Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with gastric cancer (GC), published in late 2022 and the updated ESMO Gastric Cancer Living Guideline published in July 2023, were adapted in August 2023, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with GC. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with GC representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), coordinated by ESMO and the Japanese Society of Medical Oncology (JSMO). The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with GC across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling and age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Incidence, clinicopathological features, and clinical outcomes of low HER2 expressed, inoperable, advanced, or recurrent gastric/gastroesophageal junction adenocarcinoma.

BACKGROUND: According to the DESTINY-Breast04 trial, treating patients with breast cancer and low human epidermal growth factor receptor 2 expressions (HER2-low) varies from that of those with no HER2 expression. However, it is interesting to know if HER2-low indicates for anti-HER2 therapy in the gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Hence we conducted this study to assess the incidence, clinicopathological features, and treatment outcomes of patients with HER2-low G/GEJ adenocarcinoma. PATIENTS AND METHODS: This was a single-center, retrospective observational study. Patients with previously untreated G/GEJ adenocarcinoma were classified based on their HER2 status using immunohistochemistry (IHC) with or without in situ hybridization (ISH) as follows: HER2 negative (IHC 0), HER2-low (IHC 1+ or 2+/ISH-), and HER2-positive (IHC2+/ISH+ or 3+). RESULTS: In total, 734 patients with G/GEJ adenocarcinoma were divided into three groups (HER2-negative, n = 410; HER2-low, n = 154, and HER2-positive, n = 170). The intestinal-type histology, peritoneal metastasis, and higher serum carcinoembryonic antigen (CEA) levels differed significantly among patients with negative, low, and positive HER2 statuses: intestinal-type histology (21.0%, 44.2%, and 59.8%, respectively), peritoneal metastasis (56.3%, 44.8%, and 21.8%, respectively), and higher serum CEA level (32.2%, 41.6%, and 56.5%, respectively). Improved survival was observed in the HER2-positive group than in the HER2-negative G/GEJ adenocarcinoma group [hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.59-0.89; P = 0.002]. However, the prognoses of the HER2-low and HER2-negative groups were similar (HR = 1.01, 95% CI 0.82-1.23; P = 0.843). CONCLUSIONS: Patients with HER2-low G/GEJ adenocarcinoma exhibited intermediate and distinct characteristics than those in the HER2-negative group. Similarly, the HER2-low group's prognosis was worse than that of the HER2-positive group. Therefore developing novel therapeutic strategies targeting HER2-low G/GEJ adenocarcinoma is required.

A novel clinical prognostic index for patients with advanced gastric cancer: possible contribution to the continuum of care.

BACKGROUND: The Japan Clinical Oncology Group (JCOG) prognostic index, consisting of performance status, primary tumor resected, number of metastases, and serum alkaline phosphatase, has been one of the robust prognostic indices for patients with advanced gastric cancer on the basis of which clinical trials have stratified prognosis. Only a few studies, however, have utilized the JCOG prognostic index in daily practice. METHODS: We conducted a retrospective study on patients with advanced gastric cancer who received first-line platinum-containing chemotherapy at a single institute between 2011 and 2017. Prognostic factors were evaluated using a Cox proportional regression model. RESULTS: A total of 608 patients were enrolled. Multivariate analysis showed that performance status ≥1, presence or absence of primary tumor, serum alkaline phosphatase, neutrophil-to-lymphocyte ratio ≥4, and diffuse-type histology were significantly associated with worse prognosis, whereas the number of metastases was not. Although the original prognostic index could not adequately stratify patients into three risk groups, the modified index (good: 0 and 1, moderate: 2 and 3, poor: 4-6), which was established by incorporating diffuse-type histology and high neutrophil-to-lymphocyte ratio, demonstrated excellent stratification. The median overall survival of the good (n = 315), moderate (n = 243), and poor (n = 54) risk groups was 20.5, 13.5, and 10.2 months, respectively. Hazard ratios (HRs) were 1.69 [95% confidence interval (CI), 1.40-2.04; good versus moderate] and 1.52 (95% CI, 1.11-2.08; moderate versus poor). This novel index also demonstrated a statistically significant stratification of survival after progression following first-line chemotherapy (good versus moderate: HR, 1.41; 95% CI, 1.16-1.70; moderate versus poor: HR, 2.00; 95% CI, 1.45-2.74). CONCLUSIONS: The modified JCOG prognostic index showed excellent stratification of overall survival in real-world patients, which could also help determine the need for treatment changes throughout the continuum of chemotherapy.

Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

Expression of beta-catenin, E-cadherin and cyclin D1 in adenoid cystic carcinoma of the salivary gland.

We evaluated the expression of beta-catenin, E-cadherin, and cyclin-D1 in 23 cases of adenoid cystic carcinoma (ACC) of the salivary gland. We detected beta-catenin on the cell membranes in all ACCs, but its distribution was irregular, as compared to that on normal structures. In three out of the 23 cases, beta-catenin was detected in the nuclei, as well as on cell membranes. Polymerase chain reaction (PCR) and direct sequencing revealed a missense mutation in one case in which beta-catenin had been detected in the nuclei of tumor cells. We also detected E-cadherin on cell membranes with a similar irregular distribution to that of beta-catenin. In 11 cases (almost 48%) of ACC, cyclin D1 was localized in cell nuclei but there was no correlation with the nuclear staining of the beta-catenin. Our results suggest that disturbances in the distribution of beta-catenin and E-cadherin might affect the morphology ofACC and that a small fraction of cases of ACC are characterized by a mutation in the beta-catenin gene, which is associated with the nuclear accumulation of the product of this gene but does not affect the transcription of the gene for cyclin-D1.

Expression of nitric oxide synthase by cytokines in vascular smooth muscle cells.

In cultured vascular smooth muscle cells, the baseline mRNA and protein levels of an inducible type of nitric oxide synthase were barely detectable. Interferon gamma, tumor necrosis factor-alpha, and interleukin-1 beta each markedly increased mRNA and protein levels of this enzyme in parallel with the production of nitrite, a stable oxidative metabolite of nitric oxide. Actinomycin D abolished the cytokine-induced increases in mRNA levels and nitrite production. Cycloheximide, which abolished the cytokine-induced increase in nitrite production, had no effect on the interferon-gamma-induced increase in mRNA levels but partially inhibited that induced by interleukin-1 beta and markedly inhibited that induced by tumor necrosis factor-alpha. Transforming growth factor-beta 1, which inhibited the interferon gamma-, interleukin-1 beta-, and tumor necrosis factor-alpha-induced nitrite production, did not affect the increases in mRNA levels caused by these cytokines. Transforming growth factor-beta 1, however, significantly inhibited the increase in protein levels caused by these cytokines. These findings suggest that interferon gamma directly induces the expression of the inducible nitric oxide synthase gene, whereas tumor necrosis factor-alpha and interleukin-1 beta induce it, at least in part, via the induction of intermediary protein(s), and that transforming growth factor-beta 1 inhibits cytokine-induced nitric oxide production by blocking the posttranscriptional synthesis of inducible nitric oxide synthase.

Nucleotide sequence of the insecticidal protein gene of Bacillus thuringiensis strain aizawai IPL7 and its high-level expression in Escherichia coli.

A DNA fragment carrying the insecticidal protein gene of Bacillus thuringiensis subsp. aizawai IPL7 was cloned from a 78-kb plasmid. The nucleotide sequence revealed that the cloned DNA fragment contained a 3465-bp protein-coding region with 156-bp 5'-flanking, and 168-bp 3'-flanking regions. The open reading frame encoded a 130,690 Da protein consisting of 1155 amino acid residues. Nucleotide sequence comparison of the aizawai gene with the published berliner 1715 gene showed only 8 nt changes in the coding regions. It was found that 72 bp of the 5'-flanking sequence of the cloned aizawai gene was responsible for constitutive expression of the 130-kDa protein gene in Escherichia coli. The expression was greatly enhanced by introducing the tac promoter upstream from the 72-bp 5'-flanking region of the aizawai gene. Under optimal conditions, the 130-kDa insecticidal protein amounted to 38% of the total cellular protein.

Angiotensin II transduces its signal to focal adhesions via angiotensin II type 1 receptors in vascular smooth muscle cells.

In cultured vascular smooth muscle cells (VSMCs), angiotensin II (Ang II) stimulated tyrosine phosphorylation of several proteins including a cluster of 70-80-kDa proteins as assessed by anti-phosphotyrosine immunoblotting. These 70-80-kDa proteins were identified as a focal adhesion-associated protein, paxillin, by anti-paxillin immunoprecipitation. Ang II-stimulated tyrosine phosphorylation of paxillin was detectable within 1 min and maximal at around 10 min and was concentration dependent (half-maximal effect at around 1 nM). Ang II also stimulated tyrosine phosphorylation of focal adhesion kinase in a time- and concentration-dependent manner. The Ang II type 1 (AT1) receptor antagonist, CV-11974, but not the Ang II type 2 receptor antagonist, PD123319, inhibited these reactions. These results indicate that Ang II transduces its signal to focal adhesions via AT1 receptors in cultured VSMCs.

Quantitative age-related changes in apical dendrites and dendritic spines of CA1 pyramidal neurons among senescence accelerated mice (SAMP1TA/Ngs).

SAMP1TA/Ngs, a substrain of senescence accelerated mouse, is a useful animal model for research on brain dysfunction due to senescence. In a previous study it was reported that the age-related changes in basal dendrites and spines of CA1 pyramidal neurons coincide with the behavioral characteristics found in SAMP1TA/Ngs. The goal of the present study was to investigate morphological changes in apical dendrites and dendritic spines of CA1 pyramidal neurons among 3-, 5-, 7-month-old SAMP1TA/Ngs. Pyramidal neurons of the hippocampus were stained by the rapid Golgi method, and the number of apical dendrites, the number of their spines and the density of the dendritic spines were evaluated. The number and density of the spines of apical dendrites were significantly higher at 5 months than at 3 or 7 months of age. We propose that the low number of dendritic spines in 3-month-old animals was caused by immaturity, while the changes in the density and number of dendritic spines in 7-month-old mice were due to accelerated aging. The data on the morphology of apical dendrites are a useful complement to the results reported previously. The findings of the present study also support the hypothesis that this model mouse demonstrates changes in respective developmental stages, i.e. immaturity, adulthood and senescence. This pattern of postnatal growth has special meaning because it indicates the usefulness of the strain in the study of geriatric disorders in humans.

Morules with biotin-containing optically clear nuclei in colonic tubular adenoma.

Morules have been reported in pulmonary endodermal tumors (PET) resembling fetal lung, in thyroid carcinoma, and in endometrial and colonic neoplasms. A morule has biotin-containing optically clear nuclei (OCN) in PET and thyroid carcinoma. Biotin-containing OCN have been also reported in endometrial tissue during pregnancy and in endometrioid carcinoma of the ovary, and it has been postulated that morules or OCN develop under the influence of female sex hormones. The authors report here the first case, to their knowledge, of morules with OCN in a colonic adenoma from a 68-year-old man. The colonic polyp consisted of ordinary tubular adenomatous tissue and morules. Many cells in the morules contained OCN. The OCN were immunopositive for biotin and reacted with streptavidin. The neoplastic cells in the morules were immunopositive for oncofetal antigens. Serum levels of female sex hormones were within the normal range, and no cells in the adenoma were immunopositive for receptors for progesterone and estrogen. The results indicate that OCN are rich in biotin and that morules may be embryologically immature elements that develop independently of influence by female sex hormones.

Ultrastructural and morphometric studies related to expression of the cell adhesion molecule PECAM-1/CD31 in developing rat lung.

It has recently been postulated that platelet/endothelial cell adhesion molecule-1 (PECAM-1/CD31) might play a role in vascular tube formation. To evaluate the role of PECAM-1/CD31 in the formation of the capillary network in vivo, we conducted an ultrastructural immunohistochemical evaluation of the localization of PECAM-1/CD31 and its developmentally regulated expression in the periphery of the lungs of fetal, newborn, and adult rats. PECAM-1/CD31 was present mainly on luminal surfaces and at the junctions between endothelial cells. Moreover, in fetal lung, products of the immunoreaction were also found on the abluminal surfaces of endothelial cells. To relate those findings to the developmental changes in the capillary area of the lung, we performed a morphometric study of electronmicrographs. The cross-sectional area of blood vessels at the periphery of the lungs was significantly greater in 15-19-day-old fetuses than in postpartum animals (p<0.0001). Disappearance of the expression of PECAM-1/CD31 on the abluminal endothelial surface paralleled the changes in the cross-sectional area of blood vessels that occurred during the perinatal period. (J Histochem Cytochem 48:1283-1289, 2000)

c-myc expression is associated with increased proliferation activity in thyroid follicular cells of Graves' disease as stimulated by autoantibodies.

