Kayihan Engin

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 pHes.(ABSTRACT TRUNCATED AT 250 WORDS)

Occupational physical activity, socioeconomic status, and risks of 15 cancer sites in Turkey

A multiple-site case-control study of 15 cancers (stomach; colon; rectum; larynx; lung; melanoma; skin; female breast; male breast; cervix; ovary; uterus; prostate; testis; and bladder) was conducted to evaluate their association with occupational physical activity and socioeconomic status (SES). A hospital-based study population (3,486 male cases and 379 female cases, and 2,127 male and 244 female controls) was established in an oncological treatment center in Istanbul, Turkey, from 1979–84. Assessment of physical activity and SES was based on job titles held by the study subjects. Two measures of physical activity were developed based on energy expenditure and ‘sitting time’ during working hours. Observed risks were adjusted for age, smoking, and SES. Elevated risks were observed among workers who held sedentary jobs for cancers of the colon (odds ratio [OR=1.6), rectum (OR=1.3), melanoma (OR=1.9), male breast (OR=1.4), prostate (OR=5.0), and ovary (OR=2.0). Cancers of the cervix and uterus showed significantly decreasing risks with decreased activity. Risks of cancers of the colon, rectum, larynx, ovary, and melanoma were enhanced after risks for physical activity indices were adjusted for SES, while the associations between physical activity and cancers of the prostate, cervix, and uterus were weakened after SES adjustment. Risks of melanoma rose significantly with both activity indices after SES adjustment. The results of this study support previously reported associations between physical activity and cancers of the colon and rectum observed in developed countries, and provide additional evidence for cancers of the larynx, prostate, cervix, uterus, and melanoma, and point out the importance of SES in evaluation of physical activity and cancers of the colon, rectum, larynx, prostate, breast, cervix, and melanoma in developing countries.

Biological rationale and clinical experience with hyperthermia

Hyperthermia (HT) as an adjunct to radiation therapy (RT) has been a focus of interest in cancer management in recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of HT combined with either RT or chemotherapy especially in the treatment of superficially seated malignant tumors. The major impact of HT is currently on locoregional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumor that lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissues, and HT may lead to a further decrease in blood flow and augment heat sensitivity. Three major areas of clinical investigation have borne the greatest fruit for HT as adjunctive therapy to RT. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. Thermal enhancement ratio was increased in all cases and is approximately 1.4 for neck nodes, 1.5 for breast, and 2 for malignant melanoma. In general, the most important prognostic factors for complete response (CR) are RT dose, tumor size and minimal thermal parameters minimal thermal dose (t43min), mean minimal temperature (Tmin) or T90, i.e., temperature exceeded by 90% of thermal sensors]. The number of HT fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of HT fractions delivered also appears irrelevant provided adequate HT is delivered in one or two sessions. The major prognostic factors for the duration of local control were tumor histology, concurrent RT dose, tumor depth and Tmin. Although numerous single institution studies showed increased CR rates and improved local control, the efficacy of HT as an adjunct to RT should be assessed with well-designed multi-institutional randomized clinical trials. Such clinical trials are underway.

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.

Randomized trial of one versus two adjuvant hyperthermia treatments per week in patients with superficial tumours

One test for thermotolerance development in a clinical situation is to evaluate the effects of altering the hyperthermia fractionation interval on tumour response to thermoradiotherapy. Between 1983 and 1990 44 evaluable advanced superficial tumours of miscellaneous origin in 41 patients were randomized to receive either once-weekly or twice-weekly external microwave hyperthermia treatments combined with radiation therapy. The mean age of patients was 62 years, and 85% had failed previous therapy. All lesions were less than 8 x 8 x 4 cm (L x W x D) and were heated by external 915 MHz microwaves. The mean radiation dose was 44 +/- 3 Gy (mean +/- SE) in the once-weekly group and 46 +/- 3 Gy in the twice-weekly group (p = 0.64). The mean volume of the lesions heated once weekly was 17 +/- 6 versus 23 +/- 5 cm3 for those heated twice weekly (p = 0.45). Hyperthermia was administered once weekly for 4.6 +/- 0.2 sessions (range 3-7) or twice weekly for 8.1 +/- 0.3 sessions (range 4-10). Thermometry was performed using 3.4 +/- 0.2 catheters and 5.1 +/- 0.6 thermal sensors per tumour in the once-weekly group, and 2.7 +/- 0.2 catheters and 5.8 +/- 0.3 thermal sensors per tumour in the twice-weekly group. Of the 44 evaluable randomized lesions a complete response (CR) at 2 months post-treatment was observed in 59% (13/22) heated once weekly and 55% (12/22) in those heated twice weekly. The prognostic factors predictive of tumour complete response were found by logistic regression analysis to be radiation dose and tumour volume, while the prognostic factors predictive of duration of response (Cox proportional hazards analysis) were median minimum tumour temperature (Tmin), minimum tumour temperature during the first heat treatment (Tmin1) and tumour volume. The duration of local control in lesions with Tmin < or = 39.5 degrees C was 11.7 +/- 1.9 months while for lesions with Tmin > 39.5 degrees C it was 23.0 +/- 4.2 months (p = 0.01). The ED50 was calculated by logistic regression to be 40 Gy (95% CI = 22-54 Gy) for once- and twice-weekly heated lesions. There was not a significant difference in tumour response or duration of response between populations randomized to receive once- versus twice-weekly hyperthermia treatments. There was also no difference in skin reaction rates between once- and twice-weekly hyperthermia treatments, nor could a correlation be found between any thermal parameter and skin reactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperthermia and radiation in advanced malignant melanoma

