The oncogenic transforming potential of the passage of single alpha particles through mammalian cell nuclei.

Domestic, low-level exposure to radon gas is considered a major environmental lung-cancer hazard involving DNA damage to bronchial cells by alpha particles from radon progeny. At domestic exposure levels, the relevant bronchial cells are very rarely traversed by more than one alpha particle, whereas at higher radon levels-at which epidemiological studies in uranium miners allow lung-cancer risks to be quantified with reasonable precision-these bronchial cells are frequently exposed to multiple alpha-particle traversals. Measuring the oncogenic transforming effects of exactly one alpha particle without the confounding effects of multiple traversals has hitherto been unfeasible, resulting in uncertainty in extrapolations of risk from high to domestic radon levels. A technique to assess the effects of single alpha particles uses a charged-particle microbeam, which irradiates individual cells or cell nuclei with predefined exact numbers of particles. Although previously too slow to assess the relevant small oncogenic risks, recent improvements in throughput now permit microbeam irradiation of large cell numbers, allowing the first oncogenic risk measurements for the traversal of exactly one alpha particle through a cell nucleus. Given positive controls to ensure that the dosimetry and biological controls were comparable, the measured oncogenicity from exactly one alpha particle was significantly lower than for a Poisson-distributed mean of one alpha particle, implying that cells traversed by multiple alpha particles contribute most of the risk. If this result applies generally, extrapolation from high-level radon risks (involving cellular traversal by multiple alpha particles) may overestimate low-level (involving only single alpha particles) radon risks.

Acute treatment-related diarrhea during postoperative adjuvant therapy for high-risk rectal carcinoma.

PURPOSE: The combination of pelvic radiotherapy and 5-fluorouracil-based chemotherapy is associated with an increase in acute gastrointestinal toxicity during rectal adjuvant therapy, most notably an increased incidence of diarrhea. Previous randomized, prospective studies have limited their analysis to presenting rates of severe and life-threatening diarrhea (Grade 3 or greater), and few data are available detailing the extent of mild to moderate diarrhea. To provide baseline data for future studies, we conducted a detailed analysis of diarrhea from a prior clinical trial of adjuvant therapy for rectal cancer. METHODS AND MATERIALS: In a multiinstitutional clinical trial, 204 eligible patients with rectal carcinoma that either was deeply invasive (T3-T4) or involved regional lymph nodes were randomized to receive either postoperative pelvic radiotherapy alone (45 to 50.4 Gy) or pelvic radiotherapy and bolus 5-fluorouracil-based chemotherapy. Toxicity was assessed prospectively. RESULTS: For the 99 eligible patients who received pelvic radiotherapy alone, rates of Grades 0, 1, 2, 3, and 4 diarrhea during treatment were 59, 20, 17, 4, and 0%, respectively. For the 96 eligible patients who received radiotherapy and 5-fluorouracil, the overall rates of grades 0, 1, 2, 3, and 4 diarrhea were 21, 34, 23, 20, and 2%, respectively. The increased rates of diarrhea during adjuvant rectal therapy were manifested across all toxicity levels for patients receiving chemotherapy and pelvic radiotherapy. Of primary clinical importance is the substantial increase in severe or life-threatening diarrhea (Grade 3 or more) (22 vs. 4%,p = 0.001) Additionally, increased rates of any diarrhea and also severe or life-threatening diarrhea were observed in patients who had a low anterior resection compared with those who had an abdominoperineal resection (p < 0.001 and p = 0.006, respectively). CONCLUSION: These results will be of value as a baseline for investigators who want to use treatment toxicity as an end point in cancer control or cancer therapy trials utilizing similar treatment techniques. Patients receiving 5-fluorouracil and pelvic radiotherapy compared with patients receiving pelvic radiotherapy alone and patients with a prior history of a low anterior resection compared with patients who had a prior history of an abdominoperineal resection experienced increased rates of Grades 1 through 4 acute treatment-related diarrhea, and the most important increase occurred as Grade 3 toxicity.

'Best clinical practice': assessment of processes of care and of outcomes in the US Military Health Services System.

The National Quality Management Program of the Military Health Services System of the United States has undertaken a series of projects whose objective is the active, on-going monitoring and improvement of the effectiveness and efficiency of the care provided to a broad population that encompasses troops on active duty, retirees and dependents. The analytic activities consist of (1) identification by clinical panels of conditions and procedures of interest; (2) collection of data from electronic repositories and from charts to characterize the patients, how they are managed, the clinical outcomes they experience, the resource costs their care entails, and, from questionnaires, their functional status and level of satisfaction, and (3) generation of 'report cards' that inform organizational units down to the level of the hospital of the characteristics of their patients, their practices, and the risk-adjusted outcomes they achieve. The patterns of care employed by the hospitals that obtain the best risk-adjusted outcomes and resource utilization ('best clinical practice') are identified and made known. In addition, (4) a systematic process of developing outcomes-based practice guidelines has been devised. It intent is to serve as a decision-support tool for clinicians. Initial estimates have been obtained of the probable consequences of the application of this tool to operative interventions in childbirth. Use of the tool would result in a higher occurrence of elective Caesarean sections, a reduced rate of emergency Caesarean sections and much lower use of forceps, with an overall improvement in outcomes and lower resource costs. This program is currently in the early phases of implementation. The two principal requirements for the immediate future are (1) education of the clinical and administrative communities in the use of the data and the decision-support tools and (2) evaluation of the consequences of the use of the data by the clinical and administrative communities.

