The validity of a daytime ambulatory blood pressure to diagnose masked hypertension.

Masked hypertension (MH) is traditionally diagnosed with 24-hour ambulatory blood pressure monitoring (24-ABPM). This is relatively costly and could cause discomfort during the night. We studied the validity of daytime ABP (DT-ABPM) in young National Guard soldiers and determined the prevalence in comparison to the standard 24-ABPM. A prospective study of 196 soldiers aged 21-50 years, without a history of hypertension or antihypertensive medication use. Each participant was fitted with a 12h-ABPM. Patients were diagnosed with MH if the office blood pressure (OBP) was <140/90 mmHg and the average DT-ABPM was ≥135/85 mmHg. By pairing the average OBP with the 12 h-ABPM, the prevalence of MH was estimated as 18/196 (9.2%), the SBP MH (systolic blood pressure) of 8.2% and the DPB MH (diastolic blood pressure) of 3.1%.  When we compared the daytime prevalence with the 24 h-ABPM, and the average OBP, the prevalence of MH was 29/196 (14.8%). No statistically significant difference was noted (kappa=0.74; 95% CI: 0.59 to 0.88). We conclude that DT-ABPM is a good method and convenient to detect MH, with no statistically significant difference when compared to the 24 h-ABPM. The prevalence of MH in young healthy soldiers was unexpectedly high.

FLAG/FLAG-IDA regimen for children with relapsed/refractory acute leukemia in the era of targeted novel therapies.

BACKGROUND: Outcomes of relapsed/refractory childhood acute leukemia remain poor. We analyzed the safety/efficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, with/without idarubicin (FLAG ± IDA) as salvage therapy compared with recent published results of novel therapies. METHODS: This retrospective study included children aged 1 to 15 years with relapsed/refractory acute leukemia who received FLAG ± IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded. RESULT: Fifty patients were identified: 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG ± IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG ± IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% ± 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p = 0.001). CONCLUSION: Despite a 68% complete remission rate using FLAG ± IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens.

Identifying Prognostic Factors That Influence Outcome of Childhood Acute Myeloid Leukemia in First Relapse in Saudi Arabia: Results of the Multicenter SAPHOS Study.

BACKGROUND: The outcome of childhood acute myeloid leukemia (AML) in first relapse (rAML) remains poor. Reported overall survival (OS) rates vary between high-income developed countries and those with fewer resources. The OS of rAML in high-income developing countries (HIDCs) has not been reported. PATIENTS AND MATERIALS: A multicenter study was performed in an HIDC. The outcome of patients with relapsed non-M3/non-Down syndrome AML was evaluated. Three-year OS was computed using the Kaplan-Meier method, and predictors of OS were analyzed using a Cox proportional hazards model. RESULTS: A total of 88 patients with non-M3/non-Down syndrome AML diagnosed between January 2005 and December 2012 with a first relapse were identified. Their 3-year OS was 22.6% ± 5.4%. Patients with inv(16) and t(8;21) had an OS of 75.0% ± 21.7% and 36.0% ± 16.1%, respectively. Worse outcomes were associated with "other intermediate" and 11q23 rearrangement AML (OS of 9.4% ± 8.7% and 10.7% ± 9.6%, respectively). Patients experiencing time to relapse (TTR) less than 1 year had shorter OS than those with a longer TTR (14.6% ± 5.4% vs. 41.1% ± 11.5%; P = .006). The outcome of patients after stem cell transplantation (SCT) in second complete remission (CR2) was superior compared with no SCT (50.9% ± 11.2% vs. 7.7% ± 4.6%; P = .001). TTR, risk group, CR2, and SCT in CR2 were the most significant predictors for survival. CONCLUSIONS: rAML remains a clinical challenge. Genetic variability in outcomes was observed. A majority of patients with inv(16) were successfully salvaged post-relapse, whereas patients with 11q23 rearrangement had a poor prognosis. Only one-third of those with t(8;21) rAML survived. Better access to SCT in HIDCs is needed.

Prevalence of hereditary cancer susceptibility syndromes in children with cancer in a highly consanguineous population.

BACKGROUND & AIM: Hereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population. METHODS: This multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines. RESULTS: Seven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023). CONCLUSION: Four out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations.

Challenges in the management of childhood low-grade glioma in a developing country.

