Concurrent Taxol and split-course accelerated radiotherapy for advanced head and neck cancer

AIM: The aim of this study was to investigate feasibility and toxicity of fractionated paclitaxel administration concurrently with accelerated radiotherapy in the treatment of advanced head and neck cancer. PATIENTS AND METHODS: Patients with a proven histology of inoperable head and neck carcinoma were eligible for this study. Between July 1994 and August 1995, 12 patients with stage IV (UICC) tumors were treated. Patients were required to have normal end-organ function. Exclusion criteria included: age > 70 years, metastatic disease, performance status (Karnofsky < 70), major intercurrent medical disorders, and previous chemotherapy. External radiation was delivered twice a day at 1.5 Gy per fraction, specified to the reference point (ICRU 50), with a minimum interfraction interval of 6 hours. The accelerated scheme was split into 2 courses by a rest period of 9 days (including weekends) after administration of 30 Gy within 2 weeks. After 39 days a total dose of 72 Gy was reached. Paclitaxel (30 mg/m2/d) was administered as a continuous intravenous infusion over a period of 3 hours on days 1 to 5 and 29 to 33 of radiation therapy. All patients received premedication to avoid allergic reactions and circulatory monitoring was used routinely. RESULTS: Radiochemotherapy was completed in 10 patients with 8 complete and 2 partial remissions. Most important toxicity was a short period of neutropenia, which occurred 3 to 6 days after chemotherapy and was associated with fever in 9 cases. During paclitaxel infusion there was a significant but clinically not relevant increase in blood pressure and a decrease in heart rate. No acute cardiac effects occurred and no hypersensitivity reaction was seen. CONCLUSIONS: This regimen demonstrates a high activity in locally advanced head and neck cancer. Neutropenia associated with fever was the major dose limiting toxicity.     

Water spray cooling of stainless and C-Mn steel

This paper describes laboratory cooling experiments of C-Mn and stainless steel with a water/air nozzle. Experiments included use of both the steady state and the transient experimental method. The heat transfer coefficient was calculated both analytically and by a numerical method. The heat transfer coefficient was evaluated as a function of steel surface temperature, water flux, material and water/air flow. It was found that by increasing the water flux the heat transfer coefficient also increased. The Leidenfrost point was shifted to higher temperatures. Increasing air flow was also found to increase the heat transfer coefficient. Maximum heat transfer coefficient was twice as large for the C-Mn steel as for the stainless steel. Comparison of the steady state and transient experimental method showed good agreement in the temperature range 200 – 500°C, and with a water flux of 2I/m²s. Above 500°C it was difficult to obtain stable conditions for the steady state experiments.     

The role of sulfation and/or acetylation in the metabolism of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Salmonella typhimurium and isolated rat hepatocytes

The efficacy of repopulation during treatment splits in conventional radiotherapy (5 fractions/week, 2.5, 3.5, 4.5 Gy/fraction) was studied by delayed top-up treatment of mouse tongue epithelium. Splits of 6 h to 13 days were introduced after 1 or 2 weeks of fractionated irradiation. Following 5 fractions, compensation of about 3 dose fractions was assessed after the first weekend and original tissue tolerance was restored after a split of 4-10 days. About 4.6 dose fractions were repopulated during the second treatment week, followed by a further 1.5 fractions during the first 3 split days; restoration of the initial tolerance required 3-8 days. These results indicate that repopulation was more efficient during fractionated radiotherapy than during a subsequent treatment split. Latent times to complete denudation after the top-up treatment decreased to a dose-dependent minimum after 5 fractions and remained at the decreased level when a second treatment week was added. Original values were restored within 5-8 days after 5 fractions and 6 days after 10 fractions. Epithelial cell density during treatment with 3 or 4 Gy/fraction decreased to a dose-dependent nadir of 63% and 52% of the original number after 5 fractions, and original cell counts were then restored after 5 days. Cellularity remained at 60-70% during the second treatment week and subsequently reached normal values within 4 days. In conclusion, reconstitution of epithelial cellularity precedes restoration of radiation tolerance during treatment splits.     

