VALIDATION OF MONTE CARLO DOSE CALCULATION FOR PAEDIATRIC CT EXAMINATIONS USING TUBE CURRENT MODULATION BASED ON IN-PHANTOM DOSIMETRY.

The aim of this study is to estimate tube current modulation (TCM) profiles in paediatric computed tomography (CT) examinations with a TCM scheme (Volume-EC) and evaluate the estimation accuracy of TCM profiles. Another aim is to validate organ doses calculated using Monte Carlo-based CT dosimetry software and estimated TCM profiles by comparing them with those measured using 5-year-old and 10-year-old anthropomorphic phantoms and radio-photoluminescence glass dosemeters. Dose calculations were performed by inputting detailed descriptions of a CT scanner, scan parameters and CT images of the phantoms into the software. Organ doses were evaluated from the calculated dose distribution images. Average relative differences (RDs) between the estimated and actual TCM profiles ranged from -3.6 to 5.6%. RDs between the calculated and measured organ doses ranged from -4.2 to 13.0% and -18.1 to 4.9% for 5-year-old and 10-year-old phantoms, respectively. These results validate dose calculations for paediatric CT scans using TCM.

Buruli ulcer in a nine-month-old boy.

The diagnosis of Buruli ulcer should be considered in all painless undermined ulcers in the tropics. The diagnosis and treatment are a challenge in rural settings despite the well established tuberculosis programmes. Immediate commencement on rifampicin and streptomycin is essential to halt the progression of disease and to, hopefully, reverse it. Surgery is indicated in those with complex ulcers or with complications. We report the case of a nine-month-old boy presenting to visiting British surgeons in a district hospital in Uganda with multiple ulcers to the right forearm.

[Comparison of management of advanced cancer in various organs].

The management of advanced cancer presents the greatest challenge to physicians involved in oncology. There will usually be a large burden of disease; cure is unlikely; and the needs of the patient in terms of pain control and palliation will also be important over and above the direct treatment of the disease. Different issues will arise depending on the site and pathological type of the cancer. Increasingly over the past few years, treatment protocols and guidelines have been developed for different cancers, but these can only be rough guides rather than definite treatment recommendations. Additionally in most cancers advanced disease offers the opportunity for evaluation of new treatments in Phase II studies and other trials. With the new generation of molecular targeted therapies, such as EGFR inhibitors, striking results are being seen in advanced disease that compare favourably with what has been seen previously. Other agents such as those which attack the tumour vasculature may also have promise in this setting. Palliation is also an important aspect of the management of advanced disease, and pain control in particular is an important component of patient management. In summary, the treatment of advanced disease provides a test bed for new agents, but this need to develop better cancer therapies must be balanced against patient needs for a pain-free and comfortable end to life.

[Molecular specificity of nafamostat mesilate (FUT), a drug used for the treatments of DIC and acute pancreatitis and as an anticoagulant--the pharmacodynamics and pharmacological action].

Pharmacokinetic studies of nafamostat mesilate (FUT) were reviewed in the previous report (Jpn J Cancer Chemother 27 (5): 767-774, 2000). In this report, the molecular specificity of FUT for these pharmacological behaviors were reviewed. In this study, it became clear that benzene ring inserted between ester-bond and guanidino group of the molecule and amidino group introduced in the opposite chain of guanidino group were found important for eliciting the molecular specificity of FUT.

[Results of gemcitabine hydrochloride in the treatment for pancreatic cancer].

Pancreatic cancer has extremely poor prognosis. However no satisfactory effective chemotherapy for this cancer has been established. Gemcitabine hydrochloride, a novel anti-tumor agent, had shown the remarkable clinical efficacy for pancreatic cancer. In April 2001, the indication for pancreatic cancer of this agent has been approved in Japan and it is expected to be widely and increasingly introduced for clinical use. This review summarizes the study results of gemcitabine mono-therapy for pancreatic cancer and discusses other possibility of the treatment by Gemcitabine with the reported data about its combination therapy with other anti-cancer drug or radiation.

[Clinical effects of a 3-month formulation LH-RH agonist (Zoladex LA 10.8 mg depot) in patients with prostate cancer].

Pharmacodynamics (PD), anti-tumor effects, safety and pharmacokinetics of a 3-month formulation of goserelin (Zoladex LA 10.8 mg depot: "10.8 mg depot") were investigated in a collaborative multicenter study. Study participants were 40 Japanese patients with prostate cancer comprising 20 untreated patients and 20 switch patients who had been receiving Zoladex 3.6 mg depot for 3 months or longer. Serum testosterone levels, serum LH levels, prostate-specific antigen (PSA) levels and drug concentrations were measured until 12 weeks after a single subcutaneous dose of 10.8 mg depot. Anti-tumor effects were evaluated by means of changes in the tumor lesions and the PSA levels at 12 weeks. After administration to the untreated patients, 10.8 mg depot reduced serum testosterone to the castrate range within 4 weeks and the reduction was maintained for up to 12 weeks. In the switch patients, serum testosterone suppression that had been produced by previous treatment with Zoladex 3.6 mg depot was maintained for up to 12 weeks following 10.8 mg depot administration. The anti-tumor effect at 12 weeks was 90.0% including partial response cases. The ratio of PSA normalization at 12 weeks was 75.0%. Fifty-seven adverse reactions were observed in 27 of the 40 patients (67.5%), but none were clinically significant. Although a disease flare presented as urinary retention in 1 of the untreated patients, all patients completed the study. Serum goserelin was detected up to 12 weeks after the administration of 10.8 mg depot. In conclusion a single dose of 10.8 mg depot showed a satisfactory PD-effect and brought about clinical efficacy persisting for at least 12 weeks and was well tolerated in patients with prostate cancer.

[Platinum compounds in cancer therapy--past, present, and future].

Platinum cytotoxics play an important role globally in the management of solid tumours. Cisplatin sets the standard for efficacy in both regions with careful administration to reduce nephrotoxicity. Carboplatin is associated with neurotoxicity, but has become the leading product in the US due largely to the easier to manage toxicity profile. Both agents have been widely used in both registered and non registered indications and are frequently combined with other cytotoxics. In Japan, cisplatin has been used successfully at low doses in combination with 5-FU based regimens and appears to achieve a synergistic effect, but controlled data are not yet available. More recently oxaliplatin (Europe) and nedaplatin (in Japan) have been introduced, but their clinical roles in therapy have yet to be established. One of the limiting features of the first generation of platinum compounds is that a significant proportion of tumours develop cross resistance to platins due to either changes in uptake or excretion, intracellular detoxification or accelerated DNA repair. The forum discussed the possibility for the development of better new platinum compounds, A new platin agent which had lower toxicity and higher efficacy across a wide range of cancers without the development of resistance would be a significant step forward. If the tolerability profile was suitable, an oral formulation may improve the quality of life for patients but this must not be at the expense of efficacy. Even after the introduction of new target based drugs, platinum cytotoxics are likely to be used to reduce the tumour mass and in some cases can be expected to potentiate the effects of the new agents. In preclinical studies, ZD0473 has been shown to by-pass some major mechanisms of resistance and has the potential to achieve these objectives and is now being evaluated in clinical studies in both Japan and the West.

[Development of a novel aromatase inhibitor, anastrozole (Arimidex)--its basic and clinical studies].

Anastrozole (JAN), developed by Zeneca UK (presently AstraZeneca UK), is a new aromatase inhibitor which belongs to triazole. Anastrozole shows selective aromatase inhibition and negligible effects on other steroid hormone biosyntheses. The daily dose of 3 mg/kg anastrozole inhibited the growth of DMBA mammary tumours significantly. Anastrozole inhibited the tumor growth at 5 micrograms/mouse/day (s.c.) in androstenedione-treated ovariectomized nude mice inoculated with MCF-7CA cells transfected with aromatase gene. In the Japanese Phase IIa study, the response rate was 27.8% (10/36) in the 0.5 mg group, and 38.2% (13/34) in the 1 mg group. The most common adverse drug reactions were leucopenia in the 0.5 mg group, and LDH increased and leucopenia in the 1 mg group. There were no early deaths, other serious adverse events, or adverse drug reactions of grade 3 or above in this trial; anastrozole was well tolerated. In the Japanese Phase IIb study, the response rates were 33.3% (117/351 patients) and 32.8% (114/348 patients) for anastrozole and tamoxifen, respectively, showing non-inferiority of anastrozole. The median time to disease progression (TTP) was 251 days and 252 days for anastrozole and tamoxifen, respectively. Group comparison using a Cox regression model revealed non-inferiority of anastrozole. Therefore, anastrozole was found to be at least as effective as tamoxifen (in the response rate and TTP). In US study compared anastrozole with tamoxifen, TTP with anastrozole is a significantly longer than that of tamoxifen (p = 0.005, two-sides). Anastrozole has shown to be at least as effective as tamoxifen, standard endocrine therapy for breast cancer, with good safety profiles. Thus, anastrozole is a promising first-line endocrine therapy in the treatment of postmenopausal breast cancer.

Assessment of proliferation index with MIB-1 as a prognostic factor in radiation therapy for cervical cancer.

OBJECTIVES: The relationship between the expression of murine monoclonal antibody MIB-1, which reacts with Ki-67 nuclear antigen, a marker for proliferating cells, and the prognosis of stage IIIb cervical cancer after radiation therapy was analyzed. METHODS: A total of 67 patients with stage IIIb cervical cancer who had received radiation therapy were included in the retrospective study. The labeled streptavidin-biotin method was used for immunohistochemical staining of the MIB-1 protein. RESULTS: In 32 patients showing a high MIB-1 index (percentage of cells labeled with MIB-1 >/=26.4%), the cumulative 5- and 8-year survival rates were 75.8 and 61.5%, respectively, significantly better (P < 0.05) than those in 35 patients with a low MIB-1 index (<26.4%) (59.6 and 41.1%, respectively). Serum squamous cell carcinoma antigen levels, an index of the response to radiation therapy, decreased to

Effects of bathing immediately after birth on early neonatal adaptation and morbidity: a prospective randomized comparative study.

OBJECTIVE: Because the risks and benefits of early bathing of newborn infants are not well established, we investigated the effects of bathing immediately after birth on rectal temperature, respiratory rate, heart rate, blood pressure, percutaneous arterial blood oxygen saturation (SpO2) and early neonatal morbidity. METHODS: The study was designed as a randomized prospective comparative study in the neonatal care unit of a university hospital. A total of 187 healthy term and near-term newborn infants, who were delivered vaginally without asphyxia, between January and December 1997 were the study subjects. We compared findings in newborns who were bathed 2-5 min after birth (n = 95) with those of a control group (n = 92) who received dry care instead. Groups were comparable with respect to gestational age, birthweight, male: female ratio, Apgar score and umbilical blood pH. Rectal temperature was measured with an electronic thermometer immediately before the intervention bathing or dry care and at 30 min and 1, 2, 3, 8 and 12 h after birth. Heart rate, respiratory rate, systolic and diastolic blood pressure and SpO2 were measured at 1, 2, 8 and 12 h after birth. The incidence of early neonatal morbidity, including hyperbilirubinemia and gastrointestinal and respiratory problems, was also compared. RESULTS: Rectal temperature changed over time postnatally in both groups (P < 0.0001, ANOVA) and there was a significant difference in rectal temperature between groups (P< 0.0001, ANOVA). Mean (+/- SEM) rectal temperature at 30 min after birth (i.e. approximately within 20 min after intervention) was significantly higher in the bathed group than in the control (dry care) group (37.30 +/- 0.06 is 37.00 +/- 0.05 degrees C, respectively; P = 0.000022). Respiratory rate, heart rate, blood pressure and the ratio of the number of infants with SpO2 90-94% and 95-100% did not differ significantly between the two groups. The incidence of early neonatal morbidity, including vomiting, acute gastric mucosal lesion, polycythemia, need for tube feeding, phototherapy and oxygen therapy, also did not differ between the two groups. CONCLUSIONS: Early bathing, minutes after birth, did not appear to adversely affect the adaptation of healthy full-term and near-term newborn infants.

A dose-escalation and pharmacokinetic study of subcutaneously administered recombinant human interleukin 12 and its biological effects in Japanese patients with advanced malignancies.

A pilot dose-escalation study of recombinant human interleukin 12 (rhIL-12) was conducted in Japanese patients with advanced malignancies. Cohorts of three patients received escalating doses of rhIL-12 that increased from 50 to 300 ng/kg/day s.c. three times a week for 2 weeks followed by 1-week rest. The same dosage and schedule was repeated for two additional courses. Sixteen previously treated patients were registered, and 15 were evaluated. Common toxicities were fever and leukopenia; the abnormality of laboratory tests included elevations in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and beta2-microglobin. Dose-limiting toxicity was the grade 3 elevation of aminotransferases, and was observed in two of six patients at the 300-ng/kg dose level after the first course in one patient and after the third course in the other. Leukopenia was observed at all of the dose levels; two of six patients at 300 ng/kg experienced grade 3 leukopenia. Thus, 300 ng/kg was determined to be the maximum acceptable dose. Peak plasma levels of rhIL-12 decreased in the second courses, but the areas under the curve were almost the same in the first and second courses. Biological effects included increases of plasma levels of IFN-gamma, tumor necrosis factor-alpha, IL-6, IL-10, and neopterin. In two patients with renal cell carcinoma, complete response and partial response of metastatic tumors were observed with 50 and 300 ng/kg; the responses lasted for 5 and 3.5 months, respectively. Although immunological response to rhIL-12 varies depending on administration route and schedule and on patients' physiological conditions, the recommended dose for Phase II studies is 300 ng/kg s.c. three times a week for 2 weeks followed by 1-week rest.

[Pharmacokinetics studies of nafamostat mesilate (FUT), a synthetic protease inhibitor, which has been used for the treatments of DIC and acute pancreatitis, and as an anticoagulant in extracorporeal circulation].

Nafamostat mesilate (FUT) was first reported by Fujii et al, in 1981 as a synthetic protease inhibitor. FUT has been reported as a drug for the treatments of DIC (disseminated intravascular coagulation) and acute pancreatitis and as an anticoagulant in extracorporeal circulation. FUT has a structure of ester conjugate of p-guanidinobenzoic acid and 6-amidino-2-naphthol. In in vivo, this ester site was found as the reaction center as well as the site for the catabolic changes. Plasma half life (t1/2 beta) of FUT was about 23.1 min, compared to about 55 seconds of the related compound, FOY. The inhibitory activity of FUT on the protease was found to be due to the mis-reading of serine protease in vivo.

[Antitumor effects of TZT-1027, a novel dolastatin 10 derivative, on human tumor xenografts in nude mice].

TZT-1027 was evaluated for its antitumor effects in sixteen human tumors xenografted in nude mice from gastric (H-81, H-106, H-30, H-154), breast (H-31, H-62), colon (H-110, H-143), lung (LC-376, H-74, Mqnu-1, LC-351), liver (H-181), renal cell (H-12) and ovarian (H-OC-3, SOC-4) cancer lines. In the latter three and lung (Mqnu-1, LC-351) cancers the results were compared with those obtained with CPT-11, VCR, CDDP, ADM. TZT-1027 showed effective antitumor activity (IR > or = 58%) against fifteen of the tumor lines, all but LC-351, and showed markedly effective activity (IR > or = 80%) against twelve tumor lines, including drug-resistant colon (H-110), lung (H-74) and ovarian (SOC-4) cancer lines. The complete regression was shown in five H-OC-3 tumor-bearing mice out of seven. Moreover, TZT-1027 was shown to be more potent in three cancer models (Mqnu-1, H-81, SOC-4) than CPT-11, and to have markedly effective antitumor activity in two cancers (H-12, H-OC-3) in which VCR was ineffective and in ovarian cancer (SOC-4) in which CPT-11, CDDP and ADM were ineffective. The administration of TZT-1027 induced fewer side effects; transient reduction of body weight was observed in four lines out of sixteen tested. These results suggest that TZT-1027 is an excellent candidate for clinical trials for the treatment of cancer.

Recurrent ovarian clear cell carcinoma: complete remission after radiation in combination with hyperthermia; a case study and in vitro study.

Since clear cell carcinoma of the ovary does not respond to conventional platinum-based chemotherapy, the prognosis of recurrent tumors is especially poor. In a 51-year old female who underwent surgery for clear cell carcinoma of the ovary, a solitary metastatic carcinoma developed in the pelvic cavity seven months after the initial surgery. The patient underwent a whole pelvic irradiation at a total dose of 65 Gy combined with hyperthermia. Complete remission was achieved 46 months after treatment. A study using gynecologic carcinoma cell lines showed that the mean 50% growth inhibitory dose of radiation was 1.2 +/- 0.4 Gy in several clear cell carcinoma cell lines. The value did not significantly differ from those for serous carcinoma cell lines (2.3 +/- 1.2 Gy) and uterine cervical carcinoma cell lines (1.6 +/- 0.4 Gy). Currently, no anticancer agents are effective for clear cell carcinoma. Radiotherapy combined with hyperthermia may be effective for localized tumors.

A patient with brain metastasis from ovarian cancer who showed complete remission after multidisciplinary treatment.

We describe a case with brain metastasis from ovarian cancer who showed complete remission after multidisciplinary treatment. The case was diagnosed as epithelial ovarian cancer, FIGO stage IIIc. She underwent cisplatin-based chemotherapy after optimal cytoreductive surgery and achieved clinical complete remission. Thirty-two months after surgery for ovarian cancer, a solitary metastasis occurred in the left frontal lobe of the brain. No recurrent lesions were observed outside the brain. The metastatic tumor was resected. Five days after operation, adjuvant chemotherapy comprising carboplatin and cisplatin was initiated (a total of three courses at 4-week intervals), and whole brain irradiation at 55 Gy was added. After these treatment methods, complete remission of the brain metastasis has been observed for 57 months with good quality of life.

Enhanced expression of thymidylate synthase may be of prognostic importance in advanced cervical cancer.

The enhanced expression of thymidylate synthase (TS) has been associated with a poor prognosis in patients with several types of epithelial tumors. To determine the association between TS expression and the prognosis of patients with advanced cervical cancer after radiation therapy, we immunohistochemically assayed TS levels in paraffin-embedded tissue sections from 66 patients with stage IIIb cervical cancer using a polyclonal antibody to recombinant human TS. In the 30 patients with high TS expression, the cumulative 5- and 8-year survival rates were 36.8% (95% CI: 17. 4-56.2) and 31.6% (95% CI: 12.4-50.7), respectively. In contrast, the 36 patients with low TS expression showed a significantly (p < 0. 001) better prognosis, with cumulative 5- and 8-year survival rates of 87.2% (95% CI: 75.5-99.0) and 69.2% (95% CI: 50.7-87.7), respectively. These results suggest that TS expression may be useful in determining the prognosis of patients with advanced cervical cancer.

[Clinical development in gemcitabine and its clinical pharmacological profile].

Gemcitabine Hydrochloride (hereafter: Gemcitabine) is a new anti-tumor agent being widely used in other countries for treatment of non-small cell lung cancer was recently approved in Japan. The profile of Gemcitabine is considered to be the following 2 points both for non-small cell lung cancer and for pancreatic cancer, of which the study is currently conducted in Japan: high efficacy as foreign data indicate prolongation of survival time and less frequency of serious adverse reactions than other conventional anti-tumor agents. According to the results of Japanese and foreign phase I studies, as clinical pharmacological profile of Gemcitabine, its elimination half-life is rather short such as 20 minutes. Weekly administration by injection over 30 minutes is appropriate since bone marrow suppression and hepatic disorder were frequently observed in case of administration twice a week or injection for more than 60 minutes. Also, population pharmacokinetics results showed a tendency that blood plasma clearance of Gemcitabine was lower in women and aged patients. Dose adjustment depending on gender is not considered to be necessary because the blood plasma clearance amount of Gemcitabine is large enough itself. However, influence caused by aging must be observed continuously in the future. For its profile of mild adverse reactions of Gemcitabine mentioned above, concomitant chemotherapy with other anti-tumor agents is expected be widely conducted in the future, therefore, clinically pharmacological observation of Gemcitabine is important for its appropriate use as well.

[Pharmacokinetics of azasetron (Serotone), a selective 5-HT3 receptor antagonist].

5-HT3 receptor antagonists have been established in a number of clinical trials as effective agents in the management of nausea and vomiting induced by cancer chemotherapy including cisplatin. Azasetron (Serotone) is a potent and selective 5-HT3 receptor antagonist, and classified as benzamide derivative. It has a different chemical structure from indole-type 5-HT3 receptor antagonists such as granisetron, ondansetron, ramosetron and tropisetron. The major difference is found in the pharmacokinetic profiles. Approximately 60-70% of azasetron administered i.v. and orally is excreted in urine as the unmetabolized form. Also, orally-administered azasetron has shown to be absorbed and/or secreted by the saturable transport mechanism in the small intestine, resulting in good bioavailability as approximately 90%. In this report, the relationship between the structure of 5-HT3 receptor antagonists (especially azasetron) and their pharmacokinetics were described.

[Advance in cancer chemotherapy].

From the middle of the 20th Century, many anticancer drugs have been developed, and about 40 kinds of anticancer drugs are currently have been used for cancer treatment. From the past pre-clinical and clinical studies, it was found that combination of two or more drugs was sometimes more effective than the single use, resulting the increase of cure-rates in some-type of human malignancies. Recently, new treatment regimens based on the concept of biochemical modulation have been used for the treatment of cancer of the digestive organs. Also, currently, supportive therapies against the adverse-drug reactions (side effects) became available, and sometimes improvement of QOL of the cancer patients has been expected with the use of these therapies. In facing to the 21st Century, studies of new type of drugs such as those to novel molecular targets have been progressing.

[Non-clinical studies of gemcitabine--the mode of action and antitumor activities].

Gemcitabine (2', 2'-difluorodeoxycytidine: dFdC) is a nucleoside analogue of deoxycytidine (dCyd). In the cells, dFdC is rapidly phosphorylated by dCyd kinase. dFdC inhibits ribonucleotide reductase and the subsequent decrease in cellular deoxynucleotides (particularly dCTP) is an important self-potentiating mechanism, resulting in decreased dFdC nucleotide incorporation into DNA. Other self-potentiating mechanisms of dFdC include increased formation of active dFdCDP and dFdC TP, and decreased elimination of dFdC nucleotides. After dFdC nucleotide is incorporated on the end of the DNA strand, one more deoxynucleotide is added and thereafter the DNA polymerases are unable to proceed (masked chain termination). dFdC is a better transport substrate compared with Ara-C, phosphorylated more efficiently and eliminated more slowly. These differences together with self-potentiation, masked chain termination and the inhibition of ribonucleotide reductase may explain why dFdC is active against human solid cancers compared with Ara-C. Schedule-dependent antitumor activities of dFdC were observed against various rodent tumors and human cancer xenograft systems.