Effects of puzzle feeders on pathological behavior in individually housed rhesus monkeys.

Self-injurious behavior (SIB) occurs in about 10% of individually housed monkeys. Monkeys with SIB bite their own bodies frequently, occasionally inflicting wounds as a result. At present, there is no standard treatment for this phenomenon. We examined the effectiveness of puzzle feeders in alleviating SIB in monkeys with a veterinary record of self-inflicted wounding. Two groups of monkeys (SIB and controls) were exposed to puzzle feeders for a 6 week period. Three levels of maze difficulty were examined. All monkeys used the feeders, but manipulation was confined to a brief period immediately after the feeders were loaded each day (1000 h) and was infrequent during the later sampling periods (1100 and 1400 h). The most difficult maze yielded a slight increase in usage at 1100 h. During the puzzle feeder phase, whole body stereotypies, including pacing and rocking, were reduced substantially in all monkeys at 1000 h when feeder manipulation was at its highest. However, self-biting in the SIB group was unchanged. Some monkeys actually bit themselves while manipulating the feeder. Long-term effects on abnormal behavior were assessed by comparing behavior during the feeder phase to baseline periods and to a phase in which the monkeys were provisioned with treats placed directly into their food box. Whole body stereotypies, including pacing, were reduced during both treatment phases; however, the reduction was associated only with the 1000 h observation. Puzzle feeders were more effective than treats alone in alleviating whole body stereotypies. Self-biting was unchanged through all phases. Puzzle feeders are beneficial from the perspective of eliciting manipulation. They also yield transient reductions in whole body stereotypy, an effect that does not extend beyond the direct manipulation of the feeder. Puzzle feeders are ineffective in alleviating self-injurious behavior.

Photodynamic therapy for early stage squamous cell carcinoma of the lung.

OBJECTIVE: To study the effectiveness of photodynamic therapy (PDT) as a therapeutic strategy in roentgenographically occult squamous cell carcinoma of the lung. MATERIAL AND METHODS: A carefully selected group of 21 patients (with 23 cancers) who had early stage squamous cell carcinoma of the lung and were eligible for surgical treatment were offered PDT as an alternative to resection. Patients underwent close follow-up with bronchoscopic surveillance and were offered resection if cancer persisted after no more than two sessions of PDT. RESULTS: A complete response was identified in 15 patients (16 cancers) after an initial PDT session. A complete response that lasted longer than 12 months was noted in 11 patients (52%). After PDT, the minimal follow-up period was 24 months. A subsequent primary lung cancer developed in 5 of the 21 patients (24%). Ten patients ultimately had surgical treatment, in 3 (30%) of whom N1 disease was identified at the time of resection. Two patients refused a surgical procedure and received alternative therapy. Therefore, nine patients (43%) were spared an operation (95% confidence interval, 21.8 to 66.6%). The mean duration of follow-up for these nine patients was 68 months (range, 24 to 116). CONCLUSION: On the basis of this investigation, we can conclude with 95% confidence that at least 22% of patients with early stage squamous cell lung cancer who are candidates for PDT can be spared surgical resection.

Bronchoscopic phototherapy using hematoporphyrin derivative.

Phototherapy in the presence of hematoporphyrin (HPD) produces cytotoxicity through both energy- and power-dependent mechanisms. The resulting cellular death demonstrates the promise of HPD in the therapy of small cancers. This article reports our clinical experience and follow-up results of treating 19 patients with cancer of the tracheobronchial tree, who have completed at least one course of HPD administered via the flexible fiberoptic bronchoscope.

The effect of cooling on the photodynamic action of hematoporphyrin derivative during interstitial phototherapy of solid tumors. 1983 Second-Place Resident Research Award: basic category.

Hematoporphyrin derivative (HpD), a mixture of compounds chemically prepared from naturally occurring crude hematoporphyrin, is preferentially concentrated in neoplastic cells and produces red fluorescence when irradiated with blue-violet light. In addition, HpD exhibits other photodynamic properties, which, in the presence of oxygen and visible light, result in cytotoxicity. Preliminary reports indicate that early, superficial carcinomas of the upper aerodigestive tract and tracheobronchial tree can be localized and treated successfully with HpD phototherapy (HpD-PT), in which a fiberoptic bundle transmits laser light to the tumors. To assess this modality's potential for treating solid tumors, the cytotoxic effect of HpD-PT was measured in a murine tumor model. We specifically assessed the effect of cooling on the pure photodynamic action of HpD-PT. Adult female mice with typical mammary tumors received interstitial phototherapy 24 hours after HpD was given intraperitoneally. Light from an argon-dye laser was delivered through an optical fiber, along with simultaneous cooling from a cryosurgical probe, for 15 minutes. After being cooled with a cryosurgical probe, tumors were excised 48 hours after treatment and the necrotic area was measured. The results indicate that cooling enhances the tumoricidal action of HpD-PT.

