Normal tissue and solid tumor effects of hyperthermia in animal models and clinical trials.

Localized hyperthermia therapy by high-energy radio-frequency waves was evaluated in malignant and adjacent normal tissue of 30 patients with 10 types of cancer. Hyperthermia was delivered to superficial and deep visceral cancers in awake patients who had refractory disease. Histological and clinical responses were recorded serially. Toxicity tests in dogs, sheep, and pigs showed that progressive necrosis of normal and cancer tissue occurred at temperatures above 45 degrees C (113 degrees F). However, as normal tissues approached this temperature, intrinsic heat dissipation occurred (possibly due to augmented blood flow) so that temperatures below 45 degrees C could be maintained, whereas most solid tumors did not have this adaptive capacity and could be heated to 50 degrees C (122 degrees F) with virtually no injury to normal organs, s.c. tissue, or skin. To date, 69 treatments have been administered to 36 tumors in the 30 patients. Selective heating was observed in both primary and metastatic tumors located in surface tissues and internal organs. Response appeared to be related to tumor size in that differential heating was possible more often in the larger lesions. In tumors successfully heated, moderate to marked necrosis occurred. Radio-frequency hyperthermia appears to be a safe and potentially useful form of therapy for selected cancer patients. While other cancer treatments are more effective for small tumors, hyperthermia may be uniquely beneficial against larger lesions.

In vitro and in vivo cytotoxicity of rhodamine 123 combined with hyperthermia.

Because both Rhodamine 123 (R123) and hyperthermia have been shown to be cytotoxic, we examined their effect, independently and in combination, on five different human malignant cell lines in vitro and on cultured melanoma cells grown intradermally in nude mice. The cell lines examined include two human melanomas, UCLA-SO-M14 and UCLA-SO-M21, the colon cancer cell line HT29, the human lung cancer cell line P3, and the human breast cancer cell line B231. R123 and hyperthermia, when used in combination, were found to be cytotoxic for these five different human malignant cell lines in vitro. The two agents together appear to enhance the cytotoxic effect of each alone, as documented by synergistic ratios ranging from 2.31 to 45 for the different cell lines. In the "nude" mouse model, animals were treated with a combination of R123 and hyperthermia (43 degrees C for 90 min). A statistically significant (P = 0.04) decrease in tumor growth rate was observed when compared with the rate of tumor growth in untreated animals. The results suggest a potential role for R123 in combination with hyperthermia in the treatment of malignant cells.

Thermal distribution of magnetic-loop induction hyperthermia in phantoms and animals: effect of the living state and velocity of heating.

Hyperthermia has shown promise for the treatment of cancer. The magnetrode radio-frequency magnetic-loop induction applicator was recently introduced and is being evaluated at many centers with encouraging initial results. This investigation was undertaken to delineate the thermal distribution patterns of magnetrode hyperthermia in both normal tissue phantoms and healthy dogs. Temperatures on homogeneous and heterogeneous tissue equivalents and animal tissue phantoms, a dead animal extremity, a dead dog and a live dog subjected to rapid high-dose heating showed preferential and potentially injurious peripheral heating with a central "cold spot." However, sequential moderate-dose heating in live dogs showed virtually uniform (less than 1 degree C) and potentially tumoricidal temperatures greater than or equal to 42 degrees C in both peripheral and central internal organs without injury to surface tissues. These data indicate that magnetic-loop induction can produce potentially safe and effective deep central heat in living, normal animals, but that safety and effectiveness are significantly influenced by the velocity of heat deposition. Furthermore, normal tissue phantom models and dead animals are unreliable predictors of magnetrode heat patterns in living systems.

Autogenous vein bypass grafts: biological effects of mechanical dilatation and adventitial stripping in dogs.

