Treatment of complex anterior urethral stricture disease with mesh graft urethroplasty

In this report we describe the toxicokinetics of the Tylenol Extended Relief (TER) preparation of acetaminophen in human overdose. We collected 41 cases of TER overdose from five regional poison centers. Patients who met the following criteria were studied: a single ingestion of TER alone; confirmed time of ingestion; at least four acetaminophen determinations; and normal concentrations of liver function enzymes. With the exception of standard decontamination measures, treatment with N-acetylcysteine (NAC) if any acetaminophen level was above the treatment line of the Rumack-Matthew nomogram, and additional acetaminophen determinations, no interventions were recommended. Our study group comprised 13 patients, 12 female and 1 male, with single overdoses of 10.4 to 65 g TER. The acetaminophen elimination half-life was 3.1 +/- .8 hours (mean +/- SD; range, 1.3 to 4.0 hours; n = 12). The elimination phase for patients 2, 3, 4, 6, 8, 9, 11, 13 was delayed until 8.0 +/- 2.8 hours (range, 5 to 14 hours) after ingestion. Patients 3, 8, and 11--who had initial acetaminophen levels below the "possible toxicity" line of the Rumack-Matthew nomogram--later had acetaminophen levels above this line. No patient demonstrated a late or second acetaminophen peak. We conclude that the elimination half-life of TER acetaminophen is similar to that reported in overdose of immediate-release acetaminophen overdose. In a subgroup of patients, drug absorption continued beyond the 2 to 4 hours previously reported in immediate-release acetaminophen overdose. On the basis of our data, the use of a single 4-hour acetaminophen determination may lead to failure to recognize patients with potentially toxic TER ingestion. Until more toxicokinetic data are available, a reasonable approach would be to obtain at least one additional acetaminophen determination at least 4 to 6 hours after the first, if the first is obtained 4 to 8 hours after ingestion. NAC treatment should be initiated if either level is above the nomogram line but not if both levels fall below the nomogram line.     

Henneguya malabarica sp. nov. (Myxozoa, Myxobolidae) in the Amazonian fish Hoplias malabaricus

The mainstay of treatment for acetaminophen-induced hepatotoxicity, produced by the accumulation of the toxic metabolite N-acetylbenzoquinoneimine, is an enteral 18-dose course of N-acetylcysteine (NAC). However, absence of characteristic symptomatology is a frequent reason for premature cessation of NAC and early discharge of the toxic acetaminophen poisoned patient. We report a series of confirmed acetaminophen poisonings who were discharged early with NAC and instructions to self-administer. All cases of acute acetaminophen poisoning without concomitant drugs, reported to a certified Regional Poison Information Center for a 3-mo period of time, were reviewed. Inclusion criteria included patients who were discharged with orders to complete the course of NAC outside of a hospital, despite toxic serum acetaminophen concentrations. Data parameters evaluated included age, amount taken, symptoms, laboratory results, treatment, and medical outcome. 131 cases of confirmed toxic acetaminophen poisoning yielded 6 patients who received 4 to 6 doses of NAC during hospitalization, but were discharged to home with the remaining 11-13 doses. Patients' ages ranged from 16-28 y (mean 20.0 y). Serum acetaminophen concentrations measured at 4 h post-ingestion ranged from 171-198 mcg/ml (mean 182 mcg/ml). Follow-up by the certified Regional Poison Information Center at 1-3 w post-discharge determined dosing compliance to be 83%. All 6 patients remained asymptomatic with normal liver function testing. Since health care reform encourages practitioners to reconsider established approaches to the delivery of health care, perhaps home delivery of NAC would not only be clinically preferred to premature cessation of the antidote, but also offer cost savings. Self-administration of NAC in the home setting may be representative of a new era in America's health care delivery system.     

