ErbB receptor tyrosine kinases EGFR (ErbB1), HER2 (ErbB2, neu), HER3 (ErbB3), and HER4 (ErbB4) are part of a complex network activating signaling pathways involved in cell growth and survival. Mutations causing errant ErbB activation are an oncodriver in many cancers including NSCLC. Inhibitors targeting ErbB mutations have transformed outcomes for patients; however, resistance to treatment develops rapidly. The various ErbB receptors have overlapping roles in oncogenesis and crosstalk between ErbB family members is associated with acquired resistance and metastases. For example, amplification of HER2 is a well-established mechanism of acquired resistance to EGFR-TKIs. The development of next-generation agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. Up to 80% of NSCLC patients will experience a brain lesion associated with their disease; treatment-resistant phenotypes metastasizing to the brain have become an important driver of morbidity and mortality and patients have limited therapeutic options. New agents are needed to address this important and growing unmet medical need. EO1001 is a first-in-class, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2, and ErbB4 that is positioned for near-term entry into clinical development. In vitro testing: EO1001 exhibits excellent and balanced equipotent activity against all three important ErbB receptors including EGFR, HER2, and HER4 with low nM activity (0.4 to 7.4 nM), with high specificity vs. off-target receptors. In vivo studies: Following oral administration, EO1001 treatment resulted in a statistically significant improvement in outcomes compared to positive and negative controls in erbB-positive mouse orthotopopic models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). EO1001 rapidly enters the CNS at high concentrations relative to plasma and inhibits signaling downstream of mutant ErbB receptors in tumor tissue. Treatment with EO1001 was generally well tolerated with no gastrointestinal side effects observed at efficacious doses in mouse xenograft models. Preclinical pharmacokinetic and toxicology studies have been completed. EO-1001 exhibits a half-life of 16-20 hours in rodent models. Toxicities typical of the ErbB inhibitor class, including gastrointestinal effects, weight loss, and decreased activity, were observed at higher dose groups in both rodent and non-rodent species. Extrapolation to human dosing suggests an attractive therapeutic window in comparison to other agents in the class. EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor amenable for use as a single agent and in combination regimens. First-in-man clinical testing with EO1001 is planned. Continued characterization of EO1001 activity against specific ErbB mutations will be undertaken in parallel.

Effect of hypothermia on cerebral infarcts was studied in rats embolized in the right carotid territory. Thirty-four served as normothermic controls receiving saline infusion only. In 16 rats hypothermia of 32 degrees C was induced by cooling with a fan, followed by embolization. The rats were kept hypothermic for the following 3 h before body temperature was raised to 37 degrees C. In 26 rats, treatment with human recombinant tissue plasminogen activator (20 mg/kg i.v. during 45 min), started 2 h after embolization. Finally, 14 rats were treated similarly with hypothermia for 3 h followed by additional rt-PA treatment starting after 2 h. Thrombolytic therapy reduced median infarct volume from 19.5% of affected hemisphere among controls to 4.6% (p = 0.006) in the treated group. Three hours of hypothermia reduced infarct volume to 1.6% (p = 0.0007). Additional rt-PA could not demonstrate further improvement in this experimental setting.