To evaluate whether mechanical vein dilatation and stripping of adventitia at the time of harvest may adversely alter the long-term fate of autogenous vein grafts, dogs were subjected to reversed femoral vein interposition grafting with either normal veins, mechanically dilated veins, or adventitially stripped veins. Vein segments taken before grafting and veins exposed in situ but not grafted served as controls. Animals were killed at 3 months, and five vein segments in each category were evaluated for gross and microscopic changes. All grafts subjected to arterial interposition displayed marked neointimal proliferation and fibrosis of the media and adventitia. Notably, both dilated and stripped veins appeared to be similar and were indistinguishable from normal veins that had been subjected to arterial interposition for the same duration. Veins exposed in situ but not subjected to arterial flow remained essentially normal. Adverse alterations attributed to vein dilatation or adventitial stripping were not apparent and should not be invoked in the mechanism of graft failure at 3 months' duration.

Effects of interleukin-2 on pulmonary and systemic transvascular fluid filtration.

Interleukin-2 (IL-2) therapy for patients with advanced cancer may be compromised by dose-limiting and life-threatening pulmonary and systemic edema. We studied the effects of bolus IL-2 infusion on lung and soft-tissue transvascular fluid and protein filtration in six sheep with chronic lung and soft-tissue lymphatic cannulation. Changes in lung (QL) and soft-tissue (QS) lymph flow were used as indicators of transvascular fluid filtration. A dose of 100,000 U/kg IL-2 was administered every 8 hours for 3 days. A significant increase (p less than or equal to 0.05) in both QL and QS was observed after each IL-2 infusion, with maximal flow occurring 2 to 3 hours after infusion. After 72 hours of IL-2 infusion, a fourfold maximal increase in QL occurred, which recovered to near-baseline values within 24 hours. Elevations in QL and QS were not associated with increases in pulmonary arterial or pulmonary arterial wedge pressures, but these elevations were associated with significant (p less than or equal to 0.05) increases in cardiac output (7.7 +/- 0.5 to 11.4 +/- 0.4 L/min) and a consistent decrease in systemic vascular resistance. A significant increase in lung lymph/plasma protein ratio (0.49 +/- 0.06 to 0.93 +/- 0.04 for albumin) revealed a marked increase in pulmonary microvascular porosity. This change, however, was not observed in the systemic microcirculation. Serum concentrations of tumor necrosis factor did not increase with the observed changes in pulmonary microvascular porosity. We conclude that IL-2 increases both pulmonary and systemic microvascular fluid flux. In addition, there is a marked increase in pulmonary, but not systemic, protein permeability that is not a consequence of changes mediated by tumor necrosis factor.

Natural thermal resistance of human tumor cells and the role of prostaglandin.

We found that human malignant melanoma cells had varying thermal sensitivity and that some exhibited natural thermal resistance, a heretofore unrecognized phenomenon. Samples of 73 melanoma cell suspensions were heated at 42 degrees C for 1 hour before plating in the soft agar clonogenic assay or the thymidine assay for proliferating cells. We observed greater than 75% cell kill after hyperthermia in 39 (53%) tumors. Native thermal resistance was apparent in 17 (23%) tumors and growth enhancement in 17 (23%) at this temperature and exposure time. We postulated that prostaglandin, known to protect stomach mucosa against thermal injury, has a role in stabilizing the tumor cell membrane exposed to heat. Three melanoma cell lines known to be thermosensitive were heated to 42 degrees C without and with exogenous prostaglandin E2 (PGE2). The survival of colony-forming cells was increased in all three lines in the presence of 30 microM PGE2. A naturally thermoresistant cell line was exposed to 1 microgram/ml indomethacin for 24 hours before hyperthermic treatment. The survival of colony-forming cells was significantly decreased compared to cells not treated with indomethacin. The addition of 30 microM of exogenous PGE2 to indomethacin-treated cells reestablished thermal resistance. These preliminary data suggest that some tumor cells synthesize prostaglandins to render the cell thermoresistant. Treatment with indomethacin blocks prostaglandin synthesis and induces thermosensitivity. These discoveries may have important clinical applications for hyperthermia treatment of human cancers.

Pulmonary and systemic fluid filtration after continuous versus bolus interleukin-2 infusion.

