Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide,in combination with chemotherapy in refractory or relapsed acute leukemia

Overexpression of Bcl-2 is a potential mechanism for chemoresistance in acute leukemia and has been associated with unfavorable clinical outcome. We hypothesized that down-regulation of Bcl-2 would restore chemosensitivity in leukemic cells. To test this hypothesis, we performed a phase 1 study of G3139 (Genasense, Genta, Berkeley Heights, NJ), an 18-mer phosphorothioate Bcl-2 antisense, with fludarabine (FL), cytarabine (ARA-C), and granulocyte colony-stimulating factor (G-CSF) (FLAG) salvage chemotherapy in patients with refractory or relapsed acute leukemia. Twenty patients with refractory or relapsed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were enrolled. G3139 was delivered by continuous infusion on days 1 to 10. FLAG chemotherapy was administered on days 5 to 10. Common side effects of this combination included fever, nausea, emesis, electrolyte imbalance, and fluid retention that were not dose limiting. Plasma pharmacokinetics of G3139 demonstrated steady-state concentration (Css) within 24 hours. Of the 20 patients, 9 (45%) had disease response, 6 (5 AML, 1 ALL) with complete remission (CR) and 3 (2 AML and 1 ALL) with no evidence of disease but failure to recover normal neutrophil and/or platelet counts or to remain in remission for at least 30 days (incomplete remission). Bcl-2 mRNA levels were down-regulated in 9 of the 12 (75%) evaluable patients. This study demonstrates that G3139 can be administered safely with FLAG chemotherapy and down-regulate its target, Bcl-2. The encouraging clinical and laboratory results justify the current plans for a phase 3 study in previously untreated high-risk AML (ie, age at least 60 years).     

Gender-related differences in outcome after ST-segment elevation myocardial infarction treated by primary angioplasty and glycoprotein IIb–IIIa inhibitors: insights from the EGYPT cooperation

Several studies have found that among patients with ST-elevation myocardial infarction (STEMI) treated by thrombolysis, female sex is associated with a worse outcome. The aim of this study was to investigate sex-related differences in clinical and angiographic findings in patients with STEMI treated with primary angioplasty and Gp IIb–IIIa inhibitors. Our population is represented by 1662 patients undergoing primary angioplasty included in the EGYPT database. Myocardial perfusion was evaluated by myocardial blush grade and ST-segment resolution. Follow-up data were collected between 30 days and 1 year after primary angioplasty. Among 1662 patients, 379 were women (22.8%). Female sex was associated with more advanced age, higher prevalence of diabetes, hypertension, more advanced Killip class, longer ischemia time, less often smokers, with higher prevalence of preprocedural recenalization. No difference was observed in terms of postprocedural TIMI flow, myocardial perfusion and distal embolization. Similar findings were observed in terms of enzymatic infarct size and preprocedural ejection fraction. Female gender was associated with higher mortality (6.4% vs. 3.6%, HR = 1.83 [1.12–3.0], P = 0.015). However, the difference disappeared after correction for baseline confounding factors (HR = 1.01 [0.56–1.83], P = 0.98). This study shows that in patients with STEMI treated by primary angioplasty, female gender is associated with higher mortality rate in comparison with men, and this is mainly due to their higher clinical and angiographic risk profiles. In fact, female sex did not emerge as an independent predictor of mortality.     

Management of incidental pituitary tumors

Pituitary incidentalomas are common lesions for which neurosurgical referrals may become progressively more frequent, given the increasing application of neuroimaging. The initial evaluation of a patient with radiographic evidence of an incidentaloma should focus on addressing two questions: (1) is the lesion causing neurological symptoms, and (2) is the lesion hormonally active? The answers to these two questions provide a framework for subsequent clinical management. The initial patient assessment should include a detailed history and physical examination, including the bedside assessment of visual fields. High-quality MRI imaging is essential, and formal visual field testing should be obtained in patients where the lesion abuts or compresses the optic apparatus. The initial biochemical workup is intended to assess potential pituitary hypo- or hyperfunction and should include measurement of serum levels of prolactin, insulin-like growth factor type-1, free thyroxine, testosterone, and an assessment of axis hypothalamic–pituitary–adrenal axis function. Additional testing may include serum thyroid-stimulating hormone, follicle-stimulating hormone, and luteinizing hormone levels. Neurologically-asymptomatic patients without endocrine dysfunction can be managed with observation at regular intervals, including MRI imaging at 6 months and 1 year and then annually for a period of 3 years. Follow-up biochemical assessment is not necessary in the absence of clinical symptoms or radiographic enlargement of the lesion. After 3 years the follow-up interval may be prolonged, although closer follow-up may be indicated for patients with lesions ≥1 cm. Most patients who either present with or who subsequently develop neurologic or endocrinologic symptoms should be considered for surgery as the first-line therapy.     

War-related infected tibial nonunion with bone and soft-tissue loss treated with bone transport using the Ilizarov method

Patients and methods  

This single centre retrospective study reviews the outcomes of 30 war-injured patients with established infected tibial nonunion after sustaining grade IIIB open fractures. Patients were treated by radical bony and soft-tissue resection and bone transport using the Ilizarov bifocal technique, without the use of systemic antibiotics or bone grafting.     

