Enhancement of the clinical activity of melphalan by the hypoxic cell sensitizer misonidazole.

One hundred patients with non-small cell lung cancer were entered by members of the Northern California Oncology Group into a randomized Phase II trial of i.v. melphalan versus i.v. melphalan with concomitant oral misonidazole. The patients had not received prior chemotherapy. Eighty-five patients were evaluable for assessment of response and 89 were evaluable for toxicity analysis. The melphalan/misonidazole group had a superior response rate (two complete and four partial responses among 42 patients or 14%) compared to the melphalan group in which there were no responses among 43 patients (p = 0.024, two-sided Fisher exact test). Since hematological toxicity was equivalent in the two groups, there was an improvement in therapeutic index. Data from 12 patients undergoing pharmacological studies demonstrated that the plasma concentration of melphalan was 25% higher in the misonidazole group, a difference that is not statistically significant. Although the mechanism of interaction has not been fully established, this randomized trial demonstrates that a chemosensitizer can enhance the clinical antitumor activity of an alkylating agent and suggests that chemosensitizers in combination with alkylating agents should be investigated in further clinical trials.

Phase I trial of intravenous L-phenylalanine mustard plus the sensitizer misonidazole.

Misonidazole (MISO), a hypoxic cell radiosensitizer, has been shown in vivo to enhance tumor cell killing by melphalan (LPAM) with little or no enhancement of normal tissue injury. A Phase I trial was conducted using MISO p.o. 2 hr before i.v. LPAM. The highest doses used were the single maximum tolerated doses of MISO, 4 g/sq m, and LPAM, 0.6 mg/kg. Thirty-five patients were entered; 30 were evaluable for assessment of hematological toxicity, which was predicted to be the dose-limiting toxicity. The median age was 60 years (range, 28 to 72 years). Mild to moderate nausea and vomiting occurred in 80% of patients. Five developed serious hematological toxicity defined as nadir white blood cell count less than 1000/cu mm, platelets less than 20,000/cu mm or 4-week posttreatment white blood cell count less than 2000/cu mm, platelets less than 50,000/cu mm. Four of the toxicities occurred at the LPAM dose of 0.6 mg/kg but were independent of MISO dose. One patient died of infection. Two patients whose tumor demonstrated an objective response to therapy and 10 others with disease stabilization received additional courses. Four patients developed mild MISO neuropathy. Pharmacokinetic studies demonstrated that MISO did not appear to affect the pharmacokinetics of LPAM in plasma. Both LPAM and MISO can be given safely at their individual maximum tolerated dose. This combination will proceed to Phase II trials.

Prophylaxis of urinary tract infection in persons with recent spinal cord injury: a prospective, randomized, double-blind, placebo-controlled study of trimethoprim-sulfamethoxazole.

PURPOSE: To determine the efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for prophylaxis of urinary tract infection in persons with recent spinal cord injury, during the first 4 months of intermittent catheterization. PATIENTS AND METHODS: One hundred twenty-nine adults (112 men, 17 women) with recent acute spinal cord injury participated in a randomized, double-blind, placebo-controlled trial, and were studied for up to 16 weeks. Low-dose TMP-SMX (TMP 40 mg, SMX 200 mg) or placebo was given once daily. Clinical observations, urine cultures, and cultures of rectal and urethral swabs were made weekly. Subjects who developed breakthrough bacteriuria received conventional antimicrobial therapy and prophylaxis was continued. RESULTS: Sixty-six TMP-SMX recipients (57 men, 9 women) and 60 placebo recipients (52 men, 8 women) are evaluable for efficacy. Among male subjects, bacteriuria was present during 50% or more of study weeks in 30% of TMP-SMX recipients and in 56% of placebo recipients (p = 0.003). The interval to the onset of bacteriuria was prolonged in TMP-SMX recipients (p < 0.0001). TMP-SMX recipients without bacteriuria in any given week had a lower probability of having bacteriuria the subsequent week (0.26) than did placebo recipients (0.49) (p < 0.0001). At least 1 episode of definite symptomatic bacteriuria (bacteriuria and fever and at least 1 classical manifestation of urinary infection) occurred in 4 of 57 TMP-SMX-treated men and in 18 of 52 placebo-treated men (p < 0.0003). We observed similar trends in women, but differences did not reach statistical significance, perhaps because the number of females was small. Adverse events suspected to be due to medications were frequent in this population of patients with recent severe injuries and led to discontinuation of the study in 10% of the TMP-SMX group and 8% of the placebo group. Adverse events included neutropenia (TMP-SMX: two; placebo: three), pseudomembranous colitis (TMP-SMX: one), severe skin rash (TMP-SMX: two; placebo: one), and drug fever (TMP-SMX: one). The proportion of all episodes of bacteriuria that were due to TMP-SMX-resistant organisms was unexpectedly high in the placebo group (51%), and increased progressively according to year of enrollment in the study. By Year 3, all subjects in the placebo group had at least one episode of TMP-SMX-resistant bacteriuria. Gram-negative enteric bacilli resistant to TMP-SMX were recovered from rectal swabs (TMP-SMX 49%, placebo 42%) and urethral swabs (TMP-SMX 33%, placebo 26%) in similar proportions of subjects in the two study groups. CONCLUSIONS: Prophylaxis with TMP-SMX significantly reduces bacteriuria and symptomatic urinary tract infection in persons with recent acute spinal cord injury during bladder retraining using intermittent catheterization. However, adverse reactions attributable to TMP-SMX are common in this population. Colonization and breakthrough bacteriuria with TMP-SMX-resistant organisms are frequent and may seriously limit the usefulness of this strategy, particularly in an institutional setting.

High dose-rate afterloading 192Iridium prostate brachytherapy: feasibility report.

BACKGROUND: RESULTS from localized prostate cancer series using seed implants have been most encouraging. However, with current techniques, inadequate dosimetry sometimes occurs. Remote afterloading high dose rate 192Iridium brachytherapy (HDR-Ir192) theoretically remedies some potential inadequacies of seed implantation by performing the dosimetry after the needles are in place. This study was undertaken to determine the feasibility of incorporating multifractionated HDR-Ir192 in the brachytherapy management of prostate carcinoma. METHODS: From October 1989 to August 1995, 104 patients were treated with a combination of multifractionated HDR-Ir192 and external beam. Patients ranged in age from 48-78 years, with a mean of 68.6 years. By TNM clinical stage, there were 1 T1b, 31 T1c, 28 T2a, 24 T2b, 9 T2c, 8 T3a, and 3 T3c lesions. For the group, the mean initial pretreatment PSA was 12.9 ng/ml (median 8.1), with 90% of the patients having had a pretreatment PSA greater than a normal value of 4.0 ng/ml. Patients with prostate volumes up to 105 cc were implanted. Treatment was initiated with perineal needle placement using ultrasound guidance. A postoperative CT scan was obtained to provide the basis for treatment planning. Four HDR-Ir192 treatments were given over a 40-h period, with a minimal peripheral dose (MPD) ranging from 3.00 to 4.00 Gy per fraction over the course of this study. Two weeks later, external beam radiation was added using 28 fractions of 1.80 Gy daily, to a dose of 50.40 Gy. RESULTS: Follow-up ranged from 10 to 89 months, with a mean of 46 months and median of 45 months. At various follow-up points, the patient numbers at risk were: 1 year, 101; 3 years, 69; 5 years, 28. The technique proved to be uniformly applicable to a wide range of prostate volumes and was very well tolerated by patients. Nearly all significant late in-field treatment complications were genitourinary in nature. Of the patients, 6.7% developed urethral strictures that were readily manageable. Changes in technique implemented in 1993 appear to have significantly lessened the incidence of this complication. Two patients developed significant uropathy within the first treatment year, but both resolved; 1 of these 2 patients had a prior TURP. Other bladder or rectal complications have been minimal. Using PSA progression as a marker of tumor response, approximately 84% of patients whose initial PSA was less than 20 ng/ml were free of progression at 5 years by actuarial analysis. CONCLUSIONS: We found the use of transperineal ultrasonography, postimplant CT-based dosimetry, coupled with adjustable dose delivery inherent to remote afterloading technology, to give unparalleled control in performing this complex brachytherapy task. Thus, it may be advantageous in certain clinical situations where the resultant MPD is needed to reliably cover the target volume, such as in patients with carcinomas at base locales, when the possibility of moderate to extensive intraprostatic tumor exists, and in patients with large glands. Early PSA data suggest that it may be effective as a definitive treatment with rates of adverse late tissue effects that are acceptable using current technique and doses described herein. Longer follow-up is needed to ascertain its position among the various treatment regimens for prostate carcinoma.

