Early prediction of success or failure of treatment with second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukemia

Background

Second-generation tyrosine kinase inhibitors induce cytogenetic responses in approximately 50% of patients with chronic myeloid leukemia in chronic phase in whom imatinib treatment has failed. However, it has not yet been established which of the patients in whom imatinib treatment fails are likely to benefit from therapy with second-generation tyrosine kinase inhibitors.

Design and Methods

We analyzed a cohort of 80 patients with chronic myeloid leukemia who were resistant to imatinib and who were treated with dasatinib or nilotinib while still in first chronic phase. We devised a scoring system to predict the probability of these patients achieving complete cytogenetic response when treated with second-generation tyrosine kinase inhibitors.

Results

The system was based on three factors: cytogenetic response to imatinib, Sokal score and recurrent neutropenia during imatinib treatment. We validated the score in an independent group of 28 Scottish patients. We also studied the relationship between cytogenetic responses at 3, 6 and 12 months and subsequent outcome. We classified the 80 patients into three categories, those with good risk (n=24), intermediate risk (n=27) and poor risk (n=29) with 2.5-year cumulative incidences of complete cytogenetic response of 100%, 52.2% and 13.8%, respectively (P<0.0001). Moreover, patients who had less than 95% Philadelphia chromosome-positive metaphases at 3 months, those with 35% or less Philadelphia chromosome-positive metaphases at 6 months and patients in complete cytogenetic response at 12 months all had significantly better outcomes than patients with lesser degrees of cytogenetic response.

Conclusions

Factors measurable before starting treatment can accurately predict response to second-generation tyrosine kinase inhibitors. Cytogenetic responses at 3, 6 and 12 months may influence the decision to continue treatment with second-generation tyrosine kinase inhibitors.     

High production of IL-18 by dendritic cells induced by sera from patients with primary antibody deficiency

Predominantly antibody deficiencies are a category of primary immunodeficiency diseases, which consist of several rare disorders such as common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). We evaluated the effects of CVID and XLA patients' sera as a source of microenviromental factors on maturation and function of monocyte-derived DCs. Blood was collected from 10 CVID and 5 XLA patients before immunoglobulin replacement therapy and also from 8 healthy volunteers in order to obtain necessary sera for this study. Monocyte derived DCs were generated from blood cells obtained from healthy volunteers in the presence of GM-CSF, IL-4 and 10% serum concentrations from cases and controls. Immature DCs were incubated with monocyte conditioned medium (MCM) and TNF- in order to generate mature DCs. Interleukin 18 (IL-18) production by CD40L-activated mature DCs was measured after 24 hours of culture in vitro.IL-18 production by DCs generated in the presence of CVID and XLA patients' sera were 6.75+/-2.59 and 7.08+/-1.75 ng/ml, respectively, which were significantly higher than normal serum conditioned DCs (3.55+/-0.68) ng/ml. These results suggest that the sera of patients with predominantly antibody deficiencies may contain soluble factor(s) that can induce a significant increase in IL-18 production by DCs.     

Slow atrioventricular nodal reentrant arrhythmias: clinical recognition, electrophysiological characteristics, and response to radiofrequency ablation

Background: Atrioventricular nodal reentrant tachycardia (AVNRT) is a common form of supraventricular tachycardia (SVT). Rarely, patients may present with an unusual form of atrioventricular nodal reentrant arrhythmia (AVNRA) with a cycle length greater than 600 ms. We describe the clinical presentation, electrophysiology characteristics, and response to radiofrequency ablation in a group of patients with AVNRA.
Methods and Results: Six patients with slow documented sustained supraventricular arrhythmias at rates <100 bpm underwent electrophysiology study. Baseline clinical and electrophysiologic characteristics were: mean age 77 ± 5 years; left ventricular ejection fraction 51 ± 10%; hypertension 66%; diabetes mellitus 33%; coronary artery disease 33%; sinus cycle length 874 ± 110 ms; PR 261 ± 54 ms; atrial to His (AH) 181 ± 49 ms. AVNRA was diagnosed based on previously described criteria for AVNRT. Mean tachycardia cycle length (TCL) during AVNRA was 668 ± 74 ms. The AH and His to atrial (HA) intervals during the AVNRA was 434 ± 50 and 234 ± 81 ms, respectively. Two patients had slow–fast AVNRA while the others had slow–slow AVNRA. Most common symptoms reported during AVNRA were shortness of breath, fullness in the throat, chest tightness, dizziness, near-syncope, and syncope. Radiofrequency catheter ablation (RFCA) of the slow pathway was performed successfully in five of six patients. Post-ablation AV nodal Wenckebach occurred at 666 ± 49 ms compared with 521 ± 91 ms at baseline.
Conclusion: AVNRA may occur at rates less than 100 bpm in the elderly and may be misdiagnosed as junctional rhythm. Slow AVNRA can cause significant symptoms. Slow pathway ablation can be successfully performed in AVNRA.     

