Modified primary tumour/vessel tumour/nodal tumour classification for patients with invasive ductal carcinoma of the breast.

BACKGROUND: We previously reported that the primary tumour/vessel tumour/nodal tumour (PVN) classification is significantly superior to the UICC pTNM classification and the Nottingham Prognostic Index for accurately predicting the outcome of patients with invasive ductal carcinoma of the breast in a manner that is independent of the nodal status and the hormone receptor status. METHODS: The purpose of the present study was to compare the outcome predictive power of a modified PVN classification to that of the newly devised pathological UICC pTNM classification and the reclassified Nottingham Prognostic Index in a different group of patients with invasive ductal carcinoma (n=1042) using multivariate analyses by the Cox proportional hazard regression model. RESULTS: The modified PVN classification clearly exhibited a superior significant power, compared with the other classifications, for the accurate prediction of tumour recurrence and tumour-related death among patients with invasive ductal carcinoma in a manner that was independent of the nodal status, the hormone receptor status, and adjuvant therapy status. CONCLUSION: The modified PVN classification is a useful classification system for predicting the outcome of invasive ductal carcinoma of the breast.

FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer.

BACKGROUND: Antibody-dependent-mediated cytotoxicity (ADCC) is one of the modes of action for trastuzumab. Recent data have suggested that fragment C γ receptor (FcγR) polymorphisms have an effect on ADCC. This prospective phase II trial aimed to evaluate whether these polymorphisms are associated with clinical efficacies in patients who received trastuzumab. PATIENTS AND METHODS: Patients in a neoadjuvant (N) setting received Adriamycin and cyclophosphamide followed by weekly paclitaxel/trastuzumab. Patients in a metastatic (M) setting received single trastuzumab until progression. In total, 384 distinct single nucleotide polymorphisms of different FcγR, HER2, and fucosyltransferase loci were assessed. RESULTS: Fifteen operable and 35 metastatic HER2-positive breast cancer patients were enrolled in each of the N and M settings, respectively. The FcγR2A-131 H/H genotype was significantly correlated with the pathologically documented response (pathological response) (P = 0.015) and the objective response (P = 0.043). The FcγR3A-158 V/V genotype was not correlated with the pathological response, but exhibited a tendency to be correlated with the objective response. Patients with the FcγR2A-131 H/H genotype had significantly longer progression-free survival in the M setting (P = 0.034). CONCLUSION: The FcγR2A-131 H/H polymorphism predicted the pathological response to trastuzumab-based neoadjuvant chemotherapy in early-stage breast cancer, and the objective response to trastuzumab in metastatic breast cancer.

Expression of Tn and sialyl Tn antigens in synovial tissues in rheumatoid arthritis.

OBJECTIVES: The carbohydrate chains represented by mucins (MUCs) are expressed by a variety of normal and malignant secretory epithelial cells and induce a variety of immunoreactions. Tn and sialyl Tn antigens are tumour-associated carbohydrate antigens which are borne on the core proteins of mucins. The purpose of this study is to investigate the existence of tumour-associated carbohydrate antigens in rheumatoid arthritis (RA). METHODS: . We examined the expression of Tn and sialyl Tn antigens in synovial tissues from RA and osteoarthritis (OA) patients by immunohistochemistry. In addition, mucins from synovial fluid (SF) from RA patients are purified by gel filtration and density gradient ultracentrifugation and the existence of these antigens examined by dot and Western blotting. RESULTS: We found that Tn and sialyl Tn antigens were strongly expressed in synovial cells and infiltrating mononuclear cells on the sublining layer and lymphoid follicles in synovial tissues in RA compared with those in osteoarthritis. Tn and sialyl Tn antigens were detected in purified mucins of SF from RA patients. CONCLUSIONS: Tumour-like synovial hyperplasia cells expressed Tn and sialyl Tn antigens. This finding suggests that the mucins exhibiting with abnormal glycosylation may be in part responsible for synovial hyperplasia, leading to the joint destruction in the pathogenesis of RA.

Conscious sedation with midazolam intravenously for a patient with Parkinson's disease and unpredictable chorea-like dyskinesia.

Oral surgery can be difficult in patients with chorea-like dyskinesia, which is common in those on long-term levodopa medication for Parkinson's disease, and we know of no conclusive evidence to indicate whether conscious sedation with midazolam is effective in such cases. We report a patient in whom levodopa-induced chorea-like dyskinesia disappeared when midazolam was given intravenously for conscious sedation.

ABCB1 C3435T polymorphism influences methotrexate sensitivity in rheumatoid arthritis patients.

OBJECTIVE: Methotrexate (MTX) is most widely used for the treatment of rheumatoid arthritis (RA). However, it has certain drawbacks with regard to individual differences in its therapeutic effects as well as the differences in the patients' response to MTX therapy. We investigated whether multi-drug resistance-1 (ABCB1) C3435T, reduced folate carrier-1 (RFC1) G80A, 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) C347G and a 6bp-deletion polymorphism in the 3'-untranslated region of the thymidylase synthase (TYMS) gene are predictive of MTX sensitivity and its adverse effects. METHODS: Patients whose last maintenance dosage of MTX was 6 mg/week or those in whom MTX therapy was changed due to poor response to MTX were regarded as non-responders. The data of 124 RA patients who had received MTX treatment were retrospectively analyzed for polymorphisms in the ABCB1, RFC1, ATIC and TYMS genes, MTX sensitivity and MTX toxicity. RESULTS: There were no significant differences in MTX sensitivity among the genotypes of RFC1, ATIC and TYMS genes. ABCB1 3435TT cases included statistically significantly more non-responders than 3435CC cases according to univariate analysis (crude odds ratio (OR) = 8.91, p = 0.001) and multivariate analysis (adjusted OR = 8.78, p = 0.038). There were no significant differences in MTX toxicity among the genotypes of all the genes. CONCLUSION: These results suggested that the genetic diagnosis of ABCB1 C3435T can be applied to determine MTX sensitivity for the treatment of RA patients. However, further pharmacokinetics studies are required in this regard.

Expression of the tumor suppressor gene Maspin in human pancreatic cancers.

The tumor suppressor gene maspin, a unique member of the serpin superfamily, inhibits cell motility, invasion, and metastasis in breast and prostate cancers. Maspin is expressed in normal human mammary and prostate epithelial cells but down-regulated during cancer progression. In this study, we analyzed the expression of maspin in various human cancer cells by means of Northern blot and immunohistochemistry. Maspin gene expression proved to be up-regulated in pancreatic cancer. Maspin expression was not detected in any of 6 gastric cancers, 4 melanomas, or 6 of 7 breast cancer cell lines examined. In contrast, 5 of 9 pancreatic cancer cell lines showