Cancer patients face an increased risk of arterial thromboembolism; however, it is uncertain when this excess risk begins. This study evaluated the risk of arterial thromboembolism before cancer ...diagnosis. Using the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, we identified 374 331 patients ≥67 years of age with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, gastric cancer, or non-Hodgkin lymphoma from 2005 through 2013. Cancer patients were individually matched by demographics and comorbidities to Medicare beneficiaries without cancer, who served as controls. Validated diagnosis codes were used to identify arterial thromboembolic events, defined as a composite of myocardial infarction or ischemic stroke. The Mantel-Haenszel estimator was used to compare risks of arterial thromboembolic events between cancer and noncancer groups during 30-day periods in the 360 days before date of cancer diagnosis. From 360 to 151 days before cancer diagnosis, the 30-day interval risks of arterial thromboembolic events were similar between cancer patients and matched controls. From 150 to 1 day before cancer diagnosis, the interval 30-day risks of arterial thromboembolic events were higher in cancer patients vs matched controls, progressively increasing as the cancer diagnosis date approached and peaking during the 30 days immediately before cancer diagnosis, when 2313 (0.62%) cancer patients were diagnosed with an arterial thromboembolic event vs 413 (0.11%) controls (odds ratio, 5.63; 95% confidence interval, 5.07-6.25). In conclusion, the risk of arterial thromboembolic events begins to increase 150 days before the date of cancer diagnosis in older persons and peaks in the 30 days before.
•Among 748 662 Medicare beneficiaries, the risk of arterial thromboembolic events was increased 69% in the year before cancer diagnosis.•The increased risk of arterial thromboembolic events began 5 months before cancer was officially diagnosed and peaked in the month prior.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
A study was undertaken to examine the association between incident cancer and the subsequent risk of stroke.
Methods
Using the Surveillance, Epidemiology, and End Results–Medicare linked ...database, we identified patients with a new primary diagnosis of breast, colorectal, lung, pancreatic, or prostate cancer from 2001 through 2007. These patients were individually matched by age, sex, race, registry, and medical comorbidities to a group of Medicare enrollees without cancer, and each pair was followed through 2009. Validated diagnosis codes were used to identify a primary outcome of stroke. Cumulative incidence rates were calculated using competing risk survival statistics.
Results
Among 327,389 pairs of cancer patients and matched controls, the 3‐month cumulative incidence of stroke was generally higher in patients with cancer. Cumulative incidence rates were 5.1% (95% confidence interval CI = 4.9–5.2%) in patients with lung cancer compared to 1.2% (95% CI = 1.2–1.3%) in controls (p < 0.001), 3.4% (95% CI = 3.1–3.6%) in patients with pancreatic cancer compared to 1.3% (95% CI = 1.1–1.5%) in controls (p < 0.001), 3.3% (95% CI = 3.2–3.4%) in patients with colorectal cancer compared to 1.3% (95% CI = 1.2–1.4%) in controls (p < 0.001), 1.5% (95% CI = 1.4–1.6%) in patients with breast cancer compared to 1.1% (95% CI = 1.0–1.2%) in controls (p < 0.001), and 1.2% (95% CI = 1.1–1.3%) in patients with prostate cancer compared to 1.1% (95% CI = 1.0–1.2%) in controls (p = 0.085). Excess risks attenuated over time and were generally no longer present beyond 1 year.
Interpretation
Incident cancer is associated with an increased short‐term risk of stroke. This risk appears highest with lung, pancreatic, and colorectal cancers. Ann Neurol 2015;77:291–300
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often ...transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.
•Ibrutinib/methotrexate/rituximab combination treatment is safe and shows promising clinical activity in CNSL.•Analysis of ctDNA in CSF may be useful to monitor disease burden in patients with CNSL.
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A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy ...(rdWBRT) and cytarabine in primary CNS lymphoma.
Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor.
Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33).
R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.
The risk of arterial thromboembolism in patients with cancer is incompletely understood.
The authors aimed to better define this epidemiological relationship, including the effects of cancer stage.
...Using the Surveillance Epidemiology and End Results–Medicare linked database, the authors identified patients with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, pancreatic, or gastric cancer or non-Hodgkin lymphoma from 2002 to 2011. They were individually matched by demographics and comorbidities to a Medicare enrollee without cancer, and each pair was followed through 2012. Validated diagnosis codes were used to identify arterial thromboembolism, defined as myocardial infarction or ischemic stroke. Cumulative incidence rates were calculated using competing risk survival statistics. Cox hazards analysis was used to compare rates between groups at discrete time points.
