Optimal diagnostic tool for surveillance of oesophageal varices during COVID-19 pandemic.

AIM: To study the diagnostic accuracy and utility of triphasic abdominal computed tomography (CT) in the diagnosis and grading of oesophageal varices (OVs) as an alternative to endoscopy during the COVID-19 pandemic. MATERIALS AND METHODS: A prospective analysis was undertaken of retrospective data from cirrhotic patients who underwent oesophago-gastro-duodenoscopy (OGD) and a triphasic abdominal CT from January to December 2019. Endoscopists and radiologists provided their respective independent assessment of OV grading after being blinded to the clinical details. Performance of CT grading of OVs was compared with the reference standard endoscopic grading using weighted kappa (k). Non-invasive scores such, as aspartate transaminase (AST)-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) Index, platelet: spleen (PS) ratio were correlated between the two techniques. RESULTS: OV grading between endoscopists and radiologists showed 81.73% agreement (85 out of 104 patients) in the comparative analysis of 104 cirrhotic patients, of which no varices (57.1%, n=4), small (85.1%, n=23), medium (72.2%%, n=26), and large varices (94.1%, n=32) with a weighted k score of 0.88 (95% confidence interval 0.82-0.94). Overall, the sensitivity of CT in the diagnosis of no, small, medium, and large OVs was 66.6%, 79.3%, 89.6%, and 94.1%, respectively, with an area under the receiver operating curve (AUROC) score of 0.775, 0.887, 0.839, and 0.914. Performance of APRI, FIB-4, and PS ratio correlated well with the severity of OVs with no difference between OGD and CT grading. CONCLUSION: Triphasic abdominal CT can be an invaluable tool in the diagnosis and grading of OVs during the COVID-19 pandemic.

A comparative evaluation of conventional and pretargeted radioimmunotherapy of CD20-expressing lymphoma xenografts.

Radioimmunotherapy with anti-CD20 monoclonal antibodies is a promising new treatment approach for patients with relapsed B-cell lymphomas. However, the majority of patients treated with conventional radiolabeled anti-CD20 antibodies eventually have a relapse because the low tumor-to-blood and tumor-to-normal organ ratios of absorbed radioactivity limit the dose that can be safely administered without hematopoietic stem cell support. This study assessed the ability of a streptavidin-biotin "pretargeting" approach to improve the biodistribution of radioactivity in mice bearing Ramos lymphoma xenografts. A pretargeted streptavidin-conjugated anti-CD20 1F5 antibody was infused, followed 24 hours later by a biotinylated N-acetylgalactosamine-containing "clearing agent" and finally 3 hours later by (111)In-labeled DOTA-biotin. Tumor-to-blood ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less with conventional (111)In-1F5. Tumor-to-normal organ ratios of absorbed radioactivity up to 56:1 were observed with pretargeting, but were 6:1 or less with conventional (111)In-1F5. Therapy experiments demonstrated that 400 microCi (14.8 MBq) or more of conventional (90)Y-1F5 was required to obtain major tumor responses, but this dose was associated with lethal toxicity in 100% of mice. In marked contrast, up to 800 microCi (29.6 MBq) (90)Y-DOTA-biotin could be safely administered by the pretargeting approach with only minor toxicity, and 89% of the mice were cured. These data suggest that anti-CD20 pretargeting shows great promise for improving current therapeutic options for B-cell lymphomas and warrants further preclinical and clinical testing.

Targetted localisation and imaging of a murine lymphoma using 131I-labelled monoclonal antibody.