Effect of ionizing radiation on cell-cycle progression and cyclin B1 expression in human melanoma cells

In the present study we investigated the effect of gamma-irradiation (2.5 and 10 Gy) on cell-cycle progression of a human melanoma cell line, M14, characterized by a moderate radiosensitivity (SF2 = O.5). Flow cytometric analysis showed a dose-dependent S-phase accumulation, which was detectable 8 hr after treatment with 2 and 5 Gy and was still persistent at 12 hr after 10 Gy exposure. Such a delay in S-phase was paralleled or followed by an accumulation of cells in G2M, which was transient at the lowest radiation doses and still persistent at 72 hr after 10 Gy. Such an accumulation was, at least in part, due to a block in G2-M transition, as demonstrated by mitotic index analysis. Bivariate flow cytometric analysis of DNA content and cyclin B1 expression showed that, following 2 and 5 Gy, the fraction of cyclin B1-expressing cells was superimposable upon that of G2M cells. Conversely, in cells treated with 10 Gy, the fraction of cyclin B1-expressing cells was half the G2M cell fraction. Northern-blot analysis indicated that the radiation-induced decrease in cyclin B1 protein expression was accompanied by a reduced cyclin B mRNA level. On the whole, our results indicate a direct inhibitory effect of 10 Gy irradiation on cyclin B1 expression as a possible cause for the persistent G2 block in irradiated M14 cells.     

The value of conventionally fractionated radiotherapy in the local treatment of HIV-related Kaposi's sarcoma

BACKGROUND: During the course of AIDS, 25 to 44% of homosexual patients infected with the human immunodeficiency virus develop Kaposi's sarcoma. Main manifestation is the skin. Response rates of 80 to 100% can be achieved with total dosage up to 50 Gy. Nevertheless, remissions can also be attained with 20 Gy of fractionated radiotherapy. As clinical data on low dose conventional fractionated radiotherapy are insufficient we analysed the response rates of an overall dose of 20 Gy in conventional fractionation. PATIENTS AND METHODS: From June 1991 to June 1993, 43 patients with 111 HIV-associated Kaposi's sarcoma of the skin or oral cavity were treated. Lesions were irradiated with 5 to 12 MeV electrons or 60Co gamma-rays. The fractionation scheme was 5 times 2 Gy/week for skin and endoral lesions with a total reference dosage of up to 20 Gy. Side effects were assessed during therapy and the therapeutic result 6 weeks after end of treatment. RESULTS: Thirty-eight out of 111 lesions were judged as complete response (CR) (34%), 61/111 as partial response (PR) (55%) and 12/111 were judged as no change (NC) (11%). Overall response (CR + PR) was 89%. Two patients with lesions of oral cavity suffered from RTOG grade-IV mucositis after 10 and 14 Gy. In 71/106 skin lesions (67%), radiation induced RTOG grade-1 reactions were observed. CONCLUSION: In patients with HIV associated Kaposi's sarcoma effective palliation can be achieved by means of radiotherapy with an overall dose of 20 Gy in conventional fractionation. Yet, the fraction of patients with complete responses is with 34 to 47% lower compared with doses above 20 Gy (66 to 100%). With reference to the reported data our results point to a dose-response relationship for Kaposi's sarcoma. Therefore higher total reference doses, e.g. 30 Gy with weekly 5 times 2 Gy or 24 Gy with 5 times 1.6 Gy for mucous lesions, respectively, are suggested as by this mean the complete response rate can be doubled.     

The use of a hypoxic cell radiosensitizer AK-2123 gave no improvement in thermoradiotherapy combined with hydralazine

An electron-affinic compound, AK-2123, and the anti-hypertensive agent, hydralazine, were combined with radiation and hyperthermia for treatment of murine SCC-VII tumours. Hydralazine markedly decreased tumour perfusion while AK-2123 had no influence on it. Hydralazine enhanced the tumouricidal effects of hyperthermia alone and in combination with radiation. AK-2123 provided a radiosensitization which was significant only in tumours irradiated without supplementary hyperthermia. The greatest tumour response was achieved when thermoradiotherapy was combined with hydralazine alone; the additional use of AK-2123 with this treatment combination did not further increase the effect. It is concluded that hydralazine plus heat virtually eliminated a hypoxia-related radioresistance in tumours, thus removing the requirement for AK-2123 administration.     

