Biomedical subjects

H R Alexander

Publications and source records attributed to H R Alexander.

At least 127 records · Page 7Linked to original sources

PubMed1992

Interleukin-1 alpha prevention of the lethality of Escherichia coli peritonitis.

Interleukin-1 (IL-1) is an inflammatory mediator with a variety of described physiologic functions. IL-1 alpha has been shown to confer a survival advantage to experimental animals when administered before a lethal bacterial challenge. The experiments reported here were performed to define the effective pretreatment interval of a single intravenous dose of IL-1 alpha in a murine model of bacterial peritonitis, to examine the differential induction of cytokines in animals with and without IL-1 alpha pretreatment, and to assess differences in histologic evidence of end organ damage. IL-1 alpha (27 micrograms/kg iv) conferred a survival advantage to mice given a lethal challenge of live Escherichia coli (2 x 10(8) CFU/mouse ip) when the pretreatment was given 2 to 24 hr before the bacterial inoculum. Longer pretreatment intervals were not significantly protective. Treatment with IL-1 alpha at 1 hr after bacterial inoculum also did not improve survival. Mice pretreated with IL-1 alpha developed significantly lower peak serum levels of TNF-alpha after E. coli injection than did control mice. Pretreated and control mice had similar peak serum levels of IL-6 after bacterial challenge; however, IL-1 alpha-pretreated mice had a less prolonged elevation of serum levels of IL-6. IL-1 alpha-pretreated animals were protected from the histologic evidence of end organ damage seen in control animals. Thus, in this model of E. coli peritonitis pretreatment with a single intravenous dose of IL-1 alpha confers a significant protective effect when given within a limited time range. Treatment outside this interval has no apparent beneficial effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Recombinant interleukin-1 receptor antagonist (IL-1ra): effective therapy against gram-negative sepsis in rats.

BACKGROUND: Morbidity and mortality from bacterial sepsis remain high despite aggressive diagnostic and therapeutic intervention. Interleukin-1 has been implicated as mediator of the lethal effects of endotoxemia or bacterial sepsis. The current experiments were designed to evaluate the therapeutic efficacy of a human recombinant interleukin-1 receptor antagonist (IL-1ra) against polymicrobial gram-negative septicemia in rats. METHODS: Male rats underwent placement of indwelling carotid arterial and superior vena caval catheters followed by cecal ligation and puncture (CLP). After 3 hours rats received either IL-1ra (10 mg/kg intravenous bolus followed by 5 mg/kg/hr) or an equal volume of vehicle intravenously for 24 hours. Heart rate, respirations, mean arterial blood pressure, and temperature were recorded at frequent intervals, and survival was assessed for 30 hours after CLP. RESULTS: There were no differences in vital signs between groups at baseline or before treatment, and all animals appeared ill with huddled posture, piloerection, and hyperventilation. Twenty-four hours after CLP, IL-1ra significantly ameliorated bradycardia (p = 0.01), hypothermia (p = 0.001), and hypotension (p = 0.05), and 30-hour survival was significantly improved (71% vs 20%, p less than 0.05). CONCLUSIONS: IL-1ra lessens the acute hemodynamic, hypothermic, and mortal effects of gram-negative sepsis induced by CLP in rats. These data suggest that IL-1 receptor blockade may be an important new treatment strategy against overwhelming bacterial sepsis.

Animals↗

PubMed1991

Thyroid cancer: a lethal endocrine neoplasm.

This conference focuses on the controversies about managing thyroid cancer, emphasizing the possibility that the treatment of patients with potentially fatal thyroid cancer may be improved. Although the mortality rate from thyroid cancer is low, it is the highest among cancers affecting the endocrine glands (excluding the ovary). Exposure to radiation during childhood in the 1930s and 1940s increased the incidence of but not the mortality from thyroid cancer, because these tumors are mainly papillary cancers developing in young adults. These rates may change as the exposed cohort ages. Risk factors that increase mortality include older patient age and the growth characteristics of the tumor at diagnosis, the presence of distant metastases, and cell type (for example, the tall-cell variants of papillary cancer, follicular cancer [to be distinguished from the more benign follicular variant of papillary cancer], medullary cancer, and anaplastic cancer). Local metastases in lymph nodes do not seem to increase the risk for death from papillary cancer, but they do increase the risk for death from follicular and medullary cancer. In the latter, mortality is decreased by the early detection and treatment of patients with the familial multiple endocrine neoplasia syndrome 2a. There are excellent tumor markers for differentiated cancer of the parafollicular and of the follicular cells (serum calcitonin and serum thyroglobulin levels, respectively). Measuring the calcitonin level allows early diagnosis of familial medullary cancer, whereas measuring the thyroglobulin level, although useful only after total thyroidectomy, allows early recognition of recurrence or metastases of papillary or follicular cancer. Initial surgery, protocols for follow-up, and the use of radioiodine for the ablation of any residual thyroid and the treatment of metastatic cancer are discussed. Because these tumors resist currently available chemotherapy regimens, possible ways to increase the effectiveness of radioiodine therapy are considered as are new approaches to treatment.

Carcinoma↗

PubMed1991

A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.

Interleukin 1 (IL-1) is an endogenously produced cytokine that mediates a variety of physiological effects that may be beneficial or deleterious to the host. C57Bl/6 mice treated intravenously with a recently characterized human recombinant receptor antagonist protein to IL-1 (IL-1ra) had improved survival when treated after a lethal Escherichia coli endotoxin (lipopolysaccharide [LPS]) challenge. IL-1ra was effective when treatment was initiated after LPS, and intravenous administration every 4 h for 24 h was required. Serum levels of tumor necrosis factor (TNF) activity after LPS and in vitro TNF cytotoxicity were not altered by treatment with IL-1ra. These experiments provide direct evidence that the lethal effects of LPS may be mediated through the action of IL-1 and that the IL-1ra can provide a new treatment strategy for disease processes mediated via this cytokine.

Animals↗

PubMed1991

Upper abdominal cancer surgery in the very elderly.

From January 1981 to December 1987, 59 major upper abdominal operations were performed on 57 patients aged 80 to 90 years at Memorial Sloan-Kettering Cancer Center. Procedures for primary adenocarcinoma of the stomach, distal esophagus, pancreas, or hepatobiliary system were performed with curative intent or for palliation in 34 of 59 patients (58%) and bypass with limited or no resection in 13 of 59 patients (22%) patients. Emergency operations were performed in six (10%) patients for gastric bleeding, perforation, or outlet obstruction. Six (10%) patients underwent laparotomy for benign biliary obstruction (1), splenectomy for secondary thrombocytopenia (2), or gastrectomy for sarcoma (2) or lymphoma (1). Hospital mortality was 15% overall and 9% for major resections, 15% for bypass, and 67% for emergency procedures. Major complications occurred in 10 (20%) elective procedures. Mortality was associated with respiratory or cardiac failure while complications most commonly included arrhythmias and wound infection. Mean postoperative hospitalization was 18 days overall and 45 patients (76%) were discharged home. Median survival following major resection was 17.5 months but less than 2 months after bypass procedures. A protocol of pre-operative evaluation, intra-operative hemodynamic monitoring and postoperative intensive care has been formalized for use in elderly or poor-risk patients.

Adenocarcinoma↗

PubMed1991

Human recombinant interleukin-1 alpha protection against the lethality of endotoxin and experimental sepsis in mice.

Human recombinant interleukin-1 alpha (IL-1) has a diverse range of physiological activities which may be beneficial or deleterious to the host. Pretreatment with doses of IL-1 has been shown to protect mice against a subsequent lethal bacterial injection; however, the protective effects of a single intravenous (iv) dose of IL-1 have not been well characterized. The current experiments were performed to determine the best dose, timing, and duration of action of a single iv dose of IL-1 against a subsequent lethal challenge with intraperitoneal endotoxin (LPS) or experimental sepsis induced by cecal ligation and puncture (CLP). Female C57B1/6 mice treated with iv IL-1 24 hr prior to 30 mg/kg LPS ip had improved survival compared to saline-treated controls (P less than 0.01). IL-1 was also protective when given 6 to 72 hr, but not 2 or 96 hr, prior to LPS. IL-1 protection against LPS lethality was similar to protection seen with an iv dose of tumor necrosis factor (TNF). After CLP, survival was improved with IL-1 versus saline pretreatment (P = 0.02). Unlike previous work with TNF, no toxicity or lethality was observed at any dose of IL-1 administered. A single iv dose of IL-1 protects against the lethality of LPS and CLP in mice. IL-1 may be a useful treatment strategy in patients at risk for the development of life-threatening sepsis.

Animals↗

PubMed1991

Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats.

Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.

Animals↗

PubMed1991

Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis.

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

Animals↗

PubMed1991

Pentoxifylline suppression of tumor necrosis factor gene transcription.

Pentoxifylline decreases lung injury after intravenous endotoxin; the mechanism is unknown. Tumor necrosis factor-alpha (TNF) is secreted by macrophages in response to endotoxin and mediates some of the toxicity of endotoxin. This study investigates the effects of pentoxifylline on endotoxin-stimulated TNF production in vitro and in vivo. Pentoxifylline concentrations of 100 and 1000 micrograms/ml inhibited TNF production by murine adherent peritoneal exudate cells incubated with endotoxin 1 microgram/ml. Similarly, pentoxifylline at 100 and 1000 micrograms/ml decreased the number of available TNF messenger RNA transcripts in peritoneal exudate cells assessed by Northern blot. Pentoxifylline had no effect on TNF mRNA stability, but appeared to act by inhibiting the rate of TNF mRNA production (transcription). In murine in vivo experiments at each dose of endotoxin administered from 0.01 to 30 mg/kg, pentoxifylline treatment significantly reduced serum TNF levels, suggesting a favorable shift of the endotoxin dose-response curve. Expression of murine TNF gene in the livers of these animals showed fewer TNF transcripts in the pentoxifylline-treated animals compared to controls. Pentoxifylline inhibited endotoxin-induced TNF production both in vivo and in vitro and exerted this control by inhibiting endotoxin-induced transcription of the TNF gene. This study suggests that pentoxifylline may ameliorate endotoxic shock by decreasing macrophage TNF production.

Animals↗

PubMed1990

Needle-localized mammographic lesions. Results and evolving treatment strategy.

From January 1981 to December 1987, 932 needle-localization breast biopsies were performed at our institution for mammographically detected abnormalities. We reviewed 531 needle-localization breast biopsy procedures performed during two periods (January 1981 to June 1984, n = 311; and January to August 1987, n = 220) to compare results and treatment patterns, and to determine the prevalence of the missed lesions. Mammographic abnormalities detected on routine screening accounted for a larger proportion of needle-localization breast biopsies in the later series (94 [30%] of 311 vs 94 [43%] of 220). However, the rate at which carcinoma was identified remained constant at 29% as did the percentage of cancers that were invasive (46% vs 51%). Overall, the rate of malignant diagnoses after needle-localization breast biopsy was lowest in asymptomatic women undergoing routine screening mammography (44 [24%] of 188) and significantly higher in women undergoing mammographic follow-up of the contralateral breast after treatment for breast cancer (28 [43%] of 65). There were seven missed lesions in 531 needle-localization breast biopsies, necessitating a second procedure in six and interval mammograms in one.

Biopsy, Needle↗

PubMed1990

Substrate alterations in a sarcoma-bearing rat model: effect of tumor growth and resection.

The time course of plasma substrate level alterations in the tumor-bearing (TB) host and their relationship to tumor burden or weight loss has not been well defined. Plasma glucose, lactate, pyruvate, cholesterol, triglycerides, acetoacetate, beta-hydroxy butyrate, and glycerol levels were measured in postabsorptive TB and nontumor-bearing (NTB) male Fisher 344 rats at weekly intervals for 5 weeks. Chronically starved rts (CS) had plasma substrates measured at Week 3 and compared with TB and NTB levels. Tumor burden was 0.5% of body weight at Week 1, 3.5% at Week 2, 12% at Week 3, and 20% at Week 5. Glucose levels were significantly lower in TB versus NTB (P = 0.01) at Week 1 and progressively declined in TB versus NTB through Week 5 (P less than 0.001). At Week 2, plasma triglycerides, cholesterol, acetoacetate, and beta-hydroxy butyrate were significantly elevated in TB versus NTB (P less than 0.001) and increased further to Week 5. The profile of substrate changes in TB and CS, when compared to NTB rats at Week 3, were different, suggesting that the plasma substrate alterations seen in the TB state were not secondary to starvation. In addition, when tumors were excised from TB animals at Week 3 and plasma substrates were determined 1 week later, all substrates that were different between TB and NTB animals, except cholesterol, returned to NTB levels when compared to sham-operated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

PubMed1989

Isolated breast metastases from gastrointestinal carcinomas: report of two cases.

Two patients with metastatic gastrointestinal adenocarcinoma in the breast are reported. Metastases in the breast are usually painless upper outer quadrant masses. On mammography they are typically well-circumscribed lesions without microcalcifications. A breast mass in a patient with a history of cancer, even if clinically or mammographically benign, should raise suspicion of a metastasis. Pathological features include a histologic pattern similar to the primary neoplasm and an absence of in situ carcinoma which characterizes primary breast cancer. Surgical excision for local control and systematic therapy is the most appropriate treatment.

Adenocarcinoma, Mucinous↗

PubMed1987

Hormonal responses to graded surgical stress.

We tested the hypothesis that selected hormonal responses to surgery reflect the degree of surgical stress. Plasma norepinephrine, epinephrine, thromboxane B2, cortisol, serum angiotensin converting enzyme, thyroxine, triiodothyronine, free thyroxine, and free triiodothyronine levels were measured preoperatively, and then one hour, 24 hours, and five days postoperatively in three groups of patients. The groups were as follows: group 1, "minimal" stress, eg, inguinal hernia repair (n = 10); group 2, "moderate" stress, eg, cholecystectomy (n = 12); and group 3, "severe" stress, eg, subtotal colectomy (n = 9). Patients in group 1 showed no significant surgery-induced changes in hormonal values. The stress-induced changes in patients in groups 2 and 3 were seen at one and occasionally 24 hours; however, by five days postoperatively, circulating hormone values had returned to preoperative levels. Increases in plasma cortisol, norepinephrine, and epinephrine, and decreases in serum angiotensin converting enzyme levels characterized the surgery-induced hormonal changes. Conclusions are as follows: hormonal responses do reflect the degree of surgical stress; the hormonal changes are transient, lasting no longer than 24 hours in patients after uncomplicated surgery; hormonal responses to minimal surgical stress are negligible.

Adult↗

PubMed1985

Percutaneous subclavian catheterization for prolonged systemic chemotherapy.

Recent experience with 108 Broviac catheters was reviewed. Sixty-eight were percutaneously placed in the subclavian veins of adults receiving systemic chemotherapy. For subclavian catheters perioperative and late complications were unusual. There was no pneumothorax or serious bleeding associated with insertion, even in severely thrombocytopenic patients. Mean catheter life was 93 days. Infection occurred in only five cases (7%). We conclude that percutaneous placement of right atrial catheters is a safe procedure which provides reliable access for prolonged chemotherapy in cancer patients.

Adolescent↗

PubMedDate not supplied

Isolated limb perfusion for malignant melanoma.

The technique of isolated limb perfusion for treatment of extremity melanoma has been used in the United States for almost 40 years. The treatment is based upon the ability to isolate the circulation of the afflicted extremity from the systemic circulation, thereby allowing dose-intensive delivery of anti-cancer agents to the limb while eliminating systemic exposure and toxicity. A number of agents have been used in ILP, however, the bulk of clinical experience has been with the alkylating agent melphalan, typically used under conditions of mild hyperthermia. Despite considerable clinical experience, there has been a lack of agreement about the role of ILP in the prophylaxis against or the treatment of recurrent extremity melanoma. Recently there has been renewed interest in the use of ILP based upon the very promising results using a combination of tumor necrosis factor, melphalan, and interferon-gamma which have produced complete response (CR) rates of almost 90%. The utility of this regimen in extremity melanoma is actively being evaluated by clinical trials in the United States and Europe.

Antineoplastic Agents, Alkylating↗

PubMedDate not supplied

Thrombocytopenia after isolated limb or hepatic perfusions with melphalan: the risk of heparin-induced thrombocytopenia.

