Tumor induction following intraoperative radiotherapy: late results of the National Cancer Institute canine trials

Intraoperative radiotherapy has been employed in human cancer research for over a decade. Since 1979, trials to assess the acute and late toxicity of IORT have been carried out at the National Cancer Institute in an adult dog model in an attempt to establish dose tolerance guidelines for a variety of organs. Of the 170 animals entered on 12 studies with a minimum follow-up of 2 years, 148 dogs received IORT; 22 control animals received only surgery. Animals were sacrificed at designated intervals following IORT, usually at 1, 6, 12, 24, and 60 month intervals. 102 of 148 irradiated dogs were sacrificed less than 24 months; 46 dogs were followed greater than or equal to 24 months after IORT. To date, 34 of the 46 animals have been sacrificed; the 12 remaining animals are to be followed to 5 years. These 12 animals have minimum follow-up of 30 months. In the irradiated group followed for greater than or equal to 24 months, 10 tumors have arisen in 9 animals. One animal developed an incidental spontaneous breast carcinoma outside the IORT port, discovered only at scheduled post-mortem exam. The remaining nine tumors arose within IORT ports. Two tumors were benign neural tumors--a neuroma and a neurofibroma. One animal had a "collision" tumor comprised of grade I chondrosarcoma adjacent to grade III osteosarcoma arising in lumbar vertebrae. Two other grade III osteosarcomas, one grade III fibrosarcoma, and one grade III malignant fibrous histiocytoma arose in retroperitoneal/paravertebral sites. An embryonal rhabdomyosarcoma (sarcoma botryoides) arose within the irradiated urinary bladder of one animal. No sham irradiated controls nor IORT animals sacrificed less than 24 months have developed any spontaneous or radiation-induced tumors. The time range of diagnoses of tumors was 24-58 months (median 40 months). The IORT dose range associated with tumor development was 20-35 Gy (median 30 Gy). The carcinogenesis capability of single fraction, high dose radiation in animals is discussed, as are the implications of these data for continued research and clinical usage of IORT in the treatment of humans.     

The Use of Transureteroureterostomy in the Management of Complex Ureteral Problems

Purpose

Transureteroureterostomy has primarily been performed for benign disease in children with reflux or undergoing undiversion, and in adults with lower ureteral injury. We report the use of transureteroureterostomy for other than these traditional indications, including malignant disease.

Materials and Methods

Transureteroureterostomy was performed in 6 patients at the time of tumor resection to bypass large ureteral defects and in 4 as a secondary operation, usually associated with a ureteral leak after previous surgery.

Results

Complications related to transureteroureterostomy included 1 ureteral stricture and 1 ureteral leak. Good renal function was maintained with a mean followup of 77.9 months.

Conclusions

Our experience suggests that transureteroureterostomy can be useful for urinary diversion when a segment of lower ureter is involved with malignant disease.     

Does the Impact of Managed Care on Substance Abuse Treatment Services Vary by Provider Profit Status?

Objective. To extend our previous research by determining whether, and how, the impact of managed care (MC) on substance abuse treatment (SAT) services differs by facility ownership.
Data Sources. The 2000 National Survey of Substance Abuse Treatment Services, which is designed to collect data on service offerings and other characteristics of SAT facilities in the U.S. These data are merged with data from the 2002 Area Resource File, a county-specific database containing information on population and MC activity. We use data on 10,513 facilities, virtually a census of all SAT facilities.
Study Design. For each facility ownership type (for-profit [FP], not-for-profit [NFP], public), we estimate the impact of MC on the number and types of SAT services offered. We use instrumental variables techniques that account for possible endogeneity between facilities' involvement in MC and service offerings.  

Principal Findings.

