Laura Antolini

Multicenter Independent Assessment of Outcomes in Chronic Myeloid Leukemia Patients Treated With Imatinib

BACKGROUND Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. PATIENTS AND METHODS Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan-Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch-Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ(2) distribution. All statistical tests were two-sided. RESULTS A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. CONCLUSIONS In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population.

Recurrent SETBP1 Mutations in Atypical Chronic Myeloid Leukemia

Atypical chronic myeloid leukemia (aCML) shares clinical and laboratory features with CML, but it lacks the BCR-ABL1 fusion. We performed exome sequencing of eight aCMLs and identified somatic alterations of SETBP1 (encoding a p.Gly870Ser alteration) in two cases. Targeted resequencing of 70 aCMLs, 574 diverse hematological malignancies and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval (CI) = 16–35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (P = 0.008) and worse prognosis (P = 0.01). The p.Gly870Ser alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET protein, lower PP2A activity and higher proliferation rates relative to those expressing the wild-type protein. In summary, mutated SETBP1 represents a newly discovered oncogene present in aCML and closely related diseases.

Crizotinib in Advanced, Chemoresistant Anaplastic Lymphoma Kinase–Positive Lymphoma Patients

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.

Axillary Lymph Node Nanometastases Are Prognostic Factors for Disease-Free Survival and Metastatic Relapse in Breast Cancer Patients

Purpose: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits ≤0.2 mm in diameter [pN0(i+), nanometastases] and analyzed their prognostic effect. Experimental Design: Single-institution, consecutive patients with 8 years of median follow-up (n = 702) were studied. To maximize chances of detecting micrometastases and nanometastases, whole-axilla dissections were analyzed. pN0 cases (n = 377) were systematically reevaluated by lymph node (n = 6676) step-sectioning and anticytokeratin immunohistochemical analysis. The risk of first adverse events and of distant relapse of bona fide pN0 patients was compared with that of pN0(i+), pN1mi, and pN1 cases. Results: Minimal lymph node deposits were revealed in 13% of pN0 patients. The hazard ratio for all adverse events of pN0(i+) versus pN0(i−) was 2.51 (P = 0.00019). Hazards of pN1mi and pN0(i+) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN0(i+)/pN1mi versus pN0(i−) (P = 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Grays test χ2 = 5.54, P = 0.019). Conclusion: Nanometastases are a strong risk factor for disease-free survival and for metastatic relapse. These findings support the inclusion of procedures for nanometastasis detection in tumor-node-metastasis staging.

Hepatocellular carcinoma in cirrhotic liver disease: functional computed tomography with perfusion imaging in the assessment of tumor vascularization

RATIONALE AND OBJECTIVES Our goal was to prospectively determine the value of perfusion computed tomography (CT) in the quantitative assessment of tumor-related angiogenesis in cirrhotic patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS Forty-seven patients met all the following inclusion criteria: 1) Child-Pugh class A or B liver cirrhosis; 2) presence of a single lesion suspected as HCC at screening ultrasound examination; and 3) lesion diameter between 1 and 3 cm. All patients underwent contrast-enhanced ultrasound, pre- and post-contrast triple-phase CT, and perfusion computed tomographic study using multidetector 16-slice CT. Six parameters related to the blood microcirculation and tissue perfusion were measured for the focal liver lesion and cirrhotic parenchyma: perfusion (P), tissue blood volume (BV), hepatic perfusion index (HPI), arterial perfusion (AP), portal perfusion (PP), and time to peak (TTP). Perfusion parameters were described with quartile values of their distribution; univariate paired and unpaired Wilcoxon signed rank tests were used for statistical analysis. RESULTS HCC was diagnosed in 21 of the 47 patients; in the remaining 26, HCC was not found at contrast-enhanced ultrasound and multidetector 16-slice computed tomographic study. The values of perfusion parameters measured within tumor tissue were: P (ml/s/100 g): median = 47.0 (first quartile = 36.0, third quartile = 61.4); BV (ml/100 mg): median = 24.0 (first quartile = 18.7, third quartile = 29.3); HPI (%): median = 78.4 (first quartile = 62.9, third quartile = 100); AP (ml/min): median = 45.9 (first quartile = 39.0, third quartile = 60.1); PP (ml/min): median = 9.0 (first quartile = 0.0, third quartile = 24.5); and TTP (seconds): median = 18.7 (first quartile = 16.3, third quartile = 26.5). The corresponding values calculated in cirrhotic surrounding parenchyma were P (ml/s/100 g): median = 11.5 (first quartile = 9.4, third quartile = 13.9); BV (ml/100 mg): median = 10.7 (first quartile = 7.1, third quartile = 14.2); HPI (%): median = 10.6 (first quartile = 8.7, third quartile = 11.9); AP (ml/min): median = 13.2 (first quartile = 10.1, third quartile = 15.5); PP (ml/min) median = 55.2 (first quartile = 40.1, third quartile = 79.5); and TTP (seconds): median = 41.7 (first quartile = 38.9, third quartile = 44.6). P, BV, HPI, and AP values were higher (P < .001), whereas PP and TTP were lower (P < .001) in HCC relative to the surrounding liver. Values of perfusion parameters in the cirrhotic liver of patients with and without HCC were not significantly different (P > .001). CONCLUSION In cirrhotic patients with HCC, perfusion computed tomographic technique can provide quantitative information about tumor-related angiogenesis.