Advanced melanoma (48 lesions in 40 patients) was treated with external microwave hyperthermia combined with radiation therapy between 1980-1988. Thirty-three lesions in 28 patients were evaluable for tumor response (mean age 64 years, 19 male, 9 female). Evaluable lesions received 13 to 66 Gy (mean 37 +/- 2 Gy) over 5 to 16 fractions (mean of 10) in 14 to 56 elapsed days (mean of 25). Tumor volume (pi/6*length*width*depth) was 62 +/- 16 cm3 (1-377 cm3). Hyperthermia was administered in 6.6 +/- 0.4 sessions (range 1-14), there were 3.2 +/- 0.4 thermal sensors per tumor (range 1-11) and 27 fields were treated twice-weekly (82%). Of the 33 evaluable lesions, 12 exhibited a complete response (36%), and 17 had a partial response (52%). Among the 12 complete responders four recurrences (33%) were observed at 8.6 +/- 1.4 months (median of 8.2 months). In superficial tumors with depth < or = 3 cm and with lateral dimensions within 2 cm of the boundaries of the microwave applicator, the complete response rate was 50% (11/22); whereas for patients with deeper tumors with depth > 3 cm, the complete response rate was 9% (1/11), p = 0.02. The minimal tumor thermal dose during the first hyperthermia treatment session correlated with response (t43min1 = 20 +/- 7 vs. 6 +/- 3 minEq43 degrees C for complete responders and noncomplete responders, respectively, p = 0.06); and 7 of 10 lesions that had t43min 1 > or = 8 minEq43 degrees C achieved a complete response whereas only 5 of 22 lesions (23%) that had t43min1 < 8 minEq43 degrees C did so (p = 0.01). However, neither the minimum tumor temperature during the first treatment, the median minimum tumor temperature over all treatment sessions nor the sum of minimum thermal dose over all treatment sessions correlated with tumor response. Twenty-three patients with 28 lesions died during follow-up (82%). The survival for complete responding patients with superficial lesions was 21.3 +/- 1.5 months compared to 4.5 +/- 0.5 months for patients with superficial lesions that did not experience a complete response (p = 0.0001). For patients with noncomplete responding lesions deeper than 3 cm survival was 4.4 +/- 0.6 months. Twenty lesions were treated without any skin reaction (42%, 20/48). Of the rest, 23 had erythema (48%, 23/48), seven had blistering (14%, 7/48) and one had ulceration of the skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Thermoradiation therapy for superficial malignant tumors

Background. Between 1980–1990, 126 patients were treated with radiation therapy (RT) and hyperthermia using 915‐MHz external microwave applicators. All but 11 patients had failed to respond to previous therapy.

The relationship between genetic susceptibility to head and neck cancer with the expression of common fragile sites

Numerous studies have recently been conducted to investigate genetic mechanisms in cancer causes and pathogenesis. Some of these studies have shown that there were certain specific chromosomal defects in normal cells of cancer patients and in their first‐degree relatives. It was suggested that these individuals were susceptible to cancer development when compared with people without these defects.

Effect of I.V. glucose versus combined I.V. plus oral glucose on human tumour extracellular pH for potential sensitization to thermoradiotherapy

