Biomedical subjects

A J Thistlethwaite

Publications and source records attributed to A J Thistlethwaite.

5 recordsLinked to original sources

PubMed1994

Tumor extracellular pH as a prognostic factor in thermoradiotherapy.

PURPOSE: Tumor extracellular pH measurements in 26 human tumors were evaluated for the purpose of prognostic indication of response to thermoradiotherapy. METHODS AND MATERIALS: Twenty-six patients (10 male, 16 female; mean age 62 years, range 18-89) were treated with external microwave hyperthermia (915 MHz) combined with radiation therapy. Tumor histologies included: 46% adenocarcinoma, 38% squamous cell carcinoma, 12% soft tissue sarcoma, and 4% malignant melanoma. The mean tumor depth was 1.6 +/- 0.2 cm (range 0.4-3 cm) and the mean tumor volume was 73 +/- 11 cm3 (range 1-192 cm3). The mean radiation dose administered concurrently with hyperthermia was 39 +/- 1 Gy (range 24-60 Gy, median of 40 Gy), in 15 fractions (range 8-25), over 32 elapsed days (range 15-43). The mean number of hyperthermia sessions administered was 5.4 +/- 0.5 (range 2-10). A battery operated pH meter and combination 21 ga recessed glass, beveled needle microelectrodes were used for tumor pH measurements. Calibration in pH buffers was performed before and after each pH measurement. The needle microelectrodes were 2.5 cm in length. RESULTS: A complete response (CR) was obtained in 20 of 26 patients (77%) and a partial response in six (23%). The mean extracellular tumor pH was 6.88 +/- 0.09 in CR patients while it was 7.24 +/- 0.09 in noncompletely responding (NCR) patients (p = 0.08). Logistic regression analysis indicated that the probability of obtaining a complete response was influenced by the tumor volume (p = 0.02), tumor depth (p = 0.05), and extracellular tumor pH (p = 0.08). Lesions in the pH range of 6.00-6.40 and lesions in the pH range of 6.41-6.80 exhibited a CR rate of 100%, while those lesions in the pH range of 6.81-7.20 exhibited a CR of 90% and those in the pH range of 7.21-7.52 exhibited a CR of 50% (p = 0.002). In lesions with depth < or = 1.5 cm, the CR rate was 100% when the tumor pH was < 7.15 and 75% when the tumor pH was > or = 7.15. In lesions with depth between 1.5 and 3 cm, the CR rate was 66% when the tumor pH was < 7.15 and 43% when the tumor pH was > or = 7.15 (p = 0.02). In small tumors, that is, < or = 20 cm3, tumor pH increased with volume, whereas in larger tumors, that is, > 20 cm3, tumor pH decreased as a function of tumor volume. CONCLUSION: Tumor extracellular pH may be useful as a prognostic indicator of tumor response to thermoradiotherapy.

Combined Modality Therapy↗

PubMed1994

Human tumor extracellular pH as a function of blood glucose concentration.

PURPOSE: Mammalian cells are sensitized to hyperthermia when the extracellular pH (pHe) is acutely reduced to < pH 7.0-7.2. However, cells chronically adapted to low pHe may not demonstrate such sensitivity. Although much of the extracellular environment of human tumors is at lower than normal physiological pH, it may be necessary to acutely acidify tumors to cause a change in the therapeutic response to hyperthermia. The purpose of this study was to reduce extracellular pH in human tumors by elevation of blood glucose. METHODS AND MATERIALS: The change in tumor pHe was measured as a function of the change in blood glucose concentration after oral administration of 100 g glucose in 25 fasting, nondiabetic patients. pHe was determined by needle microelectrodes, and blood glucose determined by "Chemstrips" and a glucometer. In some patients blood glucose concentration rose with time after ingestion to a peak change of 50-100 mg/dL between 30-70 min and then began to decrease. In another group of patients glucose concentration increased by 100-200 mg/dL over 30-90 min and remained elevated as if the patients in this group were Type II diabetics. RESULTS: In 14 transient hyperglycemic patients (56%), as blood glucose increased tumor pHe decreased by a mean of -0.17 +/- 0.04 pH units (p < or = 0.0001, range of -0.41-(+)0.07). By contrast in eight persistent hyperglycemic patients, tumor pHe remained unchanged or actually increased an average of 0.03 +/- 0.04 pH units (range of -0.15-(-)0.14). Normal tissue pHe in five patients was unchanged by hyperglycemia, pHe = 7.33 +/- 0.03. Among all patients, 52% exhibited a pHe decrease > or = 0.1 pH unit, and 24% exhibited a pHe decrease > or = 0.2 pH unit. In five transient hyperglycemic patients whose preglucose tumor pHe was between 6.90 and 7.22, the average decrease in pHe induced by hyperglycemia was 0.25 +/- 0.05 pH unit. A linear relationship was observed between the change of pHe and the maximum change in blood glucose such that the greatest decrease in tumor pHe occurred when the glucose change was minimal. The slope was 0.0017 +/- 0.0005 pH units/mg/dL glucose (p < or = 0.005). The linear relationship included both tumors in transient hyperglycemic patients and in persistent hyperglycemia patients. CONCLUSION: Since patients who exhibited the lowest change in blood glucose exhibited the greatest decrease in tumor pHe, it may be that cells in these patients were better able to transport glucose intracellularly which in tumor cells would permit a more rapid production of lactic acid from aerobic and/or anaerobic glycolysis. These data may be helpful in predicting the response of individual patients to oral hyperglycemia as a clinical thermosensitizer.