A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose

STUDY OBJECTIVE: To evaluate whether activated charcoal (AC) reduces the efficacy of subsequent oral N-acetylcysteine therapy during acute acetaminophen overdose. DESIGN: Prospective observational case series of all acute acetaminophen overdoses reported to three certified regional poison centers. TYPES OF PATIENTS: All patients with acute acetaminophen overdose in whom N-acetylcysteine therapy was initiated within 16 hours after ingestion. INTERVENTIONS: All patients were treated with oral N-acetylcysteine therapy for 72 hours. The decision to use AC was left to the treating physician without input from the investigator. MEASUREMENTS AND RESULTS: One hundred twenty-two patients were evaluated. Maximum recorded SGOT levels of more than 125 U/mL were defined as evidence of hepatotoxicity. AC was used in addition to N-acetylcysteine in 82 of 122 patients. Hepatotoxicity developed in four of 82 patients who received AC versus ten of 40 patients who did not receive AC (P < .005). An increasing dose of N-acetylcysteine provided no additional benefit (P > .05). Spacing the administration of AC and oral N-acetylcysteine less than or more than two hours apart did not affect outcome (P > .05). CONCLUSION: Administration of AC before the administration of oral N-acetylcysteine in acetaminophen overdose does not reduce the efficacy of N-acetylcysteine therapy and may provide some additional hepatoprotective benefit. The practice of increasing the dose of oral N-acetylcysteine therapy after the administration of AC appears unwarranted.     

Spontaneous chemiluminescence production, lipid peroxidation, and covalent binding in rat hepatocytes exposed to acetaminophen

Spontaneous chemiluminescence associated with the cell injury was observed in the isolated rat hepatocyte suspension during acetaminophen (APAP) metabolism, indicating the occurrence of oxidative stress. APAP apparently affected the hepatocytes in various manners. APAP, at low concentrations (1-2 mM), damaged the hepatocytes due to lipid peroxidation provoked during APAP metabolism, while at high concentrations (5-50 mM), APAP protected the hepatocytes due to a chemical antioxidant effect of the unmetabolized APAP that remained in the medium because of the saturation of APAP metabolism. The covalent binding of APAP to the hepatocytes increased with APAP concentration up to 50 mM without loss of cell viability. When an overdose of APAP was administered to rats, the APAP plasma concentration was around 1-3 mM, which corresponded to the concentration range where lipid peroxidation occurred in the isolated hepatocytes. Thus, it seems likely that lipid peroxidation contributes to the APAP-induced hepatotoxicity in the early stage of the toxic process.     

Metabolic bone disease of total parenteral nutrition

We compared the clinical course of pediatric patients (n = 25) with acetaminophen poisoning treated with an investigational intravenous preparation of N-acetylcysteine (IV-NAC) with that of historical control subjects (n = 29) treated with conventional oral NAC (O-NAC) therapy. Patients received IV-NAC for 52 hours; historical control subjects received O-NAC (72 hours). There were no significant intergroup differences between treatment groups in age (15.5 vs 15.9 years), gender (88% vs 90% female) or distribution of risk categories (probable risk, 12 vs 15; high risk; 13 vs 14). The peak prothrombin time was significantly higher in the IV-NAC group (14.2 vs 13.6 seconds; p = 0.048). Mean treatment delay was significantly longer in the IV-NAC group (14.4 vs 10.4 hours; p = 0.001). Hepatoxicity was noted in two (8.0%) patients in the IV-NAC treatment group and two (6.9%) patients in the O-NAC group. All patients recovered. Our results indicate that 52 hours of intravenous NAC is as effective as 72 hours of oral NAC.     

Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury

In studies designed to simulate a clinical observation in which an individual became tolerant to normally lethal doses of acetaminophen (APAP), mice were pretreated with increasing doses of APAP for 8 days and challenged on day 9 with normally supralethal doses of APAP. These animals developed minimal hepatotoxicity after a challenge dose with a fourfold increase in LD50 to 1,350 mg/kg. The pretreatment regimen resulted in hepatic changes including: centrilobular localization of 3-(cysteine-S-yl)APAP protein adducts, selective down-regulation of cytochrome P4502E1 (CYP2E1) and CYP1A2 that produced the toxic metabolite, N-acetyl-p-benzoquinone imine, higher levels of reduced glutathione (GSH), centrilobular inflammation, and a fourfold increase in hepatocellular proliferation. The protection against the lethal APAP doses afforded by pretreatment is secondary to these changes and to the associated regional shift in the bioactivation of the APAP challenge dose from centrilobular to periportal regions where CYP2E1 is not found, protective GSH is more abundant, and where cell-proliferative responses are better able to sustain repair. This shift in APAP bioactivation results in less-intense covalent binding that is more diffuse and spread uniformly throughout the hepatic lobe, most likely contributing to protection by delaying the early onset of liver injury that has been generally associated with centrilobular localization of the adducts. Intervention of APAP pretreatment-induced cell division in mice with colchicine left them resistant to a 500-mg/kg (normally lethal) dose of APAP, but unable to survive a 1,000-mg/kg APAP challenge dose. The data demonstrate multiple mechanistic components to the protection afforded by APAP pretreatment. Whereas metabolic and physiological changes not dependent on cell proliferation are adequate to protect against 500 mg/kg APAP, these changes plus a potentiated cell-proliferative response are necessary for protection against the supralethal 1,000-mg/kg APAP dose. Furthermore, the data document an uncoupling of the traditional association between covalent binding and toxicity, and suggest that the assessment of toxicity following repeated or chronic APAP exposure must consider altered drug interactions and parameters besides those historically used to assess acute APAP overdose.     

Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice

Pretreatment of mice with clofibrate (CFB) has been shown to protect against acetaminophen (APAP) hepatotoxicity. To determine if pretreatment with CFB prevents the toxicity of other model hepatotoxicants, male C57BL6J or CD-1 mice received 500 mg CFB/kg, i.p., daily for 10 days, and then were challenged with either 250 mg bromobenzene (BrB)/kg, 0.025 ml carbon tetrachloride (CCl4)/kg or 0.5 ml chloroform (CHCl3)/kg. Liver and kidney injury was assessed by plasma sorbitol dehydrogenase activity (SDH) and blood urea nitrogen (BUN), respectively and histopathology. Challenge with BrB significantly elevated plasma SDH activity in C57Bl6J mice. This was prevented in CFB pretreated mice receiving the same dose of BrB. Changes in BUN were not detected in either group of BrB treated mice. Similarly, pretreatment of male CD-1 mice with CFB significantly reduced CCl4-induced elevation in plasma SDH activity, with no BUN elevation detected in either group. CFB pretreatment also diminished elevation in plasma SDH activity produced by CHCl3 in CD-1 mice, while BUN was significantly elevated in both groups, indicating that CFB did not protect against CHCl3-induced nephrotoxicity. Histopathological examination of liver and kidney sections confirmed these results. This study shows that mice pretreated with CFB were protected from toxicity at 24 h after challenge with other model hepatotoxic agents besides APAP.     

Selective protein arylation and acetaminophen-induced hepatotoxicity

More than 20 years have passed since the early reports of acute hepatotoxicity with APAP overdose. During that period investigative research to discover the "mechanism" underlying the toxicity has been conducted in many species and strains of intact animals as well as in a variety of in vitro and culture systems. Such work has clarified the primary role of biotransformation and the protective role of GSH. Understanding the former provides explanations for the toxic interactions which may occur with alcohol or other xenobiotics, while understanding of the latter led to the development of antidotes for the treatment of acute poisoning. Acetaminophen (APAP)-induced hepatotoxicity: roles for protein arylation. Initiating events in toxicity require biotransformation of APAP to NAPQI followed by arylation of several important proteins with subsequent alteration of protein structure and function. The immediate consequence of the alterations is detectable in several organelles and these may represent multiple initiating events which are depicted as acting in concert to cause cell injury (large arrowheads). Arylation of cytosolic 58-ABP with subsequent translocation to the nucleus is depicted as a possible signaling mechanism for determining outcome at the cell or organ level (within dotted boundary). For simplicity NAPQI's potentials for oxidizing protein sulfhydryls and direct binding to DNA have been omitted. Significant light has also been shed on the biochemical and cellular events which accompany APAP-induced hepatotoxicity. However, such studies have not identified a unique mechanism of toxicity that is universally accepted. The recent identification of several protein targets which become arylated during toxicity--along with the findings that arylation of some of those target proteins results in loss of protein function--demonstrates that covalent binding does, indeed, have biological consequences and is not merely an indicator of the fleeting presence of reactive electrophiles. These observations further suggest that multiple independent insults to the cell may be involved in toxicity. it is now apparent that the concept of a multistage process that involves both initiation and progression events is appropriate for APAP toxicity, and it is unlikely that a unique initiating event will ever be identified. In light of recent findings it is more likely that a number of such cellular events occur very early after toxic overdosage, and that they collectively set in motion and perpetuate the biochemical, cellular, and molecular processes which will determine outcome. The importance of 58-ABP arylation with early, apparently selective, translocation to the nucleus remains to be elucidated. To date there is nothing to suggest that this represents an initiating event in toxicity. rather it is plausible that the translocation may play a role in signaling electrophile presence and in calling for cellular defense against electrophile insult. This is reflected in the hypothetical model presented in Fig. 3. Critical experimental testing of this model will advance our understanding of the cellular and molecular responses to toxic electrophile insult.     

Mechanism of acetaminophen-induced hepatotoxicity: covalent binding versus oxidative stress

The hepatotoxicity of acetaminophen is believed to be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine; however, the mechanism by which this metabolite produces the toxicity is unknown. The metabolite, which is both an electrophile and an oxidizing agent, may covalently bind to critical proteins, or it may initiate oxidative damage. We have previously developed a Western blot assay for detection of acetaminophen covalently bound to protein and have reported the relationship between covalent binding and the development of hepatotoxicity. Recently, we developed a Western blot assay for protein aldehyde formation, which may occur via the reactive oxygen species, the hydroxyl radical. In this paper, we have compared covalent binding to protein aldehyde formation. Toxic doses of acetaminophen (400 mg/kg) were administered to mice, and the mice were subsequently killed at 0, 1, 2, 4, and 6 h. Since the oxidizing agent FeSO4 has been reported to potentiate lipid peroxidation when administered with acetaminophen, other mice received FeSO4 (100 mg/kg) plus acetaminophen. Compared to saline-treated control mice, acetaminophen treatment significantly increased serum alanine aminotransferase levels, an index of hepatotoxicity, at 4 and 6 h, but not at 1 or 2 h. Acetaminophen plus FeSO4 treatment of mice significantly increased serum alanine aminotransferase levels at 2, 4, and 6 h compared to controls. Levels of alanine aminotransferase in serum of acetaminophen plus ferrous sulfate-treated mice were higher at 4 and 6 h than those of acetaminophen-treated mice, but not significantly different. FeSO4 alone did not increase alanine aminotransferase levels. Western blot assays revealed that acetaminophen did not cause an increase in protein aldehydes over control at any time, nor did acetaminophen plus FeSO4; however, FeSO4 alone increased the intensity of staining of the immunoblot for protein aldehydes over control at all times after 0 time. Acetaminophen-protein adducts were detected in acetaminophen- and acetaminophen plus FeSO4-treated mice. In vitro experiments indicated that FeSO4 plus tert-butyl hydroperoxide in the presence of bovine serum albumin increased protein aldehyde formation. Inclusion of acetaminophen in the incubation mixture inhibited protein oxidation of bovine serum albumin in a concentration dependent manner. The data indicate that acetaminophen quenches protein oxidation, presumably by reacting with the hydroxyl radical. These data are consistent with the theory that acetaminophen covalent binding is the primary mechanism of toxicity and argue against a role for protein oxidation in acetaminophen hepatotoxicity.     

Estrogen-receptor expression and function in thymocytes in relation to gender and age

INTRODUCTION: The mechanism of action of N-acetylcysteine in early acetaminophen poisoning is well understood, but much remains to be learned of the mechanism of its possible benefit in acetaminophen poisoning presenting beyond 15 hours. METHODS: Selective review of medical literature. N-acetylcysteine should be used in all cases of early acetaminophen poisoning where the plasma acetaminophen concentration lies "above the line;" which line is chosen depends on individual preference and whether enzyme induction is suspected. Particular care should be taken with the use of the nomogram for patients with chronic excess ingestion of acetaminophen or for those who have taken slow-release formulations. CONCLUSIONS: While there is a trend suggesting a beneficial effect of N-acetylcysteine in some patients presenting beyond 15 hours, further research is necessary to establish just how effective N-acetylcysteine is, particularly in patients presenting with fulminant hepatic failure. Candidate mechanisms for a beneficial effect in-clude improvement of liver blood flow, glutathione replenishment, modification of cytokine production, and free radical or oxygen scavenging. Hemody-namic and oxygen delivery and utilization parameters must be monitored carefully during delayed N-acetylcysteine treatment of patients with fulminant hepatic failure, as unwanted vasodilation may be deleterious to the maintenance of mean arterial blood pressure.     

Bronchoalveolar lavage studies in children without parenchymal lung disease: cellular constituents and protein levels

The hepatotoxicity of acetaminophen overdose depends on the metabolic activation to a toxic reactive metabolite by the hepatic mixed function oxidases. There is evidence that an increase in cytosolic Ca2+ is involved in acetaminophen hepatotoxicity. The effects of the Ca2+-antagonists nifedipine (NF), verapamil (V), diltiazem (DL) and of the calmodulin antagonist trifluoperazine (TFP) on the activity of some drug-metabolizing enzyme systems, lipid peroxidation and acute acetaminophen toxicity were studied in male albino mice. No changes in the drug-metabolizing enzyme activities studied and in the cytochrome P-450 and b5 contents were observed 1 h after oral administration of V (20 mg/kg). DL (70 mg/kg) and TFP (3 mg/kg). NF (50 mg/kg) increased cytochrome P-450 content, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. DL and TFP significantly decreased lipid peroxidation. NF, V, DL and TFP administered 1 h before acetaminophen (700 mg/kg orally) increased the mean survival time of animals. A large increase of serum aspartate aminotransferase(AST), and liver weight and depletion of liver reduced glutathione (GSH) occurred in animals receiving toxic acetaminophen dose. NF, V and DL prevented and TFP decreased the acetaminophen-induced hepatic damage measured both by plasma AST and by liver weight. NF, V, DL and TFP changed neither the hepatic GSH level nor the GSH depletion provoked by the toxic dose of acetaminophen. This suggests that V, DL and TFP do not influence the amount of the acetaminophen toxic metabolite formed in the liver. The possible mechanism of the protective effect of NF, V, DL and TFP on the acetaminophen-induced toxicity is discussed.     

Bioavailability of iron in cottonseed meal, ferric sulfate, and two ferrous sulfate by-products of the galvanizing industry

BACKGROUND: The aim of this study was to compare the outcome of severe blunt trauma in children receiving prehospital care from either physician-staffed advanced life support (ALS) units, or from basic life support (BLS) units staffed by emergency medical technicians. METHODS: The records of 288 children with severe blunt trauma who required intensive care in the regional level 1 trauma center or who died from their injuries were analyzed retrospectively. Patients were excluded if resuscitation at the scene was not attempted, if the level of prehospital care was unspecified, or if arrival at the level 1 trauma center was delayed beyond 150 minutes. Seventy-two patients met the inclusion criteria of BLS-, and 49 the criteria of ALS-prehospital care. RESULTS: A reduced mortality rate (22.4% v 31.9%) was seen in the ALS group, which was more apparent in a "salvageable but high-risk" subgroup, characterized by Glasgow Coma of Scale 4 through 8, Pediatric Trauma Score of 0 through 5, and Injury Severity Score (ISS) of 25 through 49. However, a statistically significant difference was only seen when trauma severity was evaluated by the ISS. CONCLUSION: An improved outcome in children with severe blunt trauma has been demonstrated when prehospital care is provided by physician-staffed ALS units compared with BLS units.     

Hepatotoxicity related to intracavernous pharmacotherapy with papaverine

OBJECTIVES: To determine the incidence of hepatotoxicity related to self-administration of intracavernous papaverine or papaverine/phentolamine (bimix). METHODS: From October 1994 through June 1996, we retrospectively reviewed the medical records of 71 consecutive patients diagnosed with organic erectile dysfunction (ED) and receiving intracavernous injection therapy. Inclusion criteria were documentation of normal baseline liver function tests (LFTs), a minimum of 6 months of follow-up that included LFTs, at least one self-injection every 2 weeks, and no other prior or concurrent treatment for ED. Thirty evaluable patients satisfied the inclusion criteria and formed group 1. Mean age was 63 years (range 40 to 77), mean follow-up was 18 months (range 6 to 32), and mean number of injections per month was 5.7 (range 3 to 12). An age-matched population of 20 patients (mean age 69 years, range 46 to 90) without ED but with similar comorbid risk factors formed the control group (group 2). All patients in group 2 had routine long-term follow-up of LFTs (mean 52 months, range 10 to 1 14). RESULTS: Two patients (6.67%) from group 1 had elevated LFTs during treatment: one experienced a mild elevation in alanine aminotransferase and the other developed transient elevations of total bilirubin and aspartate aminotransferase 6 months after beginning therapy. Both patients reported a history of alcohol abuse. Both patients remained asymptomatic. Neither patient required discontinuation of therapy. One patient (5%) from group 2 developed an elevation of total bilirubin at a follow-up of 12 months. CONCLUSIONS: Routine monitoring of LFTs is probably unnecessary during intracavernous pharmacotherapy. Patients with a history of alcohol abuse or liver disease, however, should be followed up more closely when papaverine is selected for intracavernous injection. In these patients, LFTs should be obtained before initiating treatment and at 6-month intervals.     