In vivo tumor targetting with radiolabelled monoclonal antibodies is a promising approach for the diagnosis and therapy of tumors. A specific monoclonal antibody (mAb), DLAB was generated to the Dalton's lymphoma associated antigen (DLAA) from Haemophilus paragallinarum-induced spontaneous fusion. In order to study the tumor localisation and biodistribution properties of the monoclonal antibody, scintigraphic studies were performed using the radiolabelled DLAB. 131-labelled DLAB was administered intravenously into Swiss mice bearing Dalton's lymphoma and external scintiscanning was performed at different time intervals. Clear tumor images were obtained which revealed selective and specific uptake of radiolabel and the results were compared with biodistribution data. The radioiodinated monoclonal antibody showed fast tumor uptake which increased significantly to 14.6% injected dose (ID)/g at 12 hr post-injection. Enhanced blood clearance of radioactivity resulted in higher tumor/blood ratio of 5.96 at 48 hr. 131I-labelled DLAB resulted in selective and enhanced uptake of the radioactivity by the tumor compared to the non-specific antibody and the results suggest the potential use of spontaneous fusion for producing specific monoclonal antibodies for tumor detection and therapy.

Preliminary study on immunoscintigraphy of a murine lymphoma using technetium-99M labeled chicken antibody.

AIMS AND BACKGROUND: Radiolabeled antibodies generated against tumor-associated antigens are used for immunoscintigraphy to detect tumors and tumor metastases. Although successful tumor imaging has been achieved using trace-labeled murine monoclonal antibodies, such antibodies often lead to the development of human anti-murine antibodies (HAMA), which limit their subsequent administration for tumor imaging and therapy. It has been reported recently that chicken polyclonal antibodies have high affinity and specificity for the antigen against which they are raised and do not have any immunological cross-reactivity with HAMA. METHODS: The present study deals with immunoscintigraphy of Dalton's lymphoma, an experimental tumor model using chicken antibodies generated against Dalton's lymphoma-associated antigen (DLAA) and labeled with technetium-99m ((99m)Tc). RESULTS: Scintigrams showed specific uptake of the radiolabel resulting in clear tumor images. The radioactivity uptake of the chicken anti-DLAA antibody was about twofold higher than that of the non-specific chicken antibody. CONCLUSIONS: The results demonstrate the potential of chicken antibody for in vivo radioimmunodetection and localization of tumors.

Production of monoclonal antibodies to a tumor--associated antigen by spontaneous cell fusion.

Spontaneous cell fusion induced by the bacterium Haemophilus paragallinarum has been recently reported as an alternative technique to generate hybridomas producing monoclonal antibody (mAb). In order to investigate the advantages of this technique to produce anti-tumor monoclonal antibodies we performed comparative experiments between H. paragallinarum induced spontaneous cell fusion and polyethylene glycol (PEG) mediated fusion. Hybridomas producing monoclonal antibodies to an experimental murine lymphoma antigen, the Dalton's lymphoma associated antigen (DLAA) were generated and their sensitivity and specificity were ascertained. The spontaneous fusion yielded more number of stable and specific hybridomas than PEG mediated fusion. The results suggest the advantage of H. paragalinarum induced cell fusion for the simplified production of specific antitumor monoclonal antibodies.

Intracoronary angiotensin-converting enzyme inhibition improves diastolic function in patients with hypertensive left ventricular hypertrophy.