Cocaine withdrawal symptoms identify "Type B" cocaine-dependent patients

Recent studies of substance dependence typologies briefly show that multivariate systems originally developed for identifying subtypes of alcoholics, such as Babor's Type A and B system, may also be valid in abusers of other substances, such as cocaine. Type B patients are characterized by an earlier onset of addiction and more severe symptoms of their addiction, psychopathology, and impulsivity. The Type B classification has also been associated with deficits in serotonergic function. We have found that patients who exhibit more severe cocaine withdrawal symptoms, as measured by scores on the Cocaine Selective Severity Assessment (CSSA), have poor treatment outcome and share many characteristics with "Type B" patients. In this paper, we review baseline characteristics of cocaine-dependent patients from several recently completed outpatient cocaine dependence treatment trials to assess the association of cocaine withdrawal symptom severity and the Type B profile. Identifying subtypes of cocaine-dependent patients may improve our ability to treat cocaine dependence by targeting treatments for specific subtypes of patients. We examined the ability of the CSSA scores to capture Type B characteristics in cocaine dependence by analyzing a series of cocaine medication trials that included 255 cocaine-dependent subjects. High CSSA scores at baseline were associated with a history of violent behavior, a family history of substance abuse, antisocial personality disorder, higher addiction severity, and co-morbid psychiatric diseases. Patients with high CSSA scores are also more likely to meet criteria for Type B (Type II) cocaine dependence. Identifying Type B cocaine-dependent patients may help to develop targeted psychosocial or pharmacological treatments for these difficult-to-treat patients.     

The effects of cured dentin bonding agents on secretion of pro-inflammatory cytokines, IL-1beta and TNF-alpha, by human monocytes

Dentin Bonding Agents (DBA) have been used as root-end filling materials. Present study evaluated the effects of polymerized DBA on secretion of pro-inflammatory cytokines by normal human monocytes. In this study, monocytes were directly isolated from human peripheral blood, and exposed to cured Scotch Bond 1 (single bond) and Prime and Bond for 36 and 72 hours. Secretion of IL-1beta and TNF-alpha in the presence of lipopolysaccaharide was evaluated in supernatants of monocyte culture.DBAs significantly caused reduction of cytokine production by human monocytes after 36 and 72 hours. Prime and bond exposure caused more prominent decrease in TNF-alpha production after 72 hours. We conclude that DBA in polymerized form can alter normal function of human monocytes.     

Current status of mechanical circulatory support for treatment of advanced end-stage heart failure: successes,shortcomings and needs

Introduction: Heart failure (HF) remains a major global burden in terms of morbidity and mortality. Despite advances in pharmacological and resynchronization device therapy, many patients worsen to end-stage HF. Although the gold-standard treatment for such patients is heart transplantation, there will always be a shortage of donor hearts.

Areas covered: A left ventricular assist device (LVAD) is a valuable option for these patients as a bridge measure (to recovery, to candidacy for transplant, or to transplant itself) or as destination therapy. This review describes the current indications for and complications of the most commonly implanted LVADs. In addition, we review the potential and promising new LVADs, including the HeartMate 3, MVAD, and other LVADs. Studies investigating each were identified through a combination of online database and direct extraction of studies cited in previously identified articles.

Expert commentary: The goal of LVADs has been to fill the gap between patients with end-stage HF who would likely not benefit from heart transplantation and those who could benefit from a donor heart. As of now, the use of LVADs has been limited to patients with end-stage HF, but next-generation LVAD therapy may improve both survival and quality of life in less sick patients.     