Biopharmaceutical studies on drug/conjugated-metabolite interactions. III. Effect of acetaminophen sulfate and its positional isomers on the pharmacokinetics of acetaminophen in rats

The effect of three positional isomers, o-, m- and p-acetylaminophenyl sulfate (AOAPS, AMAPS and APAPS (acetaminophen sulfate), respectively), on the pharmacokinetics of acetaminophen (APAP) was investigated in rats. All of the intravenously administered positional isomers were rapidly eliminated from plasma, and approximately 80% of the dose was excreted in an unchanged form in the urine within 4 h, while biliary excretions represented a small percent of the doses. Following the intravenous bolus injection of APAP, plasma elimination of APAP was accelerated and the distribution volume of APAP was increased under a steady state concentration (about 10 microg APAP eq/ml) of AOAPS or APAPS, but not AMAPS, as compared with saline infusion. Total body clearances of APAP were increased from 18.3 ml/min/kg for the control to 23.9 and 26.9 ml/min/kg for AOAPS and APAPS coadministration, respectively. AOAPS and APAPS competitively displaced the serum protein binding of APAP, while AMAPS had little effect. The distribution volume of unbound APAP was anomalously increased by APAPS, while it was not affected by AOAPS or AMAPS. Tissue-to-plasma concentration ratios of APAP were significantly increased by APAPS in the liver, kidney and brain, while they were only slightly increased by AOAPS. It was suggested that APAPS has not only the displacing activity of serum protein binding but also other specific effectiveness on the distribution of APAP.     

Dynamic exercise therapy in rheumatoid arthritis: a systematic review

The aim of this systematic review was to determine the effectiveness of dynamic exercise therapy in improving joint mobility, muscle strength, aerobic capacity and daily functioning in patients with rheumatoid arthritis (RA). In addition, possible unwanted effects such as an increase in pain, disease activity and radiological progression were studied. A computer-aided search of the MEDLINE, Embase and SCISEARCH databases was performed to identify controlled trials on the effect of exercise therapy. Randomized trials were selected on the effect of dynamic exercise therapy in RA patients with an exercise programme fulfilling the following criteria: (a) intensity level such that heart rates exceeded 60% of maximal heart rate during at least 20 min; (b) exercise frequency > or = 2 a week; and (c) duration of intervention > or = 6 weeks. Two blinded reviewers independently selected eligible studies, rated the methodological quality and extracted data. Six out of 30 identified controlled trials met the inclusion criteria. Four of the six included studies fulfilled > or = 7/10 methodological criteria. Because of heterogeneity in outcome measures, data could not be pooled. The results suggest that dynamic exercise therapy is effective in increasing aerobic capacity and muscle strength. No detrimental effects on disease activity and pain were observed. The effects of dynamic exercise therapy on functional ability and radiological progression are unclear. It is concluded that dynamic exercise therapy has a positive effect on physical capacity. Research on the long-term effect of dynamic exercise therapy on radiological progression and functional ability is needed.     

High-dose chemotherapy with autologous hematopoietic progenitor-cell support as part of combined modality therapy in patients with inflammatory breast cancer

PURPOSE: To evaluate the feasibility of high-dose chemotherapy (HDC) with autologous hematopoietic progenitor-cell support (AHPCS) as part of combined modality therapy (CMT) in patients with inflammatory breast cancer (IBC). PATIENTS AND METHODS: From April 1993 to March 1997, 30 patients with IBC were treated at our program. Twenty-three patients received neoadjuvant chemotherapy (NAC) before HDC; 18 patients also received adjuvant chemotherapy following surgery, but before HDC. All patients received HDC with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) with AHPCS. Every patient underwent surgery either before (27 patients) or after (three patients) HDC. Patients received radiotherapy after HDC in addition to tamoxifen if their tumors were estrogen receptor-positive. RESULTS: Thirteen patients experienced grade 3 or 4 nonhematologic noninfectious toxicities. In 12 patients (40%), this represented drug-induced lung injury, which in all cases responded to a 10-week course of corticosteroids. The only treatment-related death was secondary to hemolytic-uremic syndrome (HUS). Another patient suffered grade 4 CNS toxicity, which was completely reversible. All patients engrafted promptly. Eight patients relapsed, five of whom had a poor pathologic response to NAC. Relapses were local (five patients), local plus systemic (one), or systemic only (two). Median follow-up time from diagnosis and HDC is 23.5 (range, 7 to 49) and 19 (range, 4 to 44) months, respectively. Twenty-one patients (70%; 95% confidence interval [CI], 51% to 86%) remain alive and free of disease 4 to 44 months after HDC. Median disease-free survival (DFS) and overall survival have not yet been reached. CONCLUSION: HDC as part of CMT is feasible in patients with IBC. The toxicity of this treatment program is significant, but tolerable. Despite the short follow-up duration, the promising DFS observed in this group of patients warrants randomized studies that include a HDC-containing arm in patients with IBC.     

Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma

PURPOSE: The management of metastatic renal cell carcinoma remains challenging and controversial. There is some evidence of improved response to interleukin-2 (IL-2) based immunotherapy in patients who undergo nephrectomy before systemic treatment. However, recent reports have suggested that surgery prior to immunotherapy may not be an efficient strategy, since many patients will not be able to receive systemic treatment after nephrectomy. We describe our criteria for determining which patients are candidates for nephrectomy before immunotherapy and present our series of patients treated with this approach. MATERIALS AND METHODS: Based on our initial experience with IL-2 based immunotherapy we developed certain inclusion criteria for treatment with initial nephrectomy followed by systemic immunotherapy, including greater than 75% debulking of tumor burden possible, no central nervous system, bone or liver metastases, adequate pulmonary and cardiac function, and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients in whom biopsies show other than predominantly clear cell type histology are excluded. From 1991 through 1996, 28 patients met these criteria and were treated with this approach. Patients were followed to determine the number receiving immunotherapy as well as overall response and survival rates. RESULTS: Radical nephrectomy was performed in all patients. One patient died of respiratory failure from disease progression 1 month after nephrectomy. Another patient had poor pulmonary function and, therefore, was treated with an alternative cytokine therapy. The remaining 26 patients (93%) received at least 1 course of IL-2. Median interval between nephrectomy and initiation of immunotherapy was 1.5 months (range 1 to 3). Overall response rate was 39% with 5 complete (18%) and 6 partial (21%) responses. Actuarial median survival of the entire group was 20.5 months (range 1 to 66) from the initiation of treatment. Currently 13 patients are alive, including 8 who are disease and/or progression-free. CONCLUSIONS: Using these strict criteria nephrectomy can be effectively performed before immunotherapy without compromising the likelihood that patients will receive systemic treatment. The activity of IL-2 in patients treated with this approach is encouraging and justifies its consideration in properly selected patients.     

Penclomedine-induced DNA fragmentation and p53 accumulation correlate with reproductive cell death in colorectal carcinoma cells with altered p53 status

Acarbose reduces the absorption of monosaccharides derived from dietary carbohydrates, which play an important role in the metabolism and toxicity of some chemical compounds. We studied the effects of acarbose on the hepatotoxicity of carbon tetrachloride (CCl4) and acetaminophen (AP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 2E1 (CYP2E1). Male Sprague-Dawley rats were kept on a daily ration (20 g) of powdered chow diet containing 0, 20, 40, or 80 mg/100 g of acarbose, with drinking water containing 0% or 10% of ethanol (vol/vol). Three weeks later, the rats were either killed for an in vitro metabolism study or challenged with 0.50 g/kg CCl4 orally or 0. 75 g/kg AP intraperitoneally. The ethanol increased the hepatic microsomal CYP2E1 level and the rate of dimethylnitrosamine (DMN) demethylation. The 40- or 80-mg/100 g acarbose diet, which alone increased the CYP2E1 level and the rate of DMN demethylation, augmented the enzyme induction by ethanol. The 40- or 80-mg/100 g acarbose diet alone potentiated CCl4 and AP hepatotoxicity, as evidenced by significantly increased levels of both alanine transaminase (ALT) and aspartate transaminase (AST) in the plasma of rats pretreated with acarbose. Ethanol alone also potentiated the toxicity of both chemicals. When the 40- or 80-mg/100 g acarbose diet was combined with ethanol, the ethanol-induced potentiation of CCl4 and AP hepatotoxicity was augmented. Our study demonstrated that high doses of acarbose, alone or in combination with ethanol, can potentiate CCl4 and AP hepatotoxicity in rats by inducing hepatic CYP2E1.