Interaction of hyperthermia and chemotherapy agents; cell lethality and oncogenic potential.

Hyperthermia was combined with bleomycin, melphalan and cis-platinum in order to examine cell lethality and oncogenic transformation in C3H10T1/2 cells from the adjuvant use of heat with chemotherapy agents. When cells were exposed concurrently to 42.5 degrees C and each of the three chemotherapy agents, heat enhanced both the cytotoxic and oncogenic potential of the drugs. Hyperthermia-enhanced ratios were largest for bleomycin-treated cells. Examination of transformation incidences expressed as a function of surviving fraction, i.e. the cytotoxicity of treatment and therefore drug-heat efficacy, showed that for a given level of cell killing the combination of heat and cis-platinum resulted in fewer transformants per surviving cell than for cis-platinum alone. Hyperthermia appears to reduce the oncogenic potential of low concentrations of melphalan but has no effect on bleomycin-induced oncogenic transformation.

Interaction of heat with X-rays and cis-platinum; cell lethality and oncogenic transformation.

There is increasing concern for the oncogenic potential of agents used to treat cancer. Hyperthermia is one of the few modalities that does not, of itself, produce transformed foci in vitro. The adjuvant use of heat with X-rays or chemotherapy agents is an interesting approach to increasing the cell-killing potential while decreasing the oncogenicity of combined-modality therapy. Following a priming heat dose in C3H 10T1/2 cells, resistance to cell killing by a second heat dose develops and is maximal by 10 h. This is known as thermotolerance, and can be monitored by the appearance of proteins of specific molecular weight known as heat-shock proteins. By contrast, a priming heat dose does not confer resistance to killing by cis-platinum (cis-DDP). Indeed, heat potentiates the cytotoxicity due to cis-DDP. The interaction is greatest if heat and drug are applied simultaneously, but is still substantial if the drug is applied many hours after heating. The loss of interaction between heat and cis-DDP occurs slowly, but by 48 h, heat and drug act independently. Thermotolerant cells are less sensitive to the induction of transformation by X-rays than previously unheated cells. On the other hand, 48 h after a heat exposure, when cells have regained their normal sensitivity to killing by cis-DDP, their sensitivity to the induction of transformation by cis-DDP has also returned to normal.

Prospects for hyperthermia in human cancer therapy. Part I: hyperthermic effects in man and spontaneous animal tumors.

Systemic hyperthermia in man may occur by accident, as in heat stroke or malignant hyperthermia during general anesthesia, or it may be therapeutically induced (fever therapy). The latter has been used infrequently since the advent of antibiotics, except recently for treatment of cancer. Local or regional heating combined with x irradiation for human cancer therapy has been sporadically reported for over 60 years, but has not found its place in clinical medicine possibly due to technical limitations in heat production and dosimetry. Preliminary results are reported for treatment of spontaneous animal tumors with radiofrequency current fields and x irradiation.

Prospects for hyperthermia in human cancer therapy. Part II: implications of biological and physical data for applications of hyperthermia to man.

Laboratory data from studies of hyperthermia as a potential antitumor agent indicate that: (a) tumor cells may be more sensitive to heat than normal tissue; (b) hyperthermia enhances response to irradiation and can increase the therapeutic ratio; (c) cells are most sensitive to hyperthermia during the S-phase, when they are resistant to ionizing radiations; (d) the oxygen effect is absent for hyperthermic cell killing, and radiation effects are less oxygen-dependent when potentiated by heat treatment; and (e) biological damage changes more rapidly at temperatures above 43 degrees C. Methods of heat production and dosimetry need to be refined further before these findings can be put to practical use in tumor therapy.

Hyperthermic potentiation: biological aspects and applications to radiation therapy.

Experimental studies have provided evidence that hyperthermia may be an effective agent, either alone or in combination with ionizing radiation, in the treatment of cancer. Results have shown that temperatures in the range of 42 degrees to 45 degrees C: 1) are cytotoxic, with cell lethality showing little or no dependence on levels of oxygenation; 2) inhibit the recovery of cells from sub-lethal and potentially lethal radiation damage while enhancing the levels of lethal damage; and 3) may be combined with x-irradiation in a manner to improve therapeutic ratios. The observed interaction between hyperthermia and x-rays may in part be due to differences in the Age Response Functions and reassortment of cycling cells to these two agents. Hyperthermia may also greatly change repopulation and re-oxygenation parameters in irradiated tumor and normal tissue volumes. An overall consideration of these and other factors is essential in the design of optimal schedules of combined hyperthermia and x-irradiation treatments in the management of malignant disease.