Biopsy and definitive radiation therapy in stages I and II carcinoma of the female breast.

One hundred-twenty patients with Stages I and II carcinoma of the female breast were treated by biopsy followed by definitive radiation therapy without mastectomy. The breast received 4500-5000 cGy (rad) using a 6 MV linear accelerator followed by a supplement to the area of the primary tumor of 2000 cGy (rad) using electrons in 99 patients (83%) and interstitial implantation in 21 patients (17%). Local recurrence was not recorded in the 43 patients with Stage I disease, while three of 77 patients (4%) with Stage II disease suffered a local recurrence. The actuarial five-year relapse-free survival was 91% and 60% in Stages I and II respectively. Cosmetic results were considered excellent by both physician and patient in the majority of cases. Axillary dissection was the recommended method of staging the axilla but was noted to be more morbid than axillary sampling. Electrons may be as effective as interstitial implantation as a means of supplementation following external beam therapy if specific guidelines are followed.

Hemophilus aphrophilus vertebral osteomyelitis: a case report and literature review.

We report a 60-yr-old diabetic female who developed vertebral osteomyelitis and discitis due to Hemophilus aphrophilus, and review three previously reported cases of this uncommon infection. Predisposing factors, clinical features, and treatment of H. aphrophilus vertebral osteomyelitis are discussed.

Evaluation of diagnostic criteria for bacteriuria in acutely spinal cord injured patients undergoing intermittent catheterization.

To evaluate diagnostic criteria for bacteriuria in acutely spinal cord injured patients undergoing intermittent catheterization, we studied paired urine specimens obtained by suprapubic aspiration and intermittent catheterization. Culture of suprapubic aspirate was used to define presence or absence of bacteriuria. Fifty patients were studied for an average of 5 consecutive days; bacteriuria occurred within the study period in 47 (94%). Low-level bacteriuria was frequent; thus, the traditional diagnostic criterion, greater than or equal to 10(5) cfu/ml of midcatheter urine, had unacceptably low sensitivity (gram-positive organisms 0.45; gram-negative organisms 0.65) for bacteriuria documented by suprapubic aspiration. The best diagnostic criterion for gram-positive bacteriuria was between greater than or equal to 10(1) cfu/ml (sensitivity 0.91, specificity 0.86) and greater than or equal to 10(2) cfu/ml (sensitivity 0.85, specificity 0.93). For gram-negative bacteriuria, greater than or equal to 10(1) cfu/ml was optimal (sensitivity 0.96, specificity 0.96); a more practical criterion, greater than or equal to 10(2) cfu/ml, retained excellent sensitivity (0.91). Suprapubic or flank pain and/or tenderness occurred in five of 47 bacteriuric subjects; nonspecific symptoms, possibly associated with bacteriuria, were seen in an additional 28 subjects. We conclude that, in this unique population, a criterion of greater than or equal to 10(2) cfu/ml of midcatheter urine should be used for diagnosis of bacteriuria.

The toilet as a transmission vector of vancomycin-resistant enterococci.

An elderly woman, admitted to the intensive care unit of a large university teaching hospital, was found to be colonized with vancomycin-resistant enterococci leading to the temporary closure of the unit. She had acquired the organism nosocomially, most likely from an environmental source, which had been contaminated when the toilet of a former patient, also colonized with vancomycin-resistant enterococci, had become blocked and overflowed throughout his and the adjoining room. This is the first report of a hospital toilet as the transmission vector for vancomycin-resistant enterococci.

Analysis of utilization-related parameters on a 6-MV linear accelerator.

An analysis of unscheduled downtime and of patient treatment data for a 6-MV linear accelerator is presented for a 7-yr period. Following the initial year of clinical use, the unscheduled downtime has averaged 2.4%, with a corresponding loss of 1.3% in patient treatments. The quality assurance, preventive maintenance, and repairs are handled in-house, with an investment of approximately 500 man-hours annually.

