Bone marrow minimal disseminated disease (MDD) and minimal residual disease (MRD) in childhood T‐cell lymphoblastic lymphoma stage III,detected by flow cytometry (FC) and real‐time quantitative polymerase chain reaction (RQ‐PCR)

Background

Despite overlapping features of T‐cell lymphoblastic lymphoma (T‐LLy) and T‐cell acute lymphoblastic leukemia (T‐ALL), which respond favorably to T‐ALL treatment, clinical and biological differences exist. We retrospectively assessed the prevalence of submicroscopic bone marrow (BM) minimal disseminated disease (MDD) at diagnosis and the early response to treatment (minimal residual disease—MRD) and their prognostic significance in 17 children with stage III T‐LLy treated according to Berlin‐Frankfurt‐Munster (BFM) non‐Hodgkin lymphoma protocols.

Procedure

Four‐color flow cytometry (FC) was used for lymphoma associated immunophenotype and real‐time quantitative polymerase chain reaction (RQ‐PCR) for T‐cell receptor (TCR β/δ/γ) gene rearrangements with at least 0.01% sensitivity.

Results

Two markers per patient were identified in all cases using FC and in 80% using RQ‐PCR. BM MDD at diagnosis of ≥0.01% was detected by FC and RQ‐PCR in 88% and 80% of patients, respectively, and by at least one of the methods in all patients. A significant correlation was achieved between the methods by Pearson correlation analysis (P = 0.004). MRD levels significantly decreased to very low levels on day 33 in 9 out of 10 patients studied. The only patient that remained positive relapsed.

Conclusions

MDD was prevalent in stage III T‐LLy, for which we could not prove a prognostic significance in the context of ALL‐like treatment. This study shows that both FC and RQ‐PCR methods are efficient for MDD and MRD analyses in T‐LLy. Pediatr Blood Cancer 2009;52:20–25. © 2008 Wiley‐Liss, Inc.     

Deformation analysis of 3D tagged cardiac images using an optical flow method

Background

This study proposes and validates a method of measuring 3D strain in myocardium using a 3D Cardiovascular Magnetic Resonance (CMR) tissue-tagging sequence and a 3D optical flow method (OFM).

Methods

Initially, a 3D tag MR sequence was developed and the parameters of the sequence and 3D OFM were optimized using phantom images with simulated deformation. This method then was validated in-vivo and utilized to quantify normal sheep left ventricular functions.

Results

Optimizing imaging and OFM parameters in the phantom study produced sub-pixel root-mean square error (RMS) between the estimated and known displacements in the x (RMS_x = 0.62 pixels (0.43 mm)), y (RMSy = 0.64 pixels (0.45 mm)) and z (RMSz = 0.68 pixels (1 mm)) direction, respectively. In-vivo validation demonstrated excellent correlation between the displacement measured by manually tracking tag intersections and that generated by 3D OFM (R ≥ 0.98). Technique performance was maintained even with 20% Gaussian noise added to the phantom images. Furthermore, 3D tracking of 3D cardiac motions resulted in a 51% decrease in in-plane tracking error as compared to 2D tracking. The in-vivo function studies showed that maximum wall thickening was greatest in the lateral wall, and increased from both apex and base towards the mid-ventricular region. Regional deformation patterns are in agreement with previous studies on LV function.

Conclusion

A novel method was developed to measure 3D LV wall deformation rapidly with high in-plane and through-plane resolution from one 3D cine acquisition.     

Context-dependent role of angiopoietin-1 inhibition in the suppression of angiogenesis and tumor growth: implications for AMG 386, an angiopoietin-1/2-neutralizing peptibody

