Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.

Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.

Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study.

In this pilot study of metastatic melanoma, interleukin-2 (IL-2) and cisplatin (CDDP) chemotherapy were combined using an alternating schedule designed to explore potential synergism between these modalities. Bolus IL-2 was given at a dose of 600,000 IU/kg intravenously (IV) every 8 hours, days 1 to 5 and 15 to 19, followed by high-dose CDDP administered by two different regimens: (A) 135 to 150 mg/m2 IV bolus over 30 minutes with the chemoprotectant WR-2721 910 mg/m2 or (B) 50 mg/m2 IV over 2 hours every day for 3 days. The trial design allowed an assessment of response to each phase of therapy. Among 27 assessable patients, there were 10 (37%) overall responses, including three (11%) complete responses (CRs) with durations of 9, 16, and 30+ months. Tumor regression was noted in seven patients (partial response [PR], four; minor response [MR], three; response rate [RR], four of 27 [15%]) after IL-2 administration and in 14 patients (PR, 12; MR, two; RR, 12 of 27 [44%]) after CDDP treatment, demonstrating noncrossresistance between the components of the regimen. Major PRs (greater than 90% reduction of tumor burden) or CRs were only seen in patients responding to IL-2. Toxicity during IL-2 therapy was typical for high-dose IL-2 protocols and was reversible. Among the first 20 patients treated with CDDP regimen A, there were eight episodes of grade IV nephrotoxicity (creatinine level greater than 5.0 mg/dL), including three of six patients treated with an initial CDDP dose of 135 mg/m2. This side effect was more frequent among patients with liver metastasis (P less than .05, Fisher's exact test). No significant nephrotoxicity was noted in seven patients treated on regimen B. Although ototoxicity was frequent, minimal bone marrow and neurologic toxicity was noted. There were no treatment-related deaths. This combination showed at least additive activity against melanoma, and the more protracted CDDP schedule was well tolerated. This regimen may serve as a model for future combined immunotherapy and chemotherapy trials in metastatic melanoma.

Studies of short-term secretion of peptides produced by alternative RNA processing.

Alternative RNA processing of the calcitonin gene primary transcript results in production of two peptides, calcitonin and calcitonin gene-related peptide (CGRP). We have used the TT cell line, which produces both peptides, to ascertain whether secretion of peptides produced by alternative RNA processing is under identical regulatory control. Short-term treatment of TT cells with phorbol esters and cAMP analogs caused a rapid and parallel release of both calcitonin and CGRP. The measurement of calcitonin and CGRP mRNA levels during treatment revealed that new RNA synthesis was not required for secretion. Four potential regulators of phorbol ester-mediated and five of cAMP-mediated secretion were identified by incorporation of radioactive phosphate into protein as analysed by two-dimensional polyacrylamide gel electrophoresis and autoradiography. From these results we conclude that calcitonin and CGRP secretion in this human C cell model is not differentially affected by alternative RNA processing for the phorbol ester-, and cAMP-dependent secretory pathways.

Procurement and transplantation of colonized cadaver skin.

Cadaver skin is an important adjunct to burn care. This study was designed to measure the percentage of its contamination prior to grafting and to determine the clinical safety of its use. Cadaveric homografts from 19 donors were harvested, frozen, thawed, and used as a biological dressing. Cultures were obtained at the time of harvest, after incubation in antibiotics, and at actual transplantation. The homografts were 43 per cent, 68 per cent, and 50 per cent contaminant-free, respectively. Two of 14 patients lost their homografts due to infection. However, no patient developed an infection or lost the homograft due to an organism identified during the pretransplantation processing. Therefore, contaminant-free and slightly contaminated cadaver skin can be used safely as homografts.

The Editor's Role in the Science and Art of Physical Therapy.

James A. Gould, MS, PT, delivered the Paris Distinguished Service Award Lecture at the Combined Sections meeting in San Francisco in February. Gould is the second recipient of the Orthopaedic Section's Paris Award, which was named for its first recipient and the founder of the Orthopaedic Section, Stanley Paris, PhD, PT. In 1968, Gould graduated from Central Michigan University with a BS degree in biology. He earned a BS degree in physical therapy from the University of Kentucky in 1971 and a master's degree in education from the University of Kentucky in 1974. Gould was then appointed a faculty member of the University of Wisconsin-La Crosse, where he is now an associate professor. In 1979, Gould founded The Journal of Orthopaedic and Sports Physical Therapy and served as editor until 1990. He is currently treasurer of the Private Practice Section, editor of PT Today, and co-owner of OPTions, a clinical practice in La Crosse, WI. J Orthop Sports Phys Ther 1992;15(6):323-325.