Hematoporphyrin derivative phototherapy in the treatment of bronchogenic carcinoma.

Nineteen patients with cancer involving the tracheobronchial tree (a total of 20 carcinomas) have completed at least one course of hematoporphyrin derivative phototherapy administered via the flexible fiberoptic bronchoscope. Seven patients (eight carcinomas) have shown a complete response. In six of these patients (seven carcinomas), there has been no recurrence of tumor at the site of treatment during follow-up ranging from 8 to 31 months. One patient had a complete response lasting 12 months, but subsequently had a local recurrence producing obstruction; this patient died 24 months after the initial hematoporphyrin derivative phototherapy. Eight other patients had less than a complete response and required alternative therapy. Three of these eight patients died, one of metastases and two of airway obstruction and metastases. The four remaining patients died before results of this local therapy could be assessed; two died of metastases and two of hemoptysis. The cancers in patients who had a complete response were less than 3 sq cm in surface area and appeared superficial at bronchoscopy. Therefore, hematoporphyrin derivative phototherapy does have the potential to become an alternative to surgical resection as the primary treatment in carefully selected patients.

Use of a soft-agar colony-forming assay to determine the photosensitizing effects of several components of hematoporphyrin derivative.

The photosensitizing/cytotoxic effects of four porphyrin compounds derived from hematoporphyrin were compared using two human tumor cell lines with a soft-agar colony-forming assay. Reproducible dose- and time-dependent increases in reproductive cell death were observed for each porphyrin tested. Two fractions derived from hematoporphyrin derivative (HPD) were found to be better photosensitizers than HPD itself, indicating the potential value of this in vitro assay for detecting the most active component from a heterogeneous mixture.

Treatment of transitional cell carcinoma of the bladder with hematoporphyrin derivative phototherapy.

The demonstration that intravenously administered hematoporphyrin derivative concentrates preferentially in dysplastic and neoplastic transitional cells in the human bladder prompted a trial of hematoporphyrin derivative phototherapy in patients with transitional cell cancer of the bladder. A dose of 2.5 mg. per kg. was given intravenously 3 to 48 hours before treatment with light of a wavelength of 630 nm. from an argon ion pumped dye laser. Total light dose approximated 150 joules per cm.2. Four patients with resistant carcinoma in situ have been treated and all have had disappearance of the tumors proved by biopsy. Although there are many technical problems we believe that hematoporphyrin derivative phototherapy holds promise as an effective treatment modality, primarily for patients with resistant, recurrent in situ transitional cell carcinoma of the bladder.

Mayo Clinic and Medical School Biodynamics Research Unit.

The facilities that make up the Mayo Biodynamics Research Unit include the dynamic spatial reconstructor (DSR), which when fully operational will generate raw data at 200 million samples per second. Processing of these data will require a computer capable of several billion arithmetic operations per second.

Thermal considerations in murine tumor killing using hematoporphyrin derivative phototherapy.

Tumor cell killing utilizing hematoporphyrin derivative (HPD) phototherapy was studied in a murine tumor model to assess the relative importance of intratumor temperature in causing the tumoricidal effect. Temperature measurements and tumor killing without HPD strongly suggest that HPD phototherapy as reported previously by other workers has at least partially a hyperthermic effect. Also, it is shown that, in this tumor model, tissue light attenuation restricts the radius of action of the light-HPD interaction to approximately 4 mm.

Three-dimensional spatial, density, and temporal resolution of the dynamic spatial reconstructor.

Spatial, density, and temporal resolution of the dynamic spatial reconstructor (DSR), a multiple X-ray source, high speed, computed tomography scanning system, are evaluated. Hole-pair resolution was evaluated in a stationary phantom surrounded with air, 15 cm of water, or 20 cm of water. Temporal resolution was evaluated by rotation of one of the resolution phantoms during the scan, and with a balloon inflated to a known volume and at a known rate to approximate a typical left ventricular chamber volume and filling rate. These studies confirmed that the spatial resolution is essentially the same in the transverse and axial directions, and that retrospective manipulation of the image data is important for maximization of spatial and density resolution in any structure under examination by obtaining a tradeoff with partial-volume and motion-blurring effects. Maximum spatial resolution in the scanned volume was shown, under ideal conditions, to be greater than five hole pairs per centimeter. Under conditions of intravenous injection of contrast agent, the resolution of blood vessels in an experimental animal approximately 25 kg in weight is expected to be on the order of three hole pairs per centimeter; and in an adult human weighting approximately 60 kg, a resolution of about two hole pairs per centimeter is to be expected.

Dynamic volume imaging of moving organs.