BACKGROUND: Treatment modality impacts outcome of childhood low-grade glioma (LGG). Optimizing management in developing countries can be challenging. This study evaluates the clinical characteristics, treatment, and factors influencing outcome of childhood LGG in Saudi Arabia. PATIENTS AND METHODS: This study retrospectively evaluated 59 children consecutively diagnosed with LGG between January 2001 and June 2016. RESULTS: Median age at diagnosis was 6.0 years. Pilocytic astrocytoma represented 64.9% of cases. The anatomic site was cerebellar in 23.7%, cerebral in 18.6%, hypothalamic-optic pathway in 33.9%, and midline in 23.7%. The 5-year overall survival (OS) and progression-free survival (PFS) were 90.6 ± 4.7 and 54.3 ± 8.4%, respectively. Initial treatment was observation in 28.8%, surgery alone in 35.6%, chemotherapy in 13.6%, radiotherapy in 5.1%, and combined in 16.9% of cases. The corresponding 5-year PFS was 56.3 ± 15.6, 53.3 ± 14.0, 22.9 ± 19.7, 33.3 ± 27.2, and 88.9 ± 10.5%, respectively (p = 0.006). Among the 61% who had surgical intervention (either alone or in combination with other therapies), 22% achieved complete resection with 5-year radiation/progression-free survival (RPFS) of 87.5 ± 11.7% compared to 27.6 ± 10.8% for subtotal resection/biopsy and 62.2 ± 17.0% for no surgery (p = 0.013). Adjuvant therapy for residual tumor improved survival with 5-year PFS of 66.7 ± 19.2% for chemotherapy and 100% for radiotherapy compared to 12.5 ± 11.4% for observation (p = 0.033). CONCLUSIONS: We identified variability in the outcomes of LGG. Fewer surgeries with lower rates of total resection were noted, compared to reports from international cooperative groups. The extent of resection was predictive of RPFS. Adjuvant therapy improved the outcome of patients with residual disease, resulting in PFS rates comparable to international data.

Prophylactic use of carvedilol to prevent ventricular dysfunction in patients with cancer treated with doxorubicin.

OBJECTIVE: Deterioration in ventricular function is often observed in patients treated with anthracyclines for cancer. There is a paucity of evidence on interventions that might provide cardio-protection. We investigated whether prophylactic use of carvedilol can prevent doxorubicin-induced cardiotoxicity and whether any observed effect is dose related. METHODS: A prospective, randomized, double-blind study in patients treated with doxorubicin, comparing placebo (n = 38) with different doses of carvedilol [6.25 mg/day (n = 41), 12.5 mg/day (n = 38) or 25 mg/day (n = 37)]. The primary endpoint was the measured change in left ventricular ejection fraction (LVEF) from baseline to 6 months. RESULTS: LVEF decreased from 62 ±â€¯5% at baseline to 58 ±â€¯7% at 6-months (p = 0.002) in patients assigned to placebo but no statistically significant changes were observed in any of the 3 carvedilol groups. At 6 months, only one of 116 patients (1%) assigned to carvedilol had an LVEF < 50% compared to four of the 38 assigned to placebo (11%), (p = 0.013). No significant differences were noted between carvedilol and placebo in terms of the development of diastolic dysfunction, clinically overt heart failure or death. CONCLUSIONS: Carvedilol might prevent deterioration in LVEF in cancer patients treated with doxorubicin. This effect may not be dose related within the studied range.

Clinical characteristics and outcome of childhood acute promyelocitic leukemia (APL) in Saudi Arabia: a multicenter SAPHOS leukemia group study.

BACKGROUND: Acute promyelocytic leukemia (APL) is a rare form of acute myelogenous leukemia (AML). Survival rates exceed 80% in developed countries. Successful treatments rely on all-trans retinoic acid with anthracycline-based chemotherapy. Availability of modern care and public knowledge play important roles in pediatric APL survival. METHOD: A cytogenetic diagnosis of APL was confirmed in 30 (14.5%) out of 207 children consecutively diagnosed with de novo AML between January 2005 and December 2012 at nine cancer care centers in Saudi Arabia. Patients were treated based on the standard protocol used by the center following the PETHEMA or the C9710 treatment protocols. We modeled 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) vs. treatment and potential covariates of age at diagnosis, involvement of central nervous system (CNS), and white blood cell (WBC) levels. RESULTS: The median age was 10.4 years with a male:female ratio of 1.9. WBC was 10 × 109/l or greater in 57% and CNS involvement was confirmed in 13%. OS, EFS, and CIR were 74 ± 12%, 55 ± 19%, and, 36 ± 17% respectively. No significant difference was found by treatment protocol. WBC levels were significantly prognostic for all negative events, but treatment with C9710 significantly ameliorated negative WBC effects. Overall outcomes were comparable to those reported in developed countries. CONCLUSIONS: Access to modern care is likely to be a critical factor in successful and comparable outcomes of childhood APL across the globe. In the present study, utilizing a cytarabine-containing protocol improved outcome of high-risk pediatric patients with APL.