Jackrabbit ears: surface temperatures and vascular responses

Blood flow to the ear pinnae is curtailed at ambient temperatures of between 1.4 degrees and 24 degrees C, which minimizes heat loss across the pinnae and allows the surfaces of erect pinnae to approach ambient temperature. The pinnae are warmed by steady or pulsatile vasodilation in some animals when the ambient temperature is between 1 degree and 9 degrees C below body temperature, a response favoring heat loss. When ambient temperature exceeds body temperature by 4 degrees to 5 degrees C, the pinnae are circulated with blood cooler than ambient temperature; this response favors heat influx.     

Heterogeneous patterns of constitutive and heat shock induced expression of HLA-linked HSP70-1 and HSP70-2 heat shock genes in human melanoma cell lines

The heat shock response, which is characterized by the induction of heat shock proteins, is known to affect the ability of tumour cells to cope with potentially adverse conditions such as hypoxia, glucose starvation and cytotoxic immune reactions. To assess the heat shock response of melanoma cells, spontaneous and heat shock induced expression of heat shock proteins was analysed in a panel of 17 human melanoma cell lines. Constitutive expression of HSP27, HSP70, HSC70, HSP90alphabeta and GRP94 proteins was found in all the melanoma cell lines, and HSP70 and HSC70 were also induced by heat shock. The major heat inducible HLA-linked HSP70-1 and HSP70-2 genes were analysed at the mRNA level. Basal expression and inducibility varied between the different melanoma cell lines. In addition, in situ hybridization demonstrated heterogeneous expression of these genes among single cells of a given cell line. In general, each melanoma cell line appears to exhibit an individual type of HSP70 expression that might reflect selection during tumour progression and therapy.     

Quantitative single-photon emission tomography for tumour blood flow measurement in bronchial carcinoma

A single-photon emission tomography (SPET) technique for the absolute measurement of tumour perfusion is described. Phantom studies have shown that source-background ratios are dependent upon source size and radial position within the phantom. A means of correcting source-background count ratios for these variables has been developed and used to correct tumour-lung ratios obtained in 28 patients with bronchial carcinomas who underwent technetium-99m hexamethylpropyleneamine oxime (99mTc-HMPAO) SPET. On SPET images, the normal lung appears as a relatively homogeneous background. The relationship between 99mTc background concentration (kBq/ml) and counts/pixel was determined from phantom studies and the tumour 99mTc concentration from the background 99mTc concentration and corrected tumour-lung ratio. The total activity of the lipophilic 99mTc-HMPAO species injected was measured. The activity reaching the systemic circulation (Asys) was obtained by subtracting the activity trapped in the pulmonary circulation (obtained from background 99mTc concentration and lung volume). Tumour blood flow may then be calculated from fraction of Asys contained in the tumour provided cardiac output and extraction fraction are known. Blood flow through the central region of tumours ranged from zero to 59.0 (mean 14.1) ml min-1 100 g-1 and through the whole tumour from 0.6 to 68.0 (mean 20.6) ml min-1 100 g-1.     

Radiotherapy of glioblastoma multiforme. Feasibility of increased fraction size and shortened overall treatment

PURPOSE: With regard to the poor prognosis of patients with glioblastoma multiforme, the aspect of life quality with a minimal treatment time becomes essential. The purpose of the present study is to evaluate whether the results of a radiotherapy schedule using increased single fractions applied over a shortened treatment time is feasible without compromising treatment efficiency or providing more side effects than a conventionally fractionated treatment. PATIENTS AND METHODS: A total of 38 patients (f = 21, m = 17, mean age 58 years) with histologically proven glioblastoma multiforme were irradiated after (partial) resection (n = 29) or stereotactic surgery (n = 9) with single doses of 3.5 Gy (ICRU) 5 fractions a week up to a total dose of 42 Gy following individual treatment planning. RESULTS: Median survival was 45.7 weeks, survival rate after 6 months was 80.9% and decreased to 34.2% after 12 months. Radiotherapy was tolerated without any important acute toxicity or any late side effects during the follow-up period. CONCLUSIONS: The increase of the dose per fraction using a fraction size of 3.5 Gy enhanced neither acute nor late toxicity. The survival rate compared well to those described in the literature. Thus the shortened treatment schedule seems as efficient as conventional radiotherapy. Moreover, it seems preferable with regard to quality of life.     