The authors identified 279,719 pairs of patients with cancer and matched control patients. The 6-month cumulative incidence of arterial thromboembolism was 4.7% (95% confidence interval CI: 4.6% to 4.8%) in patients with cancer compared with 2.2% (95% CI: 2.1% to 2.2%) in control patients (hazard ratio HR: 2.2; 95% CI: 2.1 to 2.3). The 6-month cumulative incidence of myocardial infarction was 2.0% (95% CI: 1.9% to 2.0%) in patients with cancer compared with 0.7% (95% CI: 0.6% to 0.7%) in control patients (HR: 2.9; 95% CI: 2.8 to 3.1). The 6-month cumulative incidence of ischemic stroke was 3.0% (95% CI: 2.9% to 3.1%) in patients with cancer compared with 1.6% (95% CI: 1.6% to 1.7%) in control patients (HR: 1.9; 95% CI: 1.8 to 2.0). Excess risk varied by cancer type (greatest for lung), correlated with cancer stage, and generally had resolved by 1 year.
Patients with incident cancer face a substantially increased short-term risk of arterial thromboembolism.
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Abstract
BACKGROUND
Over the last 2 decades, advances in systemic therapy have increased the expected overall survival for patients with cancer. It is unclear whether the same survival benefit has ...been conferred to patients requiring surgery for metastatic spinal disease.
OBJECTIVE
To examine trends in postoperative survival over a 20-yr period for patients surgically treated for spinal metastatic disease.
METHODS
Data were obtained for 1515 patients who underwent surgery for metastatic epidural spinal cord compression or tumor-related mechanical instability. Postoperative overall survival was calculated for all included patients using Kaplan-Meier methodology from date of surgery until death or last follow-up for those who were censored. Trends were analyzed using Cox proportional hazards modeling.
RESULTS
Patients with renal, breast, lung, and colon cancers experienced a statistically significant improvement in survival over time based on the year of surgery (40%-100% improvement over the study period), whereas the overall survival trend for the entire cohort did not reach statistical significance (P = .12, median survival 0.71 yr, 95% CI 0.63-0.78). Patients presenting with synchronous metastatic disease had better survival compared to those presenting with metachronous disease (median overall survival: 0.94 vs 0.63 yr, respectively; log-rank P-value = .00001).
CONCLUSION
The postoperative survival among patients with spinal metastases has improved over the past 20 yr, particularly in patients with kidney, breast, lung, and colon tumors metastatic to the spine. The observed survival improvement emphasizes the need for long-term outcome consideration in treatment decisions for patients undergoing surgery for spinal metastatic tumors.
To examine the relationships between breast cancer and both amount of fibroglandular tissue (FGT) and level of background parenchymal enhancement (BPE) at magnetic resonance (MR) imaging.
A waiver of ...authorization was granted by the institutional review board for this retrospective HIPAA-compliant study. Among 1275 women who underwent breast MR imaging screening between December 2002 and February 2008, 39 breast carcinoma cases were identified. Two comparisons were performed: In one comparison, two normal controls--those of the women with negative (benign) findings at breast MR imaging--were matched to each breast cancer case on the basis of age and date of MR imaging. In the second comparison, one false-positive control--that of a woman with suspicious but nonmalignant findings at MR imaging--was similarly matched to each breast cancer case. Two readers independently rated the level of MR imaging-depicted BPE and the amount of MR imaging-depicted FGT by using a categorical scale: BPE was categorized as minimal, mild, moderate, or marked, and FGT was categorized as fatty, scattered, heterogeneously dense, or dense.
Compared with the odds ratio (OR) for a normal control, the OR for breast cancer increased significantly with increasing BPE: The ORs for moderate or marked BPE versus minimal or mild BPE were 10.1 (95% confidence interval CI: 2.9, 35.3; P < .001) and 3.3 (95% CI: 1.3, 8.3; P = .006) for readers 1 and 2, respectively. Similar odds were seen when the false-positive controls were compared with the breast cancer cases: The ORs for moderate or marked BPE versus minimal or mild BPE were 5.1 (95% CI: 1.4, 19.1; P = .005) and 3.7 (95% CI: 1.2, 11.2; P = .013) for readers 1 and 2, respectively. The breast cancer odds also increased with increasing FGT, but the BPE findings remained significant after adjustment for FGT.
Increased BPE is strongly predictive of breast cancer odds.
Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic ...information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas.
On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined.
Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (P(trend) < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio HR, 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage.
At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.
The purpose of this study was to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological ...insights into the carcinogenic process. Fifty-two women with contralateral breast cancer and 153 women with unilateral breast cancer were identified within the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study who were at increased risk of RCBC because they were ≤ 40 years of age at first diagnosis of breast cancer and received a scatter radiation dose > 1 Gy to the contralateral breast. A previously reported algorithm, preconditioned random forest regression, was applied to predict the risk of developing RCBC. The resulting model produced an area under the curve (AUC) of 0.62 (p = 0.04) on hold-out validation data. The biological analysis identified the cyclic AMP-mediated signaling and Ephrin-A as significant biological correlates, which were previously shown to influence cell survival after radiation in an ATM-dependent manner. The key connected genes and proteins that are identified in this analysis were previously identified as relevant to breast cancer, radiation response, or both. In summary, machine learning/bioinformatics methods applied to genome-wide genotyping data have great potential to reveal plausible biological correlates associated with the risk of RCBC.
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