Education and employment in long-term survivors of high-grade osteosarcoma: a Japanese single-center experience.

OBJECTIVE: To investigate the status of education and employment of long-term survivors who became physically handicapped after treatment for high-grade osteosarcoma. METHODS: Of the osteosarcoma patients treated at our hospital, 41 patients aged less than 18 years at the initial presentation who were free of disease for 10 years or longer after the end of treatment were studied. The status of their education and employment was investigated via a questionnaire. RESULTS: Twenty-seven patients responded to the questionnaire (response rate, 65.9%). Of these patients, 73.1% (19/26) could return to the school they had attended before the disease, and 52% (13/25) graduated from college or university. The percentage of those who went to college or university was higher in the limb-sparing group. Seventy-two percent of the patients were engaged in clerical work, and the mean annual income was 4.01 million JPY (corresponding to about 24,000 EUR). No difference was noted in the status of employment between the amputation and limb-sparing groups. CONCLUSIONS: The percentage of patients who went to college or university was similar to the percentage in all Japanese. However, the status of the diseased limb appeared to affect school attendance. The mean annual income of the patients was comparable to that of the national average, and they experienced no major problems in their employment. Physical disabilities posed few problems in their daily living.

Predictors of long-term survival with pulmonary metastasectomy for osteosarcomas and soft tissue sarcomas.

AIM: The control of pulmonary metastases is important for long-term survival of the patients with osteosarcomas and soft tissue sarcomas. METHODS: To evaluate the efficacy of aggressive pulmonary metastasectomy for those patients, we reviewed 105 cases (44 osteosarcomas, and 61 soft tissue sarcomas) treated in our hospital. RESULTS: The number of metastases was only the significant risk factor for the curability of the metastasectomy (logistic regression analysis, P=0.0274). The 5-year and 10-year survival rate were 43.6% and 32%. The curability was only independent prognostic factor on multivariate analysis (P=0.0008). CONCLUSIONS: Early detection of pulmonary metastasis, multimodal perioperative treatment, and design for minimizing the volume of resected lung tissues will enable complete and repeat resections for the achievement of long-term survival.

[Analysis of continuous hemodiafiltration after open heart surgery].

The development of renal failure after open heart surgery is associated with a high mortality. Thirteen patients were treated with continuous hemodiafiltration (CHDF) for renal failure following open heart surgery since April 1999 to December 2001. The indication of CHDF was blood purification in 8 patients and water balance control in 5 patients. Two patients with hemodialysis (HD) before operation returned to usual HD early after operation, and discharged. One patient died of severe heart failure, and another patient died of sepsis and multi organ failure. In these 2 patients, CHDF could not withdrawn. Seven patients weaned from CHDF 1 to 19 days after operation. Five of 7 patients discharged, but 2 patients died of cerebral infarction 4 month after operation. The remaining 2 patients could not wean from CHDF, and were introduced HD. Only 1 of 13 patients had bleeding tendency (cardiac tamponade). CHDF did not influence the hemodynamic state and was very effective for the treatment of renal failure in many patients.

Knee rotation-plasty for malignant musculoskeletal tumors occurring around the knee joint.

BACKGROUND: In addition to the wide excision of malignant musculoskeletal tumor around the knee joint, surgical methods, such as total knee arthroplasty and knee rotation-plasty are available. Therefore, this study was undertaken to clarify the usefulness of knee rotation-plasty. MATERIALS AND METHODS: At the Chiba Cancer Center, knee rotation-plasty was performed in 27 patients with malignant musculoskeletal tumor around the knee joint. Patients were divided into two groups: Group S, in which operations were performed as salvage surgery (8 patients), and Group I, in which operations were performed as initial surgery (19 patients). The lower limb function was investigated in 17 patients (7 patients in Group S and 10 patients in Group I). The lower limb function was assessed by the Knee Evaluation System of International Symposium on Limb Salvage and the Knahr's assessment. RESULTS: Lower limb function in Group S measured an average of 25.7 points (85.6%), while the lower limb function in Group I measured an average of 23.6 points (78.7%). The majority of patients in both groups were capable of walking without a cane or doing light exercise with below-the-knee prosthesis, revealing good lower limb function. CONCLUSION: Whether it is performed as salvage or initial surgery, knee rotation-plasty can be useful method for reconstruction of the knee after wide excision of malignant musculoskeletal tumor around the knee joint.

