Malignant astrocytomas treated with iodine-125 labeled monoclonal antibody 425 against epidermal growth factor receptor: a phase II trial.

Twenty-five patients with primary presentation of malignant astrocytoma, astrocytoma with anaplastic foci, and glioblastoma multiforme were treated with surgical resection and definitive radiation therapy followed by intravenous or intra-arterial administration of Iodine-125 labeled monoclonal antibody-425, which binds specifically to human epidermal growth factor receptor. The patients presented with primary untreated disease, positive contrast enhanced computed tomography scans of the brain, and compatible clinical symptoms. In this Phase II clinical trial, the patients had surgical debulking or biopsy followed by definitively administered external beam radiation therapy and one or multiple doses (35 to 90 mCi per infusion) of radiolabeled antibody. The total cumulative doses ranged from 40 to 224 mCi. The administrations of the radiolabeled antibody were performed in most cases 4-6 weeks following completion of the primary surgery and radiation therapy. Ten patients had astrocytoma with anaplastic foci and 15 had glioblastoma multiforme. No significant life-threatening toxicities were observed during this trial. At 1 year 60% of the patients with astrocytoma with anaplastic foci or glioblastoma multiforme are alive. The median survival for both groups was 15.6 months.     

Activation of Ca2+/calmodulin-dependent protein kinase II by stimulation with bradykinin in neuroblastoma x glioma hybrid NG108-15 cells.

To elucidate the mechanisms of the intracellular signal transduction elicited with bradykinin in NG108-15 neuroblastoma x glioma hybrid cells, we examined the activation of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) by bradykinin stimulation. When the extract of NG108-15 cells was immunoprecipitated with the affinity-purified antibody to brain CaM kinase II, a 50-kDa protein in the immunoprecipitate mainly became autophosphorylated in a Ca2+/calmodulin-dependent manner. The results suggest that the 50-kDa protein is the subunit of CaM kinase II in NG108-15 cells. The Ca2+/calmodulin-independent activity (autonomous activity) of the enzyme increased twice within 10 s by stimulation with 1 microM bradykinin in the cells. The increase in the autonomous activity of the enzyme had two phases: the transient early-peak phase and the long late-plateau phase. The former was abolished by the pretreatment of the cells with 10 mM caffeine or 20 microM BAPTA-AM, and the latter was abolished by the removal of the extracellular Ca2+ with 1 mM EGTA or by the pretreatment with 1 microM nifedipine. Stimulation of 32P-labeled NG108-15 cells with 1 microM bradykinin increased the autophosphorylation of CaM kinase II and this increase was abolished by pretreatment with caffeine or BAPTA-AM. These results suggest that CaM kinase II is activated via the inositol phospholipid signaling pathway induced with bradykinin in NG108-15 cells.     

Reduced levels of MMP-2 and TIMP-1 in dyssegmental dysplasia.

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were measured in a mild case of dyssegmental dysplasia. X-ray pictures of a female baby born vaginally at 39 weeks of gestation showed short, bent, dumbbell-shaped long bones of the limbs and profound dyssegmental ossification in the spine, findings characteristic of dyssegmental dysplasia. When the levels of MMP-1, MMP-2, MMP-9, TIMP-1, and TIMP-2 were measured, the levels of MMP-2 and TIMP-1 were significantly reduced. This case might provide a clue to disclose the etiology of dyssegmental dysplasia.     

Acute myocardial injury and repeated angina pectoris-like attacks in a young patient with Churg-Strauss syndrome]

A 23-year-old male with bronchial asthma developed eosinophilia (eosinophils greater than 2,000/mm3) and was observed at our hospital. After using a prescribed indomethacin suppository for fever at home, he experienced an attack of acute chest pain and severe dyspnea. He suffered cardiac arrest while being transferred to the ward. After resuscitation, he was diagnosed as having acute myocardial infarction on the basis of electrocardiographic and ultrasonic cardiographic findings, and marked elevation of serum concentrations of myocardial enzymes. Thereafter, he often complained of precordial pain and abdominal pain. When he was administered an analgesic in another hospital, he developed severe precordial pain, and marked ST elevation was recorded on the electrocardiogram. Coronary angiography revealed no stenosis nor atherosclerotic changes, suggesting that severe spasm of the coronary arteries and direct myocardial injury by eosinophils were the causes of the myocardial infarction-like symptoms and angina pectoris-like attacks. He was diagnosed as having Churg-Strauss syndrome (allergic granulomatous angiitis) on the basis of the clinical findings; skin biopsy and transbronchial lung biopsy findings were consistent with the diagnosis. Following steroid administration, his angina-like attacks and abdominal pain ceased. This patient developed two episodes of acute cardiovascular symptoms upon administration of antipyretic analgesics. This suggests that in cases of Churg-Strauss syndrome with aspirin-induced asthma, physicians must be aware of the cardiovascular complications, and such drugs should be administered with caution.     

Prognostic significance of the expression of ras oncogene product in non-small cell lung cancer.

