Initial Clinical Study Research Articles

Five-year results: the initial clinical trial of Mammosite balloon brachytherapy for partial breast irradiation in early-stage breast cancer

Objective Patients with early-stage invasive ductal breast cancer were prospectively evaluated using MammoSite RTS balloon brachytherapy (RTS Cytyc Corp, Marlborough, MA) as the sole modality for delivering accelerated partial breast irradiation to the lumpectomy bed with breast-conserving surgery. This report presents the 5-year results of the treated patients. Methods From May 2000 to October 2001, 70 patients were enrolled in this prospective study. Forty-three patients completed accelerated partial breast irradiation with MammoSite brachytherapy following lumpectomy and axillary staging. Thirty-six patients have been followed for a median of 5.5 years (mean 65.2 months). Criteria for entry into the study were unifocal invasive ductal carcinoma, tumor size ≤2 cm, age ≥45 years, absence of extensive intraductal component, cavity size ≥3 cm in 1 dimension, node-negative, and final margins negative per National Surgical Adjuvant Breast and Bowel Project definition. A minimum balloon-to-skin surface distance of 5 mm was required. A dose of 34 Gy was delivered in 10 fractions over 5 days prescribed to 1 cm from the applicator surface using iridium-192 high-dose-rate brachytherapy. Data on infection, seromas, cosmetic outcome, and toxicities were collected at 3 and 6 months and at yearly intervals. Local recurrences, both true recurrences in the lumpectomy bed and failures outside the initially treated target volume (elsewhere failures), were recorded. Contralateral breast failure rates were noted. Results The catheter was not implanted in 16 of the 70 enrolled patients due to cavity size not amenable to balloon placement (n = 10), ineligible by criteria (n = 4), and skin spacing (n = 2). Fifty-four patients were implanted and 43 were successfully treated with MammoSite balloon brachytherapy. Reasons for catheter explantation in 11 patients were poor cavity conformance in 7, inadequate skin spacing in 2, positive node in 1 and age less than 45 years in 1. Of the 43 patients who completed treatment, the infection rate was 9.3%. Seroma formation occurred in 32.6% of patients, of which 12% were symptomatic requiring aspiration. Asymptomatic fat necrosis was identified in 4 of the 43 patients, noted from time of catheter removal at 11, 14, 42, and 63 months. Good–excellent cosmetic outcomes were achieved in 83.3% of the 36 patients with more than 5 years of follow-up. Cosmetic outcomes were improved, with increased skin spacing having statistical significance at skin spacing ≥7 mm. The only serious adverse events were 2 infections: mastitis and abscess. Seven of the 43 treated patients have been discontinued from follow-up. None had a local recurrence recorded at last visit. Reasons for exit from the study were death from metastatic disease (n = 3), lost to follow-up (n = 2), and placed in hospice for other medical conditions (n = 2). No local recurrences (either at the tumor bed or elsewhere in the breast) or regional recurrences have occurred in the 36 patients who have been followed for a median of 5.5 years. No contralateral cancers have developed. Conclusions MammoSite balloon brachytherapy as a sole modality for delivering radiation to the tumor bed has been successful in achieving excellent local control in this initial clinical study of patients with early-stage invasive ductal breast cancer. This has been achieved with minimal toxicities and good–excellent cosmetic outcomes in 83.3%. Accelerated partial breast irradiation using the MammoSite balloon in a carefully selected group of patients has demonstrated 5-year local recurrence results comparable to those achieved with conventional whole breast radiation therapy and interstitial catheter brachytherapy as reported at 5-year data points in studies of these treatment modalities. Poor cavity conformance and inadequate skin distance were the main factors limiting use of the MammoSite device. Extended follow-up will be required to determine the long-term efficacy of this treatment modality.

MammoSite brachytherapy for low-risk breast carcinoma: Toxicity, cosmetic evaluation and quality-of-life results of a phase II study