Structure-activity relationship study of host-specific phytotoxins (AM-toxin analogs) using a new assay method with leaves from apple meristem culture.

AM-toxins are host-specific phytotoxins of the Alternaria alternata apple pathotype, which induce necrosis on apple leaves. In this study, we developed a new assay to measure the necrotic activity of AM-toxin analogs using cultured leaves from meristem cells. This method was not only more sensitive to AM-toxin I, but also more reliable than the previous one that used tree leaves due to the homogeneous nature of cultured leaves and to the method of application of toxins. Using this assay method we investigated a structure-activity relationship of AM-toxin analogs synthesized in this study. Most residues and the macrocyclic ring structure were strictly recognized by AM-toxin putative receptor, whereas the L-Ala binding subsite of the receptor allowed for side chain structures with various stereoelectronic properties. These findings are important for designing ligands for further experimental probing of the nature of the receptor.

Ligand-exchange chromatography at zirconium(IV) immobilized on IDA-type chelating polymer gel

Ligand-exchange chromatography of organo-acidic compounds at Zr(IV) immobilized on IDA-type chelating polymer gel using an aqueous mobile phase was studied, to obtain some insight into their retention on zirconia. Zirconium(IV) has no contribution to the retention of phenols, while appreciably enhancing that of benzoic acids and strongly or occasionally irreversibly adsorbing the potentially chelating substances. The presence of two stationary-phase species adsorbing benzoates was confirmed, and the retention over a wide pH range of 3.5-9.5 was quantitatively formulated. The correlation of the retention factor with the Bronsted acidity of samples and its dependence on pH were theoretically explained, and the performance of this chromatographic system was compared with that of zirconia.

Effect of sarpogrelate hydrochloride on platelet-derived microparticles and various soluble adhesion molecules in diabetes mellitus.

We measured platelet-derived microparticles, activated platelets, and various adhesion molecules in 48 patients with diabetes mellitus. We also performed a comparative study of these parameters before and after administration of sarpogrelate hydrochloride. The numbers of platelet-derived microparticles and activated platelets were increased significantly in diabetic patients, and CD63-positive platelets were increased in patients with diabetic complications and poorly controlled blood glucose. Soluble adhesion molecules and thrombomodulin were also increased significantly. After administration of sarpogrelate hydrochloride, not only CD62p- and CD63-positive platelets, but also platelet-derived microparticles were decreased significantly. Soluble adhesion molecules and thrombomodulin were also significantly decreased after the treatment. These data suggest that (a) in patients with diabetes, antiplatelet therapy with sarpogrelate hydrochloride is a useful antithrombin therapy because it suppresses the production of intrinsic coagulants by activated platelets; and (b) sarpogrelate hydrochloride decreases endothelial cell damage via adhesion molecules.

Effect of streptozotocin-induced diabetes mellitus on type 1 deiodinase (D1) in inherited D1-deficient mice.

We investigated the effects of streptozotocin (STZ)-induced diabetes on thyroid hormone levels, type 1 deiodinase (D1) activity and messenger RNA (mRNA) levels in inherited D1 deficient C3H mice in a comparative manner with control C57 mice. The apparent maximum velocity (Vmax) D1 values in C3H mice were 3% (liver) and 26% (kidney) of those in C57 mice. In C3H mice, similar serum T3, slightly higher T4, and 2.6-fold higher rT3 levels were observed compared with C57 mice. In STZ-induced diabetes, serum T4 level markedly decreased in both C3H and C57 mice. Serum T3 levels in STZ-C3H mice similarly decreased as in STZ-C57 mice. On the other hand, serum rT3 levels increased to 3.3-fold higher in STZ-C3H than in STZ-C57 mice. The Vmax values were decreased to 12% (STZ-C3H) and to 30% (STZ-C57) in liver, and decreased to 33% (both STZ-C3H and STZ-C57) in kidney. The changes in D1 mRNA levels in diabetes versus control were comparable to those of D1 activities in both strains. In summary, similar mechanism(s) to those which decrease the D1 expression and the serum T3 level in diabetes, function in D1 deficient C3H mice as in C57 mice. It appears that hepatic and renal D1 activity alone can not explain the similar reduction in T3 level in STZ-C3H mice and STZ-C57 mice.

