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BACKGROUND: Given advances in the management of cancer, it is increasingly important for clinicians to appropriately manage the risk of cardiovascular disease (CVD) among cancer survivors. It is unclear whether CVD risk is increased among cancer survivors overall, and there is inconsistency in evidence to date about CVD incidence and mortality by cancer type. METHODS: Patients aged 30-74 years entered an open cohort study at the time of first CVD risk assessment, between 2004 and 2018, in primary care in New Zealand. Patients with established CVD or cancer within 2 years prior to study entry were excluded. Cancer diagnosis (1995-2016) was determined from a national cancer registry. Cause-specific hazard models were used to examine the association between history of cancer and two outcomes: (1) CVD-related hospitalization and/or death and (2) CVD death. RESULTS: The study included 446,384 patients, of whom 14,263 (3.2%) were cancer survivors. Risk of CVD hospitalization and/or death was increased among cancer survivors compared with patients without cancer at cohort entry (multivariable-adjusted hazard ratio, mHR, 1.11, 95% CI 1.05-1.18), more so for CVD death (1.31, 1.14-1.52). Risk of CVD hospitalization and/or death was increased in patients with myeloma (2.66, 1.60-4.42), lung cancer (2.19, 1.48-3.24) and non-Hodgkin lymphoma (1.90, 1.42-2.54), but not for some cancers (e.g., colorectal, 0.87, 0.71-1.06). Risk of CVD death was increased in several cancer types including melanoma (1.73, 1.25-2.38) and breast cancer (1.56, 1.16-2.11). CONCLUSION: CVD risk management needs to be prioritized among cancer survivors overall, and particularly in those with myeloma, lung cancer and non-Hodgkin lymphoma given consistent evidence of increased risk.

BACKGROUND: People with cancer have an increased risk of cardiovascular disease. Risk prediction equations developed in New Zealand accurately predict 5-year cardiovascular disease risk in a general primary care population in the country. We assessed the performance of these equations for survivors of cancer in New Zealand. METHODS: For this validation study, patients aged 30-74 years from the PREDICT open cohort study, which was used to develop the New Zealand cardiovascular disease risk prediction equations, were included in the analysis if they had a primary diagnosis of invasive cancer at least 2 years before the date of the first cardiovascular disease risk assessment. The risk prediction equations are sex-specific and include the following predictors: age, ethnicity, socioeconomic deprivation index, family history of cardiovascular disease, smoking status, history of atrial fibrillation and diabetes, systolic blood pressure, total cholesterol to HDL cholesterol ratio, and preventive pharmacotherapy (blood-pressure-lowering, lipid-lowering, and antithrombotic drugs). Calibration was assessed by comparing the mean predicted 5-year cardiovascular disease risk, estimated using the risk prediction equations, with the observed risk across deciles of risk, for men and women, and according to the three clinical 5-year cardiovascular disease risk groups in New Zealand guidelines (<5%, 5% to <15%, and ≥15%). Discrimination was assessed by Harrell's C statistic. FINDINGS: 14 263 patients were included in the study. The mean age was 61 years (SD 9) for men and 60 years (SD 8) for women, with a median follow-up of 5·8 years for men and 5·7 years for women. The observed cardiovascular disease risk was underpredicted by a maximum of 2·5% in male and 3·2% in female decile groups. When patients were grouped according to clinical risk groups, observed cardiovascular disease risk was underpredicted by less than 2% in the lower risk groups and overpredicted by 2·2% for men and 3·

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. DEM is a humanized IgG2 anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received DEM (2.5, 5, or 7.5 mg/kg), pemetrexed 500 mg/m2, and carboplatin (AUC = 6) every 3 weeks followed by maintenance DEM (first 4 cohorts) or pemetrexed (7.5 mg/kg cohort) every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were administered as pemetrexed pre-medication. The primary study objective was to determine the maximum tolerated dose of DEM. Other objectives included: safety, efficacy, immunogenicity, pharmacokinetic and biomarkers of Notch signaling. Result(s): Thirty patients have been enrolled; 6 received 2.5 mg/kg, 20 received 5 mg/kg and 4 received 7.5 mg/kg of DEM once every 3 weeks. The median age was 63 years and 90% had stage IV disease. Related adverse events (all grades) in >=10% of pts included: nausea (53%), fatigue (50%), hypertension (37%), vomiting (33%), neutropenia (27%), increased B-type natriuretic peptide (BNP) (23%), anemia (20%), peripheral edema (20%), increased ALT (20%), increased AST (17%), dyspnea, (17%), diarrhea (17%), decreased appetite (17%), pulmonary hypertension (13%), dysgeusia (13%), thrombocytopenia (13%), constipation (10%), and rash (10%). The hypertension was managed with oral anti-hypertensives. Increased BNP values appear to be an early indicator of the cardiac effects of DEM and mildly elevated values are being used to initiate cardioprotective therapy with an ACE inhibitor or carvedilol. Two patients receiving 5 mg/kg developed reversible pulmonary hypertension and heart failure on days 16

Background: Delta-like ligand 4 (DLL4) is a ligand that activates the Notch pathway which is important for cancer stem cell (CSC) survival. Demcizumab is a humanized, anti-DLL4 antibody that has been shown to inhibit tumor growth and decrease CSC frequency in minimally passaged human xenograft models, using an in vivo tumorigenicity limiting dilution assay. In addition, inhibition of DLL4 has also been shown in preclinical studies to cause dysfunctional sprouting of new vessels resulting in an antiangiogenic effect. Material(s) and Method(s): Patients received demcizumab (2.5 or 5 mg/kg) plus pemetrexed 500 mg/m2 and carboplatin (area under the concentrationtime curve, 6 mg/mL x min) once every 3 weeks for 6 cycles followed by maintenance demcizumab once every 3 weeks until disease progression. Folic acid, vitamin B12 and dexamethasone were also administered as pemetrexed pre-medication. The primary study objective was to determine the safety profile and optimal dose of demcizumab when combined with pemetrexed and carboplatin. Other objectives included: preliminary efficacy, immunogenicity, pharmacokinetics, and biomarkers of Notch signaling and CSCs in blood, hair follicles and tumor cells. Result(s): Twelve patients have been enrolled; 6 patients received 2.5 mg/kg and 6 patients received 5 mg/kg of demcizumab. The median age was 64 years and all 12 patients had stage IV disease. Adverse events reported as related to study drug in at least 10% of patients included: fatigue (50%), hypertension (42%), dyspnea on exertion (25%), ALT increased (25%), AST increased (25%), nausea (25%), vomiting (25%), neutropenia (17%), diarrhea (17%), palpitations (17%), decreased appetite (17%) and rash (17%). The hypertension was successfully managed with anti-hypertensives and no patients developed cardiac toxicity. The pharmacokinetic, immunogenicity and blood and hair biomarker specimens are being analyzed and these data will be presented. Six of the 10 (60%) evaluable patients h