Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma

Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.     

Outcome of pregnancy in patients after repair of aortic coarctation.

AIMS: Nowadays, most women born with aortic coarctation reach childbearing age. However, data on outcome of pregnancy in women after repair of aortic coarctation are scarce. The aim of this study was to report on maternal and neonatal outcome of pregnancy in women after aortic coarctation repair. METHODS AND RESULTS: The CONCOR national registry on congenital heart disease in The Netherlands was reviewed for women of childbearing age (> or =18 years old) with a history of aortic coarctation repair. Medical history and maternal, obstetrical, and neonatal outcome were determined. Fifty-four of the 100 women included had a history of pregnancy. The 54 women had 126 pregnancies resulting in 98 successful pregnancies, 22 miscarriages, and six abortions. The success rate was estimated as 0.778 (SE 0.002) including abortions and 0.817 (SE 0.002) excluding abortions. There were 85 vaginal deliveries, seven vaginal deliveries with epidural analgesia, and six caesarean sections. There were two neonatal deaths. A total of 26 pregnancies were complicated by a hypertensive disorder of pregnancy. There were 21 pregnancies in 14 women complicated by hypertension and five pregnancies in four women complicated by pre-eclampsia. The hypertension- and pre-eclampsia-probabilities were estimated as 0.183 (SE 0.285) and 0.061 (SE 0.211), respectively. During pregnancy, five patients had an increase > or =15 mmHg across the site of repair at echocardiography, but only one patient required reintervention for recoarctation after delivery. Four of the 98 children (4%) had a congenital heart defect. CONCLUSION: Pregnancy is well tolerated in women after repair of aortic coarctation. However, an excess of miscarriages and hypertensive disorders of pregnancy were found.     

Amidolytic assay of human factor XI in plasma: comparison with a coagulant assay and a new rapid radioimmunoassay

The traditional coagulant assay for plasma factor XI suffers from a relatively high coefficient of variation, the need for rare congenitally deficient plasma, and a poor correlation between precision and sensitivity. We have developed a simple functional amidolytic assay for factor XI in plasma using the chromogenic substrate PyrGlu-Pro-Arg- p-nitroanilide (S-2366). After inactivation of alpha 1-antitrypsin, CI inhibitor, and other plasma protease inhibitors with CHCI3, plasma was incubated with kaolin, in the absence of added calcium, which limited the enzymes formed to those dependent on contact activation. Soybean trypsin inhibitor was used to minimize the action of kallikrein on the substrate. Once the reaction was complete, corn trypsin inhibitor was used to inactive factor XIIa, the enzyme generated by exposure of plasma to negatively charged surfaces, which had activated the factor XI. The assay is highly specific for factor XI, since plasma totally deficient in that zymogen yielded only 1%-3% of the enzymatic activity in normal plasma under identical conditions. The requirements for complete conversion of factor XI to XIa in plasma within 60 min were, respectively, factor XII, 0.6 U/ml, and high molecular weight kininogen, 0.2 U/ml. Prekallikrein was not an absolute requirement for complete activation but did accelerate the reaction. The intraassay coefficient of variation was 3.4%, and the mean of 35 normal plasmas was 1.00 U +/- 0.24 SD. In addition, a new rapid radioimmunoassay was devised using staphylococcal protein A as the precipitating agent for a complex of factor XI antigen with monospecific rabbit antibody. The mean was 1.01 U +/- 0.30 SD. The correlation coefficients for amidolytic versus coagulant and amidolytic versus radioimmunoassay were r = 0.95 for the former and 0.96 for the latter. Thus, a simple, accurate amidolytic assay and a radioimmunoassay have been devised for measuring factor XI in plasma that correlate well with the coagulant activity of factor XI, as determined in our laboratory.