Serum concentration and renal handling of 1,5-anhydro-D-glucitol in patients with chronic renal failure.

We measured serum and urinary 1,5-anhydro-D-glucitol (1,5-AG) during a glucose tolerance test (GTT) in patients with chronic renal failure (CRF) and compared the fractional excretion of 1,5-AG (FEAG) with that of diabetes mellitus (DM) patients and healthy controls. The mean serum 1,5-AG in CRF patients [60 +/- 23(SE) mumol/L] was significantly lower than in controls (155 +/- 7 mumol/L) in spite of a normal glycaemia. The levels in the CRF group were similar to those in the DM group. During GTT, the blood glucose profile in the CRF group was not significantly different from that of the control group, and urinary glucose excretion was negligible. However, FEAG was significantly higher in CRF patients than in controls. These data suggest that serum 1,5-AG in patients with CRF decreases due to a decrease in 1,5-AG reabsorption, independently of glucose excretion, and that serum and/or urinary 1,5-AG can be a useful marker for renal tubular dysfunction because the 1,5-AG reabsorption system is more vulnerable than the glucose reabsorption system.

Circadian heart rate rhythms in Japanese centenarians.

OBJECTIVE: To investigate age-associated changes in the circadian rhythm of the heart rate. DESIGN: The circadian rhythm was extracted from diurnal heart rate (HR) variations, and patterns of HR rhythm were compared in centenarians and controls. SETTING: Centenarians living in the metropolitan area of Tokyo and in Aichi prefecture in 1992. PARTICIPANTS: Fifty centenarians underwent 24-hour ambulatory electrocardiogram (Holter) monitoring. The control group, comprised of 100 clinically healthy subjects who underwent similar Holter monitoring, was subdivided, by age, into two groups: the younger controls (age range 23 to 54 years, mean age 41) and the older controls (age range 55 to 82 years, mean age 69). MEASUREMENTS: Harmonic analysis was used to approximate the 24-hour RR interval (the interval between two neighboring R waves on the electrocardiogram) data obtained by Holter monitoring to a summation of three cosine waves with 24-hour, 12-hour, and 8-hour periods. The power of the period was adjusted for the goodness of curve-fit. The power of each period and the circadian acrophase (the timing of the peak in a 24-hour rhythm) were compared among the centenarians, older controls, and younger controls. HR rhythms were classified by k-means cluster analysis based on the power of the period. The prevalence of each pattern was compared among the three age groups. In the centenarians, the relationship between clinical parameters (activities of daily living, cognitive function, nutritional status, and present illness) and patterns of HR rhythm was investigated. RESULTS: The power of the 24-hour period in the centenarians was significantly smaller than that in the older (P < .05) and younger (P < .001) controls. The power of the 8-hour period in the centenarians was significantly larger than that in the younger controls (P < .05). Advances or delays in the circadian acrophase were frequently observed in the centenarians compared with the younger controls. The power of each period did not differ between centenarians with (n = 11) and without (n = 39) overt diseases capable of altering HR rhythms. Five patterns of HR rhythm were identified: 24-hour period dominant (n = 84), 24-hour+12-hour period (n = 18), 12-hour period dominant (n = 11), 8-hour period dominant (n = 7), and low goodness of curve-fit (n = 30). The 8-hour period dominant pattern and the low goodness of curve-fit pattern were observed commonly in the centenarians, whereas the 24-hour period dominant pattern and the 24-hour+12-hour period pattern were observed frequently in the younger controls. Patterns of HR rhythm were not related to clinical parameters in the centenarians. CONCLUSIONS: The circadian rhythm of HR changed with aging: there was reduction in the power of the 24-hour period, augmentation in the power of the 8-hour period, and a shift in the circadian acrophase.

Effect of triiodothyronine administration on reduced expression of type 1 iodothyronine deiodinase messenger ribonucleic acid in streptozotocin-induced diabetic rats.

To examine the mechanism behind a decrease in type 1 iodothyronine deiodinase (D1) gene expression in diabetes mellitus, we evaluated the effect of administering T3 and/or insulin on D1 activity and the mRNA levels in the liver of streptozotocin (STZ)-induced diabetic rats. STZ (100 mg/kg BW) was administered to male Wistar rats, and the rats were divided into four groups as follows: (1) STZ alone, (2) STZ and T3 (5 microg/100 g BW daily for 7 days), (3) STZ and insulin (intermediate-acting insulin, 4 units/100 g BW daily for 7 days), and (4) STZ, T3, and insulin. Blood glucose levels increased in Group 1, but were normalized in Group 3. Serum T3 levels were markedly decreased in Group 1. They were within normal limits 24 hours after the last administration of T3 in Group 2 and after the administration of insulin in Group 3. T3 levels were supranormal in Group 4. TSH levels were normal in Groups 1 and 3, but were suppressed in Groups 2 and 4, suggesting that rats in Groups 2 and 4 were actually in a hyperthyroid state after injecting a large amount of T3. D1 activity in Group 1 was reduced significantly, but it was normal in Groups 2 and 3, and increased in Group 4. D1 mRNA levels in the liver in Group 1 decreased significantly, but they were increased to within normal limits by adding insulin in Group 3. They were also normal in Group 2 where hyperglycemia was evident and rats were hyperthyroid after administering T3. D1 mRNA in Group 4 increased significantly where glucose levels were normal and T3 levels were increased. We suggest that the decrease in hepatic D1 mRNA in STZ-induced diabetic rats is due to metabolic derangement caused by insulin deficiency in addition to a possible decrease in tissue T3 availability.

[High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for refractory bone and soft tissue sarcomas].

High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to 10 patients with refractory bone and soft tissue sarcoma (2 patients with primitive neuroectodermal tumor, 4 patients with Ewing's sarcoma, 3 patients with synovial sarcoma and one patient with osteosarcoma). Busulfan 4 mg/kg x 4, melphalan 140 mg/m2 and thiotepa 200 mg/m2 x 3 were used in the high-dose chemotherapy. Complications related to the treatment were limited to one patient who developed hepatic veno-occlusive disease, no serious complications were seen in the other patients. Four patients died of their disease, one patient was alive with the disease and 5 patients were alive with no evidence of disease. The prognosis for non-resectable primitive neuroectodermal tumor and Ewing's sarcoma is said to be very poor. However, there are some patients in whom the disease is kept in remission by high-dose chemotherapy with autologous peripheral blood stem cell transplantation, so this therapy may be a possible substitute for radical operation. With spindle cell sarcomas, the efficacy of this treatment was temporary, so it will be necessary to investigate frequent high-dose chemotherapy and to change the high-dose chemotherapy regimen.

Multiple spontaneous small bowel perforations due to systemic cholesterol atheromatous embolism.

A-65-year-old man was admitted for coronary and peripheral angiography to evaluate angina pectoris and peripheral vascular disease. Following angiography, he suffered from blue toes, livedo reticularis and progressive renal failure. The patient's condition continued to deteriorate, including the development of malnutrition. Four months later he suddenly developed panperitonitis, went into shock and died. The autopsy verified multiple perforations of the small bowel with disseminated cholesterol atheromatous embolism. The other organs including kidney were also invaded by atheroembolism. This was a rare case of multiple spontaneous perforations of small bowel due to systemic cholesterol atheromatous embolism.

Age- and sex-related changes in type-1 iodothyronine deiodinase messenger ribonucleic acid in rat liver and kidney.

To evaluate the age- and sex-related changes in Type 1 iodothyronine deiodinase gene expression in the liver and kidneys, we measured 5'-deiodinating activity and deiodinase mRNA in developing rats. The activity in the liver increased after birth, and that in neonates was approximately half that in adults. In contrast, the activity in neonatal kidneys remained very low. The relative importance of activity in male kidneys compared to the liver increased from the ages of 1 to 20 days. The male adult rat liver showed a higher level of activity than the female liver. Deiodinase mRNA in the male liver gradually increased from 1 to 20 days, in correlation with the activity. In kidneys, deiodinase mRNA was low before day 20, and there was no significant sex difference in all age groups. In orchiectomized male rats, the activity and mRNA in the liver was similar to the low levels found in females; however, the levels in the kidneys were not significantly different than those of normal males. These data suggest that the age- and sex-related changes in iodothyronine deiodinase gene expression are regulated mainly at the pretranslational level, and that the relative importance of kidneys to liver in iodothyronine deiodinase increases from birth to age 20 days due to the difference in the gene expression.

Effect of nicotine on type 2 deiodinase activity in cultured rat glial cells.

Intracellular generation of triiodothyronine (T3) from thyroxine (T4) by type 2 deiodinase (D2) in the mammalian brain, plays a key role in thyroid hormone action. The presence of D2 in rat astrocytes suggests the importance of glial cells in the regulation of intracellular T3 levels in the rat central nervous system (CNS). To analyze further the factors that regulate D2 activity in the CNS, we investigated the effects of nicotine and of mecamylamine, which inhibits the binding of nicotine with nicotinic acetylcholine receptors, on D2 activity in cultured mixed glial cells of the rat brain. We incubated cultured mixed glial cells obtained from neonatal Wistar rats in the presence of 10 mM dithiothreitol, 2 nM [125I] reverse T3 and 1 mM 6-N-propyl-2-thiouracil for 2 h at 37 degrees C, and the released 125I- was counted in a gamma counter. D2 activity of cultured cells was dependent on the temperature and the amount of protein. The basal D2 activity of rat mixed glial cells was 1.9 +/- 0.2 fmol of I- released/mg protein/h (mean +/- SEM). The addition of 10(-11), 2 x 10(-11), 10(-10), and 10(-9) M nicotine significantly increased D2 activity to approximately 2.2-, 2.4, 3.5- and 2.9-fold the basal level, respectively. D2 activity stimulated by 10(-8) M nicotine (2.5-fold) reached a peak after 9 h incubation. The stimulatory effect of nicotine was completely blocked by 10(-6) M mecamylamine. In conclusion, nicotine increases D2 activity probably via nicotinic acetylcholine receptors, and may influence brain function, at least in part, by affecting thyroid hormone metabolism.

Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme Q10 in diabetic patients.

Serum coenzyme Q10 (CoQ10: 2-(3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34 ,38 -tetracontadecaenyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, CAS 303-98-0) and cholesterol levels were measured to assess the effect of cholesterol-lowering therapy in patients with non-insulin-dependent diabetes mellitus (NIDDM). Twenty healthy volunteers, 97 NIDDM patients and 2 patients with familial hypercholesterolemia were studied. None had overt heart failure or any other heart disease. Mean serum CoQ10 concentrations were significantly (p < 0.01) lower in diabetic patients with normal serum cholesterol concentrations, either with or without administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) including simvastatin (normal: 0.91 +/- 0.26 (mean +/- SD) mumol 1(-1); diabetic with HMG-CoA RI: 0.63 +/- 0.19; diabetic without HMG-CoA RI: 0.66 +/- 0.21). CoQ10 concentrations were higher (1.37 +/- 0.48, p < 0.001) in diabetic patients with hypercholesterolemia. Simvastatin or low density lipoprotein apheresis decreased serum CoQ10 concentrations along with decreasing serum cholesterol. Oral CoQ10 supplementation in diabetic patients receiving HMG-CoA RI significantly (p < 0.001) increased serum CoQ10 from 0.81 +/- 0.24 to 1.47 +/- 0.44 mumol 1(-1), without affecting cholesterol levels. It significantly (p < 0.03) decreased cardiothoracic ratios from 51.4 +/- 5.1 to 49.2 +/- 4.7%. In conclusion, serum CoQ10 levels in NIDDM patients are decreased and may be associated with subclinical diabetic cardiomyopathy reversible by CoQ10 supplementation.

