Erector spinae plane block did not improve postoperative pain-related outcomes and recovery after video-assisted thoracoscopic surgery : a randomised controlled double-blinded multi-center trial.

INTRODUCTION: There is a sizable niche for a minimally invasive analgesic technique that could facilitate ambulatory video-assisted thoracoscopic surgery (VATS). Our study aimed to determine the analgesic potential of a single-shot erector spinae plane (ESP) block for VATS. The primary objective was the total hydromorphone consumption with patient-controlled analgesia (PCA) 24 h after surgery. METHODS: We conducted a randomized, controlled, double-blind study with patients scheduled for VATS in two major university-affiliated hospital centres. We randomized 52 patients into two groups: a single-shot ESP block using bupivacaine or an ESP block with normal saline (control). We administered a preoperative and postoperative (24 h) quality of recovery (QoR-15) questionnaire and assessed postoperative pain using a verbal numerical rating scale (VNRS) score. We evaluated the total standardized intraoperative fentanyl administration, total postoperative hydromorphone consumption (PCA; primary endpoint), and the incidence of adverse effects. RESULTS: There was no difference in the primary objective, hydromorphone consumption at 24 h (7.6 (4.4) mg for the Bupivacaine group versus 8.1 (4.2) mg for the Control group). Secondary objectives and incidence of adverse events were not different between the two groups at any time during the first 24 h following surgery. CONCLUSION: Our multi-centre randomized, controlled, double-blinded study found no advantage of an ESP block over placebo for VATS for opioid consumption, pain, or QoR-15 scores. Further studies are ongoing to establish the benefits of using a denser block (single-shot paravertebral with a continuous ESP block), which may provide a better quality of analgesia.

Is YouTube™ a reliable source for patient information about Holmium Laser Enucleation of Prostate?

OBJECTIVES: Prior to benign prostate surgery, the patient's informed consent is mandatory. Among the multiple source of information for patients, social networks are very popular, but the quality of information delivered is unknown. The aim of this study was to evaluate the quality of the information freely available for patients on YouTube™ regarding HoLEP. MATERIALS AND METHODS: The term "HOLEP" was searched on YouTube™ on December 24, 2020. Videos that were not in English, French or Arabic, specifically destined to the medical community, with no written or oral comment, patient testimonials, pure surgical technique or had content unrelated to HoLEP were excluded from the study. The patient information sheet by the French Urology Association (AFU) was used to create a list of 31 items classified into 4 categories as follows: anatomy and pathophysiology (6 items), technique and perioperative preparation (10 items), usual outcomes (10 items) and complications (5 items). For each item on the predefined list, correct, missing and incorrect information were rated respectively 1, 0 and -1. RESULTS: Thirty-five videos met the inclusion criteria. Their average length was 6'06"±7'03" [00'20"; 31'30"], with an average number of views of 5279±17,821 [8; 87,354]. The information provided on the videos was written and oral, oral-only and written-only in 51%, 34% and 14% of cases, respectively. 23% of the videos showed surgery sequences, 40% animations and 62% a doctor speaking. Only one video had a quality score greater than 80% and 7 videos got a score below 20%. CONCLUSION: The information about HoLEP on YouTube™ seemed not of sufficiently high quality to allow patients to make informed decisions, and was occasionally misleading. Surgeons still have the duty to give the best quality information, and may point patients towards adequate sources of information, especially those delivered by national and international professional societies.

Canadian guidelines on the management of colorectal peritoneal metastases.

Modern management of colorectal cancer (crc) with peritoneal metastasis (pm) is based on a combination of cytoreductive surgery (crs), systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy (hipec). Although the role of hipec has recently been questioned with respect to results from the prodige 7 trial, the role and benefit of a complete crs were confirmed, as observed with a 41-month gain in median survival in that study, and 15% of patients remaining disease-free at 5 years. Still, crc with pm is associated with a poor prognosis, and good patient selection is essential. Many questions about the optimal management approach for such patients remain, but all patients with pm from crc should be referred to, or discussed with, a pm surgical oncologist, because cure is possible. The objective of the present guideline is to offer a practical approach to the management of pm from crc and to reflect on the new practice standards set by recent publications on the topic.

Neoadjuvant radiotherapy followed by surgery compared with surgery alone in the treatment of retroperitoneal sarcoma: a population-based comparison.

Introduction: Retroperitoneal sarcoma (rps) encompasses a heterogeneous group of malignancies with a high recurrence rate after resection. Neoadjuvant radiotherapy (nrt) is often used in the hope of sterilizing margins and decreasing local recurrence after excision. We set out to compare local recurrence-free survival (lrfs) and overall survival (os) in patients treated with or without nrt before resection. Methods: Patients diagnosed with rps from February 1990 to October 2014 were identified in the Alberta Cancer Registry. Patients with complete gross resection of rps and no distant disease were included. Patient, tumour, treatment, and outcomes data were abstracted in a primary chart review. Baseline characteristics were compared using the Wilcoxon nonparametric test for continuous data and the Fisher exact test for dichotomous and categorical data. Survival was analyzed using Kaplan-Meier curves with log-rank test. Cox regression was performed to control for age, sex, tumour size, tumour grade, date of diagnosis, multivisceral resection, and intraoperative rupture. Results: Resection alone was performed in 62 patients, and resection after nrt, in 40. Use of nrt was associated with multivisceral resection and negative microscopic margins. On univariate analysis, nrt was associated with superior median lrfs (89.3 months vs. 28.4 months, p = 0.04) and os (119.4 months vs. 75.9 months, p = 0.04). On multivariate analysis, nrt, younger age, and lower tumour grade predicted improved lrfs and os; sex, tumour size, date of diagnosis, multivisceral resection, and tumour rupture did not. Conclusions: In this population-based study, nrt was associated with superior lrfs and os on both univariate and multivariate analysis. When feasible, nrt should be considered until a randomized controlled trial is completed.

Contralateral prophylactic mastectomy in young women with breast cancer: a population-based analysis of predictive factors and clinical impact.

Background and Objectives: Contralateral prophylactic mastectomy (cpm) has been increasingly common among women with unilateral invasive breast cancer (ibca) even though the data that support it are limited. Using a population-based cohort, the objectives of the present study were to describe factors predictive of cpm in young women (≤35 years) with ibca and to evaluate the impact of the procedure on mortality. Methods: All women diagnosed during 1994-2003 and treated with cpm were identified from the Ontario Cancer Registry. Logistic regression was used to identify patient and tumour factors associated with the use of cpm. Multivariate analyses were used to assess the effect of cpm on recurrence and mortality. Results: Of 614 women identified, 81 underwent cpm (13.2%). On multivariable analysis, factors associated with cpm included negative lymph node status, negative estrogen receptor status, and initial breast-conserving surgery with re-excision. At follow-up, breast cancer-specific mortality was similar for women who did and did not undergo cpm. Conclusions: Use of cpm in young women with ibca (compared with non-use) was not associated improved breast cancer-specific mortality. Factors found to be predictive of cpm were negative lymph node status, negative estrogen receptor status, and initial breast-conserving surgery followed by re-excision.

Prognostic and predictive value of low estrogen receptor expression in breast cancer.

PURPOSE: Anti-hormonal therapy (tamoxifen) is recommended for estrogen receptor (er)-positive breast cancer (bca); however, its effect on low-receptor cancers is unclear. We retrospectively evaluated the effect of adjuvant tamoxifen in patients with weakly er-positive bca. METHODS: We identified 2221 bca patients who had been er-tested by ligand-based assay (lba) during 1976-1995 and who had been treated and followed until 2008. Cox proportional hazards models adjusted for age, body mass index, tumour size, nodal status, surgery, and chemotherapy were used to assess the effect of er level on bca survival in patients who received tamoxifen. RESULTS: Overall, 17% (383) of patients were within 0-3 fmol/mg cytosol protein, and 12% (266) were within 4-9 fmol/mg cytosol protein. Patients with er levels of 0-3, 4-9, 10-19, 20-49, and 50 fmol/mg or more cytosol protein had 20-year bca survival rates of 56%, 56%, 63%, 71%, and 60% respectively. Of the 2221 patients studied, 661 (29.8%) received anti-hormonal therapy. Within the latter group, er levels of 0-3, 4-9, 10-19, 20-49, and 50 fmol/mg or more cytosol protein were associated with a hazard ratio for lower bca mortality: respectively, 1.00 (reference), 0.59 (p = 0.09), 0.19 (p < 0.0001), 0.26 (p < 0.0001), and 0.31 (p < 0.0001)-the risk reduction being significant only for er levels of 10 fmol/mg or more cytosol protein. CONCLUSIONS: Tamoxifen use in bca patients with a weakly positive er status (4-9 fmol/mg cytosol protein), compared with those having higher er levels (≥10 fmol/mg cytosol protein), is not associated with a significantly lower bca-specific mortality. Our results do not support treatment with anti-hormonal therapy for bca patients with a weakly positive er status as identified by lba.