A statistical analysis of ionometrically measured 6-MV x-ray beam parameters.

A statistical analysis has been made of ionometrically measured parameters related to the central-axis output, the beam symmetry, the beam flatness, and the depth dose for the 6-MV x-ray beam from the Therac-6 linear accelerator. The means and coefficients of variation of the measurements are determined on a monthly basis for each parameter. Mean coefficients of variation less than +/- 1% have been determined and are useful in establishing the optimal limits of acceptance of these parameters. The results of this study indicate that the long-term stability of the radiation parameters associated with this unit can be maintained within acceptable limits with a consistent quality-assurance program.

The diagnosis and significance of bacteriuria in people with spinal cord injury.

Quantitative urine cultures are used to identify individuals in whom urine in the bladder is not sterile, that is, those who have bacteriuria. In people with spinal cord injury the criteria which best distinguish specimen contamination from bacteriuria have been established, and are lower than the traditional ≥1055 CFU/ml criterion. Bacteriuria mayor may not be symptomatic, and the benefits of treatment mayor may not outweigh the risks.Abnormal levels of pyuria are present in the great majority of spinal cord injured people who have indwelling catheters or who use intermittent catheterization. In the latter group, catheter urine is not homogeneous, and levels of pyuria are highest in the terminal fraction of catheter urine. Absence of pyuria is a good indicator of absence of high count gram negative bacteriuria, but pyuria may be present in the absence of bacteriuria in this population. No methods suitable for routine clinical use are currently available to localize the site of urinary infection in this population.Frequently recurrent or persistent bacteriuria is extremely common in people with spinal cord injury. Bacteriuria is most often asymptomatic, yet is clearly significant in that it is responsible for measurable short-term and long-term morbidity. However, at present, quantitative urine cultures and tests for pyuria cannot, by themselves, be used to identify spinal cord injured persons who will reliably benefit from treatment for bacteriuria.

Sequential antibiotic therapy: Effective cost management and patient care.

The escalating costs associated with antimicrobial chemotherapy have become of increasing concern to physicians, pharmacists and patients alike. A number of strategies have been developed to address this problem. This article focuses specifically on sequential antibiotic therapy (sat), which is the strategy of converting patients from intravenous to oral medication regardless of whether the same or a different class of drug is used. Advantages of sat include economic benefits, patient benefits and benefits to the health care provider. Potential disadvantages are cost to the consumer and the risk of therapeutic failure. A critical review of the published literature shows that evidence from randomized controlled trials supports the role of sat. However, it is also clear that further studies are necessary to determine the optimal time for intravenous to oral changeover and to identify the variables that may interfere with the use of oral drugs. Procedures necessary for the implementation of a sat program in the hospital setting are also discussed.

The effects of coping on adjustment: Re-examining the goodness of fit model of coping effectiveness.

Abstract The primary aim of the present study was to examine the extent to which the effects of coping on adjustment are moderated by levels of event controllability. Specifically, the research tested two revisions to the goodness of fit model of coping effectiveness. First, it was hypothesized that the effects of problem management coping (but not problem appraisal coping) would be moderated by levels of event controllability. Second, it was hypothesized that the effects of emotion-focused coping would be moderated by event controllability, but only in the acute phase of a stressful encounter. To test these predictions, a longitudinal study was undertaken (185 undergraduate students participated in all three stages of the research). Measures of initial adjustment (low depression and coping efficacy) were obtained at Time 1. Four weeks later (Time 2), coping responses to a current or a recent stressor were assessed. Based on subjects' descriptions of the event, objective and subjective measures of event controllability were also obtained. Measures of concurrent and subsequent adjustment were obtained at Times 2 and 3 (two weeks later), respectively. There was only weak support for the goodness of fit model of coping effectiveness. The beneficial effects of a high proportion of problem management coping (relative to total coping efforts) on Time 3 perceptions of coping efficacy were more evident in high control than in low control situations. Other results of the research revealed that, irrespective of the controllability of the event, problem appraisal coping strategies and emotion-focused strategies (escapism and self-denigration) were associated with high and low levels of concurrent adjustment, respectively. The effects of these coping responses on subsequent adjustment were mediated through concurrent levels of adjustment.