The effect of body temperature on cerebral infarcts and thrombolytic therapy was investigated in 91 rats embolized in the right carotid territory. Hypothermia of 32 degrees C for 2 h with preembolic onset (n = 15) or hyperthermia of 39 degrees C for 2 h with postembolic onset (n = 22) was compared to normothermic controls (n = 17). After 48 h of survival, neuropathological evaluation with measurement of infarct volume was performed. Median infarct volume in percent of affected hemisphere volume was 11% (9-21, quartiles) in rats treated with hypothermia alone, compared to 46% (14-59, quartiles) in normothermic controls (P = 0.04). Hyperthermia for 2 h increased median infarct volume to 65% (37-75, quartiles). There was a positive and significant correlation between infarct volume and body temperature (R = 0.53, P = 0.0002, n = 54). Mortality rate was significantly higher among rats treated with hyperthermia compared to normothermic controls (P = 0.005). A subset of 37 rats exposed to the same temperature regimen were treated with tissue plasminogen activator (20 mg/kg i.v. during 45 min) 2 h after embolization. Judged by posttreatment carotid angiography, hyperthermic rats (n = 11) had the best degree of recanalization (P = 0.03) compared to controls (n = 17), but median infarct volume in this group was (58% (27-67, quartiles)) significantly larger (P < 0.02) than normothermic (21% (15-39, quartiles), n = 14) and hypothermic (13% (7-31, quartiles), n = 12) rats treated with thrombolytic therapy. Thrombolytic therapy following 2 h of hypothermia, could not improve the effect of hypothermia alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytomegalovirus (CMV) causes several neurological diseases in the late stages of AIDS, but their ante-mortem diagnosis is problematic.Clinical criteria (defining a presumptive diagnosis) and polymerase chain reaction $4 (PCR) assay from cerebrospinal fluid (CSF) were blindly used to predict the involvement of CMV in neurological disorders of 164 consecutive AIDS patients undergoing a lumbar puncture.During the follow-up, a definite diagnosis based on viral culture of CSF, clinical outcome and/or CNS histology was allowed in 88 patients, 27 (16 %) of whom had a proven CMV related neurological disease.The concordance between the presumptive and definite diagnosis was of 60 %, inducing a moderate agreement kappa index of 0.40.In contrast, the sensitivity and specificity of PCR were respectively of 89 and 94 %, with a positive and negative predictive values of 86 and 95 %.Cytomegalovirus related neurological diseases appeared thus as a frequent complication of AIDS, and detection of viral DNA in CSF by means of PCR seems a reliable tool for their diagnosis, allowing its use for therapeutic decisions 20 99mTC-HMPAO LEUCOCYTE SCINTIGRAPHY IN DIAGNOSIS

The effect of delayed thrombolysis with recombinant tissue plasminogen activator was tested in an embolic stroke model. The carotid territory was embolized in 103 rats with fibrin-rich clots formed and washed in polyethylene tubes. Hemispheric cerebral blood flow before and after embolization was measured by the intra arterial 133Xe injection method. At five delay times, 15–240 min after embolization, 69 animals were treated with tissue plasminogen activator, 20 mg/kg, and 34 animals with saline. Carotid angiography displayed the grade of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after 2 days, evaluated neuropathologically, and infarct volume measured. Cerebral blood flow was reduced by 56–71% after embolization. Reperfusion induced by thrombolytic therapy was demonstrated by comparing the posttreatment angiography of the pooled five treatment groups to control animals. Thrombolytic therapy significantly reduced the infarct volume and improved the prekill clinical score by up to 2 h of treatment delay, and treatment might have been beneficial even after 4 h delay. Prolonging the delay of treatment increased the infarct volume ( p < 0.001, Jonckheere–Terpstra test). Only a few hemorrhagic complications were observed. Thus, thrombolytic therapy in embolic stroke induced recanalization. The effect on clinical outcome and infarct volume was dependent on delay time.

Background and purpose: The efficacy of thrombolysis with recombinant tissue plasminogen activator and its dependency upon clot composition was tested in an embolic stroke model.

In the period from October 1990 to December 1991, 23 patients with acute ischemic stroke were treated with recombinant tissue plasminogen activator (rt-PA) at a median of 205 min (range 78-355 min) after symptom onset. In this open pilot study rt-PA was given intravenously after an acute CT scan had not shown acute changes. In 12 patients regional cerebral blood flow was measured intravenously using 99mTc-HMPAO before and within 24 h after thrombolytic therapy. Reperfusion of the ischemic area was obtained in 10 patients. In these patients clinical improvement was greater the shorter the delay from symptom onset to initiation of treatment. Three of the 23 patients died, one of a parenchymatous hematoma, one of a large middle cerebral artery infarct, and one of acute myocardial infarction.

