Clinical application of thermal isoeffect dose

Clinically, there is strong rationale for developing a method which will provide a scientific basis for comparing the efficacy of one hyperthermia treatment with another. In order to accomplish this goal, methods must first be developed which will allow the clinician to know the three-dimensional temperature distribution in heated tissue. In this paper, examples of how this goal can be achieved are presented. Techniques for compensating for various modifiers of hyperthermia effectiveness are proposed. The limitations and advantages of these approaches are described and directions for future research are discussed.     

Augmentation of Antimetastatic Activity of Interferon and Tumor Necrosis Factor by Heparin

Interferon (IFN) and tumor necrosis factor (TNF) suppress the development of experimental metastasis and when used together, TNF and IFN show synergistic activity. However, the use of TNF is limited by its ability to initiate inappropriate hemostasis. Hemostatic effects are exaggerated by the procoagulant activity of certain tumor cell lines. Therapy with anticoagulants are indicated to block the effects of tumor cell products as well as chemotherapeutic side effects. Heparin is a glycosaminoglycan with diverse biological activity, including the ability to rapidly accelerate the inactivation of active clotting factors. the present studies have explored the therapeutic effects of combining heparin with TNF or interferon on experimental metastasis in mice using a melanoma cell line (B16BL6). Our data indicate that continued heparinization augments the antitumor activity of both interferon and TNF. Alterations of the hemostatic and immune systems play a role in the producing the observed effect.     

Pancreatic cancer in Illinois. A report by 88 hospitals on 2,401 patients diagnosed 1978-84

A retrospective study of survival results for pancreatic cancer was performed. The study had two objectives: 1) to relate the extent of disease and management to survival, and 2) to determine whether newer treatment combinations have altered prognosis. Cancer registrars from 88 Illinois hospitals reviewed original medical records and submitted standardized report forms on 2,401 patients diagnosed between 1978-84. Three-year survival time was longer after laparotomy/bypass plus radiation/chemotherapy than for laparotomy/bypass alone (P less than .02). But the difference in survival between resection versus resection, radiation, and chemotherapy was not significant (P = .16). After resection, the median survival for 78 Stage I patients was 12.5 months, whereas for 181 Stage I patients after laparotomy/bypass it was 6.8 months (P less than .00001). For patients without metastases, 3-year survival was significantly better for 249 patients in whom cancer was resected versus 568 unresected patients (P less than .001). Survival was longer for 568 unresected patients without gross metastases than for 954 patients with metastatic disease found at laparotomy (P less than .05). From this study the authors concluded that: 1) since 3-year survival results were higher than expected after resection for localized cancers, resection is still desirable when it can be done with acceptable complication risks, and 2) the use of multiple treatment modalities for pancreatic cancer warrants further study in organized trials.     

High-dose DTIC in advanced soft-tissue sarcomas in the adult. A phase II study of the E.O.R.T.C. Soft Tissue and Bone Sarcoma Group

Forty-four of 50 adult patients with advanced soft-tissue sarcoma who had received previous chemotherapy were evaluable for response after treatment with DTIC. The therapeutic schedule consisted of DTIC 1.2 g/m2 infused over 20 minutes, and repeated every 3 weeks. There were 1 complete and 7 partial remissions (objective activity 18%, 95% C.I. 7%-29%), with a median duration of 8 weeks (range 5-19), with the complete remission lasting 1 yr. Hematologic toxicity was dose-limiting; W.H.O. greater than or equal to 3 values were observed for WBC in 36%, and for platelets in 26% of patients. The non-hematologic toxicity included nausea and vomiting (90%), a flu-like syndrome (49%), diarrhea (35%), pain in the infused vein (28%) and hypotensive episodes (4%). Intermittent high-dose DTIC is active in advanced soft-tissue sarcoma and should be considered for inclusion in combination regimens.     

Effects of Schistosoma mansoni on androgen regulated gene expression in the mouse

Two-dimensional gel electrophoresis of liver mRNA translation products and dot-blot hybridization revealed that the levels of mRNA encoding major urinary proteins were greatly reduced in mice infected with Schistosoma mansoni. Major urinary protein mRNA levels are known to be androgen regulated. Dot-blot hybridization analysis of RNAs from various mouse tissues with a variety of cDNA probes indicated that all androgen-regulated mRNAs tested were reduced in infected mice. Administration of testosterone to infected animals restored urinary major urinary protein levels. Direct measurement of serum testosterone levels and seminal vesicle weights confirmed that chronic schistosome infection reduces testosterone to castration levels in male mice.     

Statistical considerations of chemoprevention clinical trials in prostate cancer.

The design and analysis of chemoprevention trials in prostate cancer is more complicated than that of an ordinary treatment efficacy trial. The following issues must be taken into account when designing prospective randomized chemoprevention trials: (1) The choice of the primary endpoint: biopsy-proven prostate cancer or mortality from prostate cancer? The choice of the endpoint has a major impact on the design of the trial, its overall duration, and the number of patients required. (2) The sample size calculation which depends on the event rate in the control group, the size of the difference to be detected, the size of the type I and type II errors, the non-adherence and crossover rates, and the duration of patient entry and follow-up. (3) The possible confounding between the intervention and ascertainment of the endpoint. What is the effect of the intervention on the sensitivity and specificity of prostate screening tests? What are its implications on trial design? (4) The effect of 'noncompliance' on intent-to-treat analyses: nonadherence or treatment refusal, crossovers, loss to follow-up, biopsy refusal, and intercurrent deaths. (5) The assessment of side effects, both acute and long term.     

Postoperative irradiation for the prevention of heterotopic bone: analysis of different dose schedules and shielding considerations

Ninety-seven high risk hips were irradiated postoperatively for prevention of heterotopic bone (HTB) in the UCLA Department of Radiation Oncology from 1980 to 1988. Ninety-two hips in 82 patients were eligible for analysis with a minimum follow-up of 2 months and a median follow-up of 10 months. Forty-nine of the hips had porous coated ingrowth prostheses. From 1980 to 1986, 2 Gy fractions were used to deliver 20 Gy (8 hips), 12 Gy (1 hip), and 10 Gy (27 hips). Since December of 1986, 38 hips received 8 Gy in two increments and 18 hips received a single 7 Gy fraction. All porous ingrowth components were shielded with custom blocks. Six out of 92 hips developed clinically significant (Brooker grade 3 or 4 heterotopic bone). There was one clinically significant failure in 78 hips (1.3%) when irradiation was initiated before post-operative day (POD) #6 and shielding was properly placed. One clinical failure occurred in 38 hips which received 8 Gy in two increments. One clinical failure occurred out of the 18 hips treated with 7 Gy in one fraction. This failure could be related to block malposition. There were four clinical failures in the 36 hips treated with 2 Gy fractions to total doses of 10 Gy, 12 Gy, or 20 Gy. Three of these failures were associated with initiation of treatment after POD #5, and the fourth was related to block malposition. Unshielded trochanteric osteotomies resulted in five migrations and seven fibrous unions for a total non-osseous union rate of 12/36 (33%). Shielding of the remaining 28 trochanteric osteotomies resulted in a non-osseous union rate of 7% (0 migrations and 2 fibrous unions). There were no failures of union of components, and the only side effects noted in the series were the five trochanteric migrations. In conclusion, the use of 8 Gy in two increments or 7 Gy in one fraction was found to be as efficacious as conventional 2 Gy fractionation schemes with no increase in side effects. For optimal results, treatment should be implemented prior to POD #5 with shielding of the trochanteric osteotomy. Postoperative irradiation to prevent HTB can be used in hips with porous components using properly placed blocks to shield the porous region.