Expression on thyroid follicular cells of HLA-DR, c-myc protein and proliferating cell nuclear antigen (PCNA) was examined immunohistochemically in 28 cases of Graves' disease (GD) and in 29 cases of Hashimoto's thyroiditis (HT). Immunoreactivity for PCNA in GD was seen not only in follicular cells adjacent to a lymphocytic infiltration, where the follicular cells were positive for HLA-DR, but also in hyperplastic follicular cells without the infiltration. The distribution of expressed c-myc protein was similar to that of PCNA in GD but not in HT. Semiquantitatively graded degrees of lymphocytic infiltration and expression of HLA-DR, c-myc and PCNA in GD showed a high correlation with one another. However, the degrees of c-myc expression in HT showed no significant correlation with any other degrees. Intraperitoneal injection of bovine TSH or of immunoglobulins derived from a patient with GD in rabbits induced hyperplastic change of thyroid follicular cells, as reflected in PCNA and c-myc immunoreactivity, as well as strong peroxidase and acid phosphatase activity. Immunization with synthesized peptide of thyrotropin receptor also exhibited the same results in the rabbit thyroids. Our results indicate that c-myc expression on follicular cells of GD may reflect a stimulation by autoantibodies mediated through the thyrotropin receptor.

Clonal analysis of the epithelial component of Warthin's tumor.

The proliferation of the epithelial component of Warthin's tumor is generally considered to represent a neoplastic condition. There has been much controversy about the histogenesis of this tumor, and the clonality of the epithelial component has not been clarified. We examined the clonal status of epithelial cells of Warthin's tumor by using a polymerase chain reaction (PCR) method based on trinucleotide repeat polymorphism of the X chromosome-linked human androgen receptor gene (HUMARA) and on random inactivation of the gene by methylation. Total DNA was isolated from formalin-fixed, paraffin-embedded tissue from 16 women with Warthin's tumor. Of the 16 cases analyzed, 7 were heterozygous for the HUMARA polymorphism and informative. The epithelial components of the tumors from the 7 cases were microdissected under the light microscope, and were subjected to extraction of DNA and HUMARA analysis. Using a permanent aqueous mounting medium during microdissection, we succeeded in reducing the rate of contamination by lymphocytes in the samples to less than 10%. All 7 cases showed patterns of polyclonal proliferation in the HUMARA analysis. Our results showed the nonclonal nature of Warthin's tumor, suggesting that Warthin's tumor is a non-neoplastic tumor-like condition. HUM PATHOL 31:1377-1380.

Epithelial-myoepithelial carcinoma harboring p53 mutation.

A case of epithelial-myoepithelial carcinoma of the parotid gland harboring p53 mutation is reported. The tumor removed from a 67-year-old Japanese female was composed of an organoid biphasic population of cells: inner dark epithelial cells were surrounded by clear myoepithelial cells. The cells were immunopositive for EMA and smooth muscle actin, respectively. Some of the epithelial cells formed solid nests. Immunostaining for proliferating cell nuclear antigen (PCNA) resulted in a higher percentage of labeled cells in the solid epithelial region than in the region with the more general biphasic pattern. Genetic analysis, including polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and nucleotide sequencing, revealed a mutation in codon 207 (aspartic acid to glycine) of the p53 tumor-suppressor gene. To our knowledge, this is the first report of a mutation in the p53 gene in an epithelial-myoepithelial carcinoma of the salivary gland.

Biotin-containing intranuclear inclusions in endometrial glands during gestation and puerperium.

Intranuclear inclusions sometimes are observed in endometrial glands, especially during puerperium, and superficially they resemble those from herpesvirus-infected cells. To study the significance of the inclusions, endometrial and placental tissue from 215 subjects, including 69 pregnancy-associated samples, were examined. With screening by peroxidase-labeled avidin alone, followed by the peroxidase reaction, only pregnancy-related endometrium (in 32 cases) demonstrated reactivity in the intranuclear inclusions. These intranuclear inclusions demonstrated positive immunostaining for biotin using the peroxidase-antiperoxidase method in all but six cases, whereas there was no reaction for Herpes simplex in any of the cases. The endometrial tissues of the 32 cases were obtained from the 16th gestational week to the 37th postpartum day. Although the histogenesis of these intranuclear inclusions has not been clarified, they should not be mistaken for those in endometrial cells infected by herpesvirus because of intranuclear biotin and a false-positive histochemical reaction in the avidin-biotin-peroxidase complex method.

Effects of oxazolam, cloxazolam, and CS-386, new anti-anxiety drugs, on socially induced suppression and aggression in pairs of monkeys.

This experiment was conducted to examine effects of oxazolam, cloxazolam, CS-386, and reference drugs on socially induced suppression and aggression in pairs of monkeys. Oxazolam, cloxazolam, and CS-386, as well as other benzodiazepines, at both ataxic and non-ataxic doses, attenuated the socially induced suppression, but failed to show inhibitory effect on the on the socially induced aggression. Chlorpromazine, at both slight-sedative and non-sedative doses, reduced neither socially induced suppression nor aggression. Imipramine did not produce any significant effect in this study.

Immunohistochemical study on tissue transglutaminase and copper-zinc superoxide dismutase in human myocardium: its relevance to apoptosis detected by the nick end labelling method.

The influence of free radicals on apoptosis was studied in the human heart; 45 autopsy cases were examined by the nick end labelling method (NELM) that detects DNA fragmentation. Immunostaining for copper-zinc superoxide dismutase (CuZn-SOD) and tissue transglutaminase (tTG) induced frequently during apoptosis were also studied. Positive immunoreaction for tTG was detected in mucinous degeneration of myocardial cells; these same cells were also positive for CuZn-SOD but negative for NELM. Myocardial cells showing basophilic alterations after haematoxylin and eosin staining were also positive for CuZn-SOD but negative for the other markers examined. Positive nuclear reaction by NELM was only observed in myocardial cells showing contraction band necrosis or irregularly shaped nuclei surrounding recent or long-standing infarcted foci. In these the other two markers were negative. Since mucinous degeneration lacks the distinguishing morphological features of apoptosis, immunoreactive tTG in this lesion may not imply that the cells are undergoing apoptosis. tTG can be induced in non-apoptotic conditions and may not be involved in apoptosis induced by infarction. Histological disassociation between CuZn-SOD expression and apoptosis suggests the possibility of a cytoprotective role played by endogenous CuZn-SOD against free radical generation in the human heart.

Small carcinomas of the thyroid. A long-term follow-up of 867 patients.

OBJECTIVE: To determine the adequate extent of surgery for small carcinomas of the thyroid. DESIGN: Retrospective cohort study of 867 consecutive patients with small carcinomas of the thyroid (lesions < 10 mm in diameter) who were operated on at the Noguchi Thyroid Clinic, Oita, Japan, between 1965 and 1987. Mean follow-up was 12.8 years. SETTINGS: A center for treatment of thyroid disease, where about 1400 thyroid operations are performed per year. PATIENTS: Thyroidectomy was performed in patients with a preoperative diagnosis of Graves' disease, Graves' disease with nodules, solitary thyroid nodules, multinodular goiters, cysts, chronic thyroiditis and small carcinomas of the thyroid, in 394, 22, 136, 193, 18, 28, and 76 patients, respectively. RESULTS: Operations were conservative. Three patients who had adenomatous nodular goiters underwent total thyroidectomy. Modified radical neck dissection was performed in 66 patients. Of these 66 patients, 30 had grossly noticeable nodal metastases and 17 had microscopic metastases. Another 50 patients underwent selective lymph node excision, and 28 patients had nodal metastases. Recurrence from remnants of thyroid was seen in five patients. They were treated by surgery. Recurrence in lymph nodes was observed in five patients, and four of them were successfully treated. Recurrence in bone was observed in two patients; one with recurrence in the femur was successfully treated. Two patients died with recurrent cancer. CONCLUSIONS: Small carcinomas of the thyroid can be fatal. Total thyroidectomy is unnecessary. Modified radical neck dissection is unnecessary unless gross nodal metastases are present. Long-term follow-up is mandatory. A

Changing trends and prognoses for patients with papillary thyroid cancer.