BACKGROUND: There is increasing recognition of myocardial angiotensin-converting enzyme, which is induced with the development of left ventricular hypertrophy (LVH). The potential physiological significance of subsequent increased angiotensin I to II conversion in the presence of LVH is unclear but has been postulated to cause abnormal Ca2+ handling and secondary diastolic dysfunction. Accordingly, we hypothesized that acute angiotensin-converting enzyme inhibition would result in decreased production of angiotensin II and improved active (Ca(2+)-dependent) relaxation in patients with hypertensive LVH. METHODS AND RESULTS: Intracoronary (IC) enalaprilat was administered to 25 patients with and without LVH secondary to essential hypertension. Indexes of diastolic and systolic LV function were determined from pressure (micromanometer)-volume (conductance) analysis at steady state and with occlusion of the inferior vena cava. Patients were divided into those receiving high- (5.0 mg, n = 15) and low-dose (1.5 mg, n = 10) IC enalaprilat during a 30-minute infusion at 1 mL/min. The high-dose patients were further divided along the median normalized LV wall thickness of 0.671 cm/m2. The time constant of isovolumic relaxation (TauL) was prolonged at baseline in patients receiving high-dose enalaprilat with wall thickness > 0.671 cm/m2 (TauL, 56 +/- 2 versus 44 +/- 2 and 45 +/- 2 milliseconds, respectively, P < .01 by ANOVA) and shortened only in this patient group (TauL, 49 +/- 3 versus 46 +/- 2 and 43 +/- 2 milliseconds, respectively, P < .01 versus baseline and other groups by ANOVA). The improvement in TauL was directly proportional to the degree of LVH (r = .92, P < .001). Although there was a decrease in LV end-diastolic pressure (23 +/- 2 to 15 +/- 1 mm Hg, P < .01) and volume (86 +/- 8 to 67 +/- 9 mL/m2, P < .05) in those patients with a reduction in TauL, this is due to movement down a similar diastolic pressure-volume relation with no change in chamber elastic stiffness (0.023 +/- 0.002 to 0.025 +/- 0.004 mL-1, P = NS). CONCLUSIONS: Intracoronary enalaprilat resulted in an improvement in active (Ca(2+)-dependent) relaxation in those patients with more severe hypertensive LVH. The improvement in active relaxation was directly proportional to the severity of LVH. These results support the hypothesis that the cardiac renin-angiotensin system is an important determinant of active diastolic function in hypertensive LVH.

Why do patients with congestive heart failure tolerate the initiation of beta-blocker therapy?

BACKGROUND: Despite its negative inotropic effects, the initiation of beta-adrenergic blockade is tolerated by patients with congestive heart failure (CHF). Accordingly, we examined the acute hemodynamic effects of beta-adrenergic blockade on systolic and diastolic left ventricular (LV) function and ventriculo-arterial coupling. In addition, isolated myocardium from patients with CHF shows selective beta 1-receptor downregulation, implying a greater role for the beta 2-receptor in maintaining in vivo LV contractility. As a secondary aim, we hypothesized that nonselective beta-adrenergic blockade would have greater negative inotropic effect than beta 1-blockade in patients with CHF. METHODS AND RESULTS: Patients with clinical CHF (n = 24) and control patients without CHF (n = 24) were given either the nonselective beta-blocker propranolol or the beta 1-selective blocker metoprolol. LV pressure-volume relations were obtained before and after the administration of intravenous beta-blocker, and measures of LV systolic and diastolic function were examined. Patients with CHF had a deterioration in LV systolic function with a fall in LV systolic pressure (139 +/- 6 to 125 +/- 6 mm Hg), cardiac index (2.56 +/- 0.11 to 2.20 +/- 0.11 mL.min-1 x M-1), dP/dtmax (1173 +/- 63 to 897 +/- 50 mm Hg/s), and end-systolic elastance (0.88 +/- 0.10 to 0.64 +/- 0.10 mm Hg/mL), P < .05 for all. Although there was deterioration of active LV relaxation (isovolumetric relaxation 63 +/- 2 to 73 +/- 3 milliseconds, peak filling rate 543 +/- 33 to 464 +/- 28 mL/s, P < .05 for both), there was no change in passive LV diastolic function (pulmonary capillary wedge, 24 +/- 2 to 24 +/- 1 mm Hg; chamber stiffness, 0.0154 +/- 0.0005 to 0.0163 +/- 0.0005 mL-1, P = NS for both), and a decrease in afterload (arterial elastance 3.85 +/- 0.31 to 3.38 +/- 0.24 mm Hg/mL, P < .05). Control patients had no change in these parameters other than a prolongation of isovolumetric relaxation (48 +/- 1 to 55 +/- 2 milliseconds, P < .05). The effects of propranolol (n = 12) versus metoprolol (n = 12) on these parameters in patients with CHF were similar. CONCLUSIONS: These data do not support a greater in vivo physiological role of the myocardial beta 2-receptor in CHF. The preservation of passive diastolic function and ventriculo-arterial coupling provide possible explanations of why beta-adrenergic blockade is tolerated by patients with CHF.