We find that the impact of MC on SAT service offerings differs in magnitude and direction by facility ownership. On average, MC causes FPs to offer approximately four additional services, causes publics to offer approximately four fewer services, and has no impact on the number of services offered by NFPs. The differential impact of MC on FPs and publics appears to be concentrated in therapy/counseling, medical testing, and transitional services.
Conclusion. Our findings raise policy concerns that MC may reduce the quality of care provided by public SAT facilities by limiting the range of services offered. On the other hand, we find that FP clinics increase their range of services. One explanation is that MC results in standardization of service offerings across facilities of different ownership type. Further research is needed to better understand both the specific mechanisms of MC on SAT and the net impact on society.     

Radical reoperation for advanced pancreatic carcinoma

The indications and outcomes of aggressive reoperation in patients referred to the National Cancer Institute (NCI) for protocol therapy of locally advanced pancreatic carcinoma were investigated. Twenty-nine patients referred to the NCI after exploration and determination of unresectability elsewhere were considered to have localized disease after a metastatic work-up. These patients were then entered onto NCI adjuvant therapy protocols and taken to exploratory laparotomy. Intraoperatively, patients underwent complete resection if possible; otherwise varying palliative surgical procedures were performed. Of the 29 patients, 16 underwent complete resection of their disease, and 13 were unresectable. Two patients suffered postoperative mortality. Disease-specific survival of the resected patients was significantly better than that of the unresectable patients (P < 0.01). The two long-term survivors (53 and > 109 months) underwent definitive surgery after a palliative procedure elsewhere. Complete resection of pancreatic carcinoma contributes to increased survival. The intraoperative definition of unresectability in pancreatic cancer varies with the degree of pancreatitis present, the surgical expertise of the surgeon, and the available ancillary services. Given the extremely grave prognosis of patients with unresectable pancreatic carcinoma, locally unresectable patients without peritoneal seeding or distant metastases at exploration should be considered for referral for protocol therapy to centers where expertise in radical surgery for pancreatic cancer exists. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

Mutant prevention concentration as a measure of fluoroquinolone potency against mycobacteria

Mutant prevention concentration (MPC) has been proposed as a new measure of antibiotic potency by which the ability to restrict selection of resistant mutants is evaluated. To determine whether MPC provides potency information unavailable from the more customary measurement of the MIC, 18 fluoroquinolones were examined for their ability to block the growth of Mycobacterium smegmatis and to select resistant mutants from wild-type populations. Both MPC and MIC were affected by changes in the moiety at the fluoroquinolone C-8 position and in alkyl groups attached to the C-7 piperazinyl ring. When eight resistant mutants, altered in the gyrase A protein, were tested with fluoroquinolones having either a methoxy or a hydrogen at the C-8 position, the MIC for the most resistant mutant correlated better with the MPC than did the MIC for wild-type cells. For C-8-fluorine derivatives, which were generally less active than the C-8-methoxy compounds but which were more active than C-8-hydrogen derivatives, the MICs for both the mutant and the wild type correlated well with the MPCs. Thus, measurement of the MICs for wild-type cells can reflect the ability of a quinolone to restrict the selection of resistance, but often it does not. With the present series of compounds, the most potent contained a C-8-methoxy and a small group attached to the C-7 ring.     

Tolerance of the canine bladder to intraoperative radiation therapy: an experimental study