In a feasibility and safety study of thrombolytic therapy in acute ischemic stroke, we explored the usefulness of measurements of regional cerebral blood flow. Twenty-three patients with acute ischemic stroke were treated with 100 mg recombinant tissue plasminogen activator infused intravenously over 1 hour. Thrombolytic therapy was initiated 78 to 355 minutes after onset of symptoms. Angiography 16 to 24 hours after treatment in 17 patients showed patient intracranial arteries in 12, partial occlusion of the middle cerebral artery in 3, and total occlusion of the middle cerebral artery in 2. rCBF with 99mTc-hexamethylpropyleneamine oxime intravenously was measured 5 minutes before and within 24 hours after thrombolytic therapy in 12 patients. 10 of the 12 patients showed brain tissue reperfusion and 2, with angiographically documented middle cerebral artery occlusion, showed no reperfusion, thus documenting a relationship between reperfusion measured by regional cerebral blood flow and angiographic patency (P = .015). Three patients died. Patients who were reperfused within 24 hours (documented by repeated regional cerebral blood flow measurements) showed greater clinical improvement on the Scandinavian Stroke Scale the sooner their thrombolytic therapy was started and the more severe their neurological deficits. Acute cerebral ischemia can be documented by rCBF measurements without delay of thrombolytic therapy, and repeated rCBF measurements can reveal whether cerebral reperfusion has occurred. In our study, early reperfusion was associated with clinical improvement.

A rare case of neurofibrosuarcoma of the intrathoracic vagus nerve in a man with von Recklinghausen's neurofibromatosis is reported. Magnetic resonance imaging accurately demonstrated the tumour and its relations to surgically important structures. Resection, in accordance with general recommendations for such tumours, was successfully performed.

The efficacy of delayed thrombolysis with recombinant tissue plasminogen activator was tested in combination with the ischaemic protecting drug NBQX in an embolic stroke model. In 113 rats the carotid territory was embolized with a fibrin-rich clot formed in polyethylene tube. Hemispheric cerebral blood flow (CBF) was measured by intra-arterial 133Xenon injection method before and after embolization. Two hours after embolization 67 animals were treated with tissue plasminogen activator 20 mg kg-1, 46 control animals with saline. NBQX was given to 53 animals, of which 41 animals also received thrombolytic therapy and 12 were saline controls. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed after two days, evaluated neuropathologically, and infarct volume was measured. Embolization caused a 60-78% reduction of median CBF. The comparison of post-treatment angiography of thrombolytic treated animals to controls showed significant (p < 0.01) reperfusion in thrombolytic treated animals, while NBQX alone did not enhance reperfusion. Thrombolytic therapy significantly reduced the total infarct volume from 19.5% to 4.5% of embolized hemisphere volume (p = 0.006). NBQX alone reduced total infarct volume from 19.5% to 6.5% and cortical infarct volume from 7.9% to 0.3% (p = 0.03). In thrombolytic treated animals NBQX reduced total infarct volume from 4.5% to 2.1%. The more than 50% reduction of total infarction volume caused by NBQX was not statistically significant due to the variation of infarct size in this model. Small haemorrhagic lesions in infarcts were observed in thrombolytic treated animals. The clinical outcome correlated well with infarct volume.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was the development of a model of embolic stroke with high reproducibility concerning infarct volume. In 37 male Sprague–Dawley rats, the internal carotid artery was embolized with in vitro preformed suspensions of autologous microemboli resembling arterial thrombi. With a method of continuous flow through the carotid arterial catheter, reflux of blood with uncontrolled clotting and embolization was avoided, thereby providing control animals free of ischemic damage. The embolized animals had arterial occlusions on angiograms immediately after embolization and no spontaneous recanalization on angiograms 2 h later. The cerebral blood flow measured by the intraarterial 133Xe injection method decreased to 21–37% of baseline values. All embolized animals developed hemiparesis with spontaneous circling behavior, embolization with more than 150 μl clot suspension resulted in hemispherical infarcts. There was a strong statistically significant correlation between amount of emboli, rate of vascular occlusion, and volume of infarcted tissue. This is the first model presented utilizing autologous in vitro microemboli imitating “white” arterial thrombi. The animals developed infarction, resembling human stroke.