11016 Background: The MammoSite is a device that was developed with the goal of making breast-conserving surgery more widely available. Our objective was to evaluate the MammoSite device performances after an open cavity placement procedure and quality of life in highly selected patients with early-stage breast cancer. Methods: From March 2003 to March 2005, 43 patients with T1 breast cancer were enrolled in a phase II prospective study. Twenty-five (58%) patients were qualified for HDR brachytherapy delivery. The median age was 72 years (range: 60–75). Twenty-five (58%) were treated with high-dose rate brachytherapy using the MammoSite applicator to deliver 34 Gy prescribed at 1 cm from the balloon surface in 10 fractions over 5 to 8 days. Results: The main disqualifying factor was pathologic sentinel node involvement. After a median follow-up of 13 months, there were no local recurrences. Seventeen (68%), 13 (52%), 7 (28%), 5 (20%) and 4 (16%) patients had erythema, seroma, inflammation, hematoma and infection, respectively. Only 2 patients developed telangiectasia. At 3 months breast erythema grade ≥ 2 was significantly correlated to cosmetic results (12.5% in the ‘good to excellent‘ versus 57% in the ‘poor to fair‘ group; p = 0.045). The strongest trend of excellent cosmetic outcome was observed in patients with skin spacing ≥ 19 mm (50%) compared to patients with < 19 mm (11%; p = 0.087). At 1 year the rate of ‘good to excellent‘ cosmetic results was 84%. Significant changes in QoL were observed for emotional and social well-being between 3 and 12 months. At 24 months only emotional well-being subscore changes were statistically significant (p = 0.015). Param Conclusions: To our knowledge, this is the first study since the initial FDA clinical study showing the feasibility of MammoSite brachytherapy procedure as a sole therapy in highly selected patients older than 60 years. This is also the first report on QoL during and after APBI using HDR brachytherapy with a MammoSite device. The toxicity and cosmetic results are in the range of other series. Higher range of skin spacing allowed a significant reduction of the risk of telangiectasia. QoL evaluation indicate that baseline scores were satisfactory. Changes concerned mainly emotional and social well-being. No significant financial relationships to disclose.

Lumen Loss in the First Year in Saphenous Vein Grafts Is Predominantly a Result of Negative Remodeling of the Whole Vessel Rather Than a Result of Changes in Wall Thickness

The use of saphenous vein grafts (SVG) in coronary artery bypass surgery is established but little is known of SVG remodeling during the first year in vivo. The feasibility of measuring total vessel diameter (lumen plus wall), lumen diameter, and wall thickness by a novel computed tomography (CT) method was established in phantom model tubes (r=0.98 for lumen diameter and r=0.98 for wall thickness) and in an initial clinical study of 14 patients correlating CT and intravascular ultrasound measurements of SVG (r=0.88 for total vessel diameter, r=0.85 for lumen diameter and r=0.89 for wall thickness). In a separate group of 42 patients (aged 66+/-10 years; 36 male, 6 female) undergoing coronary artery bypass grafting, SVG total vessel diameter, lumen diameter, and wall thickness were determined prospectively with multi-slice CT angiography at 1 and 12 months postoperatively. Mean total vessel diameter decreased from 5.95+/-0.83 mm to 5.39+/-0.87 mm, P<0.001 (range, -39% to +8% change). Twenty-six patients (62%) had a decrease of SVG vessel diameter (negative remodeling) >5%. Mean lumen diameter decreased from 3.69+/-0.66 mm to 3.36+/-0.68 mm, P<0.001, (range, -40 to +11% change). Surprisingly, mean wall thickness decreased from 1.14+/-0.27 mm to 1.01+/-0.21 mm (P<0.001; range, -48 to +33% change). Lumen loss in SVG between postoperative months 1 and 12 is predominantly caused by negative remodeling of the whole vessel rather than to changes in wall thickness. Therapies targeting negative remodeling may be required for optimal maintenance of SVG lumen in the first postoperative year.

P4-312: A model-based comparison of the nonclinical and clinical effects of anti-Aβ antibodies on plasma Aβ1-40 levels

Administration of anti–Aβ antibodies to animals and humans produces increases in the total levels of Aβ in the plasma. This biomarker response provides evidence that the antibodies ‘hit the target’ and also provides insight for comparison of effects between species. Although difficult to measure directly, an understanding of antibody effects on ‘free’ Aβ levels would also be advantageous, as one of the desired effects of antibody administration is to decrease ‘free’ Aβ levels and shift Aβ equilibria away from deposition into plaque. Mechanism–based pharmacokinetic/pharmacodynamic (PK/PD) models were developed to characterize relationships between plasma anti–Aβ antibody levels and the time–course of the plasma Aβ1–40 response in PDAPP mice and Alzheimer's patients. These models allow inference of effects on both ‘total’ and ‘free’ Aβ. Simulations were performed to compare the relative biomarker responses in PDAPP mice and humans. Following intraperitoneal administration of anti–Aβ antibodies (m266) to PDAPP mice, plasma m266 concentrations showed first–order absorption followed by mono–exponential decay. In humans, intravenous anti–Aβ antibody administration led to bi–exponential pharmacokinetics that were well characterized using a 2–compartment PK model. In both mice and humans, antibody concentrations appeared to increase proportionally with administered dose. Dose–dependant plasma Aβ1–40 pharmacodynamic responses were observed in both mice and humans. These PD responses were well characterized using mechanism–based PK/PD models that incorporated antibody–antigen binding principles. Simulation results showed greater effects on ‘free’ Aβ1–40 at the dose levels administered in humans than for the dose levels used for nonclinical efficacy studies in PDAPP mice. This analysis illustrates that the dose levels studied in the initial clinical study compare favorably, from a biomarker perspective, with dose levels that demonstrated beneficial effects in PDAPP mice.