Bronchogenic cyst of the tongue in an infant.

Bronchogenic cyst of the tongue is rare. We report the case of a 17-month baby who has a lingual lesion. MRI shows a well-defined cystic lesion. Treatment consisted of a complete resection and histology found a pseudostratified respiratory type epithelium. Only 10 pediatric cases of bronchogenic cyst of the tongue have been reported in the literature. MRI is the imaging modality of choice and treatment is always surgical. The final diagnosis is made by histology.

Effects of fasting and/or postprandial glucose on heart rate recovery in patients with coronary heart disease.

AIM: The impact of both fasting and postprandial glycaemia on heart rate recovery (HRR) has not been studied in patients with coronary heart disease (CHD). For this reason, we sought to determine the relationships between HRR and both fasting and postprandial glycaemia. METHODS: A total of 4079 patients with baseline fasting plasma glucose (FPG) levels and 706 patients with 2-hour postprandial glucose (2hPG) levels were identified from the Coronary Artery Surgery Study registry, a database of 24,958 patients with suspected or proven CHD who had undergone cardiac catheterization between 1974 and 1979. Median long-term follow-up was 14.7 years (interquartile range: 9.8-16.2 years). The relationships between HRR and both FPG and 2hPG were studied. RESULTS: In univariate analyses, increasing levels of both FPG and 2hPG were significantly associated with lower HRR. In multivariate models adjusted for age, exercise tolerance in METs, resting heart rate and maximum systolic blood pressure during exercise testing, FPG remained significantly associated with HRR while 2hPG did not. CONCLUSION: Both raised FPG and decreased HRR are independent predictors of total and cardiovascular (CV) mortality in subjects with CHD. Our data suggest that the mortality risk associated with elevated FPG may in part be due to deleterious effects on autonomic regulation of CV function, as reflected by lower HRR. Further studies are required to determine whether or not non-pharmacological and/or pharmacological treatments of increased fasting glucose have a beneficial influence on HRR.

L-arginine supplemented nondiluted blood cardioplegia: a clinical trial.

AIM: L-arginine was shown to improve protection of the myocardium during coronary artery bypass graft (CABG) surgery. The objective of the present study was to determine the concentration of L-arginine to obtain the most effective protection of the myocardium during CABG surgery. METHODS: Seventy-five patients undergoing CABG surgery were randomized in 3 groups. The first group (N.=25) was administered a placebo injection in the blood cardioplegic solution, the second group (N.=25) received an injection of 4 mmol/L of L-arginine and a third group (N.=25) an injection of 6 mmol/L of L-arginine in the blood cardioplegic solution. Blood samples from the ascending aorta and the coronary sinus catheter were collected before, immediately after and at 20 minutes after aortic cross-clamping. Total plasmatic nitrite and nitrate ratio and lactate release from the myocardium in the collected blood samples were measured. RESULTS: Seventy-five patients averaging 62+/-7 years of age and undergoing 3.1+/-1 coronary bypass grafts during 41+/-17 minutes of aortic cross clamping time were recruited. Values of total plasmatic nitrite and nitrate ratio remains non-significant before and after aortic clamping and also between groups (P=0.9812 and 0.3573 respectively). Myocardial lactate release was statistically different before and after cross clamping (P=0.0002) and also between the 3 groups (P=0.0311). CONCLUSION: Nondiluted blood cardioplegic solution supplemented with 4 mmol/L of L-arginine was associated with a significant decrease of myocardial lactate release after aortic cross-clamping and reperfusion during CABG surgery.

