Dose-dependent radiation effect on microvasculature and repair.

It has been postulated that the damage to microvasculature may be a major factor in the manifestation of late radiation damage to organized tissue. In this study, the radiation damage to microvasculature was investigated in a rabbit model during the early phases of irradiation with the use of vascular permeability as a marker. By means of a triple isotopic technique, the vascular, extravascular, and intracellular spaces could be defined. A forelimb and hindlimb of New Zealand White rabbits were irradiated with single doses of 2-30 Gy. 125I- and 131I-labeled bioscreened albumin were used to determine the changes in vascular permeability due to irradiation. The rabbits were sacrificed at various intervals post irradiation. Vascular and extravascular spaces and the respective albumin concentrations in tissue samples from irradiated limbs were compared with control values from the unirradiated contralateral limbs in each animal. The results indicated a definite increase in the vascular permeability of albumin secondary to irradiation. The increase in vascular permeability was apparent instantaneously with irradiation, even at 2 Gy. The microvascular compromise appear to be dose related. When examined at 16-24 hours post irradiation, the excess extravasation of albumin was significant at and beyond 8 Gy. At 10-30 days post irradiation, injury was not apparent up to 15 Gy. Thus there appeared to be an instantaneous injury at the capillary level due to irradiation, which appeared to be dose related. A repair process became evident as early as 16-24 hours and appeared to be dose related as well as related to elapsed time post irradiation.

Deficiency in maturation process of macrophages in human cancer.

Peripheral blood mononuclear cells were cultured from normal individuals and patients with cancer. The analysis of these results indicated a lower number of macrophage precursors (monocytes) in patients with cancer as compared to the number in normal individuals. The macrophage yield was 1.9 +/- 1.1 X 10(4)/ml of blood in patients with cancer versus 7.2 +/- 2.0 X 10(4)/ml of blood in normal individuals. This low yield of macrophages in patients with cancer was not associated with serum factors. Furthermore, a study of the adherent cell population suggests in intrinsic defect in the maturation process in vitro in patients with cancer.

In vitro peripheral monocyte culture: possible use as a prognostic indicator for renal cell carcinoma patients.

An in vitro assay was applied to follow 39 patients with renal cell carcinoma. A mononuclear cell-rich fraction was cultured from peripheral blood of patients over a period of 7 days. The number of adherent matured monocytes (macrophages) was analyzed and quantitated at the end of the culture period. Functional activities were analyzed by antibody-coated sheep red blood cells and nonspecific esterase staining techniques. Macrophage yield in patients with detectable tumor burden was 2.06 +/- 2.81 X 10(4) cells/ml blood, and mean values at 3, 6, and 9 months post nephrectomy were 3.67 (n = 21), 6.73 (n = 12), and 9.41 (n = 10) X 10(4) cells/ml blood, respectively. Some of the patients were followed over 30 months. The improvement was significant, and macrophage yield was close to normal values (8.24 +/- 3.14 X 10(4) cells/ml). In the absence of other reliable in vitro assays for these patients, this assay appears to be highly useful in following these patients during the postsurgical period.

Apparent cellular ingress of albumin in Walker 256 tumor and rat muscle.

Tissue albumin distribution was measured in Walker 256 tumor and skeletal muscle in vivo in 36 rats. Vascular, extravascular-extracellular, and total tissue water spaces were determined for each tissue sample by isotopic techniques. Tissue interstitial and lymph albumin values were calculated from thoracic duct albumin concentrations, and vascular albumin was determined from serum albumin levels. Total tissue albumin was measured by dilution. These data demonstrate a third tissue albumin pool that equilibrates in 3 days compared to the rapid equilibration (2 hr) of vascular and extracellular-extravascular spaces. The pool is present in both muscle and tumor but appears to equilibrate more rapidly in tumor tissue. This finding suggests that cellular ingress of albumin occurs in vivo, which may explain increased albumin catabolism in tumor-bearing hosts.

Immediate effect of irradiation on microvasculature.

The immediate effects of irradiation on microvasculature in muscle in an animal model are described in this paper. By using triple isotopes of 125I, 131I, and 22Na, the transcapillary transfer of albumin from the vascular bed to the extravascular space is determined in terms of mg/g of tissue, after single doses of 2 to 14 Gy. These results reveal an increase in the extravascular albumin immediately after irradiation and suggest an instantaneous compromise in vascular permeability even after 2 Gy. This effect was apparently dose related.

Perioperative interstitial irradiation in the conservative management of early breast cancer.