Use of an Optical Flow Method for the Analysis of Serial CT Lung Images 1

Serial CT lung studies are difficult to compare due to misregistration between image sets. An optical flow method (OFM) was adapted for use on CT lung images to register images and visualize changes between studies. Three applications were investigated: lung nodule assessment; evaluation of pulmonary enhancement; and functional changes due to air trapping. From an initial clinical study, a follow-up study was created by digitally manipulating the images to simulate patient positioning errors and nodule growth. Nodule growth was measured from the temporal subtraction of registered images. In application to the assessment of pulmonary enhancement, pre and postcontrast images from a patient with acute pulmonary embolism (PE) were registered. A map of the perfused blood volume was computed from the ratio of aligned lung volumes. Functional changes in the lung were demonstrated using images from a patient with air trapping. End-inspiratory and end-expiratory volumes were aligned and displacement fields estimated using the OFM. Principal strains were computed from the displacement fields. All image volumes were aligned with at least 0.95 correlation. OFM estimates of displacement showed excellent agreement with the prescribed displacements with 0.33 pixel RMS error. Nodule growth was evident in the presence of significant positioning errors. In the PE case, enhancement ratios indicated a hypoperfused area consistent with an occlusive hypodense filling defect. For the air trapping case, a strain map showed functional changes along the interface of the air trap. The OFM can facilitate the detection and quantification of changes between serial CT lung studies.

The Effect of Eculizumab Therapy on Red Cell Response Kinetics in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by clonal expansion of PNH red cells that are highly sensitive to lysis by terminal complement. The primary lesion in PNH is bone marrow failure in the form of immune-mediated aplastic anemia and peripheral blood cytopenias of varying severity. We have previously reported the successful control of hemolysis and transfusion in 11 patients with the terminal complement inhibitor eculizumab. Ten of these 11 patients remain on eculizumab therapy after approximately 3 years with maintained reductions in intravascular hemolysis and transfusion. The effectiveness of eculizumab therapy in these patients is through the protection of the PNH red cell from complement-mediated lysis and the expansion of this cell population. Flow cytometry studies have shown that the percentage of PNH red cells increased significantly from a mean of 36.7% before treatment to 58.4% at week 64 of therapy. Importantly, granulocyte, monocyte and platelet PNH clone sizes were >90% before treatment and remained stable for all patients throughout the trial suggesting that the majority of hematopoiesis is derived from PNH stem cells. We hypothesize that the PNH red cell clone should approach the clone size of other myeloid hematopoietic cells in a given patient when hemolysis is prevented by eculizumab therapy as this more accurately depicts PNH stem cell activity. Furthermore, the magnitude and rapidity of response in terms of absolute red cell counts is unknown and could potentially provide important insights into the pathophysiology of PNH. In all patients hemolysis was substantially reduced by 21 days. In 9/11 patients, there was a rapid rise in PNH red cell count with the mean absolute number of PNH red cells increasing from 1.37 x 1012/L before treatment to 1.50 x 1012/L at 2 weeks (P=0.21), 1.74 x 1012/L at 4 weeks (P=0.002), and 2.11 x 1012/L at 12 weeks (P=0.001) of eculizumab treatment. The maximum theoretical red cell response was achieved in a mean of 178 days (range 49 – 419 days). The mean absolute number of PNH red cells increased to 2.37 x 1012/L at maximum response (P=0.001), an increase of 73% (range 36% – 207%). All patients achieved a maximum response prior to 18 months of treatment and clone size was subsequently stable. In 2 patients, despite the effectiveness of eculizumab in resolving hemolysis, there was no change in absolute numbers of PNH red cells pre and post-treatment. This is likely due to a combination of a lower degree of hemolysis and more profound bone marrow insufficiency in these patients. The determination of absolute PNH red cell counts during the first 12 months of eculizumab therapy may identify which patients will become transfusion independent and which patients may benefit from additional growth factor support to boost erythropoiesis. Furthermore, long-term eculizumab therapy appeared to be associated with a stable PNH red cell clone size in this initial clinical study.

Quality of care in patients with psoriasis: an initial clinical study of an international disease management programme

Patients with psoriasis have to cope with their disease for many years or even throughout their entire life. To provide optimal care, a disease management programme was developed. This programme consisted of disease education, disease management training, and psychological support, together with topical treatment. To test a disease management programme in dermatological practice, to assess patients' satisfaction with this programme, and adherence to topical treatment. Additionally, disease severity and quality of life were assessed. An initial clinical investigation was conducted in 10 European treatment centres. A total of 330 patients were included. Patient satisfaction, adherence, disease severity and quality of life were measured with study-specific and standardized self-report questionnaires. Patients reported a high degree of satisfaction with the programme, and a high degree of adherence to topical treatment. Disease severity and quality of life significantly improved. The programme was well received by the participating professionals. The disease management programme was found to be a useful tool in the management of psoriasis, providing patients with relief from the burden of psoriasis in everyday life. A full-scale evaluation is recommended.

The Safety and Pharmacokinetics of Deferitrin, a Novel Orally Available Iron Chelator.

Background: Deferitrin (GT56-252) is an orally active, tridentate, iron chelator under development to treat chronic iron overload conditions resulting from transfusion therapy. The compound is derived from desferrithiocin specifically modified to minimize toxicity associated with the parent compound (Bergeron et al., 1999). Deferitrin effects iron excretion with an efficiency of 13–18% when administered orally to Cebus apella monkeys, a species whose iron metabolism closely resembles that of humans. Iron excretion is predominantly by the fecal route (80–90%).Methods: This Phase 1 trial was an open-label, parallel-design, two-dose study. The study consisted of a screening period, a confinement period during which a single dose of deferitrin was administered on two consecutive days with pharmacokinetic measurements, and a follow-up visit. Twenty-six patients, divided in five panels, received at least one dose of deferitrin over two days, either fasted or fed, at five dose levels from 3 to 15 mg/kg. Deferitrin was administered as liquid (3 and 4.5 mg/kg), or as 50 or 250 mg capsules (4.5, 8, 11, and 15 mg/kg). Blood samples were taken at intervals up to 24 hours to characterize the pharmacokinetics of deferitrin, and 24-hour urine collections were conducted to measure deferitrin excretion. Safety laboratories included chemistry and hematology panels, coagulation parameters, urinalysis, and urine beta-2-microglobulin. Additional safety evaluations included physical examinations and electrocardiogrammes (ECG).Results: Deferitrin was well tolerated. There were no serious adverse events while patients were confined; however, one patient with pre-existing diabetes who received 4.5 mg/kg was hospitalized after an episode of hypoglycemic coma three days after the second dose. This had been a recurring phenomenon in this patient, and was determined by the investigator to be unrelated to administration of deferitrin. There were no clinically significant changes in safety laboratories, including chemistry, hematology, and coagulation studies, in urinalyses or urinary beta-2-microglobulin levels. ECGs performed before and after dosing were unremarkable. The AUC for the fed and fasted states were similar, both for the liquid and capsule, suggesting that bioavailability is not impaired by food. From 13 to 48% of the drug was present in serum as the 2:1 deferitrin: iron complex. The T½ (approximately 2 to 4 hours) was similar for all doses. Preliminary measurement of deferitrin levels in the urine showed recovery of approximately 75% at all doses. Approximately 2% of the deferitrin in the urine was complexed to iron.Conclusion: In this initial clinical study, deferitrin was safe, well-tolerated, and well-absorbed either with food and fasting in beta-thalassemia patients. Renal excretion of deferitrin uncomplexed with iron was similar to that seen in preclinical studies, which predict iron excretion to be via the fecal route. Further studies are ongoing to define the effect of deferitrin on iron balance.

Importance of lateral row perforator vessels in deep inferior epigastric perforator flap harvesting.

Free flaps based on perforator vessels, and in particular the deep inferior epigastric perforator (DIEP) flap, are currently being applied in abdominal reconstruction. However, one of the main disadvantages is the operative complexity. Through anatomical study and clinical experience with the DIEP flap in breast reconstruction, the intramuscular path of the perforator vessels was comparatively studied, to establish the main anatomical parameters that favor procedure planning. Thirty DIEP flaps from 15 fresh cadavers were used. The number, location, and intramuscular course of the perforator vessels were determined. In addition, an initial clinical study was performed in 31 patients using 35 DIEP flaps in breast reconstruction. The number, location, and the intramuscular course of the perforators were assessed. In the cadaver study, 191 perforator vessels were detected (6.4 vessels per flap). Thirty-four percent were located in the lateral row, and the rectilinear course was observed in 79.2 percent of these vessels. In the medial row, only 18.2 percent of the perforator vessels presented this configuration (p = 0.001). Thirty-one patients underwent DIEP flap breast reconstruction, with 26 immediate and four bilateral reconstructions. In 22 of 35 flaps (62.9 percent), two perforators were used. In 25 flaps (71.4 percent), the lateral row perforators with a rectilinear course were observed. Mean operative time was 7 hours and 37 minutes. Two total flap losses and two partial necroses were observed. The majority of the lateral row perforators presented a rectilinear intramuscular course, which was shorter than that of the medial row perforators. This anatomical characteristic favors dissection with reduced operative time and vascular lesion morbidity, resulting in an important anatomical parameter for DIEP flap harvesting.

COX-inhibiting nitric oxide donators (CINODs) - a new paradigm in the treatment of pain and inflammation.

The clinical utility of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) for pain relief is tempered by their propensity to cause gastrointestinal toxicity. Cyclooxygenase (COX)-inhibiting nitric oxide donators (CINODs) are a new class of drugs designed to provide analgesic efficacy through COX inhibition and gastrointestinal safety through the protective effects of controlled nitric oxide donation. Pre-clinical studies assessing the pharmacology, efficacy and gastrointestinal safety of AZD3582 [4-(nitrooxy)butyl-(2S)-2-(6-methoxy-2-naphthyl)propanoate] support this concept. Based on these studies, AZD3582 was the first CINOD to enter clinical development for the treatment of acute and chronic pain. The potential clinical utility of this new class is illustrated by a study of AZD3582 in healthy volunteers in which it caused significantly less acute gastrointestinal toxicity than an equimolar dose of naproxen. The results of the animal studies and the initial clinical study warrant long-term tolerability studies of AZD3582 along with evaluation of its anti-inflammatory and analgesic effects in humans.

The efficacy of non-contrast helical computed tomography in the prediction of urinary stone composition in vivo.

The composition of urinary stones was predicted on the basis of the differences in their Hounsfield unit (HU) densities as detected by in vivo non-contrast helical computed tomography (NCHCT). A total of 87 stones, which had been obtained from patients admitted to the emergency department with acute flank pain, were analysed biochemically. These stones had been visualized by NCHCT before spontaneous passage, ureteroscopic extraction or surgical removal, and their HU densities had been recorded. The HU densities of the stones were compared with the results of biochemical analysis. The mean HU densities of the stones composed of calcium oxalate (n = 54), struvite (n = 19) and uric acid (n = 14) were 812 +/- 135, 614 +/- 121 and 413 +/- 143, respectively. The differences between the mean HU densities of these three stone types were statistically significant. This initial clinical study demonstrated that in vivo NCHCT analysis may be used to predict the composition of urinary stones.

Real-time three-dimensional color doppler evaluation of the flow convergence zone for quantification of mitral regurgitation: Validation experimental animal study and initial clinical experience

Background: Pitfalls of the flow convergence (FC) method, including 2-dimensional imaging of the 3-dimensional (3D) geometry of the FC surface, can lead to erroneous quantification of mitral regurgitation (MR). This limitation may be mitigated by the use of real-time 3D color Doppler echocardiography (CE). Our objective was to validate a real-time 3D navigation method for MR quantification. Methods: In 12 sheep with surgically induced chronic MR, 37 different hemodynamic conditions were studied with real-time 3DCE. Using real-time 3D navigation, the radius of the largest hemispherical FC zone was located and measured. MR volume was quantified according to the FC method after observing the shape of FC in 3D space. Aortic and mitral electromagnetic flow probes and meters were balanced against each other to determine reference MR volume. As an initial clinical application study, 22 patients with chronic MR were also studied with this real-time 3DCE-FC method. Left ventricular (LV) outflow tract automated cardiac flow measurement (Toshiba Corp, Tokyo, Japan) and real-time 3D LV stroke volume were used to quantify the reference MR volume (MR volume = 3DLV stroke volume − automated cardiac flow measurement). Results: In the sheep model, a good correlation and agreement was seen between MR volume by real-time 3DCE and electromagnetic (y = 0.77× + 1.48, r = 0.87, P <.001, δ = −0.91 ± 2.65 mL). In patients, real-time 3DCE-derived MR volume also showed a good correlation and agreement with the reference method (y = 0.89× − 0.38, r = 0.93, P <.001, δ = −4.8 ± 7.6 mL). Conclusions: real-time 3DCE can capture the entire FC image, permitting geometrical recognition of the FC zone geometry and reliable MR quantification. (J Am Soc Echocardiogr 2003;16:38-45.)

Safety and shedding of an attenuated strain of Listeria monocytogenes with a deletion of actA/plcB in adult volunteers: a dose escalation study of oral inoculation.

Listeria monocytogenes is an intracellular bacterial pathogen which causes bacteremia and has a tropism for the central nervous system and a propensity to cause maternofetal infection. L. monocytogenes has been shown to be an effective prophylactic and a therapeutic vaccine vector for viral and tumor antigens in animal models. L. monocytogenes mutants lacking the ActA protein, which is essential for intracellular movement, are attenuated but retain immunogenicity in mice. Given the pathogenic potential of L. monocytogenes, we created an attenuated mutant strain bearing double deletions in the actA and plcB virulence genes for an initial clinical safety study of a prototype L. monocytogenes vector in adults. Twenty healthy volunteers received single escalating oral doses (10(6) to 10(9) CFU, 4 volunteers per dose cohort) of this attenuated L. monocytogenes, designated LH1169. Volunteers were monitored in the hospital for 14 days with frequent clinical checks and daily blood and stool cultures, and they were monitored for six additional weeks as outpatients. There were no positive blood cultures and no fevers attributable to the investigational inoculation. Most volunteers shed vaccine bacteria for 4 days or less, without diarrhea. One volunteer had a late positive stool culture during outpatient follow-up. Three volunteers had abnormal liver function test results temporally associated with inoculation; one could be reasonably attributed to another cause. In the highest-dose cohort, humoral, mucosal, and cellular immune responses to the investigational organism were detected in individual volunteers. Attenuated L. monocytogenes can be studied in adult volunteers without serious long-term health sequelae.

CRHR1 Antagonists as Novel Treatment Strategies

Research has provided considerable evidence for the hypothesis that corticotropin-releasing hormone (CRH), the key central coordinator of stress-hormone homeostasis, also plays a role in the development and course of depression and anxiety disorders. Studies using animal models of anxiety, as well as mouse mutants, in which the gene coding for the CRH type 1 receptor (CRHR1) was genetically deleted supported the notion that enhanced CRH/CRHR1 signaling underlies depression and anxiety disorders. Therefore, a number of small nonpeptide molecules that antagonize CRHR1 have been developed. In animal models, these molecules had anxiolytic and other stress-alleviating effects. An initial clinical study showed that CRHR1 antagonism has beneficial effects on depression and anxiety symptoms at doses unharmful to neuroendocrine stress responsivity.

A Phase I trial of h-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma

Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer. A continuous intravenous infusion of ISIS 2503 was administered for 14 days every 3 weeks to 23 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 2503 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/kg/day of body weight was reached. Toxicity was scored by the National Cancer Institute's Common Toxicity Criteria, and tumor response was monitored after every two treatment cycles. Pharmacokinetic studies were performed in some of the patients up to, and including, the final dose of 10 mg/kg/day/day of body weight. Levels of H-ras mRNA expression also were determined in the circulating lymphocytes of some patients by quantitative reverse transcriptase-polymerase chain reaction. A total of 23 patients received 63 cycles of ISIS 2503 at escalating doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cycles. No consistent decreases in H-ras mRNA levels were observed in peripheral blood lymphocytes. ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.

Scleral outfolding for macular translocation

PURPOSE: To report experimental study and clinical observation of scleral outfolding for macular translocation. METHODS: In six human cadaver eyes , circumferential mattress sutures to create sclera infoldings were compared with radial-interrupted mattress sutures to create scleral outfoldings. In a 75-year-old man with macular degeneration and choroidal neovascular membrane, radial-interrupted mattress sutures were used for macular translocation. RESULTS: In the human cadaver eyes, circumferential mattress sutures for scleral infolding created an average decrease in corresponding internal anteroposterior retinal contour of 0.36 mm. Radial-interrupted mattress sutures for scleral outfoldings created an average decrease in the corresponding internal anteroposterior retinal contour of 4.61 mm. The statistical significance of the difference between infoldings of the sclera versus outfoldings of the sclera had a P value of .0001. CONCLUSIONS: Initial experimental and clinical study suggests that radial-interrupted mattress sutures may generate more shortening of the internal scleral surface and greater macular translocation than circumferential mattress sutures. Additional studies are needed to evaluate the long-term effects of radial-interrupted mattress sutures and macular translocation for treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration.

No-carrier-added 123I-MIBG: An initial clinical study in patients with phaeochromocytoma

Radioiodinated meta-iodobenzylguanidine (MIBG) is used routinely for imaging and targeted radiotherapy of tumours derived from the neural crest. Since active uptake of MIBG by the noradrenaline transporter (NAT) makes a greater contribution to total drug accumulation than passive uptake when MIBG is present at low concentrations, tumour-specific uptake should be enhanced by the administration of lower molar amounts of MIBG. This could be achieved through the use of MIBG with a high specific activity. Commercially available preparations of 123I-MIBG have specific activities of approximately 200 MBq.mg-1. We have synthesized and used no-carrier-added (n.c.a.) 123I-MIBG produced by an iododesilylation reaction (specific activity 0.7 TBq.mg-1). We report here the first clinical studies comparing the commercially available and n.c.a. MIBG diagnostic preparations. Five patients with known phaeochromocytoma were studied. Unlike studies in animal models, no consistent improvement in tumour uptake was observed with the n.c.a. material. A larger patient group is required to determine whether there are significant differences between the two preparations, before proceeding to studies at therapeutic activity levels of n.c.a. 131I-MIBG. Even with no improvement in tumour uptake, n.c.a. MIBG may be the favoured formulation for therapeutic applications to reduce the molar amount of drug injected.

Assessment of Regional Wall Motion Abnormalities with Real-Time 3-Dimensional Echocardiography

Accurate characterization of regional wall motion abnormalities requires a thorough evaluation of the entire left ventricle (LV). Although 2-dimensional echocardiography is frequently used for this purpose, the inability of tomographic techniques to record the complete endocardial surface is a limitation. Three-dimensional echocardiography, with real-time volumetric imaging, has the potential to overcome this limitation by capturing the entire volume of the LV and displaying it in a cineloop mode. The purpose of this study was to assess the feasibility of using real-time 3-dimensional (RT3D) echocardiography to detect regional wall motion abnormalities in patients with abnormal LV function and to develop a scheme for the systematic evaluation of wall motion by using the 3-dimensional data set. Twenty-six patients with high-quality 2-dimensional echo images and at least 1 regional wall motion abnormality were examined with RT3D echocardiography. For 2-dimensional echocardiography, wall motion was analyzed with a 16-segment model and graded on a 4-point scale from normal (1) to dyskinetic (4), from which a wall motion score index was calculated. Individual segments were then grouped into regions (anterior, inferoposterior, lateral, and apical) and the number of regional wall motion abnormalities was determined. The RT3D echocardiogram was recorded as a volumetric, pyramid-shaped data set that contained the entire LV. Digital images, consisting of a single cardiac cycle cineloop, were analyzed off-line with a computerized display of the apical projection. Two intersecting orthogonal apical projections were simultaneously displayed in cineloop mode, each independently tilted to optimize orientation and endocardial definition. The 2 planes were then slowly rotated about the major axis to visualize the entire LV endocardium. Wall motion was then graded in 6 equally spaced views, separated by 30 degrees, yielding 36 segments per patient. A higher percentage of segments were visualized with 2-dimensional versus RT3D echocardiography (97% vs 83%, respectively, P < .001). With the use of the 2-dimensional echocardiographic results as the standard, RT3D echocardiography detected 55 (96%) of 57 regional wall motion abnormalities. Analysis of the RT3D echocardiograms resulted in 3 false-negative and 5 false-positive findings. The total number of regional wall motion abnormalities was correctly classified by RT3D echocardiography in 19 (73%) of 26 patients. RT3D echocardiography detected 11 of 13 anterior, 19 of 20 inferoposterior, 9 of 9 lateral, and 15 of 15 apical wall motion abnormalities. An excellent correlation was found between the 2 techniques for assessment of the regional wall motion score index ( r = 0.89, P < .001). This initial clinical study demonstrates the feasibility and potential advantages of RT3D echocardiography for the assessment of regional LV function. Compared with 2-dimensional echocardiography, this new method permits recording of the entire LV in a single beat, allowing the extent and location of the regional wall motion abnormalities to be determined. (J Am Soc Echocardiogr 1999;12:7-14.)

Intraoperative monitoring with stimulus-evoked electromyography during placement of iliosacral screws. An initial clinical study.

