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Biomedical subjects

N Z Mikhael

Publications and source records attributed to N Z Mikhael.

At least 19 recordsLinked to original sources
PubMed1997

Comparison of Fourier-transform infrared spectroscopic screening of exfoliated cervical cells with standard Papanicolaou screening.

To compare Fourier-transform infrared (FTIR) spectroscopy in screening cervical cytology and standard Papanicolaou (Pap) screening with colposcopic directed biopsy as a "gold standard," we prospectively gathered FTIR samples and Pap smears of all patients attending our program's colposcopy clinics, from February to October 1995. We recorded demographic data for each patient including colposcopy, cytology, treatment follow-up, and histology. Using the colposcopically directed biopsy as the gold standard, exfoliated cervical cells from 301 patients were collected to compare cytology and FTIR spectroscopy. Based on previously established criteria, we provided distinctive definitions of both negative/positive FTIR, cytology, and histology. Results of 301 cases showed 196 positive and 105 negative cytologies. The sensitivity, specificity, false-negative rate, and false-positive rate for the Pap test were 86.6, 90.5, 13.4, and 9.5%, respectively. However, FTIR results versus histology showed 215 positive and 86 negative with a sensitivity of 98.6% and specificity of 98.8%. False-negative and false-positive rates were 1.4 and 1.2%, respectively. In the 12 cervical cancers there were no false-negative FTIR results but 3 false-negative Pap smears. The positive and negative predictive values for FTIR were 99.5 and 96.5% while the Pap values were 95.9 and 72.3%. Compared to standard Pap smears, FTIR has a better false-negative rate and negative predictive value in this preliminary study. Further work, to establish the range of each of the spectral criteria for different grades of dysplasia and that among various infectious effects, needs to be conducted before applying this research tool to a population-based study.

Biopsy↗
PubMed1997

Association of cisplatin nephrotoxicity with patient characteristics and cisplatin administration methods.

OBJECTIVE: To assess factors that affect cisplatin nephrotoxicity. METHODS: In 425 patients treated with cisplatin, we assessed the effect of pretreatment factors and treatment conditions on the rise in serum creatinine with the first course of cisplatin, on the maximum rise in serum creatinine over the entire course of the cisplatin therapy, and on residual nephrotoxicity after the last cisplatin treatment ended. (Because of the nature of the relationship between serum creatinine and creatinine clearance, rise in serum creatinine was divided by pretreatment creatinine squared.) Patients were dichotomized into the upper quartile versus the lower three quartiles of degree of nephrotoxicity. Multivariate analyses were based on logistic regression, controlling for cisplatin dose per course. RESULTS: Controlling for cisplatin dose per course, factors most closely associated with nephrotoxicity during the first course of cisplatin were: serum albumin and potassium, body surface area, and administration of cisplatin over 2-5 days per course vs 1 day (negative associations). Controlling for cisplatin dose per course, the single factor most closely associated with maximum life-time cisplatin nephrotoxicity was concurrent use of a vinca alkaloid (negative association). Controlling for cisplatin dose per course, factors most closely associated with residual nephrotoxicity after the end of cisplatin therapy were cumulative dose of cisplatin, concurrent use of metoclopramide (positive associations), uric acid and concurrent use of phenytoin and a vinca alkaloid (negative associations). The association of nephrotoxicity with uric acid and with body surface area was felt to be an artifact resulting from its positive association with pretreatment serum creatinine. Nephrotoxicity during the first course of cisplatin also correlated significantly with autopsy kidney cortex platinum concentrations in 77 evaluable patients. CONCLUSIONS: (1) While several factors correlated with cisplatin nephrotoxicity, most of the observed nephrotoxicity was not explained by the variables identified. (2) While most patients received intravenous hydration, patients receiving high hydration volumes did not have significantly less nephrotoxicity than patients receiving lower hydration volumes: (3) Of the variables identified, serum albumin, metoclopramide and phenytoin may have affected nephrotoxicity by altering cisplatin uptake into or distribution within the kidney.

Antineoplastic Agents↗
PubMed1995

Factors affecting platinum concentrations in human surgical tumour specimens after cisplatin.