Treatment results in children with myeloid leukemia of Down syndrome in Saudi Arabia: A multicenter SAPHOS leukemia group study.

Despite the high incidence of Down syndrome (DS) in Arab countires, the incidence and outcomes of myeloid leukemia of DS (ML-DS) have not been studied. We evaluated 206 pediatric acute myeloid leukemia (AML) patients diagnosed between 2005 and 2012 and identified 31 (15%) ML-DS. The incidence of ML-DS was 48 per 100,000 compared to 0.6 per 100,000 for AML in non-DS children. Thus, patients with DS had 80-fold increased risk of ML-DS compared to AML in non-DS children. The median age at diagnosis was 1.8 years, male/female ratio was 1.2, majority (84%) of patients had FAB-M7 subtype, and the cytogenetic abnormalities were normal karyotype (constitutional trisomy 21) in 48%, additional trisomy in 23%, and other aberrations in 29%. Complete remission, cumulative incidences of relapse (CIR), toxic-death, and 5-year event-free survival (EFS) rates were 96.8%, 19.4%, 13.1%, and 67.7±8.4%; respectively. In the present study, multivariate analysis revealed favorable outcome (5-year EFS 86.7±8.8%) for patients with normal karyotype. The incidence and clinical characteristics of ML-DS in Saudi patients were comparable to other reports. However, there is a need to optimize risk stratification and treatment intensity to reduce CIR and toxic death rates to further improve outcomes of patients with ML-DS.

Clinical characteristics and outcome of childhood de novo acute myeloid leukemia in Saudi Arabia: A multicenter SAPHOS leukemia group study.

Geographic variation and ethnicity have been implicated to influence the outcome of pediatric acute myeloid leukemia (AML). Furthermore, survival outcomes from developing countries are reported to be inferior to developed nations. We hypothesized that risk- and response-based outcome in high-income resource-rich developing countries would be comparable to developed nations as access to care and supportive measures would be similar. A total of 193 children diagnosed with de novo AML between January 2005 and December 2012 were identified, of those 175 were evaluable for outcome. Patients were stratified into low-risk (LR), intermediate-risk (IR), or high-risk (HR) groups. The complete remission (CR), early death, and induction failure rates were: 85.7%, 2.3%, and 12%; respectively. The 5-year cumulative incidences of relapse (CIR) and non-relapse mortality (NRM) were 43.1% and 9.8% respectively; overall survival (OS) was 58.8±4% and event-free survival (EFS) 40.9±4.1%. The 5-year OS for LR, IR, and HR groups were 72.0±6.9%, 59.8±6.2%, and 45.1±7.4%; respectively (p=0.003); and EFS 50.5±8.0%, 46.3±6.4%, and 23.3±6.4%; respectively (p=0.001). This study demonstrated comparable outcomes to those reported from developed countries. This suggests that utilization of risk- and response-based protocols in developing countries can overcome ethnic and geographic variation, if access to care and supportive measures were similar.

Comparison of clinical trial versus non-clinical trial treatment outcomes of childhood acute lymphoblastic leukemia using comparable regimens.