Cefotetan: a second-generation cephalosporin active against anaerobic bacteria. Committee on Antimicrobial Agents, Canadian Infectious Disease Society.

OBJECTIVE: To offer guidelines for the use of cefotetan, a cephamycin antibiotic, in order to minimize its overprescription. OPTIONS: Clinical practice options considered were treatment of infections with the use of second- and third-generation cephalosporins, carbapenems such as imipenem as well as combination regimens of agents active against anaerobic bacteria, such as metronidazole or clindamycin with an aminoglycoside. OUTCOMES: In order of importance: efficacy, side effects and cost. EVIDENCE: A MEDLINE search of articles published between January 1982 and December 1993. In-vitro and pharmacokinetic studies published in recognized peer-reviewed journals that used recognized standard methods with appropriate controls were reviewed. For results of clinical trials, the reviewers emphasized randomized double-blind trials with appropriate controls. VALUES: The Antimicrobial Agents Committee of the Canadian Infectious Disease Society (CIDS) and a recognized expert (M.J.G.) recommended use of cefotetan to prevent and treat infections against which it has proved effective in randomized controlled trials. BENEFITS, HARMS AND COSTS: These guidelines should lead to less inappropriate prescribing of cefotetan, with its attendant costs and risk of development of resistant bacteria. RECOMMENDATIONS: Cefotetan could be considered an alternative single agent for prophylaxis of infection in patients undergoing elective bowel surgery. It may be used to treat patients with acute pelvic inflammatory disease and endometritis. VALIDATION: This article was prepared, reviewed and revised by the Committee on Antimicrobial Agents of the CIDS. It was then reviewed by the Council of the CIDS, and any further necessary revisions were made by the chairman of the committee.

Histologically proven pressure sore-related osteomyelitis in the setting of negative technetium bone scans. Case report.

Pressure sores are common in patients with spinal cord injury, stroke or debilitating medical illness. Contiguous osteomyelitis is a well recognized complication of pressure ulcers, but remains a challenging diagnostic and management problem. Technetium bone scan is purported to be an extremely sensitive, although nonspecific diagnostic test for osteomyelitis. Indeed, a negative bone scan is thought to virtually exclude bone infection. We report three cases of pressure sore-related polymicrobial osteomyelitis where technetium bone scan was normal, yet bone biopsy demonstrated characteristic histopathologic changes of osteomyelitis. These cases raise questions regarding the sensitivity of bone scanning in the setting of pressure sores, and they demonstrate the need for further investigation into the correlation between nuclear medicine scan results and bone biopsy histopathology. Bone biopsy remains the gold standard for diagnosis of osteomyelitis, which can be present in bone underlying a pressure ulcer, even in the setting of a normal bone scan.

The ataxic subgroup: a discrete outcome after traumatic brain injury.

We have observed five individuals who appear to represent a unique subgroup of patients with traumatic brain injury (TBI). Because of the prominence of severe ataxia, this group has been labelled the 'ataxic subgroup'. These individuals are distinguished by both clinical course and outcome, including severe ataxia, prolonged coma and prolonged post-traumatic amnesia (PTA). They distinguish themselves from other severely impaired TBI patients in that they spend a relatively longer length of time prior to the establishment of volition, but progress rapidly through the period of confusion. We hypothesized that this group is unique in that they have suffered Grade III diffuse axonal injury (DAI) with no or minimal complications due to other primary or secondary brain damage. In order to investigate these hypotheses, a retrospective file review of a selected group of 72 patients was undertaken to determine the specificity and sensitivity of two diagnostic criteria. The existence of severe Grade III DAI without other primary or secondary brain damage was presumed if severe ataxia was present in conjunction with normal CT scans. Results of this review indicated that 33% of the population demonstrated severe ataxia, although only 11% also had normal CT scans. These dual criteria were neither adequately sensitive nor specific to define the five patients who comprised the 'ataxic subgroup'. When rate of clearing the confused period of PTA was added to the diagnostic criteria, specificity improved. Although this attempt to define this subgroup empirically was not entirely successful, further attempts to delineate this group are important in that prognosis for clearing PTA is good despite early indicators of poor outcome.(ABSTRACT TRUNCATED AT 250 WORDS)