Serial in vivo observations of cerebral vasculature after treatment with a large single fraction of radiation.

To test whether single high doses of radiation, similar to those used with radiosurgery, given to normal cerebral vasculature can cause changes in leukocyte-vessel wall interactions and tissue perfusion, a rat pial window model was used to view the cerebral vasculature, facilitating repeated in vivo observations of microcirculatory function. An attachment for a 4 MV linear accelerator was designed to deliver a well-collimated 2.2-mm beam of radiation to a selected region of rat brain. Sequential measurements of leukocyte-endothelial cell interactions, relative change in blood flow with laser Doppler flowmetry and vessel length density were performed prior to and at 24 h and 3 weeks after treatment with 15, 22.5 or 30 Gy, given in a single fraction. Significant increases in leukocyte-endothelial cell interactions were seen 24 h and 3 weeks after irradiation that were dependent on dose, particularly in arteries. Changes were apparent in both arteries and veins at 24 h, but by 3 weeks the effects in arteries predominated. Decreases in vessel length density and blood flow were observed and became greater with time after treatment. A variety of morphological changes were observed in irradiated arteries, including formation of aneurysmal structures, endothelial denudation and thrombus formation. These results suggest that: (1) An increase in leukocyte-vessel wall interactions occurs after irradiation; (2) cerebral arterioles are more sensitive than veins to radiation administered in this fashion; and (3) the increase in leukocyte-vessel wall interactions likely contributes to reduction of or loss of arteriolar flow, with resultant loss of flow to dependent microvascular vessels.

The Family Project Approach.

The Family Project Approach (FPA) has been developed as an alternative to the placement of conduct-disordered adolescents into care. Since 1987, the target group of this project has been extended to include maltreated children and to parents who are in despair because of persistent child behaviour problems and other stressors. This article gives an overview of this home-based approach and the most important research results. One main starting point for FPA is that parents should be supported so that they can fulfil their child-rearing responsibilities. In families where the children are neglected or maltreated and in families where the parents feel desperate and powerless, the fundamental attitude of the FPA worker plays a decisive role. Process-outcome research corroborates the importance of encouraging and validating the parents' positive qualities and expertise.

Therapist-parent interaction patterns in home-based treatments: exploring family therapy process.

At the current stage of development in the family therapy field, exploratory, small-scale process studies are necessary in order to understand through what interpersonal processes child and family change occur. The goal of this article is to show how relevant therapist-parent interactions within family-based approaches can be explored and linked to the reduction in childrearing and behavior problems. Sequential analyses on 13 treatments using the Family Project Approach revealed that, within the most successful treatments, therapist and parent interact in a collaborative way in the phase of Direct Influence. In the beginning of this treatment phase, the therapist must activate the parents to tackle the problems actively. Further explorations indicated that a collaborative interaction pattern between therapist and mother during the first three sessions of therapy contributes to a better outcome.

High-dose, hyperfractionated, accelerated radiotherapy using a concurrent boost for the treatment of nonsmall cell lung cancer: unusual toxicity and promising early results.

PURPOSE: The treatment of nonsmall cell lung cancer (NSCLC) with conventional radiotherapy (RT) results in inadequate local tumor control and survival. We report results of a Phase II trial designed to treat patients with a significantly increased total dose administered in a reduced overall treatment time using a hyperfractionated, accelerated treatment schedule with a concurrent boost technique. METHODS AND MATERIALS: A total of 49 patients with unresectable Stage IIIA/IIIB (38 patients) or medically inoperable Stage I/II (11 patients) NSCLC were prospectively enrolled in this protocol. Radiation therapy was administered twice daily, 5 days/week with > 6 h between each treatment. The primary tumor and adjacent enlarged lymph nodes were treated to a total dose of 73.6 Gy in 46 fractions of 1.6 Gy each. Using a concurrent boost technique, electively irradiated nodal regions were simultaneously treated with a dose of 1.25 Gy/fraction for the first 36 fractions to a total dose of 45 Gy. RESULTS: Median survival for the entire group of 49 patients is 15.3 months. Actuarial survival at 2 years is 46%: 60% for 11 Stage I/II patients, 55% for 21 Stage IIIA patients, and 26% for 17 Stage IIIB patients. The actuarial rate of freedom from local progression at 2 years is 64% for the entire group of 49 patients: 62% for Stage I/II patients, 70% for Stage IIIA patients, and 55% for Stage IIIB patients. Patients who underwent serial bronchoscopic reevaluation (4 Stage I/II, 8 Stage IIIA, and 6 Stage IIIB) have an actuarial rate of local control of 71% at 2 years. The median total treatment time was 32 days. Nine of 49 patients (18%) experienced Grade III acute esophageal toxicity. The 2-year actuarial risk of Grade III or greater late toxicity is 30%. The 2-year actuarial rate of severe-late pulmonary and skin-subcutaneous toxicity is 20% and 15%, respectively. CONCLUSION: This treatment regimen administers a substantially higher biologically effective dose compared with conventional and pure hyperfractionation treatment schedules. The overall rate of acute and late toxicity was acceptable. Preliminary rates of overall survival and local control and freedom from local progression compare favorably to results reported with pure hyperfractionated radiotherapy and chemoradiotherapy.

