Participation of elderly patients in registration trials for oncology drug applications in Japan.

BACKGROUND: The objective of this study was to evaluate the age-based enrollment of cancer patients into registration trials of new drug applications or expanding the indications for use. MATERIALS AND METHODS: The data from 234 registration trials in Japan and overseas of 43 drugs, which were reviewed by the Pharmaceuticals and Medical Devices Agency and approved by the Ministry of Health, Labour and Welfare in Japan between 1999 and 2008, were retrospectively analyzed according to the age distribution of enrolled patients. The age distribution of the Japanese cancer population was derived from Cancer Statistics in Japan 2003 and Annual Report on Health, Labour and Welfare 2003-2004. RESULTS: In the Japanese cancer population, the estimated median age of cancer patients is 70 years, and 66% of cancer patients are aged 65 years or more. The estimated median age of cancer patients in all registration trials conducted in Japan was 59 years, whereas it was 55 years in the registration trials conducted overseas. The proportion of patients aged 65 years or more enrolled in registration trials conducted in Japan was 35%; this number was 28% in registration trials conducted overseas. CONCLUSION: Elderly patients are underrepresented in oncology registration trials in Japan.

Pathological features of mucinous carcinoma of the breast are favourable for breast-conserving therapy.

AIM: The effectiveness of breast-conserving therapy for mucinous carcinoma has not been well documented. We examined clinical and pathological features of cases to determine whether patients with mucinous carcinoma were suitable candidates for this treatment. METHOD: Cases of pure type (n=52) and mixed type (n=24) mucinous carcinomas were reviewed with emphasis on the risk factors associated with local recurrences after breast-conserving therapy. RESULTS: Large pure mucinous carcinomas had a low incidence of extensive intraductal spreading (EIS). An inverse correlation existed between the incidence of EIS and tumour size (P<0.05). Comedo type EIS was infrequent (11%) in pure mucinous carcinoma. Incidences of lymphatic vessel invasion (4%) and nodal involvement (4%) were lower in pure mucinous carcinoma than in mixed carcinoma (P<0.05). No nodal involvement occurred in patients with pure mucinous carcinoma less than 3 cm in diameter. CONCLUSIONS: Patients with pure mucinous carcinomas, except those invading the local skin, are suitable candidates for breast-conserving therapy. Most pure mucinous carcinomas, including a large tumour up to 5 cm in diameter, can be treated with this therapy.

Immunohistochemical analysis on biological markers in ductal carcinoma in situ of the breast.

BACKGROUND: The increasing use of mammographic screening has led to an increased detection of ductal carcinoma in situ (DCIS) of the breast. The detailed biological characteristics of DCIS and a new classification of DCIS based on these characteristics are needed. METHODS: Immunohistochemical studies were performed to assess the expression of c-erbB-2 (ErbB-2), estrogen receptor (ER), p53 and proliferative activity (Ki-67) in 65 patients with pure DCIS and 60 with invasive ductal carcinoma (IDC). We classified pure DCIS tumors using three classifications, the architectural, Nottingham, and Van Nuys classifications. RESULTS: ErbB-2, ER and p53 staining was positive in 34%, 66% and 21% of patients with DCIS, respectively, and 58%, 42% and 33% in patients with IDC, respectively. Ki-67 stained positively in 1.5% of patients with DCIS and 11.2% of patients with IDC. The comedo type showed a high rate of positive ErbB-2 and p53 staining. The cribriform and papillary types showed a high rate of positive ER staining. Under the Van Nuys classification, ErbB-2, p53 and Ki-67 expression were highest in the group with high nuclear grade and lowest in the group with non-high nuclear grade without necrosis. CONCLUSION: Although the biological markers of IDC tended to suggest aggressive behavior more so than those of DCIS, these differences were based on the histological sub-type, comedo or non-comedo. The Van Nuys classification best defined the subgroups of DCIS with a distinct expression pattern of biological markers, and the best candidates for breast-conserving surgery.

A collision tumor composed of adenocarcinoma and malignant lymphoma in the remnant stomach after pancreatoduodenectomy: report of a case.

The occurrence of a collision tumor in the stomach, consisting of adenocarcinoma and malignant lymphoma, is extremely rare. We report herein the case of a patient who had undergone a pancreatoduodenectomy for bile duct cancer 5 year earlier, in whom an ulcerating tumor of the remnant stomach developed and grew rapidly within 5 months. Surgical exploration revealed a tumor in the remnant stomach, multiple liver metastases, and multiple lymph node metastases. Total resection of the remnant stomach was performed, and pathological examination revealed a collision tumor consisting of adenocarcinoma and malignant lymphoma. The patient died of liver metastases and lymph node metastases 7 months after his second operation. The coexistence of both adenocarcinoma and malignant lymphoma of the remnant stomach and the etiology of this unusual combination, never previously reported, is discussed.

Thyroid metastasis from hepatocellular carcinoma as an initial presentation: a case report.

Although metastases to the thyroid are not uncommon at autopsy, most of these lesions are clinically occult. To our knowledge, this is the first report of a case of hepatocellular carcinoma initially presenting as a thyroid mass. Various radiological studies suggested malignant thyroid tumor, and core needle biopsy was performed. Metastasis from hepatocellular carcinoma was histopathologically suspected, and subsequent abdominal CT revealed advanced hepatocellular carcinoma.

Deletion of 12 carboxyl-terminal residues from pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase affects steroid metabolism.

Pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase (3alpha/beta,20beta-HSD) is 80-85% identical to human, rat, and mouse carbonyl reductases. However, pig 3alpha/beta,20beta-HSD contains an extra 12 amino acids at its COOH-terminus that these other mammalian carbonyl reductases lack. We constructed a pig 3alpha/beta,20beta-HSD mutant, G278opal, which lacks these amino acids and found that compared to wild-type 3alpha/beta,20beta-HSD, G278opal has a 10-fold lower catalytic efficiency for testosterone and progesterone. G278opal also has lower 3alpha- and 20beta-reductase and increased 3beta-reductase activity compared to wild-type 3alpha/beta,20beta-HSD. Binding of NADPH to G278opal was similar to that of wild-type 3alpha/beta,20beta-HSD. The recently determined three-dimensional structure of 3alpha/beta,20beta-HSD, without a steroid substrate, shows the 12 COOH-terminal amino acids in a random configuration. Our data indicate that the 12 COOH-terminal amino acids have a role in steroid metabolism suggesting that binding of steroid to wild-type 3alpha/beta,20beta-HSD induces a conformational change in which the 12 COOH-terminal amino acids interact with the steroid substrate.

Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid beta peptide in the brain.

Amyloid beta peptide (Abeta) is a physiological peptide that is constantly catabolized in the brain. We previously demonstrated that an endopeptidase sensitive to phosphoramidon and thiorphan conducts the initial rate-limiting proteolysis of Abeta in vivo, but the exact molecular identity of the peptidase(s) has remained unknown because of the molecular redundancy of such activity. We analyzed the brain-derived enzyme by means of immuno-depletion and gene disruption, and demonstrate here that neprilysin accounts for the majority of the Abeta-degrading activity. Furthermore, kinetic analysis, giving a K(m) value of 2.8 +/- 0.76 microM, indicated that Abeta(1-42) is a relevant substrate for neprilysin.

Rhabdoid features in leiomyosarcoma of soft tissue: with special reference to aggressive behavior.

