Faculty Bibliography

From 1975 to 1990, eighty-nine primary tumors of the thoracic skeleton; ribs, sternum, scapula, clavicle, and thoracic spine, were treated. Forty-four tumors (49%) were benign lesions. Forty-five tumors were malignant and were proportionately distributed amongst the five sites. The most common malignancies were Ewing's sarcomas, chondrosarcomas, plasmacytomas, osteogenic sarcomas, and lymphomas. All patients with Ewing's sarcomas were treated with combination chemotherapy, surgical resection, and radiation therapy for those with residual disease after surgery. Only one patient has died of disease. Patients with primary chondrosarcomas were treated by surgery alone and all are free of disease or have died without disease. Patients with solitary plasmacytomas or primary lymphomas of bone were treated with radiation therapy initially. Half the patients developed systemic disease. The patients with osteogenic sarcomas included several with radiation induced lesions and Paget's osteosarcoma and all but one died of disease.

Routine preoperative angiograms obtained in 97 consecutive patients with bone and soft-tissue tumors of the extremities were retrospectively reviewed to determine the role of angiography in surgical planning. Some degree of major vessel displacement was demonstrated in 51 patients. Encasement of major vessels, which precluded limb-salvage surgery, was seen in five of 76 bone tumors and in three of 21 soft-tissue tumors. All five patients with osteochondromas had associated vessel occlusion or compromise. For surgical planning, the demonstration of adequate anastomoses in the arches of the hands and feet is important, as branches of brachial and popliteal arteries may have to be sacrificed during limb-tumor surgery. Angiographic findings indicated or supported the need for a vascular surgeon in five cases in this series. Preoperative angiography provides important information with regard to the status of the vasculature and therefore is essential in the management of bone and soft-tissue tumors of the extremities

Limb-sparing surgery has a definite role in the treatment of osteosarcoma in children. Increased survival, however, raises problems of limb-length discrepancy and prosthetic longevity. The concept of an expandable adjustable prosthesis addresses the problem of leg-length discrepancy. The problem of prosthesis longevity will require further long-term evaluation of current designs and methods of fixation, as well as the development of a permanent prosthesis or biologic replacement. At skeletal maturity, the expandable prosthesis may either be maintained or substituted with another implant or biological alternative if warranted by the clinical situation.

The acute effects of photoradiation after administering hematoporphyrin derivative (Hpd) on capillary blood flow were studied in intrahepatic tumors and normal liver. The tumors were solitary Walker carcinosarcomas implanted within the livers of Sprague-Dawley rats. Capillary flow was measured by a laser doppler monitor with its probe positioned over the tumor or over normal liver. Within a minute after intraportal Hpd injection (1.7 mg), capillary flow in the tumors began to decrease. Minimal levels of flow were maintained for as long as 15 minutes after Hpd injection with no observed recovery of flow back to control levels. Ratio of minimal flow/control flow averaged 0.36. Similar results were seen in studies on normal liver tissue. These studies demonstrate the extremely rapid vasoactive effects caused by photoradiation of Hpd. Vasoconstriction, vascular stasis and ischemia have proven to be important mechanisms in producing tumor cell destruction by photodynamic therapy.

The antitumor activity of recombinant human tumor necrosis factor was studied in vivo as a single agent and in combination with a conventional chemotherapeutic agent. Dosages of tumor necrosis factor of 100 micrograms, 50 micrograms, and 25 micrograms were injected intraportally in Sprague-Dawley rats containing hepatic implants of Walker carcinosarcoma. An effect on the tumor was seen but was associated with a significant acute mortality. Lower dosages of tumor necrosis factor, 10 micrograms, 5 micrograms, and 1 microgram, administered with 10 mg/kg of doxorubicin (Adriamycin) significantly enhanced the antitumor effect of doxorubicin without an acute mortality. This suggests that lower dosages of tumor necrosis factor with conventional chemotherapy may augment the latter's effect without any added toxicity.

Tumor microcirculation was studied in Sprague-Dawley rats with solitary intrahepatic implants of Walker carcinosarcoma tumors. Thioflavine S (TS), a fluorescent dye that stains capillary endothelium acutely, was injected intraportally or intra-arterially in order to demonstrate patterns of blood flow through normal liver tissue and through tumor. The dye was given immediately after intraportal injection of 10 micrograms of epinephrine in some animals and 3 minutes after the epinephrine in others. Control animals received TS alone. Additional animals were given TS immediately after intra-arterial epinephrine. The degree of resulting fluorescence in tumor and liver was graded subjectively from 0 to 3+. In the controls and in animals receiving TS 3 minutes after epinephrine, fluorescence in the centers of tumors was absent or, at most, faintly present. In contrast, all animals given epinephrine either intraportally or intra-arterially immediately before the dye showed intense fluorescent staining within the centers of the tumors. Subjective grading averaged 0.6 +/- 0.1 in the controls, 2.2 +/- 0.1 in those receiving intraportal epinephrine immediately before TS, and 1.0 +/- 0.3 in those receiving TS 3 minutes after epinephrine. Results were significantly higher in the latter group (p less than 0.01). Subjective grading in animals receiving intra-arterial epinephrine immediately before TS averaged 2.5 +/- 0.3. These experiments confirm previous studies in this laboratory that demonstrated an acute short-lived redistribution of blood flow into the centers of intrahepatic tumors after administration of epinephrine.

Chemotherapy of liver metastases is dependent on adequacy of tumor microcirculation. Attempts have been made, experimentally, to improve tumor blood flow with appropriate vasoactive agents. Capillary blood flow within intrahepatic Walker carcinosarcomas and normal liver were measured with a laser doppler needle probe. Tumor capillary blood flow increased briefly but significantly with intraportally administered epinephrine. This effect was blocked by phenoxybenzamine but not by propranolol. The response of capillary flow in normal liver to epinephrine was dose related, with decreased flow with higher doses, and slight increase with lower doses. Norepinephrine and phenylephrine produced brief increases in capillary flow in tumor and liver, and isoproterenol caused a decreased flow. In studies with injected silicone rubber (Microfil, Canton Bio-Medical Products, Boulder, CO) performed previously, and on electron microscopic examination, there was evidence of increased vascular filling within central areas of tumors after epinephrine. These studies suggest that the brief but potent effect of epinephrine on tumor capillary flow could be useful in improving delivery of chemotherapeutic agents to liver tumors.

Laser Doppler capillary perfusion monitoring was performed in 25 Sprague-Dawley rats with solitary intrahepatic implants of Walker carcinosarcomas. Doses of intraportal epinephrine from 1 to 10 micrograms produced an immediate rise in capillary blood flow, reaching peak levels by 16 s. The increased flow lasted an average of 57 s. Because epinephrine selectively increased tumor blood flow, studies were performed to determine if enhancement of the chemotherapeutic effect of doxorubicin could be achieved. Forty-two rats with seven-day hepatic implants were treated sequentially with intraportal epinephrine (10 micrograms) and doxorubicin hydrochloride (10 mg/kg) or doxorubicin alone. After only two courses of chemotherapy, a significant difference in necrosis and cell viability was obtained in those animals treated with epinephrine intraportally prior to doxorubicin infusion. Enhancement of the tumoricidal effect of chemotherapy can be achieved by manipulating the blood flow to developing tumors pharmacologically.