A consecutive series of twenty-seven patients who had thirty acute unstable (type-C) fractures of the pelvic ring was studied prospectively to evaluate the use of stimulus-evoked electromyography to decrease the risk of iatrogenic nerve-root injury during the insertion of iliosacral screws. A prerequisite for inclusion in the study was a normal neurological status preoperatively; somatosensory evoked potentials were monitored to further document the neurological status both before and after insertion of the screw or screws. A total of fifty-one iliosacral screws were inserted, and a current threshold of more than eight milliamperes was selected as the level that indicated that the drill-bit was a safe distance from the nerve root. Four of the fifty-one screws were redirected because of information obtained with stimulus-evoked electromyography. Postoperatively, all patients had a normal neurological status. Computerized tomography, although not accurate for detailed measurements, demonstrated that all of the screws were in a safe, intraosseous position. Monitoring with stimulus-evoked electromyography appears to provide reliable data and may decrease the risk of iatrogenic injury to the nerve roots during operations on the pelvic ring.

Glutamine saves lives! What does it mean?

Glutamine-supplemented amino acid solutions are being utilized more frequently, especially following Food and Drug Administration approval and commercial availability of glutamine (Gln) dipeptides for parenteral infusion in Europe. It is important now, through evidence-based clinical investigation, to determine the appropriate patient groups who will benefit from this advancement. In the initial clinical outcome study, patients undergoing bone marrow transplantation were randomized to receive a Gin-supplemented parenteral mixture or standard Glnfree intravenous nutrition. I In the Gin-supplemented group, infection was decreased, length of stay was reduced, and hospital cost was significantly tess) The Gin-supplemented patients had a greater lymphocyte count at the time of bone marrow recovery, with T-cell subsets predominating. 3 These findings have been supported by other clinical investigations. Individuals receiving Gin-containing parenteral nutrition following bone marrow transplantation or major operation have a greater leukocytosis, 4 improved T-cell DNA synthesis, 5 the enhanced ability to express the anti-inflammatory cytokine interleukin-106, and the increased capacity to secrete the less toxic cystinyl-leukotrienes. 6 Gin administration has also been associated with decreased complications, improved nitrogen balance, and a reduced length of hospital stay. 4'6'7 In addition to these effects on immune function, Gln also supports the bowel, particularly by enhancing gut-barrier func, tion. 8 This clinical effect is most dramatically observed in premature infants who are born with an immature, leaky bowel. 9 Infants receiving Gin-fortified formulas reduced their bowelrelated infection rate from 30.2 to 11.4%. These and possibly other unknown effects of Gln may be important in interpreting the study by Griffiths et al. 1° published in this issue of Nutrition. This intensive-care team selected for study the most difficult group of patients cared for in their unit: those severely ill septic patients who required mechanical ventilation, couldn't be fed by the enteral route, and had a high incidence of multiple-organ failure. Only patients with liver failure and end-stage cancer (plus pregnant women and children) were excluded from this trial. Because of the heterogeneity and high mortality of this group, these patients are infrequently studied; yet it is this same patient group that requires new therapy in order to improve their outcome. One-half of the patients studied were randomized to receive a Gin-containing parenteral solution and the other half received conventional total parenteral nutrition. At entry, the groups were well matched as determined by multiple assessment criteria, including a variety of techniques to evaluate health status. As the study progressed, patient deaths occurred, initially from the underlying disease process but later from the consequences of sepsis and multiple-organ failure. Of significance, however, was the difference in late mortality observed in the two groups. In those patients fed > 10 d, 12/17 (71%) of controls died versus only 5/18 (28%)of the, Gin-fed patients (P = 0.03). At 6 mo, significantly more patients receiving Gln were alive than those who received conventional feedings (24 versus 14; P = 0.049). Why should this be so? First, we have already catalogued a number of biochemical mechanisms and physiologic functions that are influenced by Gin, and these effects may be highly beneficial to such critically ill patients. However, I would propose that Gin is playing a more global regulatory role by modifying the endogenous inflammatory response, possibly by attenuating the elaboration of proinflammatory mediators, and/or by upregulating anti-inflammatory factors. These effects could be mediated through the enhanced synthesis of the important intracellular antioxidant glutathione, which occurs with Gin administration, 11 but I suspect additional mechanisms are involved. To address such a question, one would need to harvest both serum and cells from shnilar patients so that circulating mediators and the cells' capacities to generate these signal proteins could be evaluated and the responses of these two patient groups compared. Blinded studies in acutely ill patients that extended for years (in this case 3 y, 9 mo) require unwavering faith in the scientific process. The unit must resist subtle changes in care that would jeopardize the study, and investigators must stay motivated and committed to the recruitment of patients and performing the details involved with such an investigation. All individuals involved with direct patient care must remain blinded.