Conservation of the breast in early breast cancer with limited resection and radiation is proving to be as effective as modified radical mastectomy in survival and in loco-regional control. Management at the University of Kansas Medical Center consists of an interstitial implant at the time of lumpectomy to facilitate perioperative irradiation with Iridium-192 to the tumor bed. An axillary node dissection is also performed at that time. Two to 3 weeks later external beam irradiation is delivered to the entire breast. One hundred and twenty-three breasts in 120 patients have been treated between June 1982 and June 1986. There were 49 pathological Stage I, 63 Stage II, 8 Stage III carcinomas, and 3 carcinomas in situ, consisting of 72 T1, 43 T2, 5 T3, and 3 TIS lesions. Patients have been followed for a median of 30 months. One patient had a "true" recurrence in the breast. Another patient developed recurrence in a different quadrant. Ninety percent of the patients had good to excellent cosmetic results, 7% were considered fair, and 3% had poor results. Seven patients developed mild arm edema, 4 were found to have moderate edema, and 1 had severe arm edema. Our preliminary results indicate that interstitial irradiation immediately after excision results in excellent local control, with very satisfactory cosmesis and no morbidity due to the simultaneous excision and irradiation.

Cosmetic results in early breast cancer treated with lumpectomy, peri-operative interstitial irradiation, and external beam radiation.

Patients with operable breast cancer were treated at the University of Kansas Medical Center with lumpectomy, peri-operative interstitial Iridium, and external beam radiotherapy, and concomitant adjuvant chemotherapy in a majority of node positive cases. Examination of the cosmetic results in 85 breasts followed for at least 2 years, at a median of 41 months revealed 20% to be excellent, 44% to be very good, 24% good, 9% fair, and 4% to have poor results. In this paper cosmesis is analyzed with reference to the size of the primary, its location, age of the patient, whether the patient received adjuvant chemotherapy, and whether the regional nodes were treated. In this group of patients, the size and the site of the primary, patient's age, and whether adjuvant chemotherapy was administered or not, did not adversely affect the aesthetic outcome. Treatment of the regional nodes gave a worse mean cosmetic score compared to the group in whom only the breast was treated (37.51 vs. 58.98 respectively, p less than 0.001). Among the 11 patients with fair/poor cosmesis, all had regional nodal treatment, 7/11 had inner quadrant lesions, and 7/11 had lesions greater than T1. Further follow-up and accrual would be needed to confirm our results and affirm if other factors would change.

Radiobiological advantages of an immediate interstitial boost dose in conservative treatment of breast cancer.

Minimum surgery with irradiation is emerging as one of the main modalities of therapy for operable early breast cancer. Between June 1982 and June 1986, 110 breasts with Tis, T1 to T3 lesions have been treated at our institution with lumpectomy and interstitial irradiation to the tumor bed with Iridium-192 perioperatively followed by external beam irradiation. There have been two local recurrences at or near the vicinity of the primary, at a median follow-up of 60 months. To analyze the parameters that might have contributed to the local control, we have examined the treatment volumes, prescribed dose to the tumor bed, dose at the core of the tumor bed, and dose to the surrounding normal tissue. Immediate interstitial implant has the radiobiological advantage of delivering continuous low dose irradiation, immediately upon removal of gross tumor to residual foci. Implantation of the afterloading catheters intraoperatively facilitates accurate dose delivery and avoidance of geographical misses. By precise treatment of any residual foci, immediately upon removal of the gross mass, perioperative interstitial irradiation improves local control and by facilitating less radical surgical excision, leads to better cosmetic results.

Treatment of renal cell carcinoma with renal infarction, delayed nephrectomy, medroxyprogesterone, and xenogeneic immune RNA.

The authors have used xenogeneic immune ribonucleic acid (RNA) in the treatment of patients with renal cell carcinoma. This has been used in conjunction with renal artery embolization, delayed nephrectomy, and progestational therapy, using immune RNA derived from sheep cell lymphocytes immunized with patient's tumor. Four of 5 patients with Stage I disease had extremely large primary tumors. This group is alive with no evidence of disease at twelve to twenty-four months. There are no Stage II tumors in this group. One patient with Stage III tumor is alive at twenty-two months without evidence of disease. Three patients with metastases are stable at five to twenty-two months. Two patients have progressive disease at three and six months. This treatment has not been effective in patients with massive tumor burden. The results in the other groups are encouraging.

Thermodynamic considerations of acrylic cement implant at the site of giant cell tumors of the bone.