The purpose of this study was to determine whether intravenous or combined intravenous plus oral glucose administration was more effective inducing acute tumour acidification. Seventeen nondiabetic patients at the Henan Tumour Hospital with superficial tumour deposits of various histologies and size were administered, after fasting, either 50 g glucose intravenously (i.v., in 100 ml over 10 min) or 50 g i.v. glucose (in 100 ml over 10 min) combined with 100 g oral glucose (in 200 ml; i.v. + oral). Extracellular tumour pH (pHe) was determined with one or two indwelling needle combination pH microelectrodes. Blood glucose concentration was determined every 15-20 min by finger stick with Chem-Strips and a Glucometer. Ten patients received i.v. glucose, and seven patients received i.v. + oral glucose. Blood glucose rose to 430 +/- 15 mg/dL in both groups. However, the rate of clearance of blood glucose was greater for the i.v. glucose than for the i.v. + oral glucose group (p < 0.00002), and thus the blood glucose levels remained elevated longer after i.v. + oral than after i.v. glucose administration. Relative to the initial fasting blood glucose concentration, blood glucose was -2 +/- 7 mg/dL at 110 min after glucose administration by the i.v. route, whereas, blood glucose relative to initial values was 143 + 23 mg/dL by 110 min after glucose administration by the i.v. + oral route, p = 0.000004. The initial pHe values in the two groups of tumours were similar, 7.34 +/- 0.09 (6.78-7.71) and 7.35 +/- 0.08 (6.99-7.61), respectively. After i.v. glucose, tumour acidification occurred in nine of ten patients (-0.16 + 0.02 pH unit, range -0.24 to -0.05), and after i.v. + oral glucose tumour acidification occurred in six of seven patients (-0.19 +/- 0.07 pH unit, range -0.43 to -0.06). When the initial fasting blood glucose concentration was in excess of 82 mg/dL, all patients (12/12) exhibited tumour acidification during hyperglycaemia, whereas, only 3/5 patients exhibited tumour acidification when the initial blood glucose concentration was less than 82 mg/dL (p = 0.07). The time to maximum decrease in tumour pHe was significantly shorter after i.v. + oral glucose than after i.v. glucose (e.g., 67 +/- 11 versus 102 +/- 8 min, p = 0.02) and correlated with the rate of clearance of blood glucose (p = 0.02, r = 0.55). Larger tumours tended to exhibit a greater decrease in pHe (p = 0.08, r = 0.04). The only side effects of hyperglycaemia were transient nausea and increased urinary output. The effect of hyperglycaemia induced by administration of 200 g oral glucose was similar to i.v. administration in that 83% of tumours exhibited acidification of 0.14 +/- 0.02 pH unit by 91 +/- 7 min. We conclude that i.v. and i.v. + oral glucose administration are equally effective inducing tumour acute acidification, but no more effective than 200 g oral glucose, for investigation of hyperglycemic sensitization to thermoradiotherapy.

Thermoradiotherapy with combined interstitial and external hyperthermia in advanced tumours in the head and neck with depth ≫3 cm

Advanced tumours in the head and neck 3-6 cm depth are too deep to be completely heated by external 915 MHz microwaves. A preliminary study was performed using interstitial plus external hyperthermia combined with external beam radiation therapy to heat tumours to depths > or = 3 cm. Nine advanced metastatic lesions of squamous cell carcinoma located in the head and neck were treated between 1987 and 1990 with the combined hyperthermia technique and radiation doses of 38-60 Gy (mean of 49 +/- 3 Gy). The mean tumour volume was 58 +/- 9 (SE) cm3 (range 24-94 cm3) with a mean tumour depth of 3.9 +/- 0.3 cm (range 3-5.5 cm). The deeper aspects of the tumour were heated by interstitial 915 MHz microwave antennas and the superficial aspects heated by external 915 MHz applicators. A single plane of polyurethane closed-end catheters, 16 Ga, were inserted under local anaesthesia approximately 1.5-2 cm apart in parallel arrays at the base of a lesion behind the sternomastoid muscle, or an equivalent site in a dissected neck, extending forward and angled deeply no more than 15 degrees. Hyperthermia was administered twice weekly immediately after radiation therapy in a mean of 5.3 +/- 0.7 external heat sessions (range 3-7) and a mean of 3.5 +/- 0.6 interstitial heat sessions (range of 1-6). Interstitial hyperthermia was usually administered in alternating sessions with external hyperthermia, but in some patients all of the sessions of one modality were administered followed by all of the sessions of the other modality. In no case were both interstitial and external heatings performed on the same day. Surface thermometers were used to monitor skin temperature during external hyperthermia sessions. Results showed that by 8 weeks after completion of treatment, six lesions exhibited a complete response (67%) and three a partial response (33%). One of the partial responses continued to regress and became a complete response (78% complete response). The recurrence rate in complete responders was 14% (1/7) with time to recurrence of 7.7 months. Six lesions were recurrence-free at last follow-up of 21.3 +/- 8.8 months. Skin reactions were absent in four fields (44%), erythema was noted in five (56%) and thermal blistering in one (11%). Ulceration occurred only in association with tumour breakdown when the skin was infiltrated by tumour (three patients, 33%).(ABSTRACT TRUNCATED AT 400 WORDS)