Usefulness of waist circumference for the identification of childhood hypertension.

Objective To investigate the ability of BMI and waist circumference, single and combined, in identifying children who are at risk of hypertension and in influencing absolute blood pressure values. Methods The body weight, height, waist circumference and blood pressure of 4177 5–11-year-old school children [2005 (48%) girls] were collected. Elevated blood pressure was defined if either systolic or diastolic blood pressure values or both were more than the 95th percentile according to sex, age and height (US normative blood pressure tables). Overweight and obese children were defined according to International Obesity Task Force BMI cut-offs. Results The prevalence of hypertension was 4.1% and increased together with weight class: 1.4% (n = 42/3076) in normal weight, 7.1% (n = 59/827) in overweight and 25% (n = 69/274) in obese (P < 0.001). Only BMI and waist circumference showed a remarkable ability to discriminate hypertensive children (areas under receiver operating characteristic curves, 0.84 and 0.76, respectively). The multivariate analysis showed that z-scores for both BMI and waist circumference were significantly related to the risk of hypertension with odds ratios of 3.59 (95% confidence interval, 2.55, 5.06) and 1.20 (95% confidence interval, 1.04, 1.39), respectively, after adjusting for sex and age. When the weight class was included in the multivariate analysis, waist circumference retained its ability to identify hypertensive children only in the obese class (odds ratio, 1.44; 95% confidence interval, 1.21, 1.72; P < 0.01). When considering blood pressure as a continuous variable, both weight class and waist circumference showed a significant effect on systolic and diastolic blood pressure absolute values (P < 0.01). The effect of waist circumference on blood pressure values was maintained even when corrected for BMI. Conclusion High blood pressure is strongly associated with excess weight. Waist circumference improves the ability of BMI to identify hypertension in obese children. Waist circumference is related to absolute blood pressure values in all weight classes.

Perfusion CT in cirrhotic patients with early stage hepatocellular carcinoma: Assessment of tumor-related vascularization

PURPOSE To assess the value of CT-perfusion in determining the quantitative vascularization features of early hepatocellular carcinoma (HCC) in cirrhotic patients. MATERIALS AND METHODS A total of 35 cirrhotic patients with single histologically proven HCC not exceeding 3cm in diameter underwent conventional triple-phase multidetector computed tomography (MDCT) examination. All patients were also examined with CT-perfusion (CTp) technique after i.v. injection of 50mL of iodinated contrast. Data were analyzed using a dedicated software which generated a quantitative map of liver parenchyma perfusion. The following parameters were assessed: hepatic perfusion (HP); blood volume (BV); arterial perfusion (AP); time to peak (TTP) and hepatic perfusion index (HPI). Univariate Wilcoxon signed rank test was used for statistical analysis. RESULTS In the 35 HCCs evaluated, the following quantitative data were obtained: HP (mL/s/100g): median=47.0 (1(st)qt=35.5; 3(st)qt=61.2); BV (mL/100mg): median=22.5 (1(st)qt=18.4; 3(st)qt=27.7); AP (mL/min): median=42.9 (1(st)qt=35.8; 3(st)qt=55.6); HPI(%): median=75.3 (1(st)qt=63.1; 3(st)qt=100); TTP(s): median=18.7 (1(st)qt=16.8; 3(st)qt=24.5). Perfusion values calculated in cirrhotic liver parenchyma were HP: median=10.3 (1(st)qt=9.1; 3(st)qt=13.2); BV: median=11.7 (1(st)qt=9.6; 3(st)qt=15.5); AP: median=10.4 (1(st)qt=8.6; 3(st)qt=11.3); HPI: median=17.5 (1(st)qt=14.3; 3(st)qt=19.7); TTP: median=44.6 (1(st)qt=40.3; 3(st)qt=50.1). HP, BV, HPI and AP were found to be significantly higher in HCC lesion than in liver parenchyma (p<0.001), while TTP was significantly lower (p<0.001). CONCLUSION CT-perfusion technique allows obtaining quantitative information about tumor-related vascularization of early HCC, in patients with liver cirrhosis.

