Jamal Zidan

Cisplatin ototoxicity in guinea pigs with special reference to toxic effects in the stria vascularis

The toxic effects of cisplatin (cis‐diamminedichloroplatinum [II]) on the organ of Corti are well established. Few and conflicting data on this drugs effects on the stria vascularis exist. The present study presents animal experiments on the toxic effects of cisplatin in the stria vascularis and in the organ of Corti. Cisplatin‐induced toxicity in albino and pigmented guinea pigs was evaluated morphologically and functionally, using light and transmission electron microscopy as well as auditory brainstem‐evoked potentials on the organ of Corti and the stria vascularis. The results showed variability in hearing thresholds, ranging from no change to hearing loss of 30 dB, and prominent damage in the organ of Corti and in the stria vascularis. The toxic effects to both the organ of Corti and the stria vascularis should be considered when cisplatin is used in chemotherapy.

Octreotide in the treatment of severe chemotherapy-induced diarrhea

BACKGROUND Chemotherapy-induced diarrhea (CID) is a common side effect of a number of chemotherapeutic agents. Conventional therapy for severe CID with opioids or loperamide is moderately effective. A prospective trial was conducted using octreotide acetate for treatment of severe CID refractory to loperamide. PATIENTS AND METHODS Thirty-two patients with grade 2 and 3 CID refractory to loperamide were treated with octreotide at a dosage of 100 microg subcutaneously 3x/day for three days followed by 50 microg 3x/day for three days. Previous chemotherapy consisted of regimens containing fluorouracil, leucovorin, CPT-11, cyclophosphamide, methotrexate and cisplatin. Primary tumors were colorectal (n = 23), gastric (n = 3), and other cancers (n = 6). RESULTS Complete resolution of diarrhea was obtained in 30 of 32 patients (94%); 5 within 24 hours, 14 within 48 hours, and 11 within 72 hours of treatment. Nineteen patients were treated as outpatients. Thirteen were hospitalized for a median of three days. Response was unaffected by age, gender, performance status, previous chemotherapy or primary tumor site. No side effects related to octreotide were observed. CONCLUSIONS Octreotide 100 microg subcutaneously 3x/day for three days is an effective, safe treatment for CID given primarily or as a second-line therapy after loperamide failure.

Ezetimibe's effect on platelet aggregation and LDL tendency to peroxidation in hypercholesterolaemia as monotherapy or in addition to simvastatin

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Statins demonstrate a pleiotropic effect which contributes beyond the hypocholesterolaemic effect to prevent atherosclerosis. WHAT THIS STUDY ADDS Ezetimibe has an antioxidative effect when given as monotherapy or as an add-on to the statin, simvastatin. AIMS To investigate the effect of lowering low-density lipoprotein-cholesterol (LDL-C) on platelet aggregation and LDL tendency to peroxidation by ezetimibe alone or with simvastatin in hypercholesterolaemia. METHODS Sixteen patients with LDL-C >3.4 mmol l(-1) received ezetimibe for 3 months (Part I). Twenty-two patients on fixed simvastatin dose with LDL-C >2.6 mmol l(-1) were enrolled (Part II). Part II patients continued simvastatin treatment 20 mg day(-1) for 6 weeks, then received 20 mg day(-1) simvastatin combined with ezetimibe 10 mg day(-1) for another 6 weeks. The tendency of LDL to peroxidation measured by lag time in minutes required for initiation of LDL oxidation and by LDL oxidation at maximal point (plateau) was measured before and after ezetimibe treatment. RESULTS Part I: Ezetimibe 10 mg daily for 3 months decreased plasma LDL-C level 16% (P = 0.002), prolonged lag time to LDL oxidation from 144 +/- 18 min to 195 +/- 16 min (P < 0.001), decreasing maximal aggregation from 83 +/- 15% to 60 +/- 36% (P = 0.04). Part II: Serum level LDL-C decreased 23% (P = 0.02) and lag time in minutes to LDL oxidation was prolonged from 55.9 +/- 16.5 to 82.7 +/- 11.6 (P < 0.0001) using combined simvastatin-ezetimibe therapy. There were no differences in platelet aggregation. CONCLUSIONS Ezetimibe was associated with decreased platelet aggregation and LDL tendency to peroxidation. Treatment with ezetimibe in addition to simvastatin has an additive antioxidative effect on LDL.

Follicular carcinoma of the thyroid gland: prognostic factors, treatment, and survival.

Prognostic variables and treatment outcomes of 82 patients treated at the Northern Israel Oncology Center were reviewed. There were 59 women and 23 men in this series. The female/male ratio was 2.6/1. Median age was 46 years. Median follow-up was 11.4 (range: 3.8-24 years). Median tumor size was 3.6 cm. When first seen, 4 patients had lymph node involvement and 11 (13%) had distant metastases. Surgical treatment was total thyroidectomy in 37 patients (45%), subtotal thyroidectomy in 38 (46%), and lesser procedures in 7 (9%). Sixty-six patients (80%) were treated after surgery with 131I to ablate thyroid remnants. Doses ranged between 30 and 80 mCi. The 20-year overall actuarial survival rate was 65%. The actuarial survival rate of patients <40 years of age was 96% versus 33% in patients >50 years of age (p = 0.0008). Patients with distant metastases at presentation had inferior survival compared with patients without metastases. In conclusion, we found subtotal thyroidectomy followed by 131I and hormone therapy to provide survival similar to that with total thyroidectomy, with less morbidity. Risk factors include: age > or =40 at the time of diagnosis, presence of distant metastases, capsular invasion, tumor size > or =2 cm, and male gender.

ENDOTHELIAL INJURY OF CAPILLARIES IN THE STRIA VASCULARIS OF GUINEA PIGS TREATED WITH CISPLATIN AND GENTAMICIN

The drugs cisplatin and gentamicin are used for treatment of various cancer patients suffering from infection. The authors report a detailed electron microscopic study of blood vessels in stria vascularis of guinea pigs after treatment with cisplatin alone and in combination with gentamicin. The most distinctive features expressing endothelial cellular injury were mitochondrial, including occasional paracrystalline inclusions; electron-lucent foci with depleted organelles; intracytoplasmic vacuole formations; lipid bodies; cytoplasmic extrusions located on the luminal surface; and severe luminal constriction of part of the vessels from animals treated with the combined drugs. The study suggests that the damage to strial capillaries due to treatment with cisplatin alone and in combination with gentamicin may contribute to the injurious effects of these drugs on the strial tissue. Furthermore, the results of this study may enlarge the awareness of the potential vascular damage and vascular complications in additional body systems after medical use of cisplatin alone or in combination with gentamicin.

Toxic effects of cisplatin alone and in combination with gentamicin in stria vascularis of guinea pigs.

The toxic effects on the stria vascularis of treatment with cisplatin alone and combined with the aminoglycoside antibiotic, gentamicin, were studied in guinea pigs. The toxicity induced in albino and pigmented guinea pigs was investigated morphologically with light and transmission electron microscopy, and functionally by brainstem‐evoked response audiometry. The results of hearing thresholds were variable, ranging from no change in one ear in some of the animals to a hearing loss of 20 dB in one or both ears when treated with low‐dose cisplatin alone or in combination with gentamicin. Bilateral deafness resulted from high‐dose cisplatin combined with gentamicin. The combined treatment produced prominent structural damage in the stria vascularis. The results should be considered when aminoglycoside therapy is required in conjunction with cisplatin.

Nephrotoxicity of Combined Treatment with Cisplatin and Gentamicin in the Guinea Pig: Glomerular Injury Findings

The drugs cisplatin and gentamicin are given consecutively to various cancer patients suffering from infections. Little information exists about the ultrastructural alterations of kidney glomeruli caused by treatment with these drugs. Renal glomeruli of guinea pigs treated with cisplatin alone and in combination with gentamicin were studied by transmission electron microscopy. The findings revealed foci of damage induced by cisplatin and especially by cisplatin/gentamicin in all glomerular components: glomerular capillaries, including their endothelial cells; basement membrane, epithelial podocytes, mesangial cells, and parietal cells of Bowmans capsule. The damage was expressed by endothelial cytoplasmic extrusions into the vascular lumen, thickening and lamination of capillary basement membrane, focal foot process fusion of podocytes, vacuolization in cytoplasm of endothelial cells of epithelial podocytes and of parietal cells, and the presence of lipid bodies and myeloid bodies in all glomerular cell types. Additionally, injurious effects to cytoplasmic organelles such as mitochondria, nuclei, and endoplasmic reticulum were observed. The results indicate that cisplatin alone and in combination with gentamicin is toxic to renal glomerular tissue. Since these drugs were previously found toxic for strial capillaries in the inner ear and since the main glomerular component is the glomerular capillaries, potential vascular damage and vascular complications in different body systems have to be taken into consideration when these drugs are needed in clinical use.

Prevention of chemotherapy-induced neutropenia by special honey intake

Febrile neutropenia is a serious side effect of chemotherapy. Colony-stimulating factors (SCFs) are used for primary and secondary treatment in patients with grade 4 neutropenia. The use of CSFs is expensive and accompanied by side effects. In the current study, Life-Mel Honey (LMH) was administered to prevent neutropenia and to reduce the need for CSFs in patients treated with chemotherapy. Thirty cancer patients receiving chemotherapy for primary or metastatic disease were included. All patients had grade 4 neutropenia and were treated with CSFs. The patients repeated the same chemotherapy schedule, with the addition of LMH for 5 d. Blood count was performed weekly. There was no recurrence of neutropenia after LMH intake and no need for treatment with CSFs in 12 (40%) of patients. Eighteen (60%) patients with LMH developed neutropenia grade 4 and were treaeed with CSFs (p=0.007). Hemoglobin levels remained>11 g/dL during LMH intake in 19 (64%) patients. Only three (10%) patients had thrombocytopenia. Eight (32%) patients reported improvement in quality of life. The use of LMH in patients who are at high risk of developing neutropenia as a result of chemotherapy decreases the risk of pancytopenia and the need for CSFs. LMH is inexpensive, has no side effects, and is easy to administer.

Effects of tamoxifen on bone mineral density and metabolism in postmenopausal women with early-stage breast cancer

At the present time, tamoxifen is the most widely used anti-estrogen for adjuvant therapy and metastatic disease in postmenopausal women with breast cancer, a population at high risk for osteoporosis. This prospective study was designed to evaluate the effect of adjuvant tamoxifen on bone mineral density and all biochemical markers concomitantly in women with early-stage breast cancer in one study.Using dual-energy X-ray absorptiometry, prior to and 12 mo after tamoxifen treatment, bone mineral density in lumbar spine and femoral neck was measured in 44 women with T1-T2N0M0 estrogen-receptor-positive breast cancer receiving adjuvant treatment with tamoxifen 20 mg/d. Biomarkers that can affect bone mineral metabolism were measured before and after 3 and 12 mo of tamoxifen treatment. Bone mineral density was minimally increased in lumbar spine and femoralneck after 12 mo treatment with tamoxifen (p=0.79 and 0.55, respectively). No differences were found in serum levels of calcium, phosphate, creatinine, ALAT, albumin, LDH, calcitonin, or estradiol. A significant decrease in osteocalcin levels was found after 3 and 12 mo (p≤0.01). TSH and PTH levels were increased (p≤0.05) after 3 mo, returning to baseline after 12 mo. In conclusion, tamoxifen has an estrogen-like effect on bone metabolism in postmenopausal women and is associated with preservation of bone mineral density in lumbar spine and femoral neck. Changes in serum concentration of biochemical markers may reflect decreased bone turnover or bone remodeling and add to the understanding of tamoxifen’s effect on bone mineral density.

Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ∼2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ∼5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750–1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ∼650 years ago, and into the Iraqi–Jewish community ∼450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.