The lack of impact of pelvic irradiation on small bowel mobility: implications for radiotherapy treatment planning.

PURPOSE: Small bowel contrast is frequently used during simulation for patients undergoing pelvic radiotherapy to assist in the design of blocks that exclude small bowel from the radiation field. In many instances, a large field is treated to 45 gray (Gy), followed by a field reduction to exclude the small bowel. This prospective study was designed to assess whether the position and mobility of the small bowel changed after the initial 45 Gy, thereby determining whether a special small bowel series done at initial simulation is applicable at the time of field reduction. METHODS AND MATERIALS: Twelve patients undergoing pelvic irradiation were given small bowel contrast for their initial simulation. Radiographs were taken with the bladder empty and the bladder full. The location of the small bowel and its displacement with bladder distention was measured. This entire procedure was repeated prior to field reduction (after 39.6-46.0 Gy). RESULTS: There was no demonstrable alteration in small bowel mobility after 39.6-46.0 Gy. The approximate position of the small bowel relative to bony landmarks was unchanged. CONCLUSION: The position and mobility of the small bowel appears not to be affected by 39.6-46.0 Gy of pelvic radiotherapy. Therefore, it is reasonable to design reduced pelvic fields to exclude the small bowel based on special small bowel series done at initial treatment simulation.

The management of desmoid tumors.

PURPOSE: To determine the efficacy of different treatment modalities for desmoid tumors. MATERIALS AND METHODS: We reviewed the treatment of 40 patients with histologically confirmed desmoid tumors seen at Duke University Medical Center between 1974 and 1990. RESULTS: Radiotherapy was administered to 16 patients (Group I)--14 with recurrent disease s/p surgery and in two as initial treatment. The average size of the irradiated lesions was 9.3 +/- 3.9 X 8.4 +/- 3.5 cm. With a median follow-up of 57.5 months and a median administered dose of 5400 cGy (mean 5286 cGy, range 4960-5620 cGy), local control has been obtained in 15/16 patients (94%). Complete regression (5/16), partial regression (5/16), or stable disease (5/16) was produced in 15 patients while one patient failed and was salvaged via gross total resection. Continued regression has been seen up to 60 months after treatment. Fourteen patients underwent primary gross total resection and two underwent subtotal resection (Group II). None received post-operative radiotherapy. Three of 14 patients (21%) recurred after gross total resection. All three were salvaged with subsequent gross total resection. After subtotal resection, 2/2 patients recurred. With a mean follow-up of 52 months, 14 patients are without evidence of disease, one is dead with disease (unrelated cause of death), and one was lost to follow-up after recurrence. Eight patients have been treated with combinations of chemotherapy, NSAIDS, anti-estrogens, and immunotherapy with mixed results (Group III). A subset of seven patients with retroperitoneal disease taken from all three groups had large tumor burden (mean size 17 X 15 cm), an infiltrative nature, as well as a difficult location. The disease was surgically resectable in three patients. One is without evidence of disease 9 years after gross total resection alone. Disease has been stabilized with radiotherapy in the other two patients after multiple unsuccessful surgical resections. Of four patients with unresectable disease, two are dead of disease, one died of unrelated causes with disease, and regression of disease was obtained in the other with Gamma-interferon after unsuccessful treatment with tamoxifen and vincristine, doxorubicin, and cyclophosphamide chemotherapy. CONCLUSION: Gross total resection is the indicated initial therapy, if it can be performed without significant disfigurement. Radiotherapy is also excellent for obtaining local control, even in patients with a large burden of recurrent disease. Doses in the range of 50 to 55 Gy give a chance of local control equal to that obtained with higher doses previously reported.

