Eric R. Lee

Stanford University institutional report. Phase I evaluation of equipment for hyperthermia treatment of cancer

From September 16, 1981, through April 4, 1986, a total of 21 radiative electromagnetic (microwave and radiofrequency), ultrasound and interstitial radio-frequency hyperthermia applicators and three types of thermometry systems underwent extensive phantom and clinical testing at Stanford University. A total of 996 treatment sessions involving 268 separate treatment fields in 131 patients was performed. Thermal profiles were obtained in 847 of these treatment sessions by multipoint and/or mapping techniques involving mechanical translation. The ability of these devices to heat superficial, eccentrically located and deep-seated tumours at the major anatomical locations is evaluated and the temperature distributions, acute and subacute toxicities, and chronic complications compared. Average measured tumour temperatures between 42 degrees C and 43 degrees C were obtained with many of the devices used for superficial heating; average tumour temperatures of 39.6 degrees C to 42.1 degrees C were achieved with the three deep-heating devices. When compared to the goal of obtaining minimum tumour temperatures of 43.0 degrees C, all devices performed poorly. Only 14 per cent (118/847) of treatments with measured thermal profiles achieved minimum intratumoural temperatures of 41 degrees C. Fifty-six per cent of all treatments had associated acute toxicity; 14 per cent of all treatments necessitated power reduction resulting in maximum steady-state temperatures of less than 42.5 degrees C. Direct comparisons between two or more devices utilized to treat the same field were made in 67 instances, including 19 treatment fields in which two or more devices were compared at the same treatment session. The analyses from direct comparisons consistently showed that the static spiral and larger area scanning spiral applicators resulted in more favourable temperature distributions. Three fibreoptic thermometry systems (Luxtron single channel, four channel and eight channel multiple [four] probe array), the BSD Bowman thermistor system and a thermocouple system were evaluated with respect to accuracy, stability and artifacts. The clinical reliability, durability, and patient tolerance of the thermometry systems were investigated. The BSD Bowman and third generation Luxtron systems were found clinically useful, with the former meeting all of our established criteria.

Meat preparation and colorectal adenomas in a large sigmoidoscopy-based case-control study in California (United States)

The often observed association between red meat and colorectal cancercould be due in part to mutagens, such as heterocyclic amines (HCA), that arepresent in cooked meat. HCAs are highly mutagenic and cause intestinal tumorsin animals. The hypothesis that HCAs are also carcinogenic to humans remainsto be substantiated in epidemiologic studies. We determined the associationsof meat preparation and frequency of intake (proxy variables for HCAexposure, since HCA concentration depends on the type of meat and the way itis cooked) with the prevalence of distal colorectal adenomas in asigmoidoscopy-based case-control study of 488 matched pairs of subjects fromtwo California (United States) Kaiser Permanente Medical Centers. A more thantwofold difference in adenoma prevalence between subjects at extreme ends ofestimated HCA intake was observed. For subjects who ate red meat more thanonce per week, fried it more than 10 percent of the time, and ate it with adarkly browned surface, compared with subjects who ate red meat one time orless per week, fried it 10 or less percent of the time, and ate it with alightly browned surface, the odds ratio was 2.2 (95 percent confidenceinterval = 1.1-4.3). Adenoma prevalence also increased with frequency offrying red meat (P trend = 0.004). These results are consistent with acarcinogenic effect of HCA.

Experience with a Multitransducer Ultrasound System for Localized Hyperthermia of Deep Tissues

A system employing six planar ultrasound transducers has been utilized for preclinical and pilot clinical studies with the aim of producing therapeutic heating preferentially at depth. The array consists of six 7 cm diameter PZT-4 disks mounted on a spherical shell section with a 26 cm radius of curvature. The crystals operate at different frequencies a few kilohertz above their fundamental frequencies of approximately 350 kHz for near-field peak suppression, and each has a few percent modulation to minimize standing wave effects. In water, the system can be focused to produce a high intensity region near the isocenter with a full width half maximum of approximately 1.5 cm in all directions. In attenuating tissue, the high intensity region is closer to the array of transducers by a few centimeters. For heating of realistic tumors at depth, small wedges are used to rotate the transducer axes a few degrees away from the radial direction, yielding a waist rather than a single point where the individual beam central axes come closest to each other. The waist is 3-6 cm in diameter, producing, ideally, ellipsoidal shaped temperature distributions centered deep in perfused tissue. Quantitative power deposition profile mapping, as well as qualitative studies using liquid crystal sheets, have been performed in water phantoms to characterize the system for different transducer orientations.

Vitamin D receptor polymorphisms and risk of colorectal adenomas (United States)

AbstractObjective: The purpose of this study was to determine whether vitamin D receptor (VDR) gene polymorphisms influence risk of colorectal adenoma. Methods: Polymorphisms in the 5′ and 3′ ends of the VDR gene were genotyped for 373 colorectal adenoma cases and 394 controls. Results: Overall, there was no significant association between the 5′ (FokI) or the 3′ (BsmI) polymorphisms and adenoma risk. However, risk of large (>1 cm) adenomas decreased with increasing copies of the FokI f allele (p = 0.04). Compared to the FF genotype, odds ratios for the Ff and ff genotypes were 0.79 (95% CI 0.44–1.41) and 0.32 (95% CI 0.11–0.91), respectively. FokI genotype was more strongly related to large adenoma risk among subjects with low dietary calcium intake (ORFf = 0.48; 95% CI 0.17–1.3; ORff = 0.21; 95% CI 0.04–1.3), low dietary vitamin D intake (ORFf = 0.25; 95% CI 0.09–0.69; ORff = 0.22; 95% CI 0.04–1.2), or dark skin color (ORFf = 0.66; 95% CI 0.27–1.6; ORff = 0.10; 95% CI 0.01–1.0). Conclusion: These results suggest that VDR FokI genotype influences development of colorectal adenomas, and that the effect may be modified by calcium and vitamin D status.

Two or six hyperthermia treatments as an adjunct to radiation therapy yield similar tumor responses: results of a randomized trial.

From March 1984 to February 1988, 70 patients with 179 separate treatment fields containing superficially located (less than 3 cm from surface) recurrent or metastatic malignancies were stratified based on tumor size, histology, and prior radiation therapy and enrolled in prospective randomized trials comparing two versus six hyperthermia treatments as an adjunct to standardized courses of radiation therapy. A total of 165 fields completed the combined hyperthermia-radiation therapy protocols and were evaluable for response. No statistically significant differences were observed between the two treatment arms with respect to tumor location; histology; initial tumor volume; patient age and pretreatment performance status; extent of prior radiation therapy, chemotherapy, hormonal therapy, or immunotherapy; or concurrent radiation therapy. The means for all fields of the averaged minimum, maximum, and average measured intratumoral temperatures were 40.2 degrees C, 44.8 degrees C, 42.5 degrees C, respectively, and did not differ significantly between the fields randomized to two or six hyperthermia treatments. The treatment was well tolerated with an acceptable level of complications. At 3 weeks after completion of therapy, complete disappearance of all measurable tumor was noted in 52% of the fields, greater than or equal to 50% tumor reduction was noted in 7% of the fields, less than 50% tumor reduction was noted in 21% of the fields, and continuing regression (monotonic regression to less than 50% of initial volume) was noted in 20% of the fields. No significant differences were noted in tumor responses at 3 weeks for fields randomized to two versus six hyperthermia treatments (p = 0.89). Cox regression analyses were performed to identify pretreatment or treatment parameters that correlated with duration of local control. Tumor histology, concurrent radiation doses, and tumor volume all correlated with duration of local control. The mean of the minimum intratumoral temperatures (less than 41 degrees C vs. greater than or equal to 41 degrees C) was of borderline prognostic significance in the univariate analysis, and added to the power of the best three covariate model. Neither the actual number of hyperthermia treatments administered nor the hyperthermia protocol group (two versus six treatments) correlated with duration of local control. The development of thermotolerance is postulated to be, at least in part, responsible for limiting the effectiveness of multiple closely spaced hyperthermia treatments.

Body conformable 915 MHz microstrip array applicators for large surface area hyperthermia

The optimal treatment with hyperthermia of superficially located tumors which involve large surface areas requires applicators which can physically conform to body contours, and locally alter their power deposition patterns to adjust for nonuniform temperature caused by tissue inhomogeneities and blood flow variations. A series of 915-MHz microstrip array applicators satisfying these criteria have been developed and clinically tested. Clinical and engineering design tradeoffs for practical devices are discussed. Measurements taken in tissue equivalent phantoms and a summary of clinical experiences with these microstrip arrays are presented.<<ETX>>

Variants of N-acetyltransferase NAT1 and a case-control study of colorectal adenomas.

N-acetyltransferase NAT1, together with enzymes CYP1A2 and NAT2, helps convert heterocyclic amines to mutagens. Epidemiologic studies of the association of variants of these enzymes with colorectal cancer may provide indirect support for a heterocyclic amine mechanism. We used single strand conformation polymorphism and heteroduplex analysis to screen fro mutations in the NAT1 coding region in a case-control study (n = 932) of colorectal adenomas, which are precursors to cancer. Thirteen different single-base mutations were found: C97T, C190T, T402C, G445A-G459A-T640G ( a combination of three mutations), C559T, G560A, A613G, A752T, T777C, G781A, and A787G. Function of novel mutations was tested by bacterial production of enzymes and measurements of Km, Vmax, and stability. However, on 24-control individuals and 18 cases carried an inactivating NAT1 mutation. When combined with our data on the NAT2 acetylation polymorphism, we saw no evidence for an association between N-acetyltransferases and prevalence of adenomas. Larger sample sizes are required for further evaluation.