Malignant melanoma of the vagina in pregnancy: description of a clinical case

Vaginal melanoma in pregnancy is a rare but extremely malignant tumour for which the prognosis is worsened by the fact that pregnancy increases the secretion of Melanocyte-Stimulating Hormone (MSH). The clinical case is described of a malignant vaginal melanoma in a 27 year-old woman in her 38th week of gestation, who was referred for slight vaginal bleeding. Clinical examination revealed a 3 cm pedunculate tumour on the anterior wall of the vagina. Vaginal cytology suggested a melanoma and instrumental examination failed to reveal any lymph node involvement. The vaginal tumour was removed during a caesarean section and subsequent histological examination identified it as a Breslow Stage II malignant melanoma. A 24-month follow-up showed the patient to have been completely cured.     

Experimental antitumor activity and toxicity of the selected triazolo- and imidazoacridinones

Toxicity and antitumor effects of four compounds from the groups of triazoloacridinones and imidazoacridinones were evaluated in transplantable tumor systems in mice, including P388 leukemia, B16 melanoma and 2 colon adenocarcinomas C26 and C38. Tested compounds had moderate antileukemic activity but were active against B16 melanoma and 3 of them were very efficacious against colon tumors, providing high percentages of "cures". Toxicity for healthy mice, as well as antitumor activity, were found to depend on a treatment protocol. The compounds were better tolerated and gave higher antitumor effects when given as fractionated treatment. They displayed also sex-dependent toxicity and activity.     

Potentiation of murine MCa-4 carcinoma radioresponse by 9-amino-20(S)-camptothecin

9-Amino-20(S)-camptothecin (9-AC) has demonstrated efficacy against several human cancer xenografts, including cancers of the colon, breast, lung, ovary, and stomach and malignant melanoma, and is currently undergoing Phase I clinical trials. In vitro data indicate that the addition of topoisomerase I inhibitors shortly after irradiation causes conversion of single-strand breaks to double-strand breaks, resulting in synergistic lethality to cultured log-phase or quiescent malignant cells. In our study, the efficacy of 9-AC as a potential radiosensitizing agent in vivo was assessed in C3Hf/Kam female mice bearing 7.6-8-mm MCa-4 mammary tumors implanted i.m. into the right posterior thigh. In one series of experiments to determine the dose dependence of 9-AC, mice were injected twice a week with either 0.5, 1.0, or 2.0 mg/kg 9-AC (total doses of 2, 4, and 8 mg/kg, respectively) either alone or 1 h before irradiation. In a second series of experiments, the schedule dependence of 9-AC was determined by giving a constant total dose of 4 mg/kg 9-AC once (2 mg/kg), twice (1 mg/kg every third day), or four (0.5 mg/kg every other day) times per week for 2 weeks, either alone or combined with radiation. The same radiation regimen was used in all experiments: 2-Gy fractions daily for 14 consecutive days, giving a total dose of 28 Gy to the tumor-bearing leg only. Tumor response was assessed by regrowth delay and dose modification factors (DMFs) obtained by comparing regrowth delay in the groups given 9-AC alone with those given the same dose of 9-AC and radiation. 9-AC significantly delayed tumor growth when combined with radiation, and this effect was dependent on drug dose; DMFs of 2.4 [95% confidence interval (CI), 2.0-3.1], 3.7 (95% CI, 3.1-4.6), and 3.3 (95% CI, 2.7-4.1) were obtained for groups treated with total drug doses of 2.0, 4.0, and 8.0 mg/kg 9-AC, respectively. In addition, the same total dose of 4 mg/kg 9-AC was more effective when given either twice or four times a week compared with once a week, giving DMFs of 2.8 (95% CI, 2.2-3.9), 2.6 (95% CI, 2.0-3.6), and 1.7 (95% CI, 1.3-2.4), respectively. The effect of 9-AC and radiation on normal tissue toxicity was assessed in two normal tissues, jejunum and skin, in separate groups of mice. Jejunal crypt cell survival was decreased in those mice given single doses of 9-AC ranging from 0.5-4.0 mg/kg and 12.5 Gy of total body radiation compared with those given 12.5 Gy of total body irradiation alone. The same regimen of drug and radiation did not modify acute skin reactions. These results suggest that 9-AC is an effective in vivo radiosensitizing agent when given in divided doses with fractionated irradiation. In addition, the gastrointestinal tract but not skin could be a critical target tissue for the use of 9-AC combined with radiation.     