The clinical significance of ras oncogene expression in non-small cell lung cancer was evaluated in 116 surgically treated patients. Archival paraffin sections of the tumors were analyzed immunohistochemically using anti-ras p21 monoclonal antibody (MoAb) rp-35, and p21 staining was correlated with clinicopathologic parameters and survival. Positive reactions (+ and ++) were observed in 72.5% of the adenocarcinomas and 55.6% of the squamous cell carcinomas studied. The T1 tumors showed a ++ reaction less frequently than T2 and T3 tumors (P less than 0.05). Stage I tumors also were less reactive with MoAb rp-35 than tumors in more advanced stages (P less than 0.05). Survival analysis showed that patients with p21-negative tumors had significantly longer survival times (a 5-year survival rate of 64.1%) than those with p21 + tumors (38.0%, P less than 0.05) or those with p21 ++ tumors (11.5%, P less than 0.005). The significant correlation between p21 staining and patient survival was independent of histologic type, stage of disease, tumor or node status, and the resectability of tumors. On Cox's multivariate analysis, p21 staining was a major and independent prognostic determinant of survival. These results suggest that enhanced ras p21 expression may be one of the important biologic and clinical markers indicating the malignant potential of non-small cell lung cancer.     

Aortic arch replacement with proximal first technique.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) without retrograde cerebral perfusion (RCP) has a strict time limit. We modified a surgical technique for anastomosis to shorten the period of DHCA and unilateral cerebral perfusion (UCP). METHODS: Between March 1993 and August 2001, retrospective analysis was done on 23 consecutive patients, who underwent aortic arch replacement with branches. The patients were divided into two groups: DHCA group and UCP group. The DHCA group, in which DHCA alone and without additional cerebral perfusion was performed, comprised of nine patients. Proximal aortic anastomosis was performed first during systemic cooling; then both the brachiocephalic artery and left carotid artery were reconstructed with the branches of the artificial graft during circulatory arrest; thereafter, cerebral and coronary perfusions were resumed. The UCP group, in which DHCA was not used but right hemisphere perfusion during deep hypothermia was performed when the origin of brachiocephalic artery was safely clamped, consisted of 14 patients. RESULTS: Mean time of DHCA was 18.8+/-4.2 minutes and that of right hemisphere perfusion time was 11.0+/-3.8 minutes, respectively. Twenty-one patients survived the surgery (91.3%), and two (8.7%) died during hospitalization. Transient cerebral complication occurred in four patients in the DHCA group and all recovered. Logistic regression analysis revealed that DHCA was the only parameter to significantly influence temporary neurological dysfunction. There was no other significant difference between the two groups. CONCLUSION: With our modified and simple surgical technique for aortic arch repair, we were able to successfully shorten the DHCA time and right hemisphere perfusion time. However, because DHCA was the only parameter to significantly influence temporary neurological dysfunction, some form of continuous cerebral perfusion at deep hypothermia may be a safer method to preserve cerebral function.     

The effects of mother-infant separation upon nursing and suckling behaviors of the rat

The present study was intended to evaluate the hypothesis that the nursing-suckling relationship of rats proceeds from the mother-leading-type in early postpartum days to the infants-leading-type in later postpartum. Four groups were organized to make tests on the effects of different kinds of mother-infant separation (8-hr) upon nursing-suckling behaviors. Groups were Groups MIS (a separated mother and infants group), MS (mother-separated and infants-fostered group), IS (a foster-mother and separated-infants group), and C (non-separated control group). The separation of each group, lasting for 8-hr, was made at 1-2, 6-7, 11-12, 16-17, 21-22, 26-27, and 31-32 days after parturition. In Exp. I, nursing behavior of mother and suckling and/or eating behavior of infants in mother-infant interactions were observed by time-sampling method for 30 min following 8-hr of separation. In Exp. II, the suckling test of infants (half of the litter) was made on the anesthetized mother at the presence of food pellets. The results of Exp. I showed that nursing-suckling episodes were more frequent in Groups MIS, MS, and IS than in Group C (fig. 1). Further, the differences among the first three groups were not significant before 11-12 days of age. However, the infant-separated group (Group IS) showed higher level of response at 16-17, 21-22 days of age, suggesting the active role of infants in starting nursing-suckling episodes at these ages.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sister chromatid exchange induction by benzo(a)pryene in cultured peripheral blood lymphocytes of lung cancer patients and healthy individuals with or without familial history of neoplasms

The inducibility of sister chromatid exchanges (SCEs) by benzo(a)pyrene (BP) was studied in cultured peripheral blood lymphocytes of 15 untreated lung cancer patients and 25 healthy persons including 11 high- and 14 low-cancer-risk individuals tentatively classified by the familial history of lung cancer and other neoplasms. The baseline SCE frequency in cultured lymphocytes was significantly high in lung cancer patients, as compared with all healthy persons or low-cancer-risk individuals. Following exposure to BP, the lymphocytes of lung-cancer patients and high-cancer-risk individuals exhibited significantly greater SCE yields than those of persons at low risk, although no significant difference was observed in the lymphocyte SCE yields when the levels of lung cancer patients were compared with those of all healthy persons. A comparison of the net SCE increase (delta SCE) in BP-exposed lymphocytes among the study groups, however, revealed a significant difference in delta SCE values only between high- and low-cancer-risk individuals. The present findings on both the observed SCE yields and delta SCE values suggest that lymphocytes of high-risk individuals may be more susceptible to BP-induced DNA damage than those of persons at low risk, and that such a chromosomal hypersensitivity to genotoxins may be associated with a high risk of neoplasms.