Interleukin-2 has been widely investigated as adjuvant therapy for advanced cancer and is administered by either bolus or continuous infusion. We compared the effects of bolus and continuous interleukin-2 infusion on pulmonary (QL) and systemic microvascular fluid filtration in 11 adult sheep prepared with chronic lung and soft-tissue lymph fistulas. Interleukin-2 was administered as a bolus infusion (100,000 units/kg) every 8 hours for 3 days or as a continuous infusion at the same dose for 3 days. No significant changes in pulmonary hydrostatic pressures or pulmonary vascular resistance were noted after either bolus or continuous interleukin-2 infusion. However, significantly decreased (p less than or equal to 0.05) systemic vascular resistances were observed in both groups. QL increased steadily throughout the infusion period in both groups, peaking at three times baseline on the third infusion day. The plasma/interstitial protein clearance (QL X lymph/plasma protein ratio) rose similarly in both groups, indicating increased barrier permeability. Increased lymphocyte clearance into lung lymph occurred by day 3 but was not associated with lymphocytic sequestration in the lung interstitium. We conclude that pulmonary and systemic microvascular fluid and protein flux exhibit similar changes after bolus or continuous interleukin-2 infusion. These changes are associated with increased clearance of lymphocytes into lung lymph that are not sequestered in the pulmonary interstitium after infusions of shorter duration.

Blowhold cecostomy for cecal decompression.

Blowhole cecostomy is a method for achieving decompression of the distended cecum. Emphasis is placed on a McBurney-type incision, a watertight suture line joining bowel to muscle, and avoidance of opening the cecum until the suturing is done.

Technical details of intraoperative lymphatic mapping for early stage melanoma.

The initial route of metastases in most patients with melanoma is via the lymphatics to the regional nodes. However, routine lymphadenectomy for patients with clinical stage I melanoma remains controversial because most of these patients do not have nodal metastases, are unlikely to benefit from the operation, and may suffer troublesome postoperative edema of the limbs. A new procedure was developed using vital dyes that permits intraoperative identification of the sentinel lymph node, the lymph node nearest the site of the primary melanoma, on the direct drainage pathway. The most likely site of early metastases, the sentinel node can be removed for immediate intraoperative study to identify clinically occult melanoma cells. We successfully identified the sentinel node(s) in 194 of 237 lymphatic basins and detected metastases in 40 specimens (21%) on examination of routine hematoxylin-eosin-stained slides (12%) or exclusively in immunohistochemically stained preparations (9%). Metastases were present in 47 (18%) of 259 sentinel nodes, while nonsentinel nodes were the sole site of metastasis in only two of 3079 nodes from 194 lymphadenectomy specimens that had an identifiable sentinel node, a false-negative rate of less than 1%. Thus, this technique identifies, with a high degree of accuracy, patients with early stage melanoma who have nodal metastases and are likely to benefit from radical lymphadenectomy.

Efficacy of oral and systemic antibiotic prophylaxis in colorectal operations.

A cooperative Veterans Administration study of the septic complication rate during large-bowel surgery was undertaken in two groups of patients. The first group received oral neomycin and erythromycin base plus parenteral placebo; the second, the oral antibiotics plus parenteral cephalothin sodium. During a five-year period, 1,128 patients were studied. The overall septic complication rate was 7.8% in patients receiving only oral antibiotics, and 5.7% in patients receiving both oral and parenteral antibiotics. This difference was not significant. The only significant finding was a greater incidence of fever of unknown origin in patients receiving only oral antibiotics. None of those patients were treated with additional antibiotics, and all fevers cleared spontaneously. There seems to be no discernible benefit from adding parenteral antibiotic prophylaxis when performing elective colon surgery if appropriate mechanical cleansing and oral neomycin and erythromycin therapy are employed.

Hsp-27 has no diagnostic or prognostic significance in prostate or bladder cancers.

