Biomedical subjects
Publications and source records attributed to J Shefner.
An open-label dose-escalation trial was performed to assess the safety and tolerability of high doses of coenzyme Q10 (CoQ10) in ALS. CoQ10, a cofactor in mitochondrial electron transfer, may improve the mitochondrial dysfunction in ALS. In this study, CoQ10 was safe and well tolerated in 31 subjects treated with doses as high as 3,000 mg/day for 8 months.
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PURPOSE: Immunotoxins could improve outcome in small-cell lung cancer (SCLC) by targeting tumor cells that are resistant to chemotherapy and radiation. N901 is a murine monoclonal antibody that binds to the CD56 (neural cell adhesion molecule [NCAM]) antigen found on cells of neuroendocrine origin, including SCLC. N901-bR is an immunoconjugate of N901 antibody with blocked ricin (bR) as the cytotoxic effector moiety. N901-bR has more than 700-fold greater selectivity in vitro for killing the CD56+ SCLC cell line SW-2 than for an antigen-negative lymphoma cell line. Preclinical studies suggested the potential for clinically significant cardiac and neurologic toxicity. We present a phase I study of N901-bR in relapsed SCLC. PATIENTS AND METHODS: Twenty-one patients (18 relapsed, three primary refractory) with SCLC were entered onto this study. Successive cohorts of at least three patients were treated at doses from 5 to 40 microg/kg/d for 7 days. The initial three cohorts received the first day's dose (one seventh of planned dose) as a bolus infusion before they began the continuous infusion on the second day to observe acute toxicity and determine bolus pharmacokinetics. Toxicity assessment included nerve-conduction studies (NCS) and radionuclide assessment of left ventricular ejection fraction (LVEF) before and after N901-bR administration to fully assess potential neurologic and cardiac toxicity. RESULTS: The dose-limiting toxicity (DLT) of N901-bR given by 7-day continuous infusion is capillary leak syndrome, which occurred in two of three patients at the dose of 40 microg/kg (lean body weight [LBW])/d. Detectable serum drug levels equivalent to effective in vitro drug levels were achieved at the 20-, 30-, and 40-microg/kg(LBW)/d dose levels. Specific binding of the immunotoxin to tumor cells in bone marrow, liver, and lung was observed. Cardiac function remained normal in 15 of 16 patients. No patient developed clinically significant neuropathy. However, a trend was noted for amplitude decline in serial NCS of both sensory and motor neurons. One patient with refractory SCLC achieved a partial response. CONCLUSION: N901-bR is an immunotoxin with potential clinical activity in SCLC. N901-bR is well tolerated when given by 7-day continuous infusion at the dose of 30 microg/kg(LBW)/d. Neurologic and cardiac toxicity were acceptable when given to patients with refractory SCLC. A second study to evaluate this agent after induction chemoradiotherapy in both limited- and extensive-stage disease was started following completion of this study.
PURPOSE: We attempted to assess the usefulness of urodynamic testing for diagnosing lipoma and lipomeningocele, and the late effects of early neurosurgical intervention in children less than 1 year old. MATERIALS AND METHODS: A total of 28 patients in whom spinal surgery was performed before age 1 year for correcting lipoma and lipomeningocele underwent neurological and urodynamic evaluation preoperatively, and within 3 months and up to 14.5 years postoperatively. RESULTS: Preoperatively 15 patients (54%) had an abnormal neurological examination and 7 had an abnormal urodynamic study. Of the 13 patients with a normal neurological examination 3 had an abnormal urodynamic study. Overall 10 patients (37%) had an abnormal urodynamic examination preoperatively. Immediately after surgery 8 patients (29%) had improvement (2 of 15 with an abnormal neurological examination and 6 of 10 with an abnormal urodynamic study), whereas the condition of 9 (32%) worsened, including 4 of the 13 who were neurologically and 6 of the 18 who were urodynamically normal (1 in both categories). With time an additional 7 patients (25%) had progressive deterioration, including 6 urodynamically and 5 neurologically (4 in both categories), 2 (7%) had improvement (1 each urodynamically and neurologically) and the condition of 19 (68%) remained stable. Six patients (21%) underwent secondary spinal surgery for recurrent tethering. CONCLUSIONS: Early surgical repair seems to provide a degree of protection against later spinal cord tethering, and subsequent neurological and/or urodynamic deterioration (25% of our patients versus a reported 80% of those followed expectantly).
From 1987 to 1993, 21 older individuals presented for the first time with signs and symptoms that eventually led to the diagnosis of occult spinal dysraphism. Assessment consisted of a neurological examination, urodynamic studies preoperatively and postoperatively, and spinal cord imaging. Of 21 patients 18 had an abnormal neurological examination, whereas only 15 had an abnormal urodynamic study, as judged by sphincter electromyography. Radiological imaging showed that 9 patients had a tethered cord alone, 4 each had lipomeningocele and lipoma, 2 had a bony spine abnormality and 1 each had thoracic meningocele and diastematomyelia. Of the 21 patients 19 underwent spinal surgery. Postoperatively, the neurological examination improved in 1 case (5%) and remained unchanged in 18 (95%), while urodynamic findings improved in 3 (16%), were unchanged in 11 (68%) and worsened in 5 (26%). Six patients had progressive deterioration and required secondary spinal surgery, which helped only 2 (33%). These observations confirm that older children and adults with occult spinal dysraphism are more likely to present with irreversible urological and neurological findings than younger children, and so it is imperative that a diagnosis be made and treatment be instituted as early as possible.
Nerve regeneration was followed in 15 median and 1 ulnar nerve of eight Macaca fascicularis monkeys by serial electrophysiological assessments over a period of three and a half years. Nerve gaps of 5 mm at the wrist were bridged by collagen-based nerve guides, nerve autografts, or direct suture repairs. Thenar muscle reinnervation occurred between 50 and 70 d for all groups, indicating axonal elongation rates of approximately 1 mm/d. The recovery rates of the compound muscle action potential (CMAP) and the compound sensory action potential (CSAP) amplitudes were significantly slower after direct suture repair compared to the other two procedures, although the final levels of recovery were all comparable. Similar results were achieved in one median and one ulnar nerve following nerve guide repair of a 15 mm nerve gap. The functional reinnervation of Pacinian corpuscles was detected in all cases following either nerve graft or nerve guide repair, with similar amplitudes and latencies of the tactile evoked CSAP for both types of repair. Histological analysis demonstrated a significant increase in the number of myelinated axons in the median nerve distal to the nerve lesions following both nerve graft and nerve guide repairs compared to proximal and normal controls, with significant reductions of fiber diameter and corresponding increases in g-ratio. The return of a bimodal frequency distribution of myelinated axon fiber diameter was confirmed by three-dimensional surface plots which illustrate the frequency distribution of the relationship between fiber diameter and g-ratio. These combined results demonstrate that nerve regeneration after repair of a 5 mm nerve gap with a collagen nerve guide in the nonhuman primate is similar to that after graft repair, and the final level of physiological recovery for both repair procedures is comparable to direct suture repair of the median nerve.
In patients with small-cell lung cancer (SCLC), relapse with resistant disease often causes death. N901-blocked ricin (N901-bR), a murine monoclonal antibody (MAb)-blocked ricin immunotoxin, is a potential therapeutic for SCLC. N901-bR targets CD56, present on SCLC and cells of neuro-ectodermal origin. N901-bR kills up to 5 logs of CD56-positive cells at a concentration of 0.25 nM, while CD56-negative cells require 1000-fold more drug to achieve similar cell kill. We treated 21 patients with relapsed or refractory SCLC with a single 7-day course of N901-bR as a continuous infusion. We determined the MTD and toxicity profile, demonstrated drug binding to tumor cells in biopsies of lung, liver and bone marrow, and determined the time to development of human anti-mouse and anti-ricin antibodies. One patient had a documented PR and 6 patients demonstrated stable disease. Toxicity included transient elevation of liver enzymes, mild thrombocytopenia, hypoalbuminemia, fever, malaise, and evidence of capillary leak syndrome. Toxicities were controllable and reversible. No apparent drug-related central- or peripheral-nervous-system toxicity was noted by serial neurologic examinations, EMGs, and nerve conduction studies. Trials of N901-bR are planned in SCLC patients achieving CR and PR following chemoradiotherapy, and in relapsed/refractory patients. Anti-B4-bR will be added as an immunosuppressant in order to permit delivery of multiple courses of N901-bR. Additional trials will investigate synergy with conventional chemotherapeutics and the use of N901-bR as a sensitizing agent for chemotherapy-resistant tumors.