Trunk Testing Using a Prototype Cybex II lsokinetic Dynamometer Stabilization System.

This pilot study represents Cybex II isokinetic dynamometer trunk testing on 160 subjects (98 males, 62 females). A prototype apparatus which provides stabilization in the standing (functional) position was used in the testing. The testing protocols were performed first for trunk flexion and then trunk extension. The protocols consisted of two isometric tests for 5 seconds at 0 degrees trunk angle and 45 degrees trunk angle followed by three repetitions each at the isokinetic speeds of 30, 60, 90, and 120 degrees per second. Peak torque values were measured for the isometric tests. lsokinetic data interpretation consisted of: peak torque, time rate of tension development, range of motion where peak torque occurred, and total work performed. The ratios of trunk flexors to extensors at each test were also calculated. The conclusion from this pilot study is that the use of an isokinetic testing of trunk musculature and establishing normative data provide clinically useful guidelines for sports screening, industrial medicine screening, and objective parameters for discharging patients with trunk dysfunction. J Orthop Sports Phys Ther 1982;3(4):164-170.

Descriptive Measures of lsokinetic Trunk Testing.

Measurements of isokinetic parameters during trunk flexion and extension were collected for 44 untrained adult subjects (23 females, 21 males) using a Cybex(R) 11 dynamometer and trunk stabilization system interface to a Cybex Data Reduction Computer. On each of three days, subjects performed two sets (trials) of maximal extension/flexion contractions. One trial consisted of four repetitions each at the isokinetic speeds of 30, 60, 90, and 120 degrees /sec. Data interpretation consisted of: Peak torque, range of motion from the initiation of contraction to peak torque, total range of motion, total work performed, total power generated, torques produced relative to body weight, and flexion/extension torque and work ratios. It was concluded that isokinetic testing of the trunk can provide clinically useful guidelines for trunk evaluation and rehabilitation when a large data base is collected for subject populations with various physical characteristics. J Orthop Sports Phys Ther 1985;7(2):43-49.

Toxicity episodes involving agricultural chemicals and other substances in birds in Victoria, Australia.

A series of case reports detailing observations on toxicity episodes in birds caused by a variety of agricultural chemicals and other substances is presented. These problems arose as a result of ignorance, accident and malicious intent. The episodes involved maldison, monocrotophos, fenitrothion, trichlorofon, dieldrin, chlordane, endrin, metaldehyde, bromadiolone, arsenic, lead and zinc. An unresolved episode where toxicity was implicated is also included.

Pancreatic degeneration in broilers with runting and stunting syndrome.

A number of plasma biochemical parameters were examined in five outbreaks of runting in broiler chickens. In four of the five outbreaks, runts showed consistent elevations in plasma amylase activity and reductions in glutathione peroxidase activity. In two of the five outbreaks the plasma vitamin E concentration was reduced, as was the activity of plasma alkaline phosphatase. A highly significant number of runted chickens were found to have pancreatic degeneration, elevated plasma amylase activity and reduced plasma glutathione peroxidase activity, compared with non-runted chickens. The implications of these changes are discussed in relation to the aetiology of runting and stunting syndrome and, in particular, the possible involvement of selenium.

Studies on a vaccine against infections bursal disease.

An infectious bursal disease vaccine, registered for use in breeder flocks, was studied for efficacy on the day-old offspring of vaccinated hens and for virulence in susceptible day-old and 6-week-old chickens. When given to susceptible day-old chicks and 6-week-old cockerels, the vaccine was found to induce atrophy and pathology of the bursa of Fabricius similar to that observed in field infections. Chicks vaccinated at day-old had markedly lowered titres in the haemagglutination inhibition test to Newcastle disease virus, when this was given 2 weeks later, but the response of the 6-week-old cockerel was similar to that of control birds. Maternal antibody induced by the vaccine protected chicks against infection at day-old.

Functional Examination of the Shoulder Girdle.

In brief: This article outlines a systematic and comprehensive examination that can be modified to fit the signs and symptoms of the individual athlete with traumatic or spontaneous shoulder pain. The procedures are clearly illustrated and include the subjective examination, medical history, objective examination, palpation, neurological evaluation, movement and other specific tests, and Cybex isokinetic dynamometer testing. By following the procedures in the order indicated, it should be possible to identify the involved anatomical structures, determine the nature and severity of the injury, and use the information to evaluate the athlete's progress.