BACKGROUND AND PURPOSE:Thrombolytic therapy with recombinant tissue plasminogen activator was tested in a rat embolic stroke model. METHODS:The rat carotid territory was embolized with arterial-like microthrombi formed under pressure. Hemispheric cerebral blood flow before and after embolization was measured by the intraarterial Xenon-133 injection method. Fifteen minutes after embolization, 24 rats were treated with 3 mg/kg or 10 mg/kg tissue plasminogen activator, and 27 were treated with saline. Carotid angiography displayed the rate of occlusion of the cerebral arterial supply before and after treatment. Brains were fixed and evaluated neuropathologically and infarct volume was measured. RESULTS:Cerebral blood flow was reduced 70-86% after embolization. The comparison of pretreatment and posttreatment angiography showed significant (p = 0.0005) reperfusion in the treated rats. Thrombolytic therapy significantly reduced the infarct volume from 55.1% to 24.4% of embolized hemisphere volume (p = 0.007) and increased the survival rate from 0.48 to 0.96 (p = 0.0004). Fifty-three percent of the embolized rats recanalized completely after thrombolytic treatment and developed almost no infarction (median volume 2.8%), and all survived. No hemorrhagic complications were observed. CONCLUSIONS:Early thrombolytic therapy induced recanalization and reduced mortality and infarct volume after embolic stroke in this model.

The effect of the angiotensin-converting enzyme (ACE) inhibitor captopril on regional cerebral blood flow (rCBF) was studied in 12 patients within 5 days after their first acute stroke. rCBF was studied by xenon-133 inhalation and single-photon emission computed tomography (SPECT) scan before and 1 h after oral administration of 25 mg captopril. No increase in rCBF was observed in any of the 12 patients included in the study. In only one patient was there a slight redistribution of blood flow in favor of the low-flow area, but the absolute flow value did not increase. Captopril did not cause any significant change in mean hemispheric blood flow, mean arterial blood pressure (MAP), or end-expiratory CO2 fraction (FECO2). The assumption that ACE inhibition might increase cerebral blood flow in the periinfarct zone and preserve some still viable brain tissue could not be verified in the present study.

The long-term prognosis and quality of life of 201 patients admitted to hospital with reversible ischemic attacks (RIA) were estimated in a prospective study. The median follow-up time was 58 months. Further RIAs were reported by 91 patients (45%) and 48 (24%) suffered a stroke. The risk of stroke was markedly higher in the first 6 months after RIA, after which the annual stroke rate was rather constant with an average of 4.8%, about 8 times higher than expected. The average annual mortality rate for the RIA patients was 5.9%, which is significantly higher than expected. Cardiovascular deaths accounted for more than half of all deaths, stroke for one fourth. Life-table analysis of subgroups disclosed a much more favorable prognosis for women under 60 years. High systolic blood pressure, diabetes, and previous myocardial infarction were identified as risk factors. The occurrence of RIA had significantly influenced the quality of life and occupational status for the majority of the patients, even for those who did not suffer a subsequent stroke. Decreased working capacity, general asthenia and fatigue and impaired memory were the most common complaints. We conclude that RIA may be a more serious vascular event than generally believed. Apart from carrying a substantial risk of stroke and death, even a single RIA can cause permanent psychological dysfunction influencing the quality of life.

The prognostic value of serial CEA tests was evaluated in 175 consecutive patients with progressive colorectal cancer who subsequently died of their disease. The upper normal plasma CEA limit was determined to be 8 ng/ml from serial CEA determinations in 31 patients radically operated on for colorectal cancer and observed in median 40 months without evidence of recurrence. A CEA value of greater than 8 ng/ml was highly suggestive of residual disease or recurrence, even when no clinical evidence was present. Approximately 90% of the patients dying from colorectal cancer showed an increase in CEA to greater than 8 ng/ml during the course of the disease. In 63% of the patients CEA increase preceded clinical progression or relapse, with a median time period of 4 months. Sixty-eight per cent of the patients had rising CEA values over an extended time period of many months, 14% had a preterminal increase, 13% had constantly normal and 5% constantly elevated CEA. As 6/9 patients developed a drop in CEA in relation to initiation of chemotherapy without clinical response, it is concluded that CEA is not a reliable indicator of clinical response to chemotherapy. Patients with liver metastases had higher CEA and alkaline phosphatase levels than patients with only localized disease. However, no good statistical correlation between CEA and serum alkaline phosphatase was found in patients with liver metastases (coefficient of correlation r = 0.35). An increase in CEA from normal to above 8 ng/ml predicted a decrease in survival time of median 60% counted from the time of diagnosis. The numerical CEA value was predictive of shortening of survival only when greater than 3000 ng/ml. Such high values were observed only in a minority of the patients (12%). Greater than 1000 U/l (27% of the patients) alkaline phosphatase predicted an extremely poor prognosis, with a median survival of 1 month (range 0.5-4 months). It is concluded that a rise in CEA to greater than 8 ng/ml indicates with high degree of certainty relapse or disease progression in colorectal cancer patients. CEA is not a reliable indicator of clinical response to chemotherapy, and an increase in the CEA level is of little prognostic value concerning survival. Alkaline phosphatase seems to be a more valuable predictor of a worsening of prognosis.

The establishment of a possible association between ischemic cerebral attacks and prolapsing mitral valve has been studied in 45 consecutive patients aged 60 years or less with transient cerebral ischemic attacks and reversible ischemic neurological deficits. The study comprised cardiac history, auscultation, electrocardiography and echocardiography. We found only one patient (2%) with mitral valve prolapse but 19 patients (42%) with cardiac abnormalities. Two of the patients with cardiac abnormalities had a flail posterior mitral leaflet, one had ventricular septal defect and one had sclerotic aortic valves. We conclude that all patients with transient cerebral ischemic attacks should be subjected to heart examination, if possible including echocardiography.

Intra-abdominal and pelvic malignancies not infrequently are complicated by intestinal obstruction during their progressive course. How energetically this complication should be treated is a matter of controversy. An analysis of 41 such cases is presented. Small-bowel obstruction was most commonly caused by extensive serosal carcinomatosis, whereas obstruction of the large bowel usually was due to a single tumor. There was good concordance between the preoperative assessment of blockage level (small v. large bowel) and peroperative findings. All the patients with colonic obstruction obtained palliation from surgery, with median duration 6 months. Only 63% of the patients with small-bowel obstruction were relieved. This figure fell to 44%, with median duration of relief only 2 months, when carcinomatosis was the causal condition. The corresponding figures for patients with block caused by a single tumor were 89% and 6 months. Intestinal obstruction from non-malignant mechanisms was relieved in all cases. Surgical exploration should be attempted in these patients, as conservative measures are known to be of little benefit. In patients with extensive carcinomatosis, however, a favorable outcome in terms of symptom relief and prolonged survival is relatively unlikely.

Platelet aggregability and fibrinolytic activity were studied repeatedly in 83 patients with reversible cerebral ischemic attacks over a median follow-up period of 26 months. Platelet hyperaggregability, defined as in vitro secondary aggregation obtained by adenosine diphosphate concentration less than or equal to 1 mumol/l, was demonstrated in 36.1% or the patients examined 5-8 days after the attack, but only in 6% of age- and sex-matched blood donors (p less than 0.001). Fibrinolytic activity was reduced in 57.8% of the patients, as compared with 20.5% of the controls. At the time of follow-up only 8% of the survivors showed platelet hyperaggregability, whereas the fibrinolytic activity was still reduced in 44.4%. Over the observation period 21.7% of the patients had a stroke or died. No significant correlation was found between abnormalities of platelet aggregability or of fibrinolytic activity, when observed 5-8 days after the ischemic episode, and the subsequent risk of stroke or death. It is concluded that in patients with recent cerebral ischemic attacks the demonstration of platelet hyperaggregability or reduced fibrinolytic activity appears to be without prognostic significance.