Bosutinib plus capecitabine for selected advanced solid tumours: results of a phase 1 dose-escalation study.

BACKGROUND: This phase 1 study evaluated the maximum tolerated dose (MTD), safety, and efficacy of bosutinib (competitive Src/Abl tyrosine kinase inhibitor) plus capecitabine. METHODS: Patients with locally advanced/metastatic breast, pancreatic, or colorectal cancers; cholangiocarcinoma; or glioblastoma received bosutinib plus capecitabine at eight of nine possible dose combinations using an 'up-down' design to determine the toxicity contour of the combination. RESULTS: Among 32 enrolled patients, none of the 9 patients receiving MTD (bosutinib 300 mg once daily plus capecitabine 1000 mg m(-2) twice daily) experienced dose-limiting toxicities (DLTs). Overall, 2 out of 31 (6%) evaluable patients experienced DLTs (grade 3 neurologic pain (n=1); grade 3 pruritus/rash and increased alanine aminotransferase (n=1)). Most common treatment-related adverse events (AEs) were diarrhoea, nausea, vomiting, palmar-plantar erythrodysesthesia (PPE), fatigue; most frequent grade 3/4 AEs: PPE, fatigue, and increased alanine/aspartate aminotransferase. Although diarrhoea was common, 91% of affected patients experienced maximum grade 1/2 events that resolved. Best overall confirmed partial response or stable disease >24 weeks (all tumour types) was observed in 6 and 13% of patients. CONCLUSIONS: In this population of patients with advanced solid tumours, bosutinib plus capecitabine demonstrated a safety profile similar to that previously reported for bosutinib or capecitabine monotherapy; limited efficacy was observed.

Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy.

BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.

Treatment of unruptured intracranial aneurysms: a nationwide assessment of effectiveness.

BACKGROUND AND PURPOSE: With advances in neuroimaging, unruptured cerebral aneurysms are being diagnosed more frequently. Until 1995, surgical clipping of the aneurysm was the only treatment available. Since then, a less invasive endovascular technique has been found effective in a trial of ruptured aneurysms. No efficacy studies comparing the 2 procedures for unruptured aneurysms exist to guide clinical decisions. The objective of this study was to assess effectiveness and outcomes of endovascular versus neurosurgical treatment for unruptured intracranial aneurysms. METHODS: This was a retrospective cohort study, using data collected over a 1-year time interval (between 1998 and 2000), from 429 hospitals, in 18 states, and representing 58% of the US population. A total of 2535 treated, unruptured cerebral aneurysm cases were evaluated. The measurements used were effectiveness as measured by hospital discharge outcomes: 1) mortality (in-hospital death), 2) adverse outcomes (death or discharge to a rehabilitation or nursing facility), 3) length of stay, and 4) hospital charges. Univariate analyses compared endovascular versus neurosurgical discharge outcomes. Multivariable models were adjusted for age, sex, region, Medicaid insurance status, year, hospital case volume, comorbidity score, and admission source. RESULTS: Endovascular treatment was associated with fewer adverse outcomes (6.6% versus 13.2%), decreased mortality (0.9% versus 2.5%), shorter lengths of stay (4.5 versus 7.4 days), and lower hospital charges (42,044 dollars versus 47,567 dollars) compared with neurosurgical treatment (P < .05). After multivariable adjustment, neurosurgical cases had 70% greater odds of an adverse outcome, 30% increased hospital charges, and 80% longer length of stay compared with endovascular cases (P < .05). CONCLUSIONS: The current analysis indicates that endovascular therapy is associated with significantly less morbidity, less mortality, and decreased hospital resource use at discharge, compared with conventional neurosurgical treatment for all unruptured aneurysms. Endovascular therapy, as a treatment alternative to surgical clipping, should be offered as a viable therapeutic option for all patients considering treatment of an unruptured cerebral aneurysm.

Cross-sectional relations of serum aldosterone and urine sodium excretion to urinary albumin excretion in a community-based sample.

Experimental models suggest that increased aldosterone and sodium intake are associated with renovascular damage and resultant proteinuria. We hypothesized that serum aldosterone and urinary sodium would be associated with urinary albumin excretion, an indicator of kidney damage. We evaluated 2700 participants (53% women, mean age 58 years) from the Framingham Offspring Study who attended a routine examination between 1995 and 1998, who were free of heart failure and renal failure, and underwent testing for serum aldosterone, spot urinary sodium, and urinary albumin excretion (urine albumin/creatinine ratio, UACR), the latter two indexed to urinary creatinine. Stepwise multivariable linear regression was used to evaluate the relations between UACR with urinary sodium index and serum aldosterone. In multivariable regression, log urinary sodium index was associated positively with log-UACR (P<0.0001). UACR levels in the fourth and fifth quintiles of urinary sodium index were 24% (95% confidence interval (CI) 3-49%), and twofold higher (95% CI 72-150%), respectively, relative to the lowest quintile (P-value for trend across quintiles <0.001). In multivariable models, log-transformed aldosterone was not related to log-UACR. The top quintile of serum aldosterone levels was associated with a 21% higher (95% 1-44%) UACR levels relative to the lowest quintile. Urinary albumin excretion was strongly and positively associated in a continuous fashion with urinary sodium excretion, whereas a weaker nonlinear positive relation with serum aldosterone was noted. Our cross-sectional observations raise the possibility that dietary salt intake may be associated with early renovascular damage.

Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study.

BACKGROUND: Patients with optimum (<120/80 mm Hg), normal (120-129/80-84 mm Hg), and high normal (130-139/85-89 mm Hg) blood pressure (BP) may progress to hypertension (>140/90 mm Hg) over time. We aimed to establish the best frequency of BP screening by assessing the rates and determinants of progression to hypertension. METHODS: We assessed repeated BP measurements in individuals without hypertension (BP<140/90 mm Hg) from the Framingham Study (4200 men, 5645 women; mean age 52 years) who attended clinic examinations during 1978-94. The incidence of hypertension (or use of antihypertensive treatment) and its determinants were studied. FINDINGS: A stepwise increase in hypertension incidence occurred across the three non-hypertensive BP categories; 5.3% (95% CI 4.4-6.3%) of participants with optimum BP, 17.6% (15.2-20.3%) with normal, and 37.3% (33.3-41.5%) with high normal BP aged below age 65 years progressed to hypertension over 4 years. Corresponding 4-year rates of progression for patients 65 years and older were 16.0% (12.0-20.9), 25.5% (20.4-31.4), and 49.5% (42.6-56.4), respectively. Obesity and weight gain also contributed to progression; a 5% weight gain on follow-up was associated with 20-30% increased odds of hypertension. INTERPRETATION: High normal BP and normal BP frequently progress to hypertension over a period of 4 years, especially in older adults. These findings support recommendations for monitoring individuals with high normal BP once a year, and monitoring those with normal BP every 2 years, and they emphasise the importance of weight control as a measure for primary prevention of hypertension.

Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study.

BACKGROUND: We examined the relative importance of diastolic (DBP), systolic (SBP) and pulse pressure (PP) as predictors of coronary heart disease (CHD) risk in different age groups of Framingham Heart Study participants. METHODS AND RESULTS: We studied 3060 men and 3479 women between 20 and 79 years of age who were free of CHD and were not on antihypertensive drug therapy at baseline. Cox regression adjusted for age, sex, and other risk factors was used to assess the relations of BP indexes to CHD risk over a 20-year follow-up. In the group <50 years of age, DBP was the strongest predictor of CHD risk (hazard ratio [HR] per 10 mm Hg increment, 1.34; 95% CI, 1.18 to 1.51) rather than SBP (HR, 1.14; 95% CI, 1.06 to 1.24) or PP (HR, 1.02; 95% CI, 0.89 to 1.17). In the group 50 to 59 years of age, risks were comparable for all 3 BP indexes. In the older age group, the strongest predictor of CHD risk was PP (HR, 1.24; 95% CI, 1.16 to 1.33). When both SBP and DBP were considered jointly, the former was directly and the latter was inversely related to CHD risk in the oldest age group CONCLUSIONS: With increasing age, there was a gradual shift from DBP to SBP and then to PP as predictors of CHD risk. In patients <50 years of age, DBP was the strongest predictor. Age 50 to 59 years was a transition period when all 3 BP indexes were comparable predictors, and from 60 years of age on, DBP was negatively related to CHD risk so that PP became superior to SBP.

Impact of high-normal blood pressure on the risk of cardiovascular disease.

BACKGROUND: Information is limited regarding the absolute and relative risk of cardiovascular disease in persons with high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both). METHODS: We investigated the association between blood-pressure category at base line and the incidence of cardiovascular disease on follow-up among 6859 participants in the Framingham Heart Study who were initially free of hypertension and cardiovascular disease. RESULTS: A stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age who had high-normal blood pressure was 4 percent (95 percent confidence interval, 2 to 5 percent) for women and 8 percent (95 percent confidence interval, 6 to 10 percent) for men; in older subjects (those 65 to 90 years old), the incidence was 18 percent (95 percent confidence interval, 12 to 23 percent) for women and 25 percent (95 percent confidence interval, 17 to 34 percent) for men. As compared with optimal blood pressure, high-normal blood pressure was associated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 2.5 (95 percent confidence interval, 1.6 to 4.1) in women and 1.6 (95 percent confidence interval, 1.1 to 2.2) in men. CONCLUSIONS: High-normal blood pressure is associated with an increased risk of cardiovascular disease. Our findings emphasize the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease.