Phase I study of orally administered UFT plus l-leucovorin

We describe the case of a 44-year-old woman with a delayed hemolytic transfusion reaction (DHTR). She had a history of two pregnancies and a blood transfusion, the details of which were unknown. At the time of her first vascular surgery on November 15, 1989, she received 1200 ml of crossmatch-compatible concentrated red blood cells (CRC). Before the first operation, screening for anti-RBC antibodies (Ab) was negative. At the time of the second admission on Feburary 15, 1996, anti-E Abs were detected by indirect antiglobulin test. She received 560 ml of E-antigen-negative, crossmatch-compatible, CRC for treatment of anemia on March 1 and 2, 1996. After this transfusion, total bilirubin (1.6 mg/dl) and lactate dehydrogenase (1355 IU/ml) were elevated on March 12, 1996. She had no evidence of clinical hemolysis. We suspected DHTR from these data, and therefore screened for anti-RBC Abs. Anti-E, Jka, Dia, Fyb, and S Abs were detected in blood samples obtained from the patient on March 12, 1996. Anti-E, Jka Dia, and S Abs were present more than 1 month and anti-Fyb Ab was disappeared at 18 days after transfusion.     

Bioavailability and phase II study of oral UFT plus leucovorin in patients with relapsed or refractory colorectal cancer

A summary of 733 reported cases of pancreatogastrostomy (PG) as a reconstructive procedure following pancreatoduodenectomy and the traumatically severed pancreas indicates an aggregate leakage rate of 4% over a 52-year period. Although mortality rates have declined over this period, the reported high correlation of leak with mortality seems to indicate the greater safety of PG over other methods for treating the residual pancreatic duct. The lower rate of complications related to pancreatocutaneous fistula from PG should correlate with shorter and less expensive hospital stays for patients treated with this technique. Several questions regarding technique must await further investigation.     

Phase II trial of Oral UFT and leucovorin in advanced gastric carcinoma

The action of some phosphonium betains on cholinesterases from different biological sources has been studied. It has been shown, that all studied betains are reversible inhibitors of cholinesterase hydrolysis of acetyltiocholine. Inhibiting action of these compounds on acetylcholinesterases is about ten times weaker that of the majority of known phosphonium salts, while their action on butyrylcholinesterases has no peculiarities. There were found certain differences for each betain compounds in their action on cholinesterases from different biological sources. These results may be used for detail classification of cholinesterases and allow to extend knowledge in comparative enzymology.     

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced pancreatic carcinoma: a University of Chicago phase II consortium study

BACKGROUND/OBJECTIVES: Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy. RESULTS: Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively. CONCLUSION: In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.     

Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study

PURPOSE: To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier. RESULTS: There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms. CONCLUSION: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.     

Schedule-selective biochemical modulation of 5-fluorouracil: a phase II study in advanced colorectal cancer

Based on experimental findings suggesting that 5-fluorouracil (FUra) may have different mechanisms of action depending on the schedule of administration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific. We thus tested the activity of a hybrid regimen consisting of two biweekly cycles of FUra bolus (600 mg/m2) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). Thirty-three consecutive patients with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study from February 1992 to August 1993. They were treated with two biweekly cycles of FUra bolus (600 mg/m2) preceded by (24-h interval) methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). The median Eastern Cooperative Oncology Group performance status was 1; the liver was the only metastatic site in 17 patients. Treatment outcome was evaluated by computed tomographic scan in all patients, except for two. Three complete and 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%). Performance status (Eastern Cooperative Oncology Group) influenced clinical response. The combined complete response and partial response rate was 69%, 33%, and 25% in patients with an Eastern Cooperative Oncology Group performance status of 0, 1, and 2, respectively (chi2, 4.6, P = 0.032, two-tailed Mantel test for trend). After a median follow-up time of 26 months, 10 patients are still alive. The median progression-free survival and overall survival were 9.5 and 20.2 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3%, and vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen.     

Biochemical modulation in the treatment of advanced cancer: a study of combined leucovorin, fluorouracil, and iododeoxyuridine

Multiple studies have shown that leucovorin-fluorouracil regimens are modestly superior to fluorouracil alone in the treatment of advanced colorectal cancer. Laboratory data suggest that iododeoxyuridine could further enhance the efficacy of leucovorin-fluorouracil regimens. This report describes the Phase I clinical evaluation of a leucovorin-fluorouracil-iododeoxyuridine chemotherapy regimen. Twenty-four patients received treatment with leucovorin (500 mg/m2), fluorouracil (500 mg/m2), and iododeoxyuridine (escalating doses) on days 1 and 8 of a 21-day cycle. The maximum tolerated dose of iododeoxyuridine was 1200 mg/m2, with a recommended Phase II dose of 1000 mg/m2. Myelosuppression (leukopenia) was dose limiting; other commonly observed treatment toxicities were nausea/vomiting, mucositis, and hyperlacrimation. Although the 1200 mg/m2 dose was tolerated during the initial few cycles of therapy, chronic administration could not be maintained secondary to dose-limiting neutropenia. Since neutropenia was dose limiting, in a follow-up study, 10 patients received a modified regimen (treatment on days 1 and 6 instead of days 1 and 8) with the addition of granulocyte colony-stimulating factor (days 8-19). The addition of granulocyte colony-stimulating factor, however, did not permit further escalation of the iododeoxyuridine dose. Three partial responses and six minor responses were observed. Phase II studies of this regimen are ongoing in advanced colorectal and advanced pancreatic cancer to determine response rates in these diseases.     

High-dose edatrexate with oral leucovorin rescue: a phase I and clinical pharmacological study in adults with advanced cancer

Our objective was to determine the maximum tolerated dose and toxicity of i.v. edatrexate with p.o. leucovorin. Thirty-one adults with advanced solid tumors received edatrexate as a 2-h infusion, once a week for 3 weeks, recycled every 28 days. p.o. leucovorin (10 mg/m2, every 6 h for 10 doses) began 24 h later. All had urinary alkalinization and p.o. hydration. Nine dosage levels ranging from 120 to 3750 mg/m2 were explored. Fatigue, epistaxis, nausea/emesis, mucositis, rash, myalgias, leukopenia, thrombocytopenia, and transient elevations of serum aspartate transferase were observed. Leukoencephalopathy with clinical manifestations occurred in two patients (one had prior cranial irradiation). Pharmacokinetic studies carried out at the 120- and 1080-mg/m2 dose levels revealed no significant difference in the elimination half-life at the two dose levels studied and no significant intrapatient variability between day 1 and day 8 edatrexate administration. Serum edatrexate levels measured using a dihydrofolate reductase inhibition assay correlated with those by high-performance liquid chromatography. Three major and two minor antitumor responses occurred. The maximum tolerated dose was 3750 mg/m2, with grade 3 or 4 leukopenia (one patient), stomatitis (one patient), and leukoencephalopathy (one patient). Because of the occurrence of leukoencephalopathy, further study of high-dose edatrexate with leucovorin rescue is not recommended.     

Paclitaxel plus ifosfamide in advanced ovarian cancer: a multicenter phase II study

The Canadian Cancer Society requested that the Centre for Behavioural Research and Program Evaluation of the National Cancer Institute of Canada evaluate Reach to Recovery and CanSurmount, 1-on-1 peer-support programs that provide information and support to individuals with cancer and their families. Key informant interviews (with program participants and volunteer visitors) were conducted to gather qualitative data and to help us develop a framework and tools to evaluate these programs. We found that 1) there are program objectives from the perspective of volunteers and participants in addition to those outlined in the program materials; 2) there are variations in how the programs are delivered and how patients or family members are recruited into the program; and 3) there is evidence that Reach to Recovery and CanSurmount volunteers are in a unique position to deliver the programs, either because they have personally experienced cancer or have family members who have had cancer. We describe the key informant exercise developed for this evaluation project and present the results of preliminary data-gathering activities.     

UFT and leucovorin: a review of its clinical development and therapeutic potential in the oral treatment of cancer

Different receptors mediating the release of endothelium-derived nitric oxide (EDNO) have been identified at endothelial level. In the present study we aimed to characterise, on rabbit aorta by means of pharmacological tools, the generation of EDNO by receptors located on endothelial cell membrane (M3, P2u, P2y) and by direct activation of Ca2+ entry into the endothelial cell. Four vasodilating drugs were tested (acetylcholine, UTP, A23187 and 2-methyl-thio-ATP); they were active only if the endothelial layer was intact, suggesting that they act through endothelial receptors. The effect of different nitric oxide synthase (NOS) inhibitors (0.1 mM: L- and D-NAME, L-NMMA, L-NIO and 7-NI) was investigated on NO-mediated relaxation induced by the relaxants in vessels with intact endothelium. NOS inhibitors differently affected relaxation mediated by the vasoactive drugs in isolated rabbit aorta. Reversibility of the inhibition by using a fixed concentration of L-arginine (0.1 mM) was different depending on the relaxing drug and NOS-inhibitor. The data obtained support the coexistence in aortic vessel of more than one endothelial cell NOS isoform, each provided with different receptor coupling.     

Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer

The authors report on a case of trisomy 9 mosaicism syndrome, a rare chromosome abnormality. The common features of this syndrome are growth and mental retardation, low-set malformed ears, wide sutures and fontanelles, bulbous nose, short palpebral fissures, micrognathia, microphthalmia and enophthalmos, abnormal hands and feet, hip dislocation, joint limitation, cardiovascular defects and urogenital abnormalities. Our patient presented some unusual characteristics, such as 13 pairs of ribs, a vertebral malformation, a hemivertebra and a Dandy-Walker syndrome. They compare their clinical findings with the few cases previously described and they try to contribute to the further clinical definition of the syndrome. It is possible that there is a correlation between the variability of the phenotype and the percentage of trisomic cells in the patient.     

Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group

PURPOSE: To compare raltitrexed (Tomudex; Zeneca Pharmaceuticals Ltd, Macclesfield, United Kingdom) a direct, specific thymidylate synthase (TS) inhibitor with fluorouracil (5-FU) plus high-dose leucovorin (LV) as first-line treatment for advanced colorectal cancer (ACC). PATIENTS AND METHODS: A total of 495 patients were randomized to raltitrexed (3 mg/m2) once every 3 weeks or 5-FU (400 mg/m2) plus LV (200 mg/m2) daily for 5 days every 4 weeks. RESULTS: The randomized groups were well balanced demographically. With a minimum 17-month follow-up, median survival was comparable between groups (10.9 months raltitrexed v 12.3 months 5-FU/LV; hazards ratio, 1.15; 95% confidence interval [CI], 0.93 to 1.42; P=.197), although time to progression was statistically significantly shorter in the raltitrexed group. Overall objective responses were comparable (19% raltitrexed v 18% 5-FU/LV), with more than 50% of patients in each group having stable disease. Significantly less World Health Organization (WHO) grade 3 and 4 stomatitis (2% v 16%, P < .001) and a reduced incidence of leukopenia (6% v 13%) and diarrhea (10% v 19%) occurred in the raltitrexed group (particularly at cycle 1 ). This resulted in fewer dose reductions at cycle 2 (4% raltitrexed v 28% 5-FU/LV) and early quality-of-life (QoL) benefits for raltitrexed patients. Reversible, clinically insignificant increases in transaminases were reported in 13% of raltitrexed patients. Palliative benefits of weight gain, improved performance status, and reduced disease-related symptoms were evident in both groups. CONCLUSION: Raltitrexed is confirmed as an effective option in the first-line palliative management of ACC, with comparable efficacy to and tolerability advantages (in terms of reduced incidence of stomatitis, diarrhea, and leukopenia) over 5-FU/LV. Raltitrexed has the added convenience of an every 3 weeks dosing schedule.     

Phase II study of CI-958 in colorectal cancer

We report the first cytogenetic investigation of a Dupuytren's subungual exostosis. The clonal abnormalities found suggest that at least some of these heterotopic ossifications could be neoplastic in nature, instead of being a purely reactive process or exuberant growth in response to trauma.     

Phase I and pharmacologic study of irinotecan in combination with cisplatin for advanced lung cancer

Macroscopic T-type Ca2+ currents, which are often observed in fetal and neonatal cardiac muscle cells, were not found in normal (0 of 17) adult feline ventricular myocytes. However, they were present in most (15 of 21) myocytes isolated from adult feline left ventricles with long-standing pressure-overload-induced hypertrophy. This is the first study to provide evidence in a large mammal, such as the cat, that T-type Ca2+ channels may be reexpressed in adults in association with hypertrophy resulting from slow progressive pressure overload. Importantly, this expression was stable for the duration of the hypertrophy process and was not associated with abrupt pressure overload. T-type Ca2+ currents were separated from L-type Ca2+ currents by exploiting the differences in their voltage dependence of steady-state inactivation. Depolarizations from -80 mV revealed a rapidly activating inward current that peaked in magnitude at -30 mV (-1.8 +/- 0.9 [mean +/- SD] pA/pF) and fully inactivated within 100 milliseconds in 15 of 21 hypertrophied myocytes studied. Further depolarizations activated progressively less T-type Ca2+ current, so that at +10 mV the L-type Ca2+ current predominated. In the hypertrophied myocytes that demonstrated both T-type and L-type Ca2+ currents, two distinct peaks occurred in their current-voltage relations. T-type Ca2+ currents were not evident in any of the 17 normal adult feline left ventricular myocytes studied. The purpose of T-type Ca2+ currents in hypertrophy is unclear. However, their presence may make hypertrophied myocardium more prone to spontaneous action potentials and increase the likelihood for arrhythmias in partially depolarized hypertrophied myocardium.     

Phase I and pharmacokinetic study of oral UFT, a combination of the 5-fluorouracil prodrug tegafur and uracil

UFT is an oral preparation combining the 5-fluorouracil (FU) prodrug tegafur (FT) and uracil (U) in a 1:4 ratio, which is commercially available in Japan for the treatment of breast and gastrointestinal cancers. We sought to determine the tolerance of daily oral UFT and to relate this tolerance to the pharmacokinetics of FT and/or the derived FU, while exploring the possibility of circadian FU kinetics contributing to the results. A 28-day schedule followed by 2 weeks rest was began at the initial level of 300 mg/m2/day administered either at 8 a.m. or at 6 p.m. At the following level, 400 mg/m2/day patients were randomly assigned to a split-dose administration or to the above single, timed dose administration. Intolerance to single dosing was clearly demonstrated, and only the split dosing was advanced to 500 mg/m2/day. When this level proved too toxic, 400 mg/m2 was studied further on a 7 a.m., 3 p.m., and 11 p.m. (every 8 h) schedule. Pharmacology was determined on selected patients. In the single dose administration, areas under the curves of FU were higher following p.m. dosing, although substantial interpatient variation was present. Toxicities (diarrhea and neutropenia) were more severe in patients receiving the drug in single daily doses. We conclude that the kinetics of FT are saturable, with disproportionate increases in area under the curve (and toxicities) as dose levels are increased. With divided dosing, tolerance improves. UFT at a dose of 400 mg/m2/day administered as three divided doses (every 8 h) is suitable for Phase II studies, although toxicity requiring cessation of drug administration prior to completion of 28-day cycles will occur in some patients.     

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.     

Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver

PURPOSE: Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS: Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS: Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION: Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.     

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively. We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

Phase II and pharmacokinetic study of fotemustine in inoperable colorectal cancer

An unusual case of menstrual toxic shock syndrome (TSS) is described in which the patient had persistent Staphylococcus aureus bacteremia despite therapy with iv cloxacillin. There was no demonstrable evidence of endocarditis or an abscess as a focus for persisting bacteremia. The strain of S. aureus isolated from the blood and vagina produced toxic shock syndrome toxin 1 (TSST-1) and enterotoxin A. Bacteremia occurs uncommonly in association with TSS; however, aggressive high-dose antistaphylococcal therapy should be instituted for treating this possible complication.