Placental insufficiencies in cloned animals - a workshop report.

This workshop focused on describing clinical problems identified in the placentae of cloned animals and some of the potential biological mechanisms by which these anomalies arise. It was shown that placental anomalies related to somatic cell nuclear transfer (SCNT) in cattle often can be detected by ultrasonography early in gestation, enabling preventive clinical intervention. On the mechanistic front, the vascular defects in the placenta appear to be associated with anomalies in the expression of VEGF system, which could lead to the aberrant placentomes and generalized oedema seen in some gestations. Moreover, an upstream transcription factor (Mash2) controlling the differentiation of trophoblast into binucleate cells may be involved in the poor implantation rates of SCNT embryos. Finally, epigenetic patterns in placenta can be disrupted by fairly simple in vitro manipulations, which could explain the extreme anomalies observed in the placenta of SCNT pregnancies.

Left ventricular end-diastolic pressure is a predictor of mortality in cardiac surgery independently of left ventricular ejection fraction.

BACKGROUND: Several risk factors have been shown to increase mortality in cardiac surgery. However, the importance of left ventricular end-diastolic pressure (LVEDP) as an independent risk factor before cardiac surgery is unclear. Method. This observational study investigated 3024 consecutive adult patients who underwent cardiac surgical procedures at the Montreal Heart Institute from 1996 to 2000. The primary outcome was in-hospital mortality with 99 deaths (3.3%) among these patients. RESULTS: Of the 35 variables subjected to univariate analysis, 23 demonstrated a significant association with mortality. Stepwise multivariate logistic regression identified LVEDP as an independent predictor of mortality after cardiac surgery. The area under the receiver operating characteristic curve of the model predicting mortality was 0.85. CONCLUSIONS: Elevated LVEDP is an independent predictor of mortality in cardiac surgery. This variable is independent of left ventricular ejection fraction.

Influence of diabetes and bilateral internal thoracic artery grafts on long-term outcome for multivessel coronary artery bypass grafting.

OBJECTIVE: Diabetes mellitus is a major independent risk factor for morbidity and mortality after coronary artery bypass grafting (CABG). The aim of this study was to assess the effect of bilateral (B) internal thoracic artery grafting (ITA) in diabetic patients with multivessel CABG. METHODS: Between 1985 and 1995, 4382 patients underwent primary isolated multivessel CABG with ITA grafting and concomitant saphenous vein grafting (SVG). Outcome of diabetic and nondiabetic patients undergoing single (S) ITA+SVG (n=419 and 2079) and BITA+SVG (n=214 and 1594) grafting was obtained at a mean follow-up of 11+/-3 years. RESULTS: Diabetic patients were older, included more women, and had more obesity, hypertension and peripheral vascular disease than nondiabetic patients. Deep sternal wound infection rate was 1.9% for diabetic patients vs 1.2% for nondiabetic patients (P=0.2) and 30-day mortality was 1.7 vs 1.8% (P=0.9). Cox regression analysis with interaction term and propensity scoring showed that BITA grafting decreased the risk of death (Hazard Ratio=0.72 [0.57-0.91, 95%CI]) and coronary reoperation (HR=0.38 [0.19-0.77]) in both diabetic and nondiabetic patients, with no significant interaction noted. BITA grafting decreased the risk of myocardial infarction at long-term follow-up in nondiabetic patients (HR=0.72 [0.60-0.86]) but not in diabetic patients. Ten-year freedom rate from myocardial infarction in diabetic patients was 80 and 76% for SITA and BITA grafting patients, respectively. However, survival following myocardial infarction was better for patients who underwent BITA grafting, in both diabetic and nondiabetic subgroups. CONCLUSIONS: BITA+SVG grafting in diabetic patients improves survival and decrease coronary reoperation compared with SITA+SVG at long-term follow-up. Survival following myocardial infarction is improved with BITA grafting.

Single versus bilateral internal thoracic artery grafts with concomitant saphenous vein grafts for multivessel coronary artery bypass grafting: effects on mortality and event-free survival.

BACKGROUND: The issue of superiority of single internal thoracic artery grafting versus bilateral internal thoracic artery grafting remains unresolved. The aim of this study was to compare the long-term outcome of single and bilateral internal thoracic artery grafting with concomitant saphenous vein grafting for multivessel coronary artery bypass grafting. METHODS: Between March 1985 and April 1995, 6650 patients underwent primary isolated coronary artery bypass grafting with internal thoracic artery grafts, including 4382 patients with multivessel bypass grafting requiring at least 3 grafts. Outcomes of patients undergoing single internal thoracic artery plus saphenous vein grafting (n = 2547) and bilateral internal thoracic artery plus saphenous vein grafting (n = 1835) were obtained at a mean follow-up of 11 +/- 3 years. RESULTS: Patients with bilateral internal thoracic artery grafting were younger, were mostly male, and had less diabetes, hypertension, unstable angina, and recent myocardial infarction than patients undergoing single internal thoracic artery grafting. Thirty-day mortality was 2.3% for the group undergoing single internal thoracic artery grafting versus 1.2% for those undergoing bilateral internal thoracic artery grafting (P =.007). Survival probability at 10 years was 88% for the single-graft group compared with 93% for the bilateral-graft group (P <.001). Multivariate analysis with propensity scoring showed that bilateral internal thoracic artery grafting decreased the risk of death (hazard ratio, 0.74; 95% confidence interval, 0.60-0.90), myocardial infarction (hazard ratio, 0.79; 95% confidence interval, 0.67-0.93), and coronary reoperation (hazard ratio, 0.41; 95% confidence interval, 0.21-0.80) throughout the follow-up period. Other significant predictors of death were diabetes, prior myocardial infarction, need for intra-aortic balloon pump, chronic heart failure, and peripheral vascular disease. CONCLUSION: Patients undergoing bilateral internal thoracic plus saphenous vein grafting appear to have a significantly better long-term clinical outcome than patients undergoing single internal thoracic artery plus saphenous vein grafting for multivessel coronary artery bypass grafting.

Recombinant prostate specific antigen inhibits angiogenesis in vitro and in vivo.

BACKGROUND: Prostate specific antigen (PSA) is a kallikrein family member with serine protease activity commonly used as a diagnostic marker for prostate cancer. We recently described anti-angiogenic properties of PSA [Fortier et al.: JNCI 91:1635-1640]. METHODS: Two forms of PSA were cloned and expressed in Pichia pastoris: one, an intact PSA with an N-terminus of IVGGVS em leader; the second, an N-1 PSA variant. The recombinant proteins were tested for serine protease activity and for anti-angiogenic activity in vitro and in vivo. RESULTS: The rate of substrate hydrolysis by the intact recombinant PSA was similar to that of PSA isolated and purified from human seminal plasma. In contrast, the N-1 PSA variant lacked serine protease activity. In an endothelial cell migration assay, the concentration that resulted in 50% inhibition (IC(50)) was: 0.5 microM for native PSA, 0.5 microM for intact recombinant protein, and 0.1 microM for the N-1 variant PSA. Both the intact recombinant and the N-1 recombinant PSA inhibited angiogenesis in vivo. CONCLUSIONS: Purified recombinant PSA inhibits angiogenesis, proving the concept that PSA is an anti-angiogenic, and serine protease activity, as determined by synthetic substrate hydrolysis, is distinct from the anti-angiogenic properties of PSA.

[Psychiatric complication of an implanted automatic defibrillator]. / Conséquence psychiatrique après l'implantation d'un défibrillateur automatique. A propos d'un cas.

The implantable automatic defibrillator has completely changed the prognosis of potentially fatal ventricular arrhythmias by the delivery of an electric shock in the event of ventricular tachycardia or fibrillation. This vital device is sometimes poorly accepted from the psychological point of view by patients having been traumatised by experiences of sudden death from which they have been rescuscitated. Anxiety and depression are common and they have an important effect on the quality of life. The unpredictable occurrence of painful, multiple and uncontrollable electrical shocks may induce a state of acute stress with stunning, the resemblance of which to the model of learned helplessness described experimentally in the animal by Seligman, is discussed. The authors report the case of a 20 year old man whose automatic defibrillator was activated twenty times in one night. His state of stress and impotence was such that he lay prostate in his bed. Suicide seemed to be the only possible way of escaping from the electrical shocks of the device which was perceived as being dangerous. The management of this condition is not standardised but it requires the collaboration of the cardiac rhythmological and psychiatric teams. Medication with antidepressant drugs alone is not sufficient. The regulation of the sensitivity of the defibrillator gives the patient a feeling of mastering the situation: submission is not total! Research along this line should improve the patients' acceptation of the device and their quality of life.

Administration of a liposomal FGF-2 peptide vaccine leads to abrogation of FGF-2-mediated angiogenesis and tumor development.

Basic fibroblast growth factor (FGF-2) is an important stimulator of angiogenesis that has been implicated in neoplastic progression. Attempts to neutralize or modulate FGF-2 have met with some success in controlling neovascularity and tumor growth. In the present study, two peptides: one corresponding to the heparin binding domain and the other to the receptor binding domain of FGF-2, exerted dose-dependent inhibition of FGF-2-stimulated human umbilical vein endothelial cell proliferation (IC(50)=70 and 20 microg/ml, respectively). The identification of these functional regions suggested that targeting these domains might be an approach for the modulation of FGF-2 function. To investigate this possibility, we vaccinated mice with either the heparin binding domain peptide or the receptor binding domain peptide of FGF-2 in a liposome/adjuvant format, and analyzed the effect of vaccination on FGF-2-driven angiogenesis, tumor development and immune status. Mice vaccinated with the heparin binding domain peptide generated a specific antibody response to FGF-2, blocked neovascularization in a gelfoam sponge model of angiogenesis, and inhibited experimental metastasis by >90% in two tumor models: the B16BL6 melanoma and the Lewis lung carcinoma. These effects were not observed in mice treated with the receptor binding domain peptide conjugated to liposomes or liposomes lacking conjugated peptide. These data suggest that a heparin binding domain peptide of FGF-2, when presented to a host in a liposomal adjuvant formulation, can ultimately lead to inhibition of angiogenesis and tumor growth.

Antiangiogenic activity of prostate-specific antigen.

BACKGROUND: Measurement of serum levels of prostate-specific antigen (PSA) is widely used as a screening tool for prostate cancer. However, PSA is not prostate specific, having been detected in breast, lung, and uterine cancers. In one study, patients whose breast tumors had higher levels of PSA had a better prognosis than patients whose tumors had lower PSA levels. To test the hypothesis that PSA may have antiangiogenic properties, we evaluated the effects of PSA on endothelial cell proliferation, migration, and invasion, which are key steps in angiogenesis, the process by which tumors develop a blood supply. METHODS: To assess the antiproliferative effects of PSA, we treated bovine endothelial cells and human endothelial cell lines (HUVEC and HMVEC-d) with purified human PSA (0.1-10 microM) and then stimulated them with 10 ng/mL fibroblast growth factor-2 (FGF-2). Effects on FGF-2- or vascular endothelial growth factor (VEGF)-stimulated endothelial cell migration, invasion, and tube formation were measured by use of one cell line only (HUVEC). PSA was administered to mice at 9 microM for 11 consecutive days after intravenous inoculation of B16BL6 melanoma cells to assess its ability to inhibit the formation of lung colonies (i.e., metastatic tumors). RESULTS: PSA inhibited endothelial cell proliferation, migration, and invasion at IC(50) (i. e., the concentration at which inhibition was 50%) values ranging from 0.3-5 microM. In addition, PSA inhibited endothelial cell responses to both angiogenic stimulators tested, FGF-2 and VEGF. In a mouse model of metastatic disease, daily PSA treatment resulted in a 40% reduction in the mean number of lung tumor nodules compared with phosphate-buffered saline treatment (two-sided P =.003). CONCLUSION: To our knowledge, this is the first report that PSA may function in tumors as an endogenous antiangiogenic protein. This function may explain, in part, the naturally slow progression of prostate cancer. Our findings call into question various strategies to inhibit the expression of PSA in the treatment of prostate cancer.

