The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial.

BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.

Proteinuria in metastatic pheochromocytoma is associated with an increased risk of Acute Respiratory Distress Syndrome, spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG).

Acute Respiratory Distress Syndrome (ARDS) has been reported rarely in pheochromocytoma, occurring spontaneously or after therapy with 131I-meta-iodobenzylguanidine (131I-MIBG). Our objective was to determine whether proteinuria is associated with an increased risk of ARDS. This was a retrospective analysis of a prospective cohort study of 64 patients with metastatic pheochromocytoma or paraganglioma treated with 131I-MIBG on institutional protocols. Proteinuria was defined as at least one urinalysis positive for at least trace protein within 1 month prior to 131I-MIBG or within 1 month prior to spontaneous ARDS. Proportions were compared using Fisher's exact test. Urinalyses within the defined time period were available for 48 patients, 8 of whom had proteinuria. Of the 8 patients with proteinuria, 5 developed ARDS: 3 within 10 days following 131I-MIBG, two 6 months following 131I-MIBG. Both patients who developed ARDS 6 months after 131I-MIBG had proteinuria within 1 month before apparently spontaneous ARDS. None of the 40 patients whose urinalyses were all negative for protein developed ARDS. None of the 16 patients with missing urinalyses developed ARDS. Patients with antecedent proteinuria were more likely to develop ARDS than those without proteinuria (63% vs. 0%; p<0.0001). The following variables were not significantly associated with ARDS: 131I-MIBG activities administered, number of 131I-MIBG administrations, age, hypertension, or secretion of catecholamines or metanephrines. In patients with metastatic pheochromocytoma or paraganglioma, proteinuria is associated with ARDS and urine protein should be examined prior to administering 131I-MIBG.

Abnormal longitudinal, base-to-apex myocardial perfusion gradient by quantitative blood flow measurements in patients with coronary risk factors.

BACKGROUND: A longitudinal, base-to-apex myocardial perfusion gradient has been described in patients with coronary artery disease (CAD) and was attributed to diffuse coronary luminal narrowing. We asked whether an abnormal perfusion gradient also existed in patients without CAD but with coronary risk factors. We measured myocardial blood flow (MBF) with (13)N-ammonia and PET at rest and during hyperemia in patients with coronary risk factors but without CAD. METHODS AND RESULTS: Regional MBF was measured in absolute units with (13)N-ammonia and PET at rest and during dipyridamole hyperemia in 36 patients with coronary risk factors (age, 55+/-10 years) and in 36 age-matched (age, 53+/-10 years) and in 28 young (age, 25+/-5 years) normal subjects. MBF was determined globally, for each of the 3 coronary territories, and in the mid and mid-to-apical sections of the left ventricle (LV). Myocardial perfusion on qualitative analysis was normal at rest and during hyperemia, and no flow defects were present. MBF in absolute units was similar in the 3 coronary territories. However, hyperemic MBFs in the mid-to-apical LV section were lower than in the mid LV section in the "at-risk" group (2.04+/-0.61 versus 1.71+/-0.40 mL. min(-1). g(-1); P<0.004) but not in the age-matched or in the young normal subjects. CONCLUSIONS: The abnormal longitudinal, base-to-apex perfusion gradient observed during dipyridamole MBF suggests the presence of a functional and/or structural alteration of the coronary circulation associated with coronary risk factors, possibly reflecting developing coronary atherosclerosis or preclinical CAD.

Exercise performance and quality of life following surgical repair of anomalous aortic origin of a coronary artery in the pediatric population.

OBJECTIVE: We sought to evaluate exercise performance and quality of life in children after surgical repair of anomalous aortic origin of a coronary artery with an interarterial course. METHODS: Patients who had surgery from October 2001 to January 2007 were eligible for inclusion. Exercise performance and quality of life were prospectively assessed by maximal exercise tests and age-appropriate questionnaires, respectively. We used t tests to compare pre- and postoperative exercise data and quality-of-life scores to published normative data. We performed linear regression analyses to assess associations between demographic, anatomic, and exercise variables and quality-of-life score. RESULTS: Of 25/27 patients, 64% were boys, 68% had anomalous right coronary, 32% were asymptomatic. Average age at surgery was 10.8 (+/-4.1) years; median follow-up was 14.5 (2 to 48) months. Postoperative percent-predicted exercise values were: peak heart rate 97 (+/-6), working capacity 91 (+/-15), maximal oxygen consumption 82 (+/-16). In those who had preoperative exercise testing (n = 11), resting and maximal heart rates decreased significantly without significant change in exercise performance. Average child quality of life was 85/100 (+/-13) and parent-proxy 88 (+/-11) compared with normal scores of 83 (+/-15) and 88 (+/-12), respectively. CONCLUSION: There is mild chronotropic impairment in children and adolescents following anomalous coronary artery repair without a decline in exercise performance. This does not appear to impair their overall quality of life. Because long-term effects on heart rate, exercise performance, and quality of life are unknown, serial exercise tests should be included as routine care of these patients.

Biphasic response to dobutamine predicts improvement of left ventricular dysfunction after revascularization: correlation with positron emission and rest-redistribution 201Tl tomographies.

BACKGROUND: Dobutamine echocardiography (DSE), positron emission tomography (PET) and 201Tl-single photon emission computed tomography (SPECT) have been used to identify myocardial viability. There are few reports, however, that compare high doses DSE with myocardial metabolic and perfusion imaging techniques in the same patient population. The aim of this study was to determine the correlation between high doses DSE, metabolic PET and 201Tl-SPECT imaging to predict the recovery of function after revascularization in patients with severe left ventricular (LV) dysfunction. METHODS: Twenty-five patients underwent DSE (up to 40 microg/kg/min), rest and 4-hour redistribution 201Tl SPECT, rest 13N-ammonia and 18fluoro-deoxy-glucose PET imaging and coronary angiography 7-10 days before surgical revascularization. A follow-up 2D-echocardiography was performed 6 weeks after surgery. RESULTS: Of the 109 successfully revascularized segments with severe dysfunction, 62 (57%) improved. LV ejection fraction increased from 30 +/- 10% to 42 +/- 13 at follow-up (p < 0.05). 201Tl SPECT, PET and the presence of contractile reserve determined by DSE had a similar sensitivity (77-87%) to predict recovery of function, but specificity was higher for the PET mismatch pattern and biphasic DSE (85-89%) than for any of the 201Tl viability patterns (19-64%). The highest positive predictive values were obtained by biphasic DSE and PET mismatch pattern (78-79%) compared to all other criteria (54-67%). In a multivariate model, which included evidence of viability by all imaging modalities, biphasic response was the best predictor of regional recovery of function (Odds ratio, OR: 9.9, 95% confidence intervals, 95% CI: 3.5-27.8). CONCLUSIONS: Although DSE and PET had overall comparable results, the presence of contractile reserve by the biphasic response to dobutamine was a best predictor for the improvement of LV contractile function in this group of patients.