OBJECTIVES: Treatment regimens tested in major clinical trials, conducted by cooperative groups, are often adapted as standard of care by cancer centers with the hope to replicate the treatment outcomes reported in these landmark studies. It is therefore postulated that applying clinical trial regimens in a non-clinical trial setting yield similar outcomes. The aim of the present study was to explore this hypothesis in the context of childhood acute lymphoblastic leukemia (ALL) in our institution. METHODS: We retrospectively evaluated 224 consecutive pediatric ALL cases treated between January 2001 and December 2007. Standard-risk (SR) patients were treated on CCG-1991 (regimen OD) while high-risk (HR) patients were treated on CCG-1961 (regimen D). Results were compared with those of the equivalent regimen in the original clinical trials. Statistical analysis was carried using chi-square or Fisher's exact test, Kaplan-Meier and log-rank tests. RESULTS: Comparison of treatment outcomes revealed that SR patients had inferior 5-year overall survival (OS) of (89.0 ± 2.9 vs. 96.0% ± 0.9%); event-free survival of (82.3 ± 3.5 vs. 88.7% ± 1.4%); and relapse rate of (15.8 vs. 9.3% (P = 0.034)) compared to patients treated in the clinical trial. However, no statistically significant difference in treatment outcomes was observed between HR patients. CONCLUSIONS: Despite using comparable regimens, suboptimal outcomes were noted in SR patients implying that similar treatments do not necessarily yield similar outcomes. This underscores the need to evaluate outcomes of adapted regimens to identify areas that need further improvement in centers not enrolling patients on prospective collaborative clinical trials.

Identifying causes of variability in outcomes in children with acute lymphoblastic leukemia treated in a resource-rich developing country.

BACKGROUND: The outcome of children with acute lymphoblastic leukemia (ALL) in developing countries is less favorable than in developed countries, primarily due to resource constraints. However, it is unknown whether the therapeutic results differ. Thus, we hypothesized that outcomes in resource-rich developing countries would be similar to those in industrialized regions. PROCEDURE: We performed a retrospective analysis of 224 consecutive children with ALL, who were treated according to the Children's Cancer Group (CCG) protocols between January 2001 and December 2007. High-risk (HR) and standard-risk (SR) patients were treated with modified CCG-1961 and CCG-1991 protocols, respectively. Modifications included substitution of dexamethasone for prednisone in HR patients and addition of two intrathecal methotrexate treatments for CNS2 patients during induction. All patients received double delayed intensification with two interim maintenance phases. RESULTS: Five-year overall survival (OS), event-free survival (EFS) and disease-free survival (DFS) were 84.7 ± 2.4%, 77.0 ± 2.9%, and 81.4 ± 2.7%, respectively. Remission was achieved in 98.1% of the patients. Induction failure and relapse rates were 1.9% and 15.1%, respectively. Death as the first event occurred in 6.4% of cases, of which 2.7% and 3.7% involved deaths in induction and remission, respectively. Interestingly, a significant reduction in induction deaths was observed over time. CONCLUSIONS: Despite the encouraging results observed in the present study, our patients displayed significantly lower survival outcomes compared to subjects treated in major clinical trials conducted by leading leukemia cooperative groups. Furthermore, this work underscores the need for targeted interventions to reduce death as the first event in developing regions.

Response to imatinib therapy in adult patients with chronic myeloid leukemia in Saudi population: a single-center study.

No study has been published yet in the Arab world regarding response and outcome of imatinib in patients with chronic myeloid leukemia (CML). This study evaluated a total of 122 patients with CML treated with imatinib between 2001 and 2012. Survival, hematologic, cytogenetic and molecular responses and adverse events were assessed. The 5-year overall survival (OS), event free survival (EFS) and progression-free survival (PFS) rates were: 95.4 ± 2.3%, 81.4 ± 4.6% and 90.8 ± 3.2%, respectively. Significant differences in OS (p = 0.001), EFS (p = 0.001) and PFS (p = 0.001) were noted when patients were stratified by cytogenetic response. Survival by Sokal risk groups was not significant (p = 0.293). Complete hematologic response was achieved in 94 patients (93.1%), cytogenetic response in 84 (83.2%), major molecular response in 62 (61.4%) and complete molecular response in 34 (33.7%). This article presents the first evidence on the effectiveness of imatinib in patients with CML from Saudi Arabia and highlights similarities and differences in response patterns in published studies.

Improved outcome in pediatric AML due to augmented supportive care.

We conducted a retrospective review of patients treated following the MRC acute myeloid leukemia (AML) 10 protocol to determine if supportive care measures sequentially introduced by our institution led to a significant improvement in treatment-related mortality (TRM) in newly diagnosed pediatric patients with AML. Patients were partitioned based on supportive care measures into era1, from 1996 to 2002 (n = 20), and era2, from 2003 to 2011 (n = 40). The introduced supportive care measures reduced the TRM from 23.4% in era1 to 2.5% in era2 (P = 0.034). The results demonstrate that supportive care is a significant factor in determining the outcome of childhood AML.