Spiral microstrip hyperthermia applicators : technical design and clinical performance

Spiral microstrip microwave (MW) antennas have been developed and adapted for use as clinical hyperthermia applicators. The design has been configured in a variety of forms including single fixed antenna applicators, multi-element arrays, and mechanically scanned single or paired antennas. The latter three configurations have been used to allow an expansion of the effective heating area. Specific absorption rate (SAR) distributions measured in phantom have been used to estimate the depth and volume of effective heating. The estimates are made using the bioheat equation assuming uniformly perfused tissue. In excess of 500 treatments of patients with advanced or recurrent localized superficial tumors have been performed using this applicator technology. Data from clinical treatments have been analyzed to quantify the heating performance and verify the suitability of these applicators for clinical use. Good microwave coupling efficiency together with the compact applicator size have proved to be valuable clinical assets.

Serum 25-hydroxyvitamin D, dietary calcium intake, and distal colorectal adenoma risk.

Vitamin D has recently emerged as a potentially protective agent against colorectal neoplasia. We assessed the associations between dietary vitamin D, plasma 25-hydroxyvitamin D [25(OH)D], dietary calcium, and colorectal adenomas in a large screening sigmoidoscopy-based case-control study in Southern California. Because conversion of serum 25(OH)D to serum 1,25-vitamin D is highly regulated by serum calcium, we also assessed modification of the 25(OH)D-adenoma association by calcium intake. Cases were 473 subjects with a primary adenoma, and controls were 507 subjects who had no adenomas at sigmoidoscopy and no history of adenomas. Compared with those in the lowest quartile of intake, those in the highest quartile of dietary vitamin D had an adjusted odds ratio (OR) of 0.83 [95% confidence interval (CI) = 0.49-1.41] and those in the highest quartile of dietary calcium had an OR of 0.82 (95% CI = 0.49-1.25). There was a suggestion that plasma 25(OH)D may be protective in this population (OR for highest vs. lowest quartile = 0.74, 95% CI = 0.51-1.09). A significant protective effect of 25(OH)D was cLawrence Erlbaum Associatesrly evident only in those with calcium intakes below (OR = 0.40 for highest vs. lowest quartile, 95% CI = 0.22-0.71, p for trend = 0.005) and above (OR = 1.17, 95% CI = 0.69-1.99, p for trend = 0.94) the median calcium intake.

Hyperthermia and radiation therapy of local-regional recurrent breast cancer: Prognostic factors for response and local control of diffuse or nodular tumors

Over the past decade, hyperthermia has been extensively studied as an adjuvant to radiation therapy in the management of local-regional metastases from adenocarcinoma of the breast. A retrospective review of our experience from July 1982 to January 1990 identified 241 fields in 89 patients which satisfied the following criteria: biopsy confirmation of recurrent or metastatic adenocarcinoma of the breast; involvement of the chest wall and/or regional lymph nodes with diffuse or nodular metastases; treatment which included radiation therapy and externally administered hyperthermia during which mechanically-mapped and/or multipoint normal tissue and intratumoral temperatures were monitored; and at least one follow-up evaluation at 3 weeks or more after completion of treatment. The majority of fields were in patients who had extensive prior treatment including radiation therapy (68%), chemotherapy (86%), and hormonal therapy (58%). Treatment consisted of radiation therapy (average dose: 39.88 Gy) and hyperthermia (1-12 treatments; average 3.12); concurrent chemotherapy or hormonal therapy were also administered in 3% and 32% of the fields, respectively. Parameters characterizing the initial breast cancer, the patient and tumor at the time of hyperthermia, and the treatment were studied in univariate and multivariate analyses with complete response rate at the time of maximum tumor regression and duration of local control as endpoints. The treatments were well tolerated with no life-threatening complications noted. The means for all fields of the mean minimum, mean maximum, and mean average measured intratumoral temperatures were 40.3 degrees C, 44.6 degrees C, and 42.4 degrees C, respectively. At 3 weeks following completion of radiation therapy, response rates were: complete response (52%), partial response (8%), no response (17%), and continuing regression (monotonic regression to less than 50% of initial volume) was noted in 22% of the fields. At the time of maximum tumor regression local control was noted in 72% of the fields. Five parameters correlated with higher complete response in univariate and multivariate analysis: lower T-stage of the initial breast cancer; at the time of hyperthermia age less than 50 years, Karnofsky status greater than 95%, and the absence of distant metastases; and the use of concurrent hormonal therapy. The absence of a family history of breast cancer and concurrent radiation dose greater than or equal to 25 Gy significantly correlated with higher complete response in the univariate but not in the best multivariate models.(ABSTRACT TRUNCATED AT 400 WORDS)