Role of Ki-67 as a prognostic factor in gastrointestinal stromal tumors

AIM:To investigate primarily the prognostic value of Ki-67,as well as other parameters,in gastrointestinal stromal tumors(GISTs).METHODS:Ki-67,c-KIT,platelet-derived growth factor receptor-alpha(PDGFRα),smooth muscle actin(SMA),CD34,S100 were stained for immunohistochemistry which was performed on formalin-fixed,paraffinembeded sections on representative block from each case.Proliferation index counted by Ki-67 antibody was calculated as a number of positive nuclear reaction over 100 cells.Immunoreactivity for c-KIT and PDGFRα was evaluated semiquantitatively(weak,intermediate,strong) and for c-KIT type of reactivity was analyzed(cytoplasmic,membrane and "dot-like" staining).Immunoreactivity for SMA,CD34 and S100 were was evaluated as positive or negative antigen expression.Pathologic parameters investigated in this study included tumor size,cell type(pure spindle,pured epitheloid mixed spindle and epitheloid),mitotic count,hemorrhage,necrosis,mucosal ulceration.Clinical data included age,gender,primary tumor location and spread of disease.χ 2 test and Student’s t-test were used for comparisons of baseline characteristics.The Cox’s proportional hazard model was used for univariable and multivariable analyses.Survival rates were calculated by Kaplan-Meier method and statistical significance was determined by the log-rank test.RESULTS:According to the stage of disease,there were 36 patients with localized disease,29 patients with initially localized disease but with its recurrence in the period of follow up,and finally,35 patients had metastatic disease from the very beginning of disease.Tumor originated most commonly in the stomach(41%),small intestine was the second most common location(36%).The mean size of primary tumors was 6.5 cm.The mean duration of follow-up was 60 mo.Multiple parameters were analyzed for their effect on overall survival,but no one reached statistical significance(P = 0.06).Analysis of time to progression/relapse in initially localized disease(univariate analysis),tumor size,mitotic     

Pharmacokinetics of levobupivacaine 0.5% after superficial or combined (deep and superficial) cervical plexus block in patients undergoing minimally invasive parathyroidectomy

STUDY OBJECTIVE: To evaluate the pharmacokinetic profile of 0.35 mL/kg of 0.5% levobupivacaine during superficial and combined (deep and superficial) cervical plexus block (CPB) in patients undergoing minimally invasive parathyroidectomy. DESIGN: Prospective randomized study. SETTING: Operating theater of a university hospital. PATIENTS: 12 ASA physical status II and III patients (11 women and 1 man), scheduled for minimally invasive parathyroidectomy. INTERVENTIONS: Seven and 5 patients were randomly assigned to receive either superficial or combined CPB, respectively. The superficial CPB was performed with an injection of 0.35 mL/kg of 0.5% levobupivacaine subcutaneously along the posterior border of the sternocleidomastoid muscle and deeper on its medial surface. The combined CPB was initiated by the deep block at the C3 level vertebra by injecting 0.2 mL/kg of 0.5% levobupivacaine, followed by the superficial block with an injection of the remaining 0.15 mL/kg. After completion of the block, venous blood was sampled at the intervals of 5, 10, 15, 20, 30, 45, and 60 minutes. MEASUREMENTS AND MAIN RESULTS: Venous plasma concentrations were measured using gas chromatography-mass spectroscopy. Mean +/- SD of maximal concentrations of levobupivacaine was 0.58 +/- 0.41 mg/L in group superficial and 0.52 +/- 0.28 mg/L in group combined (P = 0.71). The median (range) time required to reach the maximal concentrations was 30 minutes (20-30 min) in group superficial and 20 minutes (15-30 min) in group combined (P = 0.45). The areas under the drug concentration/time curve (AUC(10-60)) were also similar in both groups. No signs of central nervous system or cardiovascular toxicity or other untoward events were observed in any patient. CONCLUSION: With the given dose regimen, levobupivacaine plasma concentrations were within safe ranges.     

Detection of feigned cognitive dysfunction using special malinger tests: a simulation study in naïve and coached malingerers

The aim of the present study was to compare the accuracy of the Amsterdam Short Term Memory (ASTM) test with that of the Structured Inventory of the Malingered Symptomatology (SIMS) in detecting feigning of cognitive dysfunction in na?ve and coached participants. Ninety undergraduate students were administered the ASTM and the SIMS and asked to respond honestly (controls; n = 30), or instructed to malinger cognitive dysfunction due to head injury. Before the both instruments were administered, na?ve malingerers received no further information (n = 30), whereas coached malingerers were given some information about brain injury and a warning not to exaggerate symptoms (n = 30). Both tests correctly classified 90% of the na?ve malingerers. The ASTM detected 70% of the coached malingerers, whereas the SIMS continued to detect 90% of them. The findings suggest that coaching undermines the diagnostic accuracy of the ASTM, but does not seem to influence the accuracy of the SIMS.