OBJECTIVE: To analyze differences in the demographic backgrounds, and in treatments, prognosis, and risk factors of patients with papillary thyroid cancer operated on from 1965 to 1990, by dividing them into 3 chronological groups. DESIGN: Retrospective cohort study of 2423 patients with papillary thyroid cancer (tumor size, > or = 10 mm) who underwent curative surgery at the Noguchi Thyroid Clinic, Oita, Japan. SETTING: A center for the treatment of thyroid disease, at which about 1400 thyroid operations are performed per year. PATIENTS: There were 596 patients treated during from January 1, 1965, to December 31, 1973; 964 patients treated from January 1, 1974, to December 31, 1982; and 959 patients treated from January 1, 1983, to December 31, 1990. RESULTS: Of the 2519 patients treated, 96 were excluded from the study because they had undergone noncurative surgery. Therefore, the analyses are based on data for 2423 patients who underwent curative surgery. Three groups were defined as follows: group 1, underwent surgery during the period 1965-1973 (n = 577); group 2, underwent surgery during the period 1974-1982 (n = 924); and group 3, underwent surgery during the period 1983-1990 (n = 922). The mean age of the patients in group 1 was 42.4 years, in group 2, 45.0 years, and in group 3, 47.8 years. The mean tumor size was 30.4 mm, 26.5 mm, and 24.6 mm, respectively, for groups 1, 2, and 3. The 10- and 20-year disease-specific survival rates were significantly improved from group 1 (95.5% and 90.3%, respectively) to group 2 (97.8% and 93.9%, respectively), and the 10-year rate was significantly improved for group 3 (98.2%). In the multivariate analysis, age, sex, tumor size, and gross nodal metastasis were significant predictors of survival for group 1; however, only age and gross nodal metastasis were significant for group 3. CONCLUSIONS: Over time, papillary thyroid cancer has become diagnosed at an earlier stage, but the age of the patients at diagnosis is older. The disease-specific survival rate was significantly improved, mainly owing to earlier treatment, and the change in the risk factor profile for cancer mortality may be due to the changes in the demographic backgrounds and diagnostic and therapeutic modalities. These considerations derived from risk factor analysis should be considered for treating the patient and for the prediction of patient survival.

Single- and multiple-dose pharmacokinetics of intravenous cefpirome (HR810) to healthy volunteers.

The safety and pharmacokinetics of single and multiple administrations of cefpirome (HR810), a new cephalosporin antibiotic agent with a broad antibacterial spectrum, were studied in healthy male volunteers. The single administration protocols included a 3-minute intravenous injection of 0.5 g or 1 g, and a 1-hour intravenous drip infusion of 0.5 g, 1 g, or 2 g. The multiple administration protocols included nine intravenous injections and 1-hour intravenous drip infusions of 1 g of cefpirome twice a day at intervals of 12 hours. Cefpirome was tolerated, and only a few mild, subjective and hepatic-function side effects were observed. There were no severe abnormalities. The drug concentrations in the plasma and the urine were determined by means of HPLC and bioassay, and the results correlated well (r = 0.99). The pharmacokinetic parameters were calculated using a two-compartment model. The elimination half-life (t1/2 beta) was about 1.7 hours for both intravenous injection and intravenous drip infusion and was not dose-dependent. AUC and Cmax were dose-dependent in this study, although an accumulation due to multiple administrations was not observed, and there were no changes in the pharmacokinetic parameters after the initial and the final administrations. The recovery rate of the unchanged compound in the urine was more than 80% in the 24 hours after a single administration and was the same after multiple administrations. Bioautography did not show any active metabolites in the plasma or the urine. The results, for safety and pharmacokinetics, show that cefpirome can be expected to have excellent clinical efficacy for bacterial infections.