Heat shock protein 27 (hsp-27) is a cytosol protein of unknown function that is concentrated in many estrogen-sensitive normal target organs and is expressed to a varying degree in many tumors, including ductal carcinoma of the breast, malignant fibrous histiocytoma (MFH) of the soft tissues, adenocarcinoma of the prostate, and transitional cell carcinoma (TCC) of the urinary bladder. Overexpression of hsp-27 has independent prognostic significance in patients with breast cancer and MFH, but its potential predictive value with prostate and bladder cancers has not been evaluated. Differential expression of hsp-27 may occur between invasive cancer and host tissue that could aid in diagnosis, and varying expression among invasive cancers may have potential prognostic significance that could influence the use of adjuvant therapy. To test these hypotheses, hsp-27 expression was evaluated by immunohistochemistry in archival formalin-fixed paraffin-embedded sections of primary prostate and bladder carcinomas where the outcome of the patient was known. In 36 prostate cancer specimens from patients who had undergone radical prostatectomy (Stages T1, T2; N0; M0), no normal glandular elements or invasive cancers expressed this protein. In 24 bladder cancer specimens from patients who had undergone radical cystectomy (Stages T2, T3A, T3B, T4A; N0, N1; M0), 12 (50%) cancers overexpressed this protein. Hsp-27 did not correlate with degree of histologic differentiation, T-stage, nodal status, local recurrence, metastases, or survival. From these observations, we conclude that hsp-27 expression has neither diagnostic nor prognostic significance and will not serve as a predictive biologic marker with these important genitourinary cancers.

Malignant melanoma of the head and neck.

Sixty-nine patients with head and neck melanoma were prospectively evaluated from 1971 to 1977. Patients presenting for initial therapy underwent wide excision of their primary tumor, and those with deeply invasive melanoma also underwent regional lymphadenectomy, whether their nodes were clinically positive or negative. The results suggest that the prognosis of this tumor is similar to that of melanoma arising at other sites. Clinical stage and primary-tumor histopathologic microstage both correlated with disease recurrence. At 1 to 75 months, patients with clinical Stage I disease had a 13% recurrence rate, while 58% of those with Stage II disease developed recurrence. Patients with superficially invasive melanoma had a 10% recurrence rate, while 17%-33% of those with deeply invasive disease developed recurrence. However, the presence of node metastases, rather than the microstage of the primary tumor, appeared to be the dominant indicator of outcome. Radical excision of the primary tumor may reduce the incidence of local disease recurrence. We believe that regional lymphadenectomy is indicated for deeply invasive melanoma.

Clinical hyperthermia and chemotherapy.

Hyperthermia may act additively or synergistically with a majority of clinically useful chemotherapeutic agents in vitro. In some cases enhanced responses are essentially linear at temperatures from 39 to 43 degrees C (thiotepa, the nitrosoureas, cisplatin), while other drugs become more effective only at 42 to 43 degrees (doxorubicin, bleomycin, amphotericin B). Synergism has been observed in vivo with methotrexate, cyclophosphamide, the nitrosoureas, doxorubicin, bleomycin, and cisplatin. Optimum enhancement occurs when heat and drug are given simultaneously. Clinical studies employing WBH at 41 to 41.8 degrees C have shown evidence of potential usefulness, but have been limited by high toxicity and a low benefit-to-risk ratio. Regional perfusion of metastatic melanoma of the extremity treated with L-phenylalanine mustard at 40 to 41 degrees C was significantly better than when treated with the drug alone, but some investigations suggest that heat alone may be just as effective. Localized hyperthermia combined with nearly all the standard types and doses of single and combination agents has shown objective responses in about one third of patients treated, without evidence of increased drug toxicity by either the IV or IA route. Responses appear to be thermal-dose related. Maximum enhancement appears at about 40 to 43 degrees C and prior drug resistance does not appear to confer heat resistance. The lack of enhanced drug toxicity with loco-regional hyperthermia with potential improvement in response of advanced disease suggests that thermochemotherapy is a viable and important option to drug treatment alone. Further in vitro, in vivo, and clinical studies are needed to increase our understanding of drug-heat interactions for the optimization of therapy.

Value of therapeutic hyperthermic limb perfusion in advanced recurrent melanoma of the lower extremity.