The lipid composition of the membrane of the brush border in the rat small intestine in the late period after gamma irradiation

The lipid composition of membrane of the small intestine brush border was studied 1, 2, 3 and 6 months after the whole-body fractionated gamma irradiation of the one-month-old rats of 80 g weight with a dose of 6 Gy (2 Gy x 3 at a week intervals). Three months after exposure the amount of cholesterol, total phospholipids, phosphatidylcholine, phosphatidyl-ethanolamine in brush border membrane was the same as in control. The role of phospholipids and cholesterol catabolism suppression in membrane regulatory function disturbances after irradiation is discussed.     

Angiotensin-II-induced hypertension chemotherapy: evaluation of hepatic blood flow with oxygen-15 PET

We quantitatively measured blood flow in liver parenchyma and hepatic tumors in two patients using 15O-carbon dioxide (steady state) and 15O-water (dynamic) PET imaging. Images were acquired before and during administration of angiotensin-II to achieve a hypertensive state. Blood flow in the hepatocellular carcinoma was greater than that of the parenchyma. Blood flow in the colon metastasis was similar to that in the parenchyma and lower in the center than in the periphery. During a hypertensive state induced by angiotensin II, blood flow in both the primary and secondary liver tumors did not change, while blood flow in the liver parenchyma decreased. As a result, there was a relative increase in tumor blood flow during the hypertensive state on PET images. Furthermore, blood flow to the spleen decreased to 55% of baseline during the hypertensive state. These findings suggest that hypertensive cancer chemotherapy may protect normal tissue. Furthermore, PET imaging may be able to predict the efficacy of hypertensive cancer chemotherapy in the patients with liver tumors.     

High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome

Activation of endothelin receptors on the vasculature can produce a variety of responses from potent vasoconstriction to mild vasodilation, depending on the receptor complement within the tissue. To elucidate the potential role of endothelin analogues as tumour blood flow modifiers, we have evaluated the effect of the ET(B) receptor agonist, IRL 1620 ([Suc-(Glu9, Ala(11,15))-ET-1(8-21)]) in CBH/CBi rats bearing an HSN fibrosarcoma. Tissue blood flow and vascular resistance were determined, 20 min following administration of IRL 1620 (bolus intravenous), using the uptake of radiolabelled iodoantipyrine (125I-IAP). Blood flow was unchanged in most tissues. However, at doses > or = 1.0 nmol kg(-1) IRL 1620, blood flow in the brain and heart was increased, whereas in the small intestine it was reduced. Blood flow in the skeletal muscle was reduced at 1.0 nmol kg(-1) only. Tumour blood flow was significantly reduced at 3.0 and 5.0 nmol kg(-1). Vascular resistance was unchanged in most tissues although it was increased in the skeletal muscle at 1.0 nmol kg(-1), in the kidney at 1.0 and 3.0 nmol kg(-1) and in the brain and heart, it was reduced at 5.0 nmol kg(-1) IRL 1620. Vascular resistance was significantly increased in the tumour and the small intestine at doses > or = 1 nmol kg(-1) IRL 1620. Pretreatment of rats with BQ-788, an ET(B) receptor antagonist, selectively attenuated the tumour vascular response to 3 nmol kg(-1) IRL 1620 with no changes observed in the normal tissue responses. Our results demonstrate that the HSN tumour vasculature is selectively responsive to IRL 1620 at doses > 1 nmol kg(-1) compared with the majority of normal tissues with the exception of the small intestine, and that only the tumour response is highly sensitive to BQ-788 antagonism, under the experimental dosing regime investigated. These differences may be exploitable for therapeutic benefit.     