Serum uric acid and blood pressure in children at cardiovascular risk.

OBJECTIVES: Hyperuricemia has been shown to be a strong correlate of hypertension in children. However, the complex interaction between serum uric acid (UA), systemic blood pressure (BP), and possibly confounding factors has been elucidated only in part. METHODS: We evaluated office BP as well as clinical and biohumoral parameters in a cross-sectional cohort of 501 children (280 boys and 221 girls) aged between 6 and 18 years (mean = 10.8 years) consecutively referred for cardiovascular risk assessment. RESULTS: Overall, 156 (31.1%) were normotensive, 122 (24.4%) showed transient hypertension, 87 (17.4%) had prehypertension, and 136 (27.1%) had hypertension. Altogether 33.3% and 40.5% of the study group were overweight or obese, respectively. There was a trend toward greater weight and waist circumference and higher BMI, Homeostasis Model Assessment index, and UA levels as the BP categories rose. Moreover, the prevalence of pubertal children, obesity, and waist-to-height ratio above 0.50 progressively increased from lower to upper BP categories. After adjusting for puberty, gender, BMI (z-score), Homeostasis Model Assessment index, and renal function, UA was found to be directly related to systolic and diastolic BP values (P = .03). Using normotensive children for comparison, the risk of showing prehypertension or hypertension increased by at least 50% for each 1 mg/dL UA increase (P < .01), whereas it doubled for children in the top gender-specific UA quartile (P < .03). CONCLUSIONS: Increased UA levels showed an independent predictive power for the presence of higher BP levels among a cohort of children at relatively high cardiovascular risk.

Hypertension, Prehypertension, and Transient Elevated Blood Pressure in Children: Association With Weight Excess and Waist Circumference

BACKGROUND To assess the prevalence of hypertension (H), prehypertension (PH), and transient elevated blood pressure (TH) and their relationship with weight class and waist circumference (WC) in an unselected population of Northern Italian children. METHODS A cross-sectional study was conducted in 5,131 children (5-11 years). Weight class was defined according to the International Obesity Task Force references, H and PH according to the National High Blood Pressure Education Program. A child was classified as having PH or H when systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) at first screening were > or =90th percentile and the mean of three subsequent measures was between the 90th and 95th or > or =95th percentile, respectively. When BP values at the first screening were > or =90th percentile but the mean of three subsequent measures was <90th percentile the child was classified as having TH. RESULTS A proportion of 3.4% presented H, 2.7% PH, and 10.4% TH, 20% overweight, and 6% obesity. Weight class and WC were significantly associated to an increased risk of falling into any of the hypertensive categories. In children with TH BP z-scores of the mean of the three subsequent measurements following the first screening were significantly higher than BP z-scores observed in normotensive children (P value <0.001). CONCLUSIONS Weight class and WC are associated with BP. This is observed not only for H but also for PH, and for nonsustained forms of H. Prospective studies are needed to assess whether children with PH and TH will develop sustained H.

Cardiovascular risk assessment in children: role of physical activity, family history and parental smoking on BMI and blood pressure

Objective: Aim of the study was to assess the role of family history, physical activity and parental smoking in the prediction of BMI, SBP and hypertension risk in children. Participants and methods: In a paediatric primary care setting, a sample of 1310 children aged 5–14 years was systematically selected by 48 family paediatricians in northern Italy. BMI, waist circumference-to-height ratio (WtHr), SBP and DBP were measured and the information on the presence of small birth weight for gestational age (SGA) and early adiposity rebound (EAR) was collected. Data concerning exercise, video time, family history for cardiovascular diseases and parental smoking were derived from parental interview. Data were collected using an ’ad hoc designed’ electronic sheet available online. Results: Multiple linear regression showed that the presence of EAR, low exercise (<2 h/week), high video time (>2 h/day TV/videogames/computer) and parental smoking were associated to higher BMI (z-score; P < 0.005). Age, BMI (z-score), WtHr, presence of SGA, low exercise, high video time and family history of cardiovascular diseases were associated to SBP values (P < 0.03). Logistic regression analysis showed that factors related to risk of hypertension and prehypertension were BMI (z-score; odds ratio, OR 2.63; 95% confidence interval, CI 2.12–3.28), WtHr (OR 1.13; 95% CI 1.10–3.28) and low exercise (OR 1.58; 95% CI 1.12–2.24; P <0.01). Conclusion: Our study demonstrates that a simple tool like a cardiovascular multi-item sheet can provide useful information to paediatricians for child health. Physical exercise plays a pivotal role in obesity prevention and protection from hypertension risk.