A discussion of the thermodynamic aspects of a relatively new treatment method for giant cell tumors of the bone is presented in this paper. The advantages of implanting methylmethacrylate acrylic bone cement into a curetted tumor site are briefly discussed and placed in perspective relative to more prevalent surgical treatments. As the bone cement self-heats while curing, the possibility of heat necrosis in the bone exists. However, the damage due to heat may be beneficial in reducing the rate of tumor recurrence. A thermodynamic consideration of the treatment situation appears to be warranted. After a general introduction and a brief literature review, the theoretical thermodynamic equations are developed. Once the basic equations for the heat transfer from the cement or the bone are derived, there is then a discussion of the various characteristics of bone and methylmethacrylate crucial to the analysis, such as, thermal conductivity, specific heat, density, and heat generation parameters. Finally, in order to reduce the theory to a form which may be used practically, the equations derived are written in terms of finite-difference equations, which approximate them numerically. Different equations are written for each type of heat transfer condition encountered in the cement-bone system as spacial variances in material and geometry occur. The equations derived may be used to model the system allowing one to predict the time-dependent temperature distribution in bone during the curing of acrylic cement. Using computer techniques to reduce the equations obtained from this analysis, and knowing the temperature at which adjacent cells die, a zone of necrosis may be mapped surrounding the acrylic impact.

Consideration of physical parameters to predict thermal necrosis in acrylic cement implants at the site of giant cell tumors of bone.

In the previous paper we had developed a general thermodynamic equation describing a polymethylmethacrylate implant at the site of giant cell tumors. In this paper we consider various characteristics of bone and methylmethacrylate crucial to the analysis such as thermal conductivity, specific heat, density, and heat generation. Also, an estimation of the temperature at which adjacent cells die is analyzed from literature. Finally, using the physical constants measured in laboratory situations a temperature profile is developed at various depths of bone that could facilitate predicting the zone of necrosis. These analyses show the maximum temperature attained in the acrylic cement-bone system depends primarily on the volume of the implant, the relative proportion of polymerization of the monomer, the temperature at which the monomer and polymer are mixed together, and the time lapse between the beginning of polymerization and implantation into the bone cavity. The temperature profile is shown to be relatively insensitive to the geometry of the system, greatly simplifying the analysis.

Effect of silicone gel breast prosthesis on electron and photon dose distributions.

The effect of a silicone gel breast prosthesis on the absorbed dose distribution of 9-20 MeV electron beams and 1.25-15 MV photon beams was studied. Compared to water measurements, at depths smaller than the practical range of the electron beams, the central axis depth dose values below the prosthesis were lower for all energies by as much as 3.5%. However, at depths near the practical range, the central axis depth dose values for the prosthesis were greater than that of water by as much as 33%. Since this occurs near the end of the electron range, the resultant difference may not be clinically significant. Results of the effect of breast prosthesis on photon depth dose distributions reveal that no clinically significant perturbation is produced by the breast prosthesis using Co-60, 6- and 15-MV radiations.

Quantitative assay for the radiosensitivity of malignant melanomas.

There exists a controversy regarding the radiosensitivity of malignant melanomas. Several in vitro and in vivo studies have suggested that the 'radioresistance' of melanomas may be due to a 'large shoulder' on the cell survival curve. As yet, however, there is no consensus relating to the effects of total dose, the fraction size and the time between fractions. In this study, we have used a B16 mouse melanoma model to evoke a response with single doses of irradiation, and have attempted to evaluate the growth kinetics of in vivo irradiated and unirradiated tumour cells implanted in an unirradiated limb. The radiosensitivity of B16 melanoma cells was quantified by comparing the growth of tumour from an inoculum of 10(6) melanoma cells irradiated in vivo with various doses of radiation to the growth of tumour following inoculae of 10(3) to 10(7) cells derived from unirradiated melanoma. Using this bioassay we found that a single dose of 18 Gy leads to close to 99% of the surviving cells becoming nonclonogeneic. It is hoped that this assay will further the development of the most efficacious fractionation scheme in the treatment of malignant melanomas.

Electron beam irradiation after reconstruction with silicone gel implant in breast cancer.