Partial characterisation of human melanoma cell-derived factors that stimulate fibroblast glycosaminoglycan synthesis

Glycosaminoglycans (GAGs), and in particular hyaluronan, are known to play a role in tumour cell migration, invasion and metastasis. Conditioned medium from two human metastatic melanoma cell lines (Hs294T and C8161) shows potent fibroblast GAG-synthesis-stimulating activities which are active in fibroblast cultures derived from different anatomical sites. This ability is not specific to melanoma cells and is observed in several carcinoma cell lines. Initial characterisation studies have demonstrated that the GAG-stimulating activities in the medium conditioned with melanoma cells show a degree of heat and trypsin resistance. Fractionation of the conditioned medium with Amicon ultrafiltration membranes of various molecular weight cut-offs, ranging from 1 to 30 kD, resulted in a total loss of activity. Activity could be regained by recombination of the concentrated fraction with the filtrate, suggesting more than one factor to be involved in GAG stimulation, with a degree of interdependence between the individual fractions. The fraction greater than 30 kD and that less than 1 kD appear to contain the majority of the GAG-stimulating activity.     

Cloning of Drosophila MCM homologs and analysis of their requirement during embryogenesis

Modification of blood flow by endothelin-1 (ET-1) was examined in the s.c. HSN fibrosarcoma and compared to normal tissues of anaesthetised CBH/CBi rats. The ET receptor subtypes involved in the response were investigated using the ET(A) and ET(B) receptor antagonists BQ-610 and BQ-788, respectively. Blood flow and vascular resistance were determined using the uptake of radiolabelled iodo-antipyrine (125I-IAP). BQ-610 or BQ-788 was infused for 30 min prior to blood flow determination. ET-1 was administered 15 min into the infusion time. BQ-610 and BQ-788 infused alone did not modify any vascular parameters. Tumour blood flow increased slightly following ET-1, contrasting with most normal tissues, in which blood flow was reduced. Vascular resistance increased in all tissues, including the tumour. Neither antagonist significantly modified the ET-1-induced changes in tumour blood flow or vascular resistance, whereas in the majority of normal tissues BQ-610 attenuated and BQ-788 potentiated the vascular resonse to ET-1. Our results show that the HSN tumour vasculature is only weakly responsive to ET- 1 and antagonism of its effects by BQ-610 and BQ-788. This contrasts with the majority of normal tissues, in which ET- 1 induces an intense vasoconstriction.     

The effects of a health newsletter for foster parents on their perceptions of the behavior and development of foster children

Intracerebroventricular (i.c.v.) injection of endothelin-1 (ET-1; 100 ng. i.c.v.) produced an initial pressor (24%) (peak at 3 min following ET-1 administration) and a delayed depressor (-40%) (30 and 60 min following ET-1 administration) effects in urethane anesthetized rats. The pressor effect of ET-1 was due to an increase (21%) in cardiac output, while the depressor effect of ET-1 was associated with a marked decrease (-46%) in cardiac output. Stroke volume significantly decreased at 30 and 60 min after the administration of ET-1. No change in total peripheral vascular resistance and heart rate was observed following central administration of ET-1. The effects of ET-1 on Blood pressure, cardiac output and stroke volume were not observed in BQ123 (10 micrograms, i.c.v.) treated rats. Blood flow to the cerebral hemispheres, cerebellum, midbrain and brain stem was not affected at 3 min, but a significant decrease in blood flow to all the regions of the brain was observed at 30 and 60 min following central administration of ET-1. BQ123 pretreatment completely blocked the central ET-1 induced decrease in blood flow to the brain regions. It is concluded that the pressor effect of centrally administered ET-1 is not accompanied by a severe decrease in brain blood flow, however, a subsequent decrease in blood pressure is associated with a decrease in blood flow to the brain. The cardiovascular effects of ET-1 including decrease in brain blood flow are mediated through central ET receptors.     

Changes in canine bladder perfusion with distension

Using a radioisotope-labeled microsphere technique, canine bladder perfusion was investigated. Blood flow was measured in in flaccid and distended conditions. A slight decrease in total bladder blood flow was recorded. There was a relative decrease in bladder mucosal flow with distension. There was no difference in perfusion of dome versus trigone.