Rudolph E. Nerlinger

pH DISTRIBUTION IN HUMAN TUMORS

The effectiveness of hyperthermia in tumor therapy may depend on a lower extracellular pH of tumor compared to that of normal tissue. A technique for measuring extracellular pH in human tumors has been devised to test the usefulness of this parameter as prognostic indicator of tumor hyperthermia response. In a preliminary study 50 of 53 pH readings from 14 human tumors (both heated and unheated) were below normal physiological pH. Tumor pH values ranged between 5.55-7.69 (average for unheated tumors 6.81 +/- 0.09, SEM, only one determination was above 7.40). Although there was considerable heterogeneity of pH within tumors, the accuracy and drift of the 21 gauge needle electrode were not a problem. Fifteen minutes were required for pH stabilization after insertion of an 18 gauge open-ended catheter, and less than 5 min for equilibration after electrode insertion into the catheter. A saline wheal was used for anesthesia to preclude modification of pH by anesthetics. Central portions of tumors were no more acidic than peripheral regions, but large tumors tended to be more acidic than small tumors. The pH of several tumors of various sizes and histologies was also determined immediately before subsequent treatment sessions. These measurements were made by reinsertion of catheters in approximately the same locations at each session. The trend appeared to be that pH increased with the number of treatment sessions. Measurements of pH were made in four patients immediately prior to and at the termination of a heating session (same locations since catheter remained in place during heating sessions). Three of the four tumors showed increased pH readings of 0.25-0.54 units during heating. However, none of the four tumors achieved temperatures exceeding 42 degrees C. The pH measurement technique developed provides a safe and relatively easy method for determining extracellular pH in human tumors. There appears to be a correlation of pH values with tumor size, treatment session, and possibly blood flow.

Response of human tumor blood flow to local hyperthermia

The effect of heat on blood flow in human tumors was studied as a function of time during 1 hour of local hyperthermia induced by 915 MHz microwaves. Blood flow was determined from the rate of thermal clearance by use of the bio-heat transfer equation. The rate of thermal clearance was measured at intervals of approximately 10 minutes throughout the treatment session by turning off the microwave power for 50 seconds. Tumor blood flow increased by amounts varying from 15 to 250% during the first 20-50 minutes of heating at 41-45 degrees C, after which it remained relatively constant during the remainder of the treatment session. The sharp reduction in blood flow or vascular stasis reported in most transplantable rodent tumors after comparable heating was not observed in human tumors. The maximum blood flow observed in heated human tumors ranged from 10-40 ml/min/100 gm. The systematic error due to thermal conduction was estimated to be equivalent to a blood flow of less than 3 ml/min/100 gm.

The pathology of breast cancer detected by mass population screening.

Breast cancer was detected in 156 of 17,526 asymptomatic women, (8.9/1000), aged 45‐64 years, screened by mammography, thermography, and physical examination. Twenty‐six percent of 149 pathologically reviewed cases metastasized to axillary nodes. Thirty‐six percent of tumors were in situ, minimally invasive, or low grade tubular carcinomas, none of which metastasized. Increased rates of detection were shown for intraductal and tubular types. Frankly invasive ductal and lobular carcinomas had a mean diameter of 2.3 cm., 46% of which had axillary lymph node metastases. Seventy‐percent of these were to only one to three nodes, however. Multicentricity with intraductal and lobular carcinoma in situ was frequently observed. Metastatic potential was related to tumor size, degree of stromal invasion, lymphatic permeation, and histologic grade. Few histological parameters other than size could be considered favorable. Forty‐two percent of tumors were not palpable, the majority being in situ, minimally invasive, and tubular types. Only five nonpalpable invasive carcinomas metastasized. While the initial results of mass screening appear favorable, prolonged follow‐up is needed to determine its impact on the population at risk.

Thermography, Mammography, and Clinical Examination in Breast Cancer Screening

Breast cancer screening detected 139 biopsy-proved malignancies in 16,000 slef-selected women (8.7/1,000). In these, xeroradiography detected 78% (109), clinical examination 55% (76), and thermography 39% (54). In all 16,000 women, the thermogram was interpreted as positive in 17.9% (2,864). The greatest effectiveness of mammography vs. clinical examination was seen in detection of early breast cancers (small lesions with negative axillary lymph nodes). In this group, thermography was less effective than it was in patients with larger lesions and lymph node metastases.

Blood flow in human tumors during local hyperthermia.

The response of tumor blood flow during local hyperthermia was studied at 40 different points in 15 superficial human tumors. Hyperthermia was administered for 60 minutes by use of 915 MHz microwaves. Blood flow was determined from the rate of thermal clearance by use of the bioheat equation. The rate of thermal clearance was sampled at 10-15 minutes intervals by turning the applied power off for 30 seconds. A correction was made for thermal conduction from orthogonal profiles of the tumor temperature. No measurements were made during the first 10-15 minutes of heating. The response of tumor blood flow was found to be independent of temperature in the range of 40-44 degrees C. The mean blood flow rate increased 10-15% between 15 and 30 minutes, but remained nearly constant thereafter. The coefficient of variation in this pattern is 15-20%. No evidence of a sharp reduction in flow was observed. Furthermore, the mean temperature elevation, net forward power, and rate of thermal conduction all remained nearly constant with time, providing further evidence of stability in the blood flow rate. Data obtained in one tumor suggest that a reduction in flow may occur at temperatures above 44 degrees C. The mean blood flow rates obtained in this study range from 0-34 ml/100g/min with an average value of 15 ml/100g/min.