Blood Glucose↗

PubMed1987

Modification of human tumor pH by elevation of blood glucose.

Nine patients with metastatic or recurrent superficial tumors of varying size and histology were administered 100 g oral glucose to investigate whether hyperglycemia can selectively lower tumor pH. pH was measured by a 21 ga modified glass needle electrode inserted through an 18 ga open-ended Angiocath. Serum glucose was monitored every 7.5 min by finger stick and a blood glucose analyzer. Tumor pH was measured over 50-80 min concomitantly with determination of blood glucose. In five nondiabetic patients (eight measurement points) tumor pH decreased 0.05-0.5 units from a pre-glucose range of 6.8-7.4 (7.14 +/- 0.08) to 6.4-7.3 (6.90 +/- 0.10) as blood glucose increased from a baseline of 80-120 mg/dl to 165-215 mg/dl. There was considerable heterogeneity from patient to patient regardless whether blood glucose increased to a peak at 40-60 min post-ingestion and then decreased, or whether it remained elevated up to the end of the 80 min observation period. In general, tumor pH decreased as blood glucose increased and then continued to fall throughout the period of observation. In one patient, tumor pH did not change although blood glucose increased to 175 mg/dl. Normal tissue pH was 7.36 +/- 0.02 when determined on four occasions in three patients (subcutaneous and intramuscular sites), and was unaffected by glucose administration. As a further control for tumor tissue and pH probe stability, pH probes in two patients were left in place for 30 min before glucose ingestion. The tumor pH was stable for the entire interval. Interestingly, three patients had an abnormal glucose response: two of those patients (one patient on two separate occasions) had an increase in blood glucose to 230-260 mg/dl in 40-60 min and pH actually increased 0.1-0.3 units. The third patient had a transient increase in blood glucose to 290 mg/dl along with a corresponding increase and subsequent decrease in tumor pH. In summary, whether glucose was given pre- or post-hyperthermia, independently of position in the tumor, and independently of whether pH increased or decreased, the slope of the curve of pH = f(time) was similar in a given patient tumor on all measurement occasions. These preliminary results suggest that hyperglycemia may be useful in non-diabetic patients, and perhaps in diabetic patients given insulin, to selectively reduce tumor pH and sensitize tumors to hyperthermia.

Administration, Oral↗

PubMed1985

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.

Adenocarcinoma↗

PubMedDate not supplied

Extracellular pH distribution in human tumours.

Extracellular pH (pHc) was determined by needle microelectrodes in 67 tumour nodules in 58 patients. The objective was to evaluate the relationship between pHe, tumour histology and tumour volume. The mean age of the patients was 62 years, mean depth of the lesions was 2.7 +/- 0.2 cm, and mean tumour volume was 187 +/- 60 cm3. Lesions were located in readily accessible areas such as on the limbs, neck or chest wall. Tumour histologies included: 48% adenocarcinoma; 34% squamous cell carcinoma; 8% soft tissue sarcoma; and 10% malignant melanoma. The mean tumour pHe for the entire group of tumours was 7.06 +/- 0.05 (range 5.66-7.78). Variation in pHe measurements between tumours was greater than the variation in measurements within tumour (F = 7.11, p < 0.01). In adenocarcinomas pHe was 6.93 +/- 0.08 (range 5.66-7.78), in soft tissue sarcomas 7.01 +/- 0.21 (6.25-7.45), in squamous cell carcinomas 7.16 +/- 0.08 (6.2-7.6), and in malignant melanomas 7.36 +/- 0.1 (6.98-7.77). Tumour pHe was significantly different between the four histological groups (p < 0.001). When adenocarcinoma and soft tissue sarcoma lesions were grouped together, pHe was 6.94 +/- 0.08 compared with 7.20 +/- 0.07 in squamous cell carcinomas and malignant melanomas lesions (p < 0.01). Tumour pHe increased as a function of the logarithm of tumour volume at 0.07 +/- 0.02 pH unit/ln cm3 (p = 0.006, r = 0.34). In conclusion, tumour histology and tumour volume were the most important factors determining the range of pHe's.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