Irradiation for breast cancer in the presence of a silicone gel breast prosthesis is sometimes necessary. There is a concern among radiation and other oncologists as to whether the presence of the prosthetic implant would interfere with delivery of the needed irradiation doses. Electron beams, with their finite penetration and rapid fall-off, offer a mode of adequately treating the recurrence and minimizing the radiation to the underlying normal structures, such as the lung and the heart. The dose distribution using 9-20 MeV electrons in the presence of a breast prosthesis is compared to the dose distribution without the implant in a tissue equivalent water phantom. The results reveal no significant difference in the dose delivered due to the presence of the prosthesis. Clinical verification of the dosimetry in the presence of the prosthesis confirmed that the presence of the silicone gel implant does not compromise treatment by irradiation in the management of breast cancer.

Breast conservation treatment with perioperative interstitial irradiation.

Limited resection of the breast combined with radiation has proved to be as effective as more radical surgery in treating early breast cancer. At the University of Kansas Medical Center, the radiotherapy consists of an interstitial implant at the time of lumpectomy to deliver an interstitial boost dose to the tumor bed with iridium-192 immediately following the surgical procedure. An axillary node dissection is also performed at the time of lumpectomy. A dose of 2,000 cGy is delivered to the tumor bed between 40 and 60 h. Two to three weeks later, 4,500-5,000 cGy is delivered to the entire breast with external beam radiation over 5-5.5 weeks. One hundred breasts in 98 patients were so treated between June 1982 and February 1986, with 2 carcinomas in situ, 40 stage I, 51 stage II, and 7 stage III cancers, consisting of 2 TIS, 54 T1, 39 T2, and 5 T3 lesions. Locoregional control with a median follow-up of 31 months was 98%. One recurrence was in a different quadrant, and the other revealed predominantly the in situ component. Immediate implant did not compromise wound healing or cosmesis. The cosmetic result was graded as good to excellent in 88% of the breasts. Our preliminary results appear to suggest a better local control with immediate interstitial irradiation.

Lactic acidosis and hypoglycemia: experimental evidence to show lactate prevents insulin induced seizures in rats.

A 52-year-old man with lactic acidosis and severe hypoglycemia was fully conscious and alert with a blood sugar of 8 mgs%. We believe normal level of consciousness was maintained due to the presence of hyperlactatemia. We show experimental evidence to suggest that lactate prevents the development of insulin-induced seizures in rats.

Characterization of Fc receptors associated with human malignant tumors.

Fc receptors from human tumors were isolated by sucrose gradient fractionation and affinity chromatography techniques. The isolated Fc receptors showed specificity for IgG(Fc) in the closed chamber hemadsorption technique and also in the inhibition experiments using radiolabeled Fc receptors. The results indicate that Fc receptors isolated from tumor tissue are similar to Fc receptors isolated from normal human spleen, dog macrophages, and peripheral white blood cells (WBCs). However, the Fc receptors isolated from macrophages are more potent inhibitors when compared with tumor, spleen, and peripheral WBC Fc receptors. Also, Fc receptors isolated from the various sources are independent of species specificity.

Immunoglobulins and immunoglobulin receptors associated with human malignant tumors.

Over the past five years 86 malignant tumors were assayed for cell surface IgG, elutable Ag-Ab complexes, and/or cell surface Fc receptors. Surface IgG was measured by indirect radioimmunoassay, using single-cell suspensions and tumor eluates. Fc receptors in tissue sections were identified by the closed chamber technique. The results confirm our previous finding that human tumors are coated in vivo with IgG and that there is a population of cells within solid tumors capable of binding Ag-Ab complexes. In addition, Ag-Ab complexes appear to attach to the cell surface membrane by the Fc zone of antibody. Ag-Ab binding was inhibited by antibody raised against the tumor. Indirect complement consumption assay indicated the presence of Ag-Ab complexes in tumor eluates. It appears that most cell surface immunoglobulin is complexed.

Effect of irradiation on microvasculature: a quantitative study.

In clinical radiation therapy, normal tissues and organs are unavoidably irradiated during the course of treatment of neoplastic diseases. Rubin and Cassaret [Clinical radiation pathology. Philadelphia: W.B. Saunders, 1968; Vols 1, 2] have postulated that microvascular damage may be the major contributing factor to late manifestation of radiation damage. It has been theorized that vascular leakage of the protein-rich fluid leads to fibrosis caused by the accumulation of fibroblasts and macrophages. Vascular changes after irradiation have been demonstrated qualitatively. To quantitate the alteration in permeability characteristics at different doses and time-dose fractionations, we have developed an isotopic technique using 125I, 22Na, and 3H2O that allows us to define vascular, interstitial, and intracellular water spaces. Using these values it is possible to quantitate the vascular changes and membrane integrity. Results show that the permeability of the vascular bed is altered by irradiation.