Zinc ligand-disrupted recombinant human Endostatin: potent inhibition of tumor growth, safety and pharmacokinetic profile.

Endostatin, a potent endogenous inhibitor of angiogenesis, inhibits the growth of primary tumors without induction of acquired drug resistance in mice. We report that a soluble recombinant human (rh) Endostatin produced with characteristics of the native Endostatin, effectively inhibited the growth of primary tumors and pulmonary metastases in a dose-dependent manner. We also show that deletion of two of the four zinc ligands of rhEndostatin did not affect this potent tumor inhibiton. The growth of established Lewis lung primary tumors implanted into mice was inhibited (80-90%) upon systemic treatment with 50 mg/kg/12 h of rhEndostatin. Using the B16-BL6 murine experimental pulmonary metastases model, rhEndostatin administered at 1.5 mg/kg/day or 4.5 mg/kg/day beginning 3- or 11-days post tumor cell injection, respectively, resulted in an approximate 80% inhibition of tumor growth. At effective anti-tumor doses of 1.5 and 50 mg/kg, pharmacokinetic modeling in mice showed (a) the protein was 100% bioavailable, (b) the AUC ranged from 16 to 700 ng ml/h and (c) the Cmax ranged from 161 to 4582 ng/ml. At the highest dose tested (300 mg/kg), delivered as a single bolus, no drug-related toxicity was observed in a Cynomolgus monkey infused with rhEndostatin. No toxicity was observed even at AUC and Cmax values that were 1.3- to 56-fold higher than those observed in mice with tumors that were potently inhibited. Our production system yields a well characterized, soluble and potent rhEndostatin at quantities sufficient for human use. The preclinical studies described herein are an important first step toward the assessment of Endostatin in the clinic.

A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer.

Endogenous murine angiostatin, identified as an internal fragment of plasminogen, blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. A recombinant protein comprising kringles 1-4 of human plasminogen (amino acids 93-470) expressed in Pichia pastoris had physical properties (molecular size, binding to lysine, reactivity with antibody to kringles 1-3) that mimicked native angiostatin. This recombinant Angiostatin protein inhibited the proliferation of bovine capillary endothelial cells in vitro. Systemic administration of recombinant Angiostatin protein at doses of 1.5 mg/kg suppressed the growth of Lewis lung carcinoma-low metastatic phenotype metastases in C57BL/6 mice by greater than 90%; administration of the recombinant protein at doses of 100 mg/kg also suppressed the growth of primary Lewis lung carcinoma-low metastatic phenotype tumors. These findings demonstrate unambiguously that the antiangiogenic and antitumor activity of endogenous angiostatin resides within kringles 1-4 of plasminogen.

Quantitative comparison of prone and supine myocardial SPECT MIBI images.

The myocardial count distribution and the stress/rest ratio distribution were compared between prone and supine Tc-99m MIBI myocardial SPECT acquisitions. Ninety-nine male patients with a low stress supine inferior wall count underwent stress and rest acquisitions in the supine and prone positions successively. For each study, values depicting the inferior, anterior, septal, and lateral wall counts were extracted from a medioventricular normalized circumferential profile and underwent a statistical analysis (Student's paired t-test). On prone imaging, when compared to supine imaging, counts showed a highly significant mean relative increase of 11% +/- 1% in the inferior wall and of 7% +/- 1% in the septum. Conversely, these counts showed a significant mean relative decrease of 4% +/- 1% in the anterior wall and of 3% +/- 1% in the lateral wall. Moreover, the inferior wall stress/rest ratio showed a highly significant mean relative increase (6% +/- 2%). The prone position is probably preferable for interpreting the inferior wall and septum, where relative counts are enhanced, as with TI-201, and because the inferior stress-rest discrepancies are reduced in that position. But the anterior and lateral wall information is impaired in the prone position. The authors suggest, in case of a low stress supine inferior count, the combination of both positions, which is feasible with Tc-99m MIBI, in order to prevent a misleading interpretation.