From 1986 to 1991, 12 boys and 23 girls underwent surgery for lipomyelomeningocele removal. Of these patients 29 were 15 months old or younger (average age 3 months), while 6 were 4.5 to 19 years old (average age 10 years). Preoperative and postoperative urodynamic studies, including external urethral sphincter electromyography, were done on everyone. All 29 infants had a cutaneous lesion overlying the lower back and 14 had an abnormal neurological examination. Preoperative urodynamic studies were abnormal in 11 patients, consisting of an upper motor neuron lesion in 6, and a mixed upper and lower motor neuron lesion in 5. Postoperatively, 10 of 14 children with an abnormal neurological examination improved, while 9 of 11 with abnormal lower urinary tract function normalized. In 1 of 18 children (6%) with normal preoperative urodynamic studies detrusor-sphincter dyssynergia developed postoperatively. In all 6 older children urinary incontinence developed, and this led to the diagnosis. Everyone had an abnormal neurological examination and abnormal preoperative urodynamic studies. One child had a lower motor neuron lesion, and 5 had a mixed upper and lower motor neuron lesion. Postoperatively, the neurological examination improved in only 1 patient (16%), and the urological symptoms and urodynamic findings improved in another child. Lipomyelomeningocele has a progressive effect on lower spinal cord function because infants tend to present with fewer urinary manifestations and physical findings than older children. Individuals who escape early detection tend to have a more subtle cutaneous abnormality. As a result, older children are more likely to present with urological and neurological complaints. Surgical correction in infancy provides a degree of reversibility not seen in older children. It is imperative that early identification, evaluation and treatment be undertaken to prevent this progression and permanency of neurological changes and urinary dysfunction.
When a peripheral nerve is severed and left untreated, the most likely result is the formation of an endbulb neuroma; this tangled mass of disorganized nerve fibers blocks functional recovery following nerve injury. Although there are several different approaches for promoting nerve repair, which have been greatly refined over recent years, the clinical results of peripheral nerve repair remain very disappointing. In this paper we compare the results of a collagen nerve guide conduit to the more standard clinical procedure of nerve autografting to promote repair of transected peripheral nerves in rats and nonhuman primates. In rats, we tested recovery from sciatic nerve transection and repair by 1) direct microsurgical suture, 2) 4 mm autograft, or 3) entubulation repair with collagen-based nerve guide conduits. Evoked muscle action potentials (MAP) were recorded from the gastrocnemius muscle at 4 and 12 weeks following sciatic nerve transection. At 4 weeks the repair group of direct suture demonstrated a significantly greater MAP, compared to the other surgical repair groups. However, at 12 weeks all four surgical repair groups displayed similar levels of recovery of the motor response. In six adult male Macaca fascicularis monkeys the median nerve was transected 2 cm above the wrist and repaired by either a 4 mm nerve autograft or a collagen-based nerve guide conduit leaving a 4 mm gap between nerve ends. Serial studies of motor and sensory fibers were performed by recording the evoked MAP from the abductor pollicis brevis muscle (APB) and the sensory action potential (SAP) evoked by stimulation of digital nerves (digit II), respectively, up to 760 days following surgery. Evoked muscle responses returned to normal baseline levels in all cases. Statistical analysis of the motor responses, as judged by the slope of the recovery curves, indicated a significantly more rapid rate of recovery for the nerve guide repair group. The final level of recovery of the MAP amplitudes was not significantly different between the groups. In contrast, the SAP amplitude only recovered to the low normal range and there were no statistically significant differences between the two groups in terms of sensory recovery rates. The rodent and primate studies suggest that in terms of recovery of physiological responses from target muscle and sensory nerves, entubulation repair of peripheral nerves with a collagen-based nerve guide conduit over a short nerve gap (4 mm) is as effective as a standard nerve autograft.(ABSTRACT TRUNCATED AT 400 WORDS)