemotherapy was $US 42,628. In multivariate analysis, stage II or III diagnosis (compared with stage I), NCI Co-morbidity Index score 1 or ≥2 (compared with 0), or FAC or standard AC-T (each compared with AC) were associated with significantly higher IPW 48-month costs. Adjusting for patient demographic and clinical factors, costs in the G-CSF primary prophylaxis group were not significantly different from those not receiving primary prophylaxis (the other three study groups combined). In an analysis that included four separate study groups, G-CSF treatment was associated with significantly greater costs (incremental cost = $US 2938; 95% CI 285, 5590) than no G-CSF. CONCLUSIONS: Direct medical costs after initial chemotherapy were not statistically different between those receiving G-CSF primary prophylaxis and those receiving no G-CSF, after adjusting for potential confounders.

Genetic contributions to the association between adult height and testicular germ cell tumors.

BACKGROUND: Previously, we have shown that increasing adult height is associated with increased risk of testicular germ-cell tumor (TGCT). Recently, a number of single nucleotide polymorphisms (SNPs) have been found to be related to height. We examined whether these SNPs were associated with TGCT and whether they explained the relationship between height and TGCT. METHODS: We genotyped 15 height-related SNPs in the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) case-control study. DNA was extracted from buccal cell samples and Taqman assays were used to type the selected SNPs. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS: There were 561 cases and 676 controls for analysis. Two SNPs were found to be associated with risk of TGCT, rs6060373 (CC vs TT, OR = 1.51, 95% CI: 1.06-2.15) and rs143384 (CC vs TT, OR = 1.53, 95% CI: 1.09-2.15). rs6060373 is an intronic polymorphism of ubiquinol-cytochrome c reductase complex chaperone (UQCC), and rs143384 is a 5'UTR polymorphism of growth differentiation factor 5 (GDF5). No individual SNP attenuated the association between height and TGCT. Adjustment for all SNPs previously associated with adult height reduced the associations between adult height and TGCT by ~8.5%, although the P-value indicated only weak evidence that this difference was important (P = 0.26). CONCLUSIONS: This novel analysis provides tentative evidence that SNPs which are associated with adult height may also share an association with risk of TGCT.

Body size, IGF and growth hormone polymorphisms, and colorectal adenomas and hyperplastic polyps.

OBJECTIVE: We examined the risk of colorectal polyps in relation to body size factors and candidate polymorphisms in selected genes of insulin-like growth factor (IGF1) (rs5742612), IGF1 receptor (IGF1R) (rs2229765), IGF binding protein 3 (IGFBP3) (rs2854746) and growth hormone (GH1) (rs2665802). DESIGN: Cases with colorectal adenomas (n=519), hyperplastic polyps (n=691), or both lesions (n=227), and controls (n=772), aged 20-74 years, were recruited from patients who underwent colonoscopy between December 2004 and September 2007 at a large integrated-health plan in Washington state. Subjects participated in a 45-minute telephone interview to ascertain body size and physical activity, and provided a buccal DNA sample for genetic analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable polytomous regression. RESULTS: Compared to those of normal weight, higher body mass index (BMI) was associated with elevated risk of colorectal adenomas (OR=1.65, 95% CI 1.22-2.25 BMI>or=30 kg/m(2), p-trend=0.002) and both lesions (OR=2.15, 95% CI 1.43-3.22 BMI>or=30 kg/m(2), p-trend=0.003), but there was no relationship with hyperplastic polyps. Obesity at age 18 and a weight gain of >or=21 kg since age 18 were also significantly associated with an increased risk of colorectal adenomas and both lesions, but not hyperplastic polyps. There was a reduced risk of colorectal adenomas (OR=0.63, 95% CI 0.42-0.94) and hyperplastic polyps (OR=0.7, 95% CI 0.5-0.9) associated with the homozygous variant genotype for GH1. Few meaningful results were evident for the other polymorphisms. CONCLUSIONS: There is an increased risk of colorectal adenomas and presence of both adenomas and hyperplastic polyps in relation to increasing body size. Some genetic variation in GH1 might contribute to a reduced risk of colorectal adenomas and hyperplastic polyps.

International trends in the incidence of testicular cancer, 1973-2002.

BACKGROUND: Whereas testicular cancer incidence rates have been widely reported in populations of Northern European ancestry, rates in other populations have been less frequently examined. In a prior report, global testicular cancer incidence rates and trends for the years 1973 to 1997 were summarized. The current report extends these analyses with an additional 5 years of data from Cancer Incidence in Five Continents. METHODS: Age-standardized incidence rates over successive 5-year time periods were obtained for populations in the Americas, Asia, Europe, and Oceania. RESULTS: In general, testicular cancer incidence remained highest in Northern European populations (8.0-9.0 per 100,000) and lowest in Asian and African populations (<1 per 100,000). One notable exception to this pattern, however, was the very high rate reported by the Valdivia, Chile registry (8.8 per 100,000). In many populations, rates rose between 1973 and 2002, although the increases were strongest and most consistent among populations of European ancestry. In certain European populations, such as those of Denmark and of Geneva, Switzerland, some recent plateauing of rates was evident. There was little evidence of increase and possible evidence of a modest decline in rates among east Asian populations. Trends by histology (seminoma and nonseminoma) were generally similar to one another. CONCLUSIONS: Risk of testicular cancer remains relatively high in Northern European populations and low in Asian and African populations. Similar trends by histology suggest common risk factors. EFFECT: Reasons for increasing rates among Northern Europeans and stable or declining rates among East Asians are unexplained, supporting the need for future etiologic studies.