Localized hyperthermia adjuvant to irradiation in superficial recurrent carcinomas: A preliminary report on 46 patients☆

Abstract The pilot study using externally applied microwave (2450 MHz) in concert with surface heating (44°C water bag) has accrued 46 patients and treated 59 areas. Intralesional probe measurements have documented effectiveness (41°C or beyond) to a depth of 3.0 cm, while most superficial tumor nodules (0–2.0 cm thick) easily achieve a temperature of 42.5–43.5°C maintained for 30–40 minutes twice weekly for 6–8 sessions. This heat program, given as an adjuvant to electron beam irradiation (600–800 rad/week for 3–4 weeks) has resulted in a 50% complete response rate among the 32 evaluable patients who completed this combined modality program. The highest responses were achieved among recurrent superficial tumor masses secondary to breast adenocarcinoma (815 complete response) and within deposits of melanoma. This pilot information has been sufficiently encouraging to justify plans for deep heating of advanced, inoperable primary tumor in which less than a 50% local control can be achieved using all existing cancer modalities (chemotherapy and radiation).

Catheter induced temperature artifacts in ultrasound hyperthermia.

Temperature artifacts were evaluated at 72 different sensor locations in 10 different tumour sites heated by use of planar ultrasound transducers operated at 1 and 3 MHz. Thermometry was carried out by single- and multisensor thermocouple probes inserted into 19- and 16-gauge polyurethane catheters, respectively. Nearly all catheters were oriented approximately perpendicular to the ultrasound beam. The artifacts were determined by backward extrapolation of the thermal decay 30-60s after the power was turned off. The effective blood flow and specific absorption rate (SAR) at the sensor locations were determined from the rate of decay and the steady-state temperature. The sample mean steady-state temperature, effective blood flow, and SAR were 41.4 degrees C, 17.5 ml/100 g/min, and 46.3 W/kg, respectively. The most frequent artifact was in the range 0-0.2 degrees C and the mean artifact was 0.6 degrees C. Less than 15% of the artifacts were above 1 degree C. The magnitude of the artifact correlates with the SAR of ultrasonic power, the effective blood flow rate, and the steady-state temperature. These results indicate that the artifact produced at 1 MHz by a multisensor, Teflon-sheathed thermocouple inserted into a 16-gauge polyurethane catheter is 1.7 +/- 0.4 degrees at an SAR of 100 W/kg.

Prognostic Factors of Breast Neoplasms Detected on Screening by Mammography and Physical Examination

A total of 183 neoplasms detected on screening women between the ages of 45 and 64 by mammography and physical examination were analyzed according to multiple histologic parameters. In general, tumors apparent only on mammography should be associcated with favorable long-term survival because of their early stage. These lesions had histologic features indicating significant potential for subsequent metastatic spread. This analysis strongly suggests that mammographic screening of asymptomatic women both above and below 50 years of age can substantially reduce breast cancer mortality.

Mechanisms of heat removal during local hyperthermia

Mechanisms of heat removal were studied in five recurrent squamous cell head or neck carcinomas, 50-150 cm3, heated by use of external 915 MHz microwave applicators. Thermal clearance measurements were made at a single point in each tumor. Three profiles of the tissue temperature were also measured in orthogonal directions about this point. The conduction term of the bioheat equation was evaluated from the orthogonal temperature profiles by the method of finite differences. The perfusion term of the bioheat equation was determined from the rate of temperature decay corrected for conduction. The results show that thermal conduction plays a major role in the dissipation of thermal energy during local hyperthermia. The rate of removal thermal energy by conduction ranged between 20 and 150 percent of that by perfusion. The temperature profiles show that conduction is higher than is generally expected due to heterogeneities in the blood flow which produce rapid changes in the temperature gradient. The results of this study demonstrate that the heat transport by thermal conduction in perfused tissue cannot be assumed to be small, or negligible, in comparison to that by perfusion.

The effect of coupling materials on specific absorption rate distributions at 915 MHz.

Deionized water is commonly used to couple microwave applicators to the patient surface in the administration of local hyperthermia. Profiles of the specific absorption rate (SAR) at 1-cm depth show that deionized water coupling significantly distorts the SAR distributions of the Clini-Therm 915-MHz 10 X 10 and 15 X 15 cm2 applicators. Maxima and minima that are discernible in the SAR profiles obtained by direct applicator load contact are amplified producing unexpected hot and cold regions in the heating pattern. An exception is coupling achieved by use of the Clini-Therm cooling pad, oriented such that the direction of deionized water flow is perpendicular to the electric field. The distortion in the SAR distribution can also be eliminated by replacing deionized water with mineral oil, a material having a much lower dielectric constant (epsilon = 2). The SAR profiles for mineral oil coupling are comparable to those obtained for direct contact; however, the efficiency of power transfer is slightly less (70%) and the level of microwave leakage is approximately four times greater.