The use of hydralazine to manipulate tumour temperatures during hyperthermia.

Hydralazine is an antihypertensive drug which theoretically could increase tumour temperatures during hyperthermia via reduction in tumour blood flow from a vascular 'steal' phenomenon. Doses that are therapeutically effective in reducing blood pressure in hypertensive patients would probably cause postural hypotension and other side-effects in normotensive patients beyond the hyperthermia treatment session, however. This study was designed to evaluate whether hydralazine, when administered at a safe dose for normotensive patients (0.125 mg/kg, i.v.) would be effective in increasing tumour temperatures during hyperthermia. The working hypothesis was that hydralazine at a dose of 0.125 mg/kg would be effective in raising tumour temperatures during hyperthermia treatment with minimal change in blood pressure. Fourteen human and five canine subjects were given hydralazine (0.125 mg/kg, i.v.) at the midpoint of a hyperthermia session. Temperatures and blood pressures were monitored before and after drug administration. Although hydralazine resulted in slight reduction in blood pressure, it was ineffective in increasing tumour temperatures in human patients (average maximum rise in median temperature was 0.26 +/- 0.32 degrees C). In canine subjects the same dose of hydralazine was effective in reducing blood pressure in four of five subjects studied (mean maximum drop was 22.7 +/- 4.1 mmHg) and the median temperature rose 0.8 +/- 0.7 degrees C. In the canine subjects the greater the decrease in blood pressure, the greater the increase in temperature. These results suggest that a rise in tumour temperature induced by hydralazine is dependent on creating a drop in blood pressure. Future studies in this laboratory will include tumour blood flow manipulation with antihypertensives which have a shorter half-life and a titratable effect. Using this approach, hypotension, which seems to be required to raise tumour temperature, will be more controllable in terms of magnitude and duration.

Blood perfusion measurements in human tumours: evaluation of laser Doppler methods.

Laser Doppler flowmetry is a simple method of determining, directly and continuously, tissue blood flow. However, its applicability to monitoring tumour blood flow interstitially during hyperthermia treatments is still being evaluated. The purposes of this study were to physically characterize the measurement probes, to evaluate potential sources of artifact with the interstitial use of the probes during hyperthermia treatment, and to obtain measurements in human tumours during hyperthermia sessions. The accuracy of the method in quantifying blood flow, velocity and volume during hyperthermia was found to be unaffected by heating the measurement probe to 42-46 degrees C or by exposing it to various intensities of 915 MHz microwave fields (10-40 W), or 1 MHz ultrasound fields. Catheter insertion methods were developed to place the flow probes interstitially in tumours. Tissue damage was confined to a distance of no greater than 0.12 mm away from the catheter tract, and physical evidence of vascular disruption was within a distance of 0.05 mm as measured in a rat tumour model. This degree of damage/disruption is unlikely to affect LDF measurements which represent blood flow averaged over a 1.0-1.5 mm radius from the probe tip. Concurrently, the device was used to monitor tumour blood flow parameters interstitially in human subjects during hyperthermia treatments given in combination with conventional radiotherapy. Blood-flow data from multiple sites of measurement showed marked heterogeneity within individual tumours (up to 55-fold differences) and between different tumours (greater than 100-fold differences). Measurements made by translating the probe along a tumour radius, beginning at the tumour core and advancing to the tumour edge, were consistent with a two-component tumour perfusion model (shell and core). Data are presented from one patient illustrating a persistent change in perfusion distribution during the hyperthermia treatment course, which occurred concomitantly with increases in thermal data. These results suggest that the technique might be of value in monitoring change in flow between treatments. Responses during hyperthermia treatment sessions were also investigated. Four temporal patterns of flow were observed, ranging from a steady increase in flow to a plateau level to a steady drop in flow during heating. These patterns were not well correlated with average temperature recorded at the site of flow measurement. Further study is needed to determine if this LDF technique is to be useful for evaluation of heat transfer by blood perfusion.