We assessed factors which affect cisplatin concentrations in human surgical tumour specimens. Cisplatin 10 mg m-2 was given i.v. to 45 consenting patients undergoing surgical resection of neoplasms, and platinum was assayed in resected tumour and in deproteinated plasma by flameless atomic absorption spectrophotometry. By multiple stepwise regression analysis of normalised data, patient characteristics that emerged as being most closely associated (P < 0.05) with tumour platinum concentrations (after correcting for associations with other variables) were tumour 'source' [primary brain lymphomas, medulloblastomas and meningiomas ('type LMM') > 'others' > lung cancer > head/neck cancer > gliomas) or tumour 'type' (LMM > brain metastases > extracerebral tumours > gliomas), serum calcium and chloride (positive correlations) and bilirubin (negative). Tumour location (intracranial vs extracranial) did not correlate with platinum concentrations. If values for a single outlier were omitted, high-grade gliomas had significantly higher platinum concentrations (P < 0.003) than low-grade gliomas. For intracranial tumours, the computerised tomographic scan feature that correlated most closely with platinum concentrations in multivariate analysis was the darkness of peritumoral oedema. Tumour source or type is a much more important correlate of human tumour cisplatin concentrations than is intracranial vs extracranial location. Serum calcium, chloride and bilirubin levels may affect tumour cisplatin uptake or retention. CT scan characteristics may help predict cisplatin concentrations in intracranial tumours.

Blood-Brain Barrier↗
PubMed1994

Factors affecting human autopsy kidney-cortex and kidney-medulla platinum concentrations after cisplatin administration.

The objective of this study was to determine factors that affect cisplatin concentrations in human kidney cortex. We used flameless atomic absorption spectrophotometry to assay platinum in autopsy specimens of kidney cortex obtained from 83 cisplatin-treated patients. Concentrations were correlated with pretreatment factors and treatment conditions using univariate nonparametric statistics. Hierarchical stepwise multiple regression analyses of transformed (to normalize) data were then used to assess which factors were most important, controlling for other factors. Kidney-cortex platinum concentrations varied from 0 to 14.8 micrograms/g (median, 2.04 micrograms/g). The cumulative lifetime dose of cisplatin ranged from 10 to 1120 mg/m2 (median, 112 mg/m2). The time from the last cisplatin dose to death was < 1-609 days (median, 38 days). According to univariate statistics, factors that correlated (P < 0.05) with kidney-cortex platinum concentrations were the cisplatin dose per course, the pretreatment serum urea level, metoclopramide use (positive correlations), the time from the last cisplatin treatment to death, and the pretreatment serum albumin value (negative correlations). Factors that approached significance (0.05 < or = P < or = 0.10) were a history of hypertension, hyperbilirubinemia (positive), the serum calcium level, and phenytoin use (negative). In the multiple regression analysis, after controlling for the cisplatin dose per course and the time from the last treatment to death, only concurrent metoclopramide and phenytoin use entered the model. The hydration volume did not affect corrected kidney-cortex or kidney-medulla platinum concentrations. The following conclusions were reached: (1) it may be feasible to use lower hydration volumes than those used routinely, (2) any effect of hydration volume on cisplatin nephrotoxicity may not be mediated via a reduction in kidney-cortex platinum concentrations, (3) higher cisplatin doses might be tolerated with new 5-hydroxytryptamine-3 (5HT-3) antiemetics than were tolerated with metoclopramide, and (4) phenytoin should be tested for its ability to reduce cisplatin nephrotoxicity.

Autopsy↗
PubMed1993

Human autopsy tissue distribution of the epipodophyllotoxins etoposide and teniposide.

Autopsy tissues were collected from ten patients who had received etoposide, 150-3480 mg, from 1 to 412 days antemortem and from five patients who had received teniposide, 234-1577 mg, from 3 to 52 days antemortem. Tissues were assayed for etoposide and teniposide using high-pressure liquid chromatography with electrochemical detection. Etoposide was detectable in tissues of three of four patients dying < 5 days after their last etoposide treatments to cumulative doses of 150-432 (median, 280) mg but was detectable in tissues of only one of six patients dying 7-412 (median, 37) days after their last etoposide treatment to a cumulative dose of 607-3600 (median, 1553) mg. The highest tissue concentrations were in the small bowel, prostate, thyroid, bladder, spleen, and testicle. Intermediate concentrations were found in the lymph node, skeletal muscle, adrenal gland, stomach, tumor, liver, lung, pancreas, and kidney, and the lowest concentrations were found in the heart, brain, diaphragm, vagina, and esophagus. Teniposide was detectable in one patient dying 3 days after a cumulative teniposide dose of 576 mg (spleen, prostate, heart > large bowel, liver, pancreas > thyroid, adrenal, stomach, small bowel, bladder, testicle, and skeletal muscle) but was not detectable in any tissue from four patients dying 5-52 (median, 8) days after their last treatment to a cumulative teniposide dose of 234-1577 (median, 520) mg. The very short tissue half-life contrasts with our previous observations for human autopsy tissue concentrations of mitoxantrone, doxorubicin, menogaril metabolites, diaziquone, and amsacrine. The short tissue half-life may help explain the schedule dependency of epipodophyllotoxin efficacy and may also help explain the lack of visceral toxicity of these compounds.

Chromatography, High Pressure Liquid↗
PubMed1991

Evaluation of a simple line width test involving magnetic resonance spectroscopy of plasma in carcinoma of the ovary.

Magnetic resonance spectroscopic (MRS) measurement of human plasma has been reported as a generally applicable marker for malignancy: patients with malignancy had a MRS line width significantly different from patients with benign diseases or healthy controls. The authors investigated the value of this test in 213 women with ovarian carcinoma, benign pelvic masses, benign nongynecologic diseases, and healthy controls. The MRS measurements were performed on plasma samples at 21 degrees C or 27 degrees C. The line width parameters were obtained by averaging the width at half the height of the methyl and methylene peaks on the resonance spectra. At 27 degrees C using 33 Hz as the threshold for an abnormal result, there was a significant correlation between the result of the test and the presence or absence of malignancy. However, the study demonstrates that the specificity (0.44) and positive predictive value (0.42) are too low for the test to be useful in the management of patients with carcinoma of the ovary. At 21 degrees C no correlation between the results of the test and the clinical status of women with carcinoma of the ovary were observed. In 47 patients the test did not predict preoperatively the benign or malignant nature of a pelvic mass.

Carcinoma↗
PubMed1991

The clinicopathological significance of cytomegalovirus inclusions demonstrated by endocervical biopsy.

A healthy 20 yr old woman presented for evaluation following a cervical smear which showed viral effects typical of human papilloma virus. Colposcopy showed changes of cervicitis with the main finding on histologic examination of biopsy material being an acute and chronic cervicitis associated with typical features of cytomegalovirus (CMV) infection. Viral identification was confirmed by immunoperoxidase staining, in situ hybridization and electron microscopy. The patient was lost to follow up for 18 mths. Following this, a repeat colposcopy again showed inflammation, with cervicitis, mild dysplasia and CMV inclusions on biopsy. Full immunological work-up, including human immunodeficiency virus (HIV) study, was performed and was normal. Only 11 other cases of endocervical biopsies with histological evidence of CMV inclusions were found in the literature, although the reported rate of detection of genital CMV in women on culture is 4-12%. In the 9 cases where information was available, endocervical inflammation was present. One patient was on immunosuppressive medication for systemic lupus erythematosus and another was found to have Acquired Immune Deficiency Syndrome (17% of total). These cases demonstrate that although histologic examination is an insensitive marker for CMV within the cervix, its presence may signify immunodeficiency and so immunological assessment of a patient with this finding is advisable.

Adolescent↗
PubMed1988

Relationship between urine beta-2-microglobulin and platinum levels during cisplatin treatment.

We evaluated whether urine beta 2-microglobulin (beta 2M) excretion as a function of nephrotoxicity correlated with plasma and urine platinum levels in patients receiving cisplatin. Thirty-one patients had urine platinum measurements in urine samples collected at 0 to 6 and 6 to 24 h after cisplatin administration, 25 of these patients had serial plasma platinum measurements. Sixteen of the 31 patients had an increase in urine beta 2M. A significant correlation was obtained between urine platinum and beta 2M in the 6- to 24-h samples (r = 0.61, p less than 0.02). The mean plasma platinum levels were higher (12.6 +/- 6.1 mumol/L) in the patients with an increase in urine beta 2M compared to those patients with no change in beta 2M (6.8 +/- 4.1 mumol/L) (p less than 0.02). Our study indicates that tubular damage occurs within 24 h after cisplatin administration and that the damage correlates with urine platinum levels.

Adult↗
PubMed1988

Platinum concentrations in human autopsy tumor samples.

Platinum concentrations were determined in autopsy tumor samples obtained from 27 patients who had received cisplatin 40-1,029 mg/m2 from 0 to 240 days antemortem. Liver metastases had significantly higher platinum concentrations than did tumors in other sites (p less than 0.005). Platinum concentrations in liver metastases were similar to platinum concentrations in normal liver. Platinum concentrations in gliomas and brain metastases were similar to platinum concentrations in other extrahepatic tumors. Platinum concentration generally decreased with increasing distance into brain from tumor. By multiple stepwise linear regression analysis, the factors that were independently most closely associated with tumor platinum concentration were time from last cisplatin treatment, cumulative lifetime dose of cisplatin, route of cisplatin administration (intraarterial vs. other), and site of tumor deposit (liver vs. other) (r = 0.69, p less than 0.001). Patients whose tumors had responded to cisplatin-containing regimens had mean tumor platinum concentrations that were higher than the mean tumor platinum concentrations in patients whose tumors had not responded to cisplatin (p less than 0.05).

Autopsy↗
PubMed1987

Use of skin surface sampling and ion mobility spectrometry as a preliminary screening method for drug detection in an emergency room.

We have evaluated the use of a novel method for detecting drug residues on the hands of emergency patients suspected of drug overdose. The residues are collected by means of a suction probe and subsequently analyzed by thermal desorption directly into an ion mobility spectrometer. All patients admitted to the Emergency Room had their palms, fingers and nostrils sampled. Of the 101 drug related ingestions, 50 were related to tablets, 47 to film or sugar-coated tablets and 4 to cocaine powder. Positive identification was possible in 42% of tablet related ingestions, 29% of coated tablet or capsule ingestions and in all patients using cocaine. In 53% of the cases where positive drug identification was made, sampling had been carried out within 30 minutes of the patient's arrival at the Emergency Room.

Adult↗
PubMed1986

Hyperuricemia and hypoalbuminemia predispose to cisplatin-induced nephrotoxicity.

The usefulness of pretreatment biochemical parameters in the prediction of nephrotoxicity associated with cisplatin treatment was studied. Twenty-two patients, who received 29 cycles of cisplatin, were evaluated. Cisplatin was given every 3-4 weeks with saline and mannitol. Azotemia occurred in almost all patients and was transient, peaking 1-2 weeks after therapy. The change in serum creatinine from baseline to peak correlated inversely with pretreatment serum albumin (r = -0.73; P less than 0.01) and with pretreatment uric acid (r = 0.76; P less than 0.01). Ten patients with uric acid levels of less than 6 mg/dl were receiving allopurinol. The competition between organic anions and cisplatin for excretion may, in part, explain the protective effects of hypouricemia. Hypoalbuminemia affects peritubular oncotic pressure and may in turn affect platinum excretion. Hypoalbuminemia also reduces the half-life of cisplatin, exposing the kidney to more of the unbound filterable drug.

Cisplatin↗
PubMed1986

Hypoalbuminemia in patients receiving cisplatin: correlation between liver platinum and decrease in serum albumin.

We evaluated changes in serum albumin concentrations in 15 patients with advanced malignancy who were also receiving cisplatin. All 15 patients had serial measurements of serum albumin. The decrease in serum albumin from the time of the first dose of cisplatin to death correlated with liver platinum levels at autopsy (r = 0.46, p less than 0.05). The decrease in serum albumin concentration associated with liver platinum concentration of less than or equal to 1.5 micrograms/g was 0.16 +/- 0.23 g/dl (range 0-0.6). The decrease associated with liver platinum concentrations of greater than 1.5 micrograms/g was 1.0 +/- 0.45 g/dl (range 0.5-1.9; p less than 0.02). The decrease in serum albumin may be secondary to a hepatotoxic effect of cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Digoxin concentrations in postmortem human tissues.

An extraction procedure is described that allows the application of a commercially available enzyme-multiplied immunoassay technique to the measurement of digoxin in whole blood, liver, and kidney. The concentrations of digoxin were measured in tissues obtained at autopsy from five patients who had been taking therapeutic doses of digoxin prior to death. Blood concentrations at autopsy were found to be higher than the therapeutic range, perhaps due to postmortem redistribution. Liver concentrations of digoxin showed a positive correlation with blood concentrations; this was not found for kidney concentrations of the drug.

Cadaver↗
PubMed1986

Human autopsy tissue concentrations of mitoxantrone.

A sensitive high-performance liquid chromatography method was used to measure mitoxantrone in autopsy tissue samples of 11 patients who had received the drug iv 10-272 days antemortem. Mitoxantrone was readily detectable in tissues from all patients. Tissue concentrations were proportional to lifetime cumulative dose of mitoxantrone, and decreased very slowly with time. The thyroid and the liver had the highest mitoxantrone concentrations, followed by the heart. These high cardiac concentrations of mitoxantrone could be partially responsible for the occasional case of cardiotoxicity seen with mitoxantrone. The brain had the lowest mitoxantrone concentrations. Organ mitoxantrone concentrations did not conform to a flow-limited model. Tumor mitoxantrone concentrations varied quite markedly from one site to another in the same patient. Tumors generally had lower mitoxantrone concentrations than did surrounding normal tissues. Mitoxantrone concentrations were consistently highest in intrahepatic tumors and lowest in intracerebral tumors. It is unclear whether the low concentrations in brain tumors were due to a partially intact blood-brain barrier or to the fact that most brain tumors had been irradiated prior to mitoxantrone administration. Further studies are warranted to more fully explore the relationship between human tissue mitoxantrone concentrations and efficacy and toxicity.

Autopsy↗
PubMed1985

Adverse tissue reactions to drugs: a five-year surveillance study.

Over a 5-year duration a total number of 57 881 tissue specimens from hospitalized patients were evaluated clinicopathologically for evidence of adverse tissue reactions to drugs. The incidence of alleged adverse tissue reactions was 3.7% of which 1.5% were definitely shown to be caused by a specific pharmacological agent. Regardless of the category of the adverse tissue reaction, the frequency of drug-related responses occurred most often in females, especially between the ages of 41 and 60 years. The target tissue affected adversely most often was endometrium where hyperplasia was the predominant response noted. An oestrogenic preparation was found most frequently to be implicated in the observed adverse tissue reaction. Evaluation of adverse drug reactions with the use of morphologic technique provides a rigorous and reliable mechanism to monitor deleterious effects in hospitalized patients.

Adolescent↗
PubMed1985

Renal and hepatic concentrations of platinum: relationship to cisplatin time, dose, and nephrotoxicity.

Autopsy tissues were obtained from 30 patients who had received cisplatin antemortem; the tissues were assayed for platinum by flameless atomic absorption spectrometry. Patients with antemortem evidence of renal toxicity had higher renal cortical platinum concentrations than did patients without evidence of kidney damage. In addition, patients with nephrotoxicity were more likely than patients without toxicity to have renal cortical platinum concentrations that were higher than renal medullary platinum concentrations. Overall, the two variables most closely associated with an increase in serum creatinine with treatment were renal cortical platinum concentration (P less than .02) and cumulative dose of cisplatin (P less than .05). These two variables were important independently of one another. Renal cortex platinum concentrations correlated inversely with time from last treatment until death, whereas hepatic platinum concentrations did not. In contrast, hepatic platinum concentrations correlated with dose of cisplatin while renal platinum concentrations did not. Our results suggest the following: (1) cisplatin-induced renal toxicity is tissue-platinum-concentration dependent and cisplatin-dose dependent; and (2) cisplatin may be handled differently at the molecular level in liver and kidney.

Adult↗