The Dynamic Spatial Reconstructor system has been developed to dynamically (up to 60/sec) image the entire 3-D volume (up to 240 adjacent 1-mm-thick transverse sections) encompassing moving organs of the body, particularly the heart and lungs, or the circulation in any organ. This capability permits accurate regional and global measurements to be made of the important relationships between structure and function within and among these organs, which in turn facilitates achievement of new insights into the basic physiological processes of these organs, and promises increased sensitivity and specificity in the diagnosis of pathology that affects normal organ function. This article explains the biomedical and technological rationale for development of the DSR, describes the design concepts and practical operation of the system, and presents preliminary results obtained with the system, including initial data from one of the first patient studies.

Hematoporphyrin derivative in the detection and localization of radiographically occult lung cancer.

Hematoporphyrin derivative used in conjunction with the Mayo Clinic bronchofiberscopic fluorescence detection system allows accurate localization of radiographically occult early squamous cell carcinoma. Thirteen tumors were localized in 10 patients with radiographically occult lung cancer. Six were in situ with or without microinvasion and were also bronchoscopically occult. Localization of these 6 tumors was expedited by the use of hematoporphyrin derivative and the bronchoscopic fluorescence detection system. Hematoporphyrin-derivative fluorescence was not specific for carcinoma and was also detected in areas of moderate and marked squamous cellular atypia. Thus, although detection of hematoporphyrin-derivative fluorescence suggests the presence of cancer, proof depends on histologic or cytologic confirmation.

Hematoporphyrin-derivative phototherapy for local treatment of cancer of the tracheobronchial tree.

In this paper the potential use of hematoporphyrin-derivative (HpD) phototherapy in the local treatment of bronchogenic carcinoma is discussed. Ten patients with cancer involving the tracheobronchial tree have completed at least one course of HpD-mediated laser phototherapy administered by means of the flexible fiberbronchoscope. Complete response was obtained in four cases, and in each case the tumor was small and superficial. Larger tumors with greater degrees of invasion showed only a partial response. Two patients with tumors eroding through the bronchial wall died following treatment. It appears that HpD phototherapy may be useful for control of only small, superficial squamous cell carcinomas of the tracheobronchial tree and only those within the range of the flexible fiberbronchoscope.

Endoscopic management of lung cancer with hematoporphyrin derivative phototherapy.

This paper demonstrates the potential use of hematoporphyrin derivative in the phototherapy of bronchogenic cancer. We report on 10 patients (a total of 11 carcinomas) with cancer involving the tracheobronchial tree who completed one course of this new treatment administered via the flexible fiberoptic bronchoscope. Four superficial carcinomas showed a complete response; five larger carcinomas showed a partial response, Two patients, each with a large cancer extending beyond the bronchial wall, died within 11 days after treatment.

Detection and localization of In situ carcinoma of the bladder with hematoporphyrin derivative.

The extent and localization of in situ carcinoma of the urinary bladder are frequently difficult to assess. We have studied this problem by employing intravenous hematoporphyrin derivative, an endoscopic detection device, and complete pathologic bladder mapping. These preliminary investigations indicate that hematoporphyrin derivative localizes in dysplastic and neoplastic transitional cell epithelium and that these abnormal areas can be detected during a cytoscopic examination with the use of our detection device.

Photodynamic effect of hematoporphyrin derivative as a function of optical spectrum and incident energy density.

Tumor cell killing effect of hematoporphyrin derivative (HPD) and light was studied in culture to determine the dependence of this effect on treatment variables. Particular attention has been given to the spectral characteristics of the light and the absorption properties of hematoporphyrin. A human tumor cell line was treated using HPD and three broad bands of light ranging from the short- to the long-wavelength end of the visible spectrum. Cell killing was assessed by trypan blue exclusion. A transformed mouse embryo cell line was treated in a similar manner, and its reproductive efficiency was determined following treatment. Results of both studies are consistent with the hypothesis that the photocytotoxic action of HPD plus light is directly proportional to the number of light quanta absorbed by the HPD in each cell. For thin layers of cells, such as in situ carcinoma, it appears that short-wavelength radiation falling in the porphyrin Soret band around 400 nm may have from 12 to 30 times the killing power as does red light.

Computed tomographic imaging of the heart: the dynamic spatial reconstructor.

A particularly important potential value of the Dynamic Spatial Reconstructor approach is that all the above data will be obtainable from a single injection of contrast agent into the right ventricle or pulmonary artery. On the basis of preliminary experimental data, a concentration of at least 80 mg of iodine per ml of contrast agent should be present in the aortic root for adequate opacification of the coronary arteries and myocardium; a bolus of at least 0.5 ml of contrast medium per kg, injected into the venous circulation, is required. As high-speed, volumetric imaging, computed tomographic scan machines such as the Dynamic Spatial Reconstructor become available with higher density resolution, perhaps a single injection of contrast agent into the right atrium or even a peripheral vein may be adequate to obtain all these measurements.