AMG 386 is an investigational first-in-class peptide-Fc fusion protein (peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 (Ang1) and Ang2 with their receptor, Tie2. Although the therapeutic value of blocking Ang2 has been shown in several models of tumorigenesis and angiogenesis, the potential benefit of Ang1 antagonism is less clear. To investigate the consequences of Ang1 neutralization, we have developed potent and selective peptibodies that inhibit the interaction between Ang1 and its receptor, Tie2. Although selective Ang1 antagonism has no independent effect in models of angiogenesis-associated diseases (cancer and diabetic retinopathy), it induces ovarian atrophy in normal juvenile rats and inhibits ovarian follicular angiogenesis in a hormone-induced ovulation model. Surprisingly, the activity of Ang1 inhibitors seems to be unmasked in some disease models when combined with Ang2 inhibitors, even in the context of concurrent vascular endothelial growth factor inhibition. Dual inhibition of Ang1 and Ang2 using AMG 386 or a combination of Ang1- and Ang2-selective peptibodies cooperatively suppresses tumor xenograft growth and ovarian follicular angiogenesis; however, Ang1 inhibition fails to augment the suppressive effect of Ang2 inhibition on tumor endothelial cell proliferation, corneal angiogenesis, and oxygen-induced retinal angiogenesis. In no case was Ang1 inhibition shown to (a) confer superior activity to Ang2 inhibition or dual Ang1/2 inhibition or (b) antagonize the efficacy of Ang2 inhibition. These results imply that Ang1 plays a context-dependent role in promoting postnatal angiogenesis and that dual Ang1/2 inhibition is superior to selective Ang2 inhibition for suppression of angiogenesis in some postnatal settings.     

Management of catheter-induced pulmonary artery perforation: a rare complication in cardiovascular operations

Background. Pulmonary artery perforation is a rare but often fatal complication of the pulmonary artery catheter occurring in cardiovascular operations and at catheterization facilities. We used our experience and a review of the literature to formulate diagnostic and management strategies.

Methods. During a 13-year period, 12 patients with pulmonary artery perforations were treated in a center that performed an average of 860 open-heart procedures per year. Clinical presentation varied from minor hemoptysis to major airway hemorrhage, hypoxia, exsanguination, and cardiac arrest. Airway bleeding occurred shortly after weaning from cardiopulmonary bypass in 5 patients or postoperatively after wedging the catheter in 6. One patient developed a hemothorax and had a cardiac arrest. Treatment included assurance of gas exchange, endobronchial lavage, isolation of the bleeding bronchus and control of hemorrhage by conservative therapy, pulmonary resection, pulmonary artery repair, and arterial embolization.

Results. Five of the 12 patients died (42%). Recurrent hemorrhage occurred in 40% of patients (2 of 5) treated conservatively compared with none of the patients (0 of 7) having surgical treatment. Forty three percent of patients (3 of 7) treated surgically died; 20% of patients (1 of 5) treated conservatively died. One patient succumbed without treatment.

Conclusions. Pulmonary artery perforation is a rare and often fatal complication of pulmonary artery catheterization. This was apparent with patients who had airway hemorrhages as a result of weaning from cardiopulmonary bypass or after balloon inflation. Recurrent and fatal hemorrhage was frequent in patients treated by conservative therapy alone. Surgical intervention was effective in control of hemorrhage but did not reduce the number of deaths. Treatment remains highly individualized. It is advisable to be cautious in inserting Swan-Ganz catheters and to avoid their use unless absolutely necessary.     

Fluorescence of putative chromophores in Skh-1 and citrate-soluble calf skin collagens

BACKGROUND/PURPOSE: Fluorescence of Skh-1 hairless mouse and calf skin acid-soluble type I collagens are envelopes of several bands putatively due to tyrosine (excitation/emission peak at 275/300 nm), dihydroxyphenylalanine (dopa; 280/325 nm), tyrosine aggregate (285/360 nm), dityrosine 325/400 nm), and advanced glycation end (AGE) product (370/450 nm), respectively. As these fluorophores can be markers of pathological conditions, we wish to present further evidence for or against these assignments. METHODS: We analysed intact type I mouse collagens and AGE by conventional fluorescence spectroscopy, synchronous spectroscopy, high-performance liquid chromatography (HPLC), and borate quenching. RESULTS: The relative amount of each fluorophore depends on the collagen sample. Acid- or enzyme-hydrolysis results in loss of fluorescence intensity at 350-400 nm, and enhanced emission 400-500 nm which could be reproduced by controlled dopa oxidation. Borate buffer quenches fluorescence at lambda>400 nm from intact collagens, dityrosine, dopa, and oxidized dopa but does not quench tyrosine or AGE fluorescence. CONCLUSION: Collagen fluorescence depends on its source and previous history. The data indicate that collagen fluorescence is derived from tyrosine, dopa, interacting tyrosine residues, covalent dityrosine, and dopa oxidation product(s), but not AGE.