An experimental study of bladder tolerance to intraoperative radiotherapy (IORT) was designed using a large animal model (adult American Foxhounds, weight 25-30 kg) to access acute and late radiation effects. Dogs were subjected to laparotomy where the bladder was mobilized and IORT was delivered using a 5 cm circular cone through a cystotomy incision with 12 MeV electrons. The bladder trigone including both ureteral orifices and the proximal urethra was irradiated in groups of 3 dogs with doses of 0, 20, 25, 30, 35, and 40 Gy. Dogs were followed clinically with repeat urinalysis, intravenous pyelogram (IVP), and cystometrogram at 1 month and then Q6 months for up to 4 years. One dog from each dose group was sacrificed electively at 1 and 2 years, whereas the other dog is being followed clinically for a minimum of 4 years. Complete autopsies were performed with particular attention to genitourinary and pelvic structures. No clinically detectable acute toxicity resulted from IORT to the bladder. Three of 15 IORT dogs (1 each at 25, 35, and 40 Gy) showed obstruction of a ureteral orifice with 2 dogs dying of renal failure secondary to bilateral hydronephrosis within 1-2 years of treatment. The remaining 12 IORT dogs and 3 control dogs have normal repeat IVP's and renal function with up to 4 years of follow-up. Serial cystometry demonstrates no major loss of bladder contractility or volume. At autopsy, histological changes of mucosal thinning and telangiectasia with submucosal fibrosis were confined to the IORT field and appeared dose-related. However, the bladder epithelium remained intact at all doses. The ureterovesical junction in animals receiving 20 Gy showed mild fibrosis of the lamina propria and moderate chronic inflammation. Above 20 Gy, these histological changes at the U-V junction were more pronounced with gross stenosis in 3 animals as predicted by the IVP. We conclude that the bladder trigone will tolerate IORT to 20 Gy without major clinical sequellae. Above 20 Gy, progressive inflammation and fibrosis of the U-V junction resulted in obstructive hydronephrosis in three animals within 1-2 years of IORT. The bladder mucosa remained intact with doses to 40 Gy, although submucosal fibrosis and chronic inflammation were evident and appeared dose-related. However, bladder function as measured by cystometry showed essentially no change with follow-up to 4 years. From this large animal study, IORT for early-stage bladder carcinoma is technically feasible and deserves a careful clinical study.     

Hydroxamic acids as pharmacological agents

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.     

Attenuation of diabetic hyperphagia in neuropeptide Y--deficient mice

The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY's role in the hyperphagic response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient (Npy(--/--)) and wild-type (Npy(+/+)) mice. In Npy(+/+) mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 +/- 0.6 g/day; P < or = 0.05), an effect that was not seen in STZ-treated Npy(--/--) mice (+0.8 +/- 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy(--/--) mice exhibit intact hyperphagic responses to fasting (Erickson et al. [1], Nature 381:415-418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy, we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy(--/--) and Npy(+/+) mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50-80%) compared with the effect of fasting (approximately 20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in the ARC of Npy(+/+) mice (P less-than-or-equal 0.05) but by only 11% in Npy(--/--) mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast, NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling appears to be suppressed more effectively by fasting than by uncontrolled diabetes, which provides a plausible explanation for differences in the feeding response to these two stimuli in mice lacking NPY.     

Benefit-cost analysis of addiction treatment: methodological guidelines and empirical application using the DATCAP and ASI

OBJECTIVE: To provide detailed methodological guidelines for using the Drug Abuse Treatment Cost Analysis Program (DATCAP) and Addiction Severity Index (ASI) in a benefit-cost analysis of addiction treatment. DATA SOURCES/STUDY SETTING: A representative benefit-cost analysis of three outpatient programs was conducted to demonstrate the feasibility and value of the methodological guidelines. STUDY DESIGN: Procedures are outlined for using resource use and cost data collected with the DATCAP. Techniques are described for converting outcome measures from the ASI to economic (dollar) benefits of treatment. Finally, principles are advanced for conducting a benefit-cost analysis and a sensitivity analysis of the estimates. DATA COLLECTION/EXTRACTION METHODS: The DATCAP was administered at three outpatient drug-free programs in Philadelphia, PA, for 2 consecutive fiscal years (1996 and 1997). The ASI was administered to a sample of 178 treatment clients at treatment entry and at 7-months postadmission. PRINCIPAL FINDINGS: The DATCAP and ASI appear to have significant potential for contributing to an economic evaluation of addiction treatment. The benefit-cost analysis and subsequent sensitivity analysis all showed that total economic benefit was greater than total economic cost at the three outpatient programs, but this representative application is meant to stimulate future economic research rather than justifying treatment per se. CONCLUSIONS: This study used previously validated, research-proven instruments and methods to perform a practical benefit-cost analysis of real-world treatment programs. The study demonstrates one way to combine economic and clinical data and offers a methodological foundation for future economic evaluations of addiction treatment.