The surgical management of sacrococcygeal chordoma.

BACKGROUND: Complete excision of sacrococcygeal chordoma is necessary at initial surgery due to its poor sensitivity to radiotherapy and chemotherapy. However, due to the anatomic characteristics of this tumor, intralesional excision tends to be employed, resulting in local recurrences in many patients. METHODS: The clinical features and results of surgical treatment of 13 patients with sacrococcygeal chordoma who were treated at the Chiba Cancer Center and Chiba University beginning in 1972 were analyzed. RESULTS: Intralesional excision was performed in eight patients, marginal excision in two patients, and wide excision in three patients. Local recurrence was observed in six patients, with a high proportion occurring in the gluteal muscles attached to the sacrum (the gluteus maximus muscle and piriform muscle). Seven patients died of their disease and six patients were alive with no evidence of disease. The 5-year survival rate was 81.8% and the 10-year survival rate was 29.1%. CONCLUSIONS: It is highly possible that residual chordoma infiltrating the gluteal muscles accounts mainly for the local recurrences. Therefore, a precise preoperative assessment of the tumor infiltration into the gluteal muscles by magnetic resonance imaging is important for the prevention of local recurrence. For complete tumor removal, a radical wide posterior surgical margin of the gluteal muscles should be employed. A less radical anterior surgical margin is sufficient because there is a firm presacral fascia anterior to the sacrum. The appropriate surgical margin for the complete removal of the chordoma differs according to the location of the tumor and tissues involved.

Primary aldosteronism with aldosterone-producing adrenal adenoma in a pregnant woman.

A 30-year-old pregnant woman complained of muscle weakness at 29 weeks' gestation. She was hypertensive with severe hypokalemia. Lower plasma renin activity and higher aldosterone level than the normal values in pregnancy suggested primary aldosteronism. A cesarean delivery was performed at 31 weeks' gestation because of pulmonary congestion. The neonatal course was uncomplicated. The laparoscopic adrenalectomy for a 2.0-cm right adrenal adenoma resulted in normalizing of her blood pressure and serum potassium level. Although primary aldosteronism is rare, especially during pregnancy, it should be always considered as one of etiologies of hypertension in pregnancy.

Significance of platelet-derived microparticles and activated platelets in diabetic nephropathy.

We measured levels of platelet-derived microparticles (PMP), which have coagulative activity and are produced by platelet activation or physical stimulation, and CD62P/CD63-positive platelets in patients with diabetes mellitus to determine their clinical significance and effects on complications of diabetes including diabetic nephropathy. We also compared these levels before and after administration of the antiplatelet drug cilostazol. Plasma PMP and CD62P/CD63-positive platelet levels were significantly higher in patients with diabetes mellitus than normal controls. CD62P-positive platelet levels were significantly higher in patients with nephropathy than in patients without complications. After administration of cilostazol, PMP and CD62P/CD63-positive platelet levels were significantly decreased. The increases in platelet activity and its related procoagulant activity appear to account in part for the hypercoagulability observed in diabetes mellitus. Our findings suggest that activated platelets might play a role in the development of diabetic nephropathy. Furthermore, antiplatelet therapy with cilostazol for diabetic patients may be useful as antithrombin therapy including antiplatelet therapy, since it suppresses the production of intrinsic coagulants produced by platelet activation.

Two cases of osteosarcoma occurring as second malignancy of childhood cancer.

We report on two patients in whom osteosarcoma occurred as second malignancy of childhood cancer. One patient had a malignant teratoma and the other adrenocortical carcinoma as the primary cancer. The emergence of cancer in cured cases and long-term survival cases of childhood cancer may result in an increase in the number of osteosarcomas seen in adolescence occurring as second malignancy. Anti-cancer drugs in large does were used for the treatment of a malignant teratoma in the former. These anti-cancer drugs may be involved in the occurrence of the second malignancy. In the latter, the patient has the germ-line mutation of p53 tumor suppressor gene, so genetic factors are presumably related to the occurrence of the second malignancy.