Site localization and characterization of pain during radiofrequency ablation of the pulmonary veins

BACKGROUND: Characteristics of radiofrequency (RF) lesions producing pain with an 8-mm catheter during pulmonary vein (PV) ablation have not been prospectively studied. METHODS: We studied 46 (30 men, age 56 +/- 10 years) patients with AF who underwent RF ablation of PVs. PV isolation was achieved by using an 8F, 8-mm Biosense ablation catheter (Biosense Webster, Diamond Bar, CA, USA) guided by intracardiac echocardiography (ICE). An electroanatomic map was used to document the location of all RF lesions and the time; PV location and maximum temperature of every lesion were recorded. Location of the esophagus was determined by magnetic resonance imaging prior to the procedure and by both ICE and barium swallows during procedure. RESULT: A total of 1,448 (33 +/- 12) RF lesions were delivered to 180 veins. Thirty-nine patients (85%) had at least one lesion associated with pain (mean: 8 +/- 5 lesions) during ablation. The RF generator setting during lesions resulting in pain sensation was 48.6 +/- 7.0 Watts and 51.5 +/- 2.9 degrees C. Maximum temperature attained at the time of pain sensation was 45.7 +/- 4.2 degrees C. By logistic regression analysis the left superior PV (OR 1.54, CI 1.06-2.24, LS vs RI, P < 0.05) and left inferior PV (OR 2.74, CI 1.79-4.19, LI vs RI, P < 0.001) location were both positively correlated with the production of pain. The location of lesions associated with pain was not near the esophagus during any of the pain-producing lesions. CONCLUSION: Pain sensation is relatively common during RF ablation of PVs. There was no correlation between pain and the location of esophagus. Pain was more common during RF ablation of left inferior and left superior PVs.     

Effect of Helicobacter pylori eradication on glycaemia control in patients with type 2 diabetes mellitus and comparison of two therapeutic regimens

Background and study aimsThe eradication rate of Helicobacter pylori (H. pylori) has been reported as being lower in patients with type 2 diabetes mellitus (DM) than in those without DM. The aim of the study was to assess the efficacy of the two H. pylori eradication regimens in patients without and with type 2 DM and to study the effect of H. pylori treatment on glycaemia control.Patients and MethodsA total of 93 consecutive type 2 DM (non-insulin users) and 98 non-diabetic age- and sex-matched patients were enrolled. Patients were randomly assigned to one of the two treatment protocols all given twice daily: (a) a 14-day quadruple therapy comprising of omeprazole 20 mg, metronidazole 500 mg, amoxicillin 1 g and bismuth subcitrate 240 mg (OMAB) and (b) a 14-day triple regimen comprising of omeprazole 20 mg plus clarithromycin 500 mg and amoxicillin 1 g (OCA). Cure was defined as a negative ¹³C-urea breath test at least 6 weeks after treatment.ResultsThe H. pylori eradication rate with the OCA regimen was 63% in patients with type 2 DM (non-insulin users) and 87.7% in the control group (p = 0.017). The H. pylori eradication rate with the OMAB regimen was 38.2% in patients with type 2 DM and 55.1% in the control group (p < 0.001). Mean decrease of fasting plasma glucose and HbA1c level shows no statistically significant difference after H. pylori eradication.ConclusionThis study suggests that the eradication rate of H. pylori with OCA or OMAB treatment is lower in patients with type 2 diabetes than in non-diabetics and H. pylori treatment in patients with type 2 DM has no role in the control of the glycaemia. The triple therapy (OCA) is superior to the quadruple protocol (OMAB) in H. pylori eradication of both DM and non-DM cases.     

Canal of Nuck incarcerated ovarian hernia with strangulation,a case report

Canal of Nuck ovarian hernia is a rare medical entity which presents as labia majora swelling in female babies. The serious complications of strangulation and torsion may happen which requires urgent surgical intervention. Here an incarcerated labium majus ovarian hernia with strangulation is presented in a six-month-old female baby. The diagnosis was made by ultrasonography and then urgent surgery was performed.Key words: Canal of Nuck, Labia majus, Ovarian hernia, Incarceration, Strangulation, Ultrasonography