The presence of rhabdoid cells has been reported in various types of malignant neoplasms and has been determined to be a predictor of aggressive behavior of neoplasms regardless of tumor histogenesis. One hundred and thirteen cases of leiomyosarcoma, selected from 1800 soft tissue sarcomas, were reviewed on hematoxylin and eosin sections, and immunohistochemical staining when available, and seven cases with rhabdoid features were retrieved. Clinicopathologic differences were analyzed to compare between cases with rhabdoid features and those without rhabdoid features. In the seven cases with rhabdoid features, two were intra-abdominal, and the others arose in external soft tissues including muscle, subcutis, and cutis. Patient age ranged from 33 to 84 years, three were female, and four were male. Tumor size ranged from 3 to 22 cm. Clinical evidence showed no differences from those cases without rhabdoid features. Histologically, one of the abdominal cases was epithelioid leiomyosarcoma. Two of the 7 cases were better subclassified as pleomorphic leiomyosarcoma, in which rhabdoid cells are diffusely scattered. In cases other than those with pleomorphic leiomyosarcomas, foci of anaplastic areas were observed, and collections of rhabdoid cells were present in those areas. Immunohistochemical examination of the cases confirmed myogenic differentiation, and showed rhabdoid cells being positive for vimentin and desmin in the inclusion bodies, and diffusely so for muscle actin in the cytoplasm. After dividing all the cases of leiomyosarcoma by their location, prognostic analysis was performed. Leiomyosarcoma of external soft tissue with rhabdoid cells showed a tendency for poorer prognoses than cases without rhabdoid features. On the contrary, retroperitoneal cases did not. This study indicates that rhabdoid features are associated with aggressive biological behavior in leiomyosarcoma of the external soft tissue.

Axillary lymph node metastases in patients with small carcinomas of the breast: is accurate prediction possible?

OBJECTIVES: To find out whether macroscopic classification of the tumour margin is predictive of axillary lymph node metastases and to identify a combination of clinical and pathological findings by which axillary node status can be predicted accurately in small carcinomas (T1) of the breast. DESIGN: Retrospective study. SETTING: Municipal referral centre, Japan. SUBJECTS: All 1003 patients with T1 invasive carcinoma of the breast who had axillary lymph node dissection between January 1970 and December 1996 as part of their treatment. MAIN OUTCOME MEASURES: The association between the incidence of axillary lymph node metastases and 10 clinical and pathological factors (age, palpability and size of tumour, macroscopic classification of tumour margin, clinical axillary status, radiating spiculation on a mammogram, histological type, lymphatic invasion, oestrogen and progesterone receptor status) were analysed. RESULTS: Clinical axillary node status, macroscopic classification of tumour margin, lymphatic invasion, and age of the patient were significant predictors of axillary lymph node metastases (p < 0.01 in each case). Among 47 patients aged 65 or more whose tumours had well-defined margins and with a clinical N0 status in the axillae, the incidence of histological axillary lymph node metastasis was only 6% (n = 3) whereas it was 65% in 57 patients with tumours of ill-defined margins whose axillae were N1 or N2. CONCLUSIONS: Macroscopic classification of tumour margins is an independent predictor of axillary lymph node metastases for patients with small carcinomas of the breast. However, even with combinations of the examined predictors of axillary node metastases, the subgroup of patients at minimal risk of metastasis was less than 5% in T1 breast cancer, whereas three-quarters of the patients had clear axillary lymph nodes. Most patients with T1 breast cancer will need surgical staging of the axillae by methods such as sentinel node biopsy.

Activating Gs(alpha) mutation in intramuscular myxomas with and without fibrous dysplasia of bone.

Activating missense mutations in the Arg 201 codon of the gene encoding the alpha subunit of Gs, the G protein that stimulates cAMP formation, have been recognized as the cause of many endocrine diseases, McCune-Albright syndrome and isolated fibrous dysplasia of bone. On the other hand, intramuscular myxomas with fibrous dysplasia, so-called Mazabraud's syndrome, have been sporadically reported, but it has not been confirmed whether intramuscular myxoma, with or without fibrous dysplasia, is associated with the Gs(alpha) mutations. We investigated the presence of the Gs(alpha) mutations in intramuscular myxomas with or without fibrous dysplasia by a PCR-SSCP assay, using formalin-fixed, paraffin-embedded tissues. In five of the six intramuscular myxomas (three with and two without fibrous dysplasia), point mutations were detected as aberrant bands by SSCP, which were confirmed by a subsequent sequence analysis (three Arg to His and two Arg to Cys). This result suggests that the Gs(alpha) mutations are related to tumorigenesis in intramuscular myxoma and that intramuscular myxoma is one of the diseases induced by abnormal Gs(alpha) protein.

