The relationship between the reproducibility of holmium laser enucleation of the prostate and prostate size over the learning curve.

The purpose of this study was to analyze the relationship between the reproducibility of holmium laser enucleation of the prostate (HoLEP) and prostate size over the learning curve. We compared the outcome among three institutions in three subgroups on the basis of the weight of tissue retrieved. There were no significant differences in operating time, efficiency of the procedure, decrease in hemoglobin level and postoperative urinary incontinence among three institutions, only in patients with prostates >or=20 g-<40 g retrieved. Our data indicate that HoLEP is more reproducible in patients with a moderate-sized prostate over the learning curve.

Use of antisense oligonucleotides targeting the antiapoptotic gene, clusterin/testosterone-repressed prostate message 2, to enhance androgen sensitivity and chemosensitivity in prostate cancer.

BACKGROUND: Androgen resistance develops, in part, from upregulation of antiapoptotic genes after androgen withdrawal. Identification and targeting of genes mediating androgen-independent (AI) progression may lead to development of novel therapies that delay hormone-refractory prostate cancer. Clusterin is a cell survival gene, that increases after androgen ablation. Here, we review clusterin's functional role in apoptosis and the ability of antisense oligonucleotides (ASOs) against clusterin to enhance apoptosis in prostate cancer xenograft models. RESULTS: Immunostaining of radical prostatectomy specimens confirm that clusterin is highly expressed in 80% prostate cancer cells after neoadjuvant hormone therapy, but is low or absent (<20%) in untreated specimens. Clusterin levels increase >10 fold in regressing Shionogi tumors after castration. Pretreatment of mice bearing androgen-dependent Shionogi tumors with calcium antagonists inhibited castration-induced apoptosis, tumor regression, and clusterin gene upregulation, illustrating that clusterin is an apoptosis-associated gene and not an androgen-repressed gene. Clusterin ASOs reduced clusterin levels in a dose-dependent and sequence-specific manner. Adjuvant treatment with murine clusterin ASOs after castration of mice bearing Shionogi tumors decreased clusterin levels by 70% and resulted in earlier onset and more rapid apoptotic tumor regression, with significant delay in recurrence of AI tumors. Species-specific clusterin ASOs also increased the cytotoxic effects of paclitaxel, reducing the 50% inhibitory concentration (IC(50)) of PC-3 and Shionogi cells by 75% to 90%. Although clusterin ASOs had no effect on the growth of established AI Shionogi or PC-3 tumors, clusterin ASOs synergistically enhanced paclitaxel-induced tumor regression in both Shionogi and PC-3 models. CONCLUSIONS: Collectively, these data identify clusterin as an antiapoptosis protein, upregulated in an adaptive cell-survival manner by androgen ablation and chemotherapy, which confers resistance to various cell-death triggers. Inhibition of clusterin upregulation using clusterin ASOs can enhance cell death after treatment with androgen ablation and chemotherapy.

Skin temperature measurements during intense pulsed light emission.

BACKGROUND: Although lasers and intense pulsed light sources have improved the capability of injuring veins without affecting the overlying skin, work is needed to improve the procedure. OBJECTIVE: To create a method for predicting skin reaction to pulsed light. METHODS: Twenty patients were divided into four groups according to skin type (I-IV). An industrial thermometer equipped with a laser-aiming system was adapted to the intense pulsed light source handpiece. Patients received shots of increasing intensity while the skin temperature was measured. RESULTS: Fluence and temperature data were analyzed by logistic regression to evaluate possible injury. The stepwise method selected skin type and temperature variation as predictors of skin injury. Logistic curves indicated the maximum temperature variation tolerable for each skin type. More pigmented skin types tolerated less temperature increase. CONCLUSION: Skin type can predict cutaneous reaction to intense pulsed light through measurements of temperature variation. This method may help achieve successful selective photothermolysis.

Optimal timing and dosage of chemotherapy as a combined treatment with androgen withdrawal in the human prostate LNCaP tumour model.

Although numerous chemotherapeutic agents have been evaluated for patients with advanced prostate cancer, none have demonstrated improved survival benefits. Here, in order to determine whether the efficacy of chemotherapy can be enhanced by changing the regimen, we evaluated the effect of the varied timing and dosage of chemotherapy in combination with androgen withdrawal on time to androgen-independent (AI) progression in the human androgen-dependent LNCaP tumour model. We first demonstrated the synergistic effect of mitoxantrone on induction of apoptosis in LNCaP cells maintained in the steroid hormone-depleted charcoal-stripped media (CSM) compared to those in the standard media. In addition, this synergy was most remarkable during the simultaneous treatment of LNCaP cells with mitoxantrone and CSM compared to the pre- or post-use of mitoxantrone with CSM. LNCaP tumour growth in athymic nude mice and their increase in serum PSA levels were significantly inhibited by the simultaneous injection of mitoxantrone with castration, compared to the administration of mitoxantrone 2 weeks before or after castration. The TUNEL staining revealed that apoptotic cell death was extensively induced in LNCaP tumours treated with simultaneous castration and mitoxantrone compared to tumours treated with the other schedules. Furthermore, nude mice bearing LNCaP tumours were injected with a total of 0.5 mg mitoxantrone divided into 2, 5 and 10 days, with the most significant therapeutic effect and delayed AI progression observed in mice given injection of mitoxantrone for 2 days. These findings suggest that this might be the optimal way to perform cytotoxic chemotherapy and androgen withdrawal simultaneously in patients with advanced prostate cancer and to administer chemotherapeutic agents at high dosage within short intervals.

Cardioprotective effects of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on cardiac dysfunction induced by ischemia/reperfusion in isolated rat hearts.

Inhibition of fatty acid metabolite accumulation may be beneficial for treatment of cardiac dysfunction induced by ischemia. MET-88, 3-(2,2,2-trimethylhydrazinium)propionate dihydrate, inhibits gamma-butyrobetaine hydroxylase which catalyzes conversion of gamma-butyrobetaine to carnitine. In this study, we investigated whether MET-88 has cardioprotective effects against cardiac dysfunction induced by ischemia/reperfusion. Rats were divided into four groups: (1) control; (2) MET-88 at 50 mg/kg; (3) MET-88 at 100 mg/kg; (4) nifedipine at 30 mg/kg. MET-88 was administered orally once a day for 10 days, and nifedipine was administered orally 30 min before the experiments. Cardiac functions (heart rate, left ventricular systolic pressure and coronary flow) were measured in rat working heart preparations for 30 min under ischemia followed by 20 min under reperfusion. Myocardial carnitine levels were measured at the end of the experiments. Before ischemia, MET-88 did not affect cardiac functions, but nifedipine significantly increased only coronary flow. Under the ischemic condition, cardiac functions were markedly decreased in all groups. During reperfusion, MET-88 and nifedipine promoted recovery of cardiac functions and decreased the incidence of ventricular fibrillation. MET-88 also prevented the accumulation of long-chain acylcarnitine induced by ischemia. These results indicated that MET-88 protected against cardiac dysfunction in ischemia/reperfusion, and preventing the accumulation of long-chain acylcarnitine may be responsible for the cardioprotective effects.

Primary aldosteronism in pregnancy.

Aldosteronism is a rare complication of pregnancy. We report a case of a 26-year-old woman who became pregnant soon after a diagnosis of primary aldosteronism due to left adrenal adenoma was made. Only oral potassium supplementation was required in addition to routine prenatal care until 36 weeks' gestation. Subsequently, antihypertensive medication was needed to control elevated blood pressure. A healthy male infant was delivered by cesarean section because of abruptio placentae. The postoperative course was uneventful. Left adrenalectomy was conducted eight months after delivery under laparoscopic visualization. In this case report, we discuss management of aldosteronism in pregnancy and review the literature.

Effects of cerivastatin sodium, a new HMG-CoA reductase inhibitor, on biliary lipid metabolism in patients with hypercholesterolemia.

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has become common in the treatment of hypercholesterolemia. The present uncontrolled study was undertaken to determine the effect of cerivastatin sodium (BAY w 6228), a new HMG-CoA reductase inhibitor, on biliary lipid levels in patients with hypercholesterolemia. Twenty-one hypercholesterolemic patients (World Health Organization type IIa = 16 patients; type IIb = 5 patients) received placebo during a 4- to 6-week observation period, after which they received cerivastatin sodium 0.2 mg/d for 12 weeks. Fasting blood samples were drawn for the measurement of serum lipid levels early in the morning before the start of treatment and once a month for each of the 12 weeks of cerivastatin sodium treatment. Gallbladder bile samples were aspirated with a duodenal tube by cerulein stimulation to assess bile lithogenicity. Serum total cholesterol levels decreased markedly after 12 weeks. However, no significant difference was found in the molar percentage composition of biliary lipids (e.g., cholesterol, phospholipids, and total bile acids) or in individual biliary bile acids. Consequently, no significant change in bile cholesterol saturation index was found. The index values before and after 12 weeks of treatment were 0.81 +/- 0.38 and 0.80 +/- 0.47, respectively, whereas when patients were grouped by type of hypercholesterolemia, there was a tendency toward decreased lithogenicity in patients with type IIb but not type IIa hypercholesterolemia. We concluded that cerivastatin sodium was an effective cholesterol-lowering drug that did not appear to worsen biliary lipid metabolism and that may decrease lithogenicity in patients with type IIb hypercholesterolemia.

Anastomotic recurrence after curative resection of a transverse colon carcinoma: a case report.

We report a case of anastomotic recurrence after curative surgery for transverse colon cancer in a 53-year-old man. The recurrence was first detected as a submucosal tumor 1.3 cm in diameter, located on the suture line, during an annual follow-up barium enema and colonoscopy. A repeat examination 3 months later showed the lesion to be a typical colon cancer, 2.5 cm in size, with a large ulcerated area. Right hemicolectomy was performed with curative intent. Anastomotic recurrence is much rarer after colonic resection than after anterior resection. This was the first time that we had detected a recurrent lesion as a submucosal tumor during annual follow-up examination.

Dose-response relationship between coffee and the risk of pancreas cancer.

A case-control study was conducted and previous epidemiological data were reviewed in order to investigate the dose-response relationship between coffee and the risk of pancreas cancer. The case-control study was community-based and was carried out in Hokkaido, Japan, employing 141 patients with pancreas cancer and 282 controls (two for each case) matched for sex, age and place of residence. The dose-response relationship between coffee (cups/day) and the relative risk of this disease formed a U-shaped curve. The lowest relative risks (0.18 for male and 0.53 for female) were found among "occasional" drinkers. Epidemiological articles published between 1981 and 1993 were selected from Index Medicus using the two key words "coffee" and "pancreas cancer". In many of the previous case-control studies the curve of the dose-response relationship was also U-shaped, when the relative risks were calculated specifically using four or five levels of coffee dose. The nadirs of the relative risks, most of which ranged from 0.5 to 0.7, were found most frequently at small doses (1-2 or 3-4 cups/day). The results of meta-analysis of these studies formed a U-shaped curve. Studies of other types showed almost the same results. Thus it appears that small amounts of coffee might prevent pancreas cancer, whereas large amounts might cause the disease.

[Role of neoadjuvant chemotherapy for management of resectable head and neck cancer].

This review covers the clinical significance of neoadjuvant chemotherapy as initial treatment for squamous cell carcinoma of the head and neck, especially focusing on advanced but resectable disease. The rates of complete response (CR) after chemotherapy depended on the regimens and varied from 15% to 35%. Combined use with DDP/5-FU was considered as a most effective regimen. In addition of leucovorin to DDP/5-FU regimen, CR rate increased more than 50%. A randomized clinical trial has not shown any advantage for survival in advanced head and neck cancer. Recent reports have shown that distant metastases diminished in patients treated with neoadjuvant chemotherapy. When primary lesions disappeared completely after neoadjuvant chemotherapy, sequential use of radiotherapy can make the long term relapse-free in those lesions. This effort may lead to a modality of cancer treatment without surgery, so organ preservation will be possible.

A new point mutation in the deoxyribonucleic acid-binding domain of the vitamin D receptor in a kindred with hereditary 1,25-dihydroxyvitamin D-resistant rickets.

Hereditary 1,25-dihydroxyvitamin D [1,25-(OH)2D]-resistant rickets (HVDRR) is a rare disorder characterized by rickets, alopecia, hypocalcemia, secondary hyperparathyroidism, and normal or elevated serum 1,25-dihydroxyvitamin D levels. We describe a patient with typical clinical characteristics of HVDRR, except that elevated levels of serum phosphorus were present coincident with increased levels of serum intact PTH. The patient was treated with high dose calcium infusion after an ineffective treatment with 1 alpha-hydroxyvitamin D3; serum calcium and phosphorus as well as intact PTH and alkaline phosphatase levels were normalized. Evaluation of phytohemagglutinin-activated lymphocytes derived from this patient revealed that 1,25-(OH)2D3 was unable to inhibit thymidine incooperation, a result that contrasts with the capacity of 1,25-(OH)2D3 to inhibit uptake into normal activated lymphocytes. 1,25-(OH)2D3 did not induce human osteocalcin promoter activity after transfection of this DNA linked to a reporter gene into patient cells. Cointroduction of a human vitamin D receptor (VDR) cDNA expression vector with the reporter plasmid, however, restored the hormone response. Evaluation of extracts from the patient cells for VDR DNA binding revealed a defect in DNA binding. Analysis of genomic DNA from the patient's cells by PCR confirmed the presence of a point mutation in exon 2 of the VDR. This exon directs synthesis of a portion of the DNA-binding domain of the receptor. We conclude that the genetic basis for 1,25-(OH)2D3 resistance in this kindred with VDR-positive HVDRR is due to a single base mutation in the VDR that leads to production of a receptor unable to interact appropriately with DNA.

[A case control study of cancer of the pancreas].

We report the findings of a case-control study of cancer of the pancreas, which was conducted in Hokkaido Prefecture. Seventy-one patients with pancreatic cancer were matched on sex and age (+/- 3 years) to 142 community-based controls. The latter had telephone interviews. We questioned all subjects about demographic factors, diet, beverage consumption, and medical and surgical history. Significantly decreased risks were associated with consumption of raw vegetables and green tea. The risk increased significantly with consumption of the fat of meat, boiled fish, coffee, black tea and alcoholic beverages.

Therapy of sudden deafness.

A vicious circle in the mechanism of sudden deafness is proposed. In order to block this cycle, various drug therapeutics, particularly OHP treatment, are recommended. A beneficial effect can be obtained by starting treatment within 10 days after the onset of sudden deafness. In studies undertaken to elucidate the mechanism of sudden deafness, the fact that relapse is rarely observed may be of importance.

Time dependent effects of selenium on cadmium-induced acute mouse testicular damage.

Twenty-four hr after a single subcutaneous injection of Cd (0.024 mmol/kg), the testis showed severe and widespread degeneration. The damage was accompanied by an increase of lipoperoxide and a decrease of glutathione in the testis. Se (0.048 mmol/kg) injections 2 hr before, at the same time, and 1 hr after the Cd injection, decreased the damage. In these groups, the level of glutathione and lipoperoxides was restored to the control level. With a Se injection 6 hr after the Cd injection, the preventive effect of Se was no longer found. In the testis in which Se injection alleviated the damage caused by Cd, the changes in Ca, Mg and Zn were also restored to the control level. Uptake of Cd into the testis was stimulated by the Se injection. However, the uptake still remained at a low level in the testis in which the Se preventive effect was not found. These results suggest that the preventive effect of Se against testicular Cd toxicity is dependent on the interval between Cd and Se injections.

[Research on experimental cerebral infarction in cats with in vivo TMR (topical magnetic resonance) approach].

Metabolic changes in the ischemic brains of cats were investigated in vivo with high energy phosphate compounds as parameters by using a topical magnetic resonance (TMR) spectrometer. The experimental focal cerebral ischemia was made in four cats by modifying the method of O'Brien and Waltz. The stem of left middle cerebral artery was exposed and set the occlusive device 5-7 days before the in vivo measurement. 31P-NMR spectrum was taken under general anesthesia with Ketamine HCI and with decreased blood flow. The following points must be considered in obtaining 31P-TMR spectrum in a cat brain: Firstly, as much muscle as possible must be removed from the detective area because it contains phosphate compounds. Our experiment showed that bone and blood had little or no effect on the 31P-TMR spectrum. Secondly, although same procedure was repeated, it was difficult to obtain constant ischemic lesion; in site and size. The detective area in setting was not changed in the particular area. However there was a possibility of the detective area also including various non-ischemic regions. Thirdly, 31P-TMR spectrum had several peaks in a cat brain; which were sugar phosphate, inorganic phosphate, phosphodiesters, phosphocreatine, gamma-, alpha-, beta-ATP in the pre-occlusive conditions. These peaks did not appear in clear volume separation with one another. We drew the perpendicular line from through between two neighbour peaks to the horizontal base line and artificially divided two peaks. The area of each peak did not represent correctly the density of each component. Fourthly, unnecessary components were rationalistically excluded from the 'raw' spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

[Moderate dose methotrexate with citrovorum factor rescue therapy in the treatment of head and neck cancer].

A clinical trial of moderate dose methotrexate (MTX)-CF rescue was conducted in 12 institutions. Thirty-seven patients with head and neck carcinoma entered this trial, of which 32 were evaluable. MTX was administered 350 mg/m2 (500 mg/body) by i.v. drip over 6 hours. Three hours after completion of MTX infusion, CF rescue was started. There was no complete response in 32 patients. Nine patients showed partial response with the response rate of 28%. The response rates were 21% for the group of patients treated previously, and 75% for the group untreated previously. MTX concentration in plasma was determined at 6, 24, 48 and 72 hours after the initiation of MTX infusion, and the assay results revealed a safe range. GI disturbances were seen at the rates of 11 to 38%. Bone marrow suppression was mild and no renal toxicity was observed. We concluded that the moderate dose MTX-CF rescue therapy was useful for head and neck carcinoma. As a next step, we are planning to conduct a clinical trial of high-dose MTX.