BACKGROUND: Three cases of heparin-induced thrombocytopenia (HIT) were observed in patients undergoing isolated limb perfusion (ILP) with melphalan. This occurrence prompted the discontinuation of prophylactic postoperative heparin in ILP patients and its avoidance in patients undergoing isolated hepatic perfusion (IHP). The need to reassess these decisions led to a review of thrombocytopenia in both patient populations. METHODS: Records of all patients treated with ILP or IHP at our institution from July 1992 through November 1996, were reviewed. Nine IHP patients were tested prospectively for heparin-related antibodies using serum samples obtained perioperatively and during the second postoperative week. RESULTS: Thrombocytopenia (< 100,000 platelets/microL) developed postoperatively in 30% of 131 ILP patients and in 77% of 56 IHP patients. No cases of HIT were identified other than the three who had been previously diagnosed. The prevalence of HIT in heparinized ILP patients was 2.8% (3/108). All nine IHP patients developed heparin-related antibodies postoperatively. CONCLUSIONS: Because the prevalence of HIT following ILP is in the range observed in other clinical settings, postoperative heparin prophylaxis is an option. However, it probably should be limited to the first week, and daily platelet counts should be reviewed for a pattern of thrombocytopenia consistent with HIT. The prevalence of heparin-related antibodies after IHP is so high that prophylactic heparin should be avoided in this setting.

Adult↗

PubMedDate not supplied

Isolated organ perfusion does not result in systemic microembolization of tumor cells.

BACKGROUND: Isolated organ perfusion with hyperthermia and melphalan with or without tumor necrosis factor-alpha has been effectively used to treat regionally confined, unresectable malignancies of both the limb and liver. Many patients, however, will eventually relapse at distant sites. We used reverse transcription-polymerase chain reaction (RT-PCR) to determine whether significant tumor microembolization occurs in patients undergoing isolated limb perfusion (ILP), isolated hepatic perfusion (IHP), or hepatic resection. METHODS: Primers specific for the human tyrosinase gene or carcinoembryonic antigen gene were designed for RT-PCR to screen melanoma or colon adenocarcinoma, respectively. RNA from human melanoma lines (Pmel and 1286) and human colon adenocarcinoma lines (H508 and HT29) were used to generate positive control cDNA. Normal human blood was inoculated with tumor cells at concentrations that ranged from 10(-2) to 10(5) tumor cells/ml of blood to define the sensitivity. Systemic and perfusate blood samples were drawn from 15 patients (8 patients underwent IHP, 5 patients underwent ILP, and 2 patients underwent resection) before the start of the operation, immediately before and during the perfusion, and postoperatively. Mononuclear cell fractions were separated from the blood samples and RNA was extracted for the RT-PCR assay. Standard primers for human beta-actin were used to confirm that cDNA was generated after the RT reaction. RESULTS: RT-PCR assay sensitivity was determined to be 10 tumor cells/ml of whole blood. Of the 8 IHP patients, 6 had colon metastases and 2 had ocular melanoma metastases to the liver. All 5 ILP patients had in transit melanoma of the extremity. Two patients with colon metastases to the liver were found to have resectable disease. There were no detectable circulating tumor cells in the systemic circulation either preoperatively or postoperatively in all 15 patients that were screened. CONCLUSIONS: RT-PCR is a highly sensitive method of detecting tumor cells in perfusate or blood. Manipulation of the limb or liver followed by resection or isolated hyperthermic perfusion does not cause detectable release of circulating tumor cells. The late development of distant metastases observed in many of these patients does not correlate with the ability to measure circulating tumor cells during regional therapy.

Adenocarcinoma↗

PubMedDate not supplied

The role of interferon-alpha as a modulator of fluorouracil and leucovorin.

Several preclinical studies have demonstrated that interferon-alpha (IFN-alpha) may enhance the cytotoxicity of fluoropyrimidines in a greater-than-additive manner in a variety of human cancer cell lines. The underlying mechanism(s) have varied in different cancer cell lines, and include increased fluorouracil anabolism to fluorodeoxyuridine monophosphate, further inhibition of thymidylate synthase, stimulation of thymidine and uridine phosphorylase activities, greater DNA damage, and enhanced natural killer cell-mediated lysis of tumour targets. These preclinical studies stimulated clinical evaluation of IFN-alpha in combination with 5-fluorouracil (5-FU) with and without leucovorin (LV), and the initial clinical results appeared promising. We summarise preclinical research concerning the interaction of 5-FU and IFN-alpha. The rationale for combining 5-FU with IFN-alpha and LV is discussed, and we describe our clinical experience with the combination of 5-FU, LV and IFN-alpha-2a. The insights and unresolved questions concerning the clinical application of this combination are also discussed.

Antidotes↗