Twenty-six patients with advanced melanoma metastases confined to the lower extremity underwent 28 therapeutic limb perfusions without a major complication or treatment-related death. A complete response to treatment occurred in 21 patients (81 percent). Of 16 patients, response persisted until death in 13 and was noted at 75, 87, and 96 months follow-up in 3. In five patients, response lasted a median of 5 months (range 3 to 14 months), and repeat perfusion in two of these patients was not beneficial. Unfortunately, despite locoregional disease control, most patients died from distant metastases at a median of 15 months after treatment. In fact, regardless of response to perfusion, the 3 year survival rate of patients with advanced metastatic melanoma of the extremity was only 25 percent or less. Thus, although limb perfusion can be a safe and highly effective means of achieving locoregional disease control, there appears to be little survival benefit. Therefore, perfusion should be reserved for palliative treatment of selected patients with locally advanced melanoma.

Operative endoscopy in the management of biliary tract neoplasms.

Operative endoscopy of the biliary system has been employed with ever increasing frequency at the UCLA Hospital during the last three years. In addition to its established value with respect to disclosing unsuspected stones in the bile ducts, choledochoscopy has been of great value in terms of more accurate diagnosis and staging of periampullary and bile duct neoplasms. It has been observed that many biliary tract carcinomas are multicentric in origin and that cholangiography is not adequate to identify small intrahepatic ductal lesions. More than one cell type of bile duct carcinoma may be present in the same patient. Choledochoscopy should be used in addition to the conventional criteria for resectability in all patients with ductal or periampullary carcinoma. Use of this technic will spare some patients needless radical procedures and should improve long-term cure rates by identifying those patients with truly localized disease for curative resections.

Natural history of surgically treated mucosal melanoma.

Thirty-three patients with melanoma arising in a mucosal site were reviewed. Sixteen patients were treated either with abdominoperineal resection or radical vulvectomy and superficial inguinal lymphadenectomy. Three patients were treated palliatively. Fourteen patients were treated conservatively with local excision, wide local excision, and radiation therapy. One patient received systemic chemotherapy and radiation therapy. Local recurrence developed in seven patients. The overall survival rate was poor. Neither local control nor survival appeared to be influenced by the initial surgical approach.

Human hyperthermic therapy: relation between tumor type and capacity to induce hyperthermia by radiofrequency.

There is mounting evidence that hyperthermia of 42 degrees C or greater is tumoricidal to cell cultures and to animal and human tumors. However, temperatures of 45 degrees C or greater may have greater potential therapeutic benefit. The ability to selectively achieve such highintratratumor temperatures without injury to normal tissue may be due to the relatively poor blood flow in tumors compared with that in normal tissues. While vascularity and blood flow are known to vary significantly among tumors, we found that of 52 tumors evaluated, temperatures of 42 degrees C or greater in 42 tumors (81 per cent) and of 45 degrees C or greater in 23 tumors (44 per cent) appeared to be independent of the histologic type of tumor. Therefore, therapeutic hyperthermia may be possible for most varieties of human solid cancer.

Retroperitoneal masses, adenopathy, and adrenal glands.

The diagnosis of primary retroperitoneal masses is approached best by CT scan-guided transretroperitoneal core biopsy or by open biopsy. Excisional or wedge biopsy is the preferred method for undiagnosed lymphadenopathy. Resection without biopsy is indicated for large or enlarging nonfunctional primary adrenal masses.

A comparison of deep-heating electrode concepts for hyperthermia.

There is mounting evidence that localized hyperthermia produced by electromagnetic waves may be useful in the treatment of cancer, and many innovative devices have been designed for this purpose. Most applicators employed for deep heating operate in the frequency region of 10-100MHz to provide greatest depth of penetration. Two basic categories of launching devices exist: E-field and H-field. The E-field applicators include conductive plates and fringing field devices; either may be used individually or in a multiple feed system. The H-field applicators include cylindrical and planar devices configured to produce specific heating patterns. We have analyzed and compared the performance of each of these devices, particularly in terms of engineering principles, design characteristics and their ability to transfer potentially therapeutic energy safely and at depth.