Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO-2001-03.     

In Vitro Confirmation of Artemisinin Resistance in Plasmodium falciparum from Patient Isolates,Southern Rwanda, 2019

Artemisinin resistance in Plasmodium falciparum is conferred by mutations in the kelch 13 (K13) gene. In Rwanda, K13 mutations have increased over the past decade, including mutations associated with delayed parasite clearance. We document artemisinin resistance in P. falciparum patient isolates from Rwanda carrying K13 R561H, A675V, and C469F mutations.     

Non-obstetrical acute abdomen during pregnancy

Acute abdomen in pregnancy remains one of the most challenging diagnostic and therapeutic dilemmas today. The incidence of acute abdomen during pregnancy is 1 in 500-635 pregnancies. Despite advancements in medical technology, preoperative diagnosis of acute abdominal conditions is still inaccurate. Laboratory parameters are not specific and often altered as a physiologic consequence of pregnancy. Use of laparoscopic procedures as diagnostic tools makes diagnosis of such conditions earlier, more accurate, and safer. Appendicitis is the most common cause of the acute abdomen during pregnancy, occurring with a usual frequency of 1 in 500-2000 pregnancies, which amounts to 25% of operative indications for non-obstetric surgery during pregnancy. Surgical treatment is indicated in most cases, as in nonpregnant women. Laparoscopic procedures in the treatment of acute abdomen in pregnancy proved safe and accurate, and in selected groups of patients are becoming the procedures of choice with a perspective for the widening of such indications with more frequent use and subsequent optimal results. Despite these advances, laparotomy still remains the procedure of choice in complicated and uncertain cases.     

Incremental prognostic value of coronary computed tomographic angiography over coronary artery calcium score for risk prediction of major adverse cardiac events in asymptomatic diabetic individuals

Background

Coronary artery disease (CAD) diagnosis by coronary computed tomographic angiography (CCTA) is useful for identification of symptomatic diabetic individuals at heightened risk for death. Whether CCTA-detected CAD enables improved risk assessment of asymptomatic diabetic individuals beyond clinical risk factors and coronary artery calcium scoring (CACS) remains unexplored.

Methods

From a prospective 12-center international registry of 27,125 individuals undergoing CCTA, we identified 400 asymptomatic diabetic individuals without known CAD. Coronary stenosis by CCTA was graded as 0%, 1–49%, 50–69%, and ≥70%. CAD was judged on a per-patient, per-vessel and per-segment basis as maximal stenosis severity, number of vessels with ≥50% stenosis, and coronary segments weighted for stenosis severity (segment stenosis score), respectively. We assessed major adverse cardiovascular events (MACE) – inclusive of mortality, nonfatal myocardial infarction (MI), and late target vessel revascularization ≥90 days (REV) – and evaluated the incremental utility of CCTA for risk prediction, discrimination and reclassification.

Results

Mean age was 60.4 ± 9.9 years; 65.0% were male. At a mean follow-up 2.4 ± 1.1 years, 33 MACE occurred (13 deaths, 8 MI, 12 REV) [8.25%; annualized rate 3.4%]. By univariate analysis, per-patient maximal stenosis [hazards ratio (HR) 2.24 per stenosis grade, 95% confidence interval (CI) 1.61–3.10, p < 0.001], increasing numbers of obstructive vessels (HR 2.30 per vessel, 95% CI 1.75–3.03, p < 0.001) and segment stenosis score (HR 1.14 per segment, 95% CI 1.09–1.19, p < 0.001) were associated with increased MACE. After adjustment for CAD risk factors and CACS, maximal stenosis (HR 1.80 per grade, 95% CI 1.18–2.75, p = 0.006), number of obstructive vessels (HR 1.85 per vessel, 95% CI 1.29–2.65, p < 0.001) and segment stenosis score (HR 1.11 per segment, 95% CI 1.05–1.18, p < 0.001) were associated with increased risk of MACE. Beyond age, gender and CACS (C-index 0.64), CCTA improved discrimination by maximal stenosis, number of obstructive vessels and segment stenosis score (C-index 0.77, 0.77 and 0.78, respectively). Similarly, CCTA findings improved risk reclassification by per-patient maximal stenosis [integrated discrimination improvement (IDI) index 0.03, p = 0.03] and number of obstructive vessels (IDI index 0.06, p = 0.002), and by trend for segment stenosis score (IDI 0.03, p = 0.06).

Conclusion

For asymptomatic diabetic individuals, CCTA measures of CAD severity confer incremental risk prediction, discrimination and reclassification on a per-patient, per-vessel and per-segment basis.