Loss of heterozygosity and microsatellite instability in ductal carcinoma in situ of the breast.

To investigate the alterations of genetic instabilities in carcinogenesis of the breast, we analyzed the allelotypic profile of 65 ductal carcinomas in situ (DCIS), compared with that of 207 invasive ductal carcinomas (IDC) of the breast. These studies were performed by means of examining microsatellite-length polymorphisms at seven loci (AluVpa, ESR, D11S988, D13S267, D16S398, D17S1159, and D17S855) from microdissected paraffin sections. Allelic loss or imbalance, considered a loss of heterozygosity (LOH), tended to be more frequently seen in IDC than in DCIS. In particular, the frequency of LOH at the 17p locus was significantly higher in IDC than in DCIS (42 vs. 23%, P=0.022). LOH in DCIS was most frequently seen at D16S398 (26%). LOH frequency at D16S398 in low- and intermediate-grade DCIS was higher than that in high-grade DCIS, while LOH frequencies at D11S988 and D17S1159 in low- and intermediate-grade DCIS was lower than those in high-grade DCIS. LOH frequency at D11S988 in non-comedo type DCIS was lower than that in comedo type DCIS. Furthermore, the frequency of microsatellite instability (MSI) at only one locus in DCIS (28%) was statistically higher than that in IDC (6%) (P<0.001), while there was no difference between the frequency of MSI at multiple loci in DCIS (6%) and that in IDC (3%). Together, these observations indicate that chromosomal losses of 16q may occur in low- and intermediate-grade DCIS and those of 11p and 17p may occur high-grade DCIS, and that MSI occurring at only one locus is not yet clear and MSI at multiple loci is uncommon in not only IDC but also DCIS of the breast.

Tubular carcinoma of the breast: a histologic subtype indicative of breast-conserving therapy.

We reviewed the clinical and pathologic features of pure tubular carcinoma of the breast with particular emphasis on the reported risk factors associated with local recurrences and survival following breast-conserving therapy. Of 1653 cases of invasive breast cancer, 12 (0.7%) were identified as pure tubular carcinoma. Clinical/pathologic features of pure tubular carcinoma were compared with those of T1 invasive carcinoma of all other histologic types (T1 IC). Of the 12 patients with pure tubular carcinoma (median tumor diameter 1.4 cm; range 0.5-3.0 cm), a multicentric association was identified in one patient while a multifocal association was seen in two. One patient had nodal metastatic disease out of the ten who underwent axillary dissection. No lymphatic vessel invasion was identified in any tumors (P < 0.1 vs T1 IC). In addition, extensive intraductal spread was not present in any tumors (P < 0.05 vs T1 IC). This study shows that patients with pure tubular carcinoma are appropriate candidates for breast-conserving therapy based on the clinical/ pathologic features. When a multifocal association is suspected preoperatively, either a wide local excision or a quadrantectomy which includes other lesions is thus recommended.

Transient association of the nicotinamide adenine dinucleotide phosphate oxidase subunits p47phox and p67phox with phagosomes in neutrophils from patients with X-linked chronic granulomatous disease.

Optimal microbicidal activity of polymorphonuclear leukocytes (PMNs) requires recruitment of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to the phagosome. In this study, we used a synchronized phagocytosis assay and immunofluorescence microscopy (IFM) to examine the association of cytosolic NADPH oxidase subunits with phagosomes containing opsonized zymosan (OpZ). Ingestion of OpZ began within 30 seconds of particle binding and forming phagosomes were enriched for both F-actin and the actin-binding protein p57. NADPH oxidase subunits p47phox and p67phox were also recruited to forming phagosomes and were retained on mature phagosomes for at least 15 minutes. Colocalization of F-actin, p57, and p47phox on phagosomes was confirmed by immunoblotting. Translocation of p67phox, but not p57, to forming phagosomes was deficient in PMNs lacking p47phox. Surprisingly, we found that in PMNs from six individuals with X-linked chronic granulomatous disease (CGD), p47phox and p67phox accumulated in the periphagosomal area during ingestion of OpZ. However, in marked contrast to normal PMNs, p47phox and p67phox were shed from nascent phagosomes along with F-actin and p57 once OpZ was internalized (approximately 5 minutes). These data support a model in which flavocytochrome b is required for stable membrane binding of p47phox and p67phox, but not their association with the cytoskeleton or transport to the cell periphery.

Apoptosis and cell proliferation in medullary carcinoma of the breast: a comparative study between medullary and non-medullary carcinoma using the TUNEL method and immunohistochemistry.

BACKGROUND AND OBJECTIVES: Medullary carcinoma of the breast has generally been considered to result in better prognosis than ordinary invasive ductal carcinoma, which would seem to be discrepant when one considers its anaplastic histology and high mitotic rate. We attempted to elucidate the prognostic implications of apoptosis and cell proliferation in medullary carcinoma of the breast. METHODS: Formalin-fixed, paraffin-embedded specimens of 50 cases of typical medullary carcinoma (MC) of the breast and those of 50 control cases of non-medullary invasive ductal carcinoma (N-MC), which were matched to the MC cases in both age and TNM classification, were investigated utilizing the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method and immunohistochemistry for p53, bcl-2, and Ki-67. RESULTS: Mean values of the apoptotic index (AI), the proliferative index (PI), and the ratio of AI to PI (AI/PI) were significantly higher in MC than in N-MC (P < 0.0001). MC exhibited significantly lower positivity for bcl-2 than N-MC (P = 0.00003), while there was no significant difference in p53 positivity between MC and N-MC. CONCLUSIONS: A high frequency of apoptosis may be related to a favorable prognosis in MC, even though it demonstrates a high proliferative activity, exhibiting a rapid cell turnover.

Role of diffusion-weighted echo-planar MRI in distinguishing between brain brain abscess and tumour: a preliminary report.

Our purpose was to evaluate diffusion-weighted (DW) echo-planar MRI in differentiating between brain abscess and tumour. We examined two patients with surgically confirmed pyogenic brain abscess and 18 with metastatic brain tumours or high-grade glioma, using a 1.5 T system. The apparent diffusion coefficient (ADC) of each necrotic or solid contrast-enhancing lesion was measured with two different b values (20 and 1200 s/mm2). All capsule-stage brain abscesses (4 lesions) and zones of cerebritis (2 lesions) were identified on high-b-value DWI as markedly high-signal areas of decreased ADC (range, 0.58-0.70 [(10-3 mm2/s; mean, 0.63)]). All cystic or necrotic portions of brain tumours (14 lesions) were identified on high-b-value DWI as low-signal areas of increased ADC (range, 2.20-3.20 [(10-3 mm2/s; mean, 2.70)]). Solid, contrast-enhancing portions of brain tumours (19 lesions) were identified on high-b-value DWI as high-signal areas of sightly decreased or increased ADC (range, 0.77-1.29 [(10-3 mm2/s; mean, 0.94)]). Our preliminary results indicate that DW echo-planar MRI be used for distinguishing between brain abscess and tumour.

Histopathological Predictors of Axillary Lymph Node Metastases in Patients with Breast Cancer.

BACKGROUND: A tumor 30 mm or less in diameter is a standard candidate for breast conserving surgery (BCS) in Japan. Axillary lymph node metastases (ALNM) is the most important prognostic factor for survival in patients with breast cancer, but the role of axillary node dissection has been controversial. Histopathological predictive factors of axillary lymph node involvement have not been established. The purpose of this study was to determine the association between the incidence of ALNM and histopathological factors by univariate and multivariate analysis METHODS: Sixty-five patients with noninvasive ductal carcinoma, and 993 patients with tumors 30 mm or less in diameter who underwent axillary dissection between 1988 and 1997 at our institute were reviewed. The association between ALNM and 13 histopathological factors (size, age, histological subtype, histological invasiveness, lymphatic invasion, vascular invasion, macroscopic classification, histological daughter mass, ductal spread, ER, PgR, p-53, and c-erbB-2) were analyzed by univariate and, when significant, by multivariate analysis. RESULTS: Only one patient with noninvasive ductal carcinoma had ALNM, and 33.1% of 993 patients with a tumor 30 mm or less in size had ALNM. Multivariate analysis identified six factors as independent predictors for ALNM: lymphatic invasion, size, histological invasiveness, macroscopic classification, age and histological daughter mass. CONCLUSION: Axillary lymph node dissection can be omitted in patients with noninvasive ductal carcinoma. Histopathological features of tumors 30 mm or less in diameter can be used to estimate the risk of ALNM, and routine axillary node dissection might be spared in selected patients at minimal risk of ALNM, if the treatment decision is not influenced by lymph node status, such as in elderly patients.

Mediastinal parathyroid cyst: treatment with thoracoscopic surgery--a case report.

Parathyroid cysts are rarely located in the mediastinum. This report describes a 45-year-old man with a mediastinal parathyroid cyst. Video-assisted thoracic surgery was successfully performed to remove the cyst.

Malignant melanoma imaging with Tl-201.

Two patients with malignant melanoma were evaluated using Tl-201 scintigraphy. Planar scintigraphy showed tumor accumulation, and SPECT Tl-201 imaging revealed exact tumor localization. The findings indicate the utility of Tl-201 to detect the primary lesion and to identify postoperative recurrence in malignant melanoma.

Mutation of tyrosine-194 and lysine-198 in the catalytic site of pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase.

Pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase is an NADPH-dependent enzyme that catalyses the reduction of ketones on steroids and aldehydes and ketones on various xenobiotics, like its homologue carbonyl reductase. 3alpha/beta,20beta-Hydroxysteroid dehydrogenase and carbonyl reductase are members of the short-chain dehydrogenases/reductase family, in which a tyrosine residue and a lysine residue have been identified as catalytically important. In pig 20beta-hydroxysteroid dehydrogenase these residues are tyrosine-194 and lysine-198. Here we report the effect on the reduction of two ketone and two aldehyde substrates by pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase in which tyrosine-194 has been mutated to phenylalanine and cysteine, and lysine-198 has been mutated to isoleucine and arginine. Mutants with phenylalanine-194 or isoleucine-198 are inactive. Depending on the substrate, the mutant with cysteine-194 has a catalytic efficiency of 0.4-1% and the mutant with arginine-198 has a catalytic efficiency of 4-23% of the wild-type enzyme. We also mutated tyrosine-81 and tyrosine-253 to phenylalanine. Although both tyrosines are conserved in 3alpha/beta,20beta-hydroxysteroid dehydrogenase and carbonyl reductase, depending on the substrate, the mutant enzymes are as active as, or more active than, wild-type enzyme.

Composite glandular-neuroendocrine carcinoma of the hilar bile duct: report of a case.

We report herein an unusual case of a composite glandular-neuroendocrine carcinoma of the hilar bile duct. A 71-year-old Japanese woman was admitted to our hospital suffering from general fatigue, progressive jaundice, and a high fever. Computed tomography and angiography findings revealed a solid hypervascular mass in the hepatic hilus. Thus, a subsegmentectomy of the liver (S4, S5) and bile duct resection with lymph node dissection were performed. A tumor measuring 6.0 x 3.0 cm was found to be located in the bile duct of the hepatic hilus. Histologically, the tumor was composed of well-differentiated adenocarcinoma and small cell neuroendocrine carcinoma cells, with a histological transition between the two components. Grimelius' method revealed the presence of diffuse positive tumor cells in neuroendocrine carcinoma. The neuroendocrine tumor cells were also diffusely immunoreactive to chromogranin A. To the best of our knowledge, only 22 previous cases of composite glandular-neuroendocrine carcinoma in the biliary tract have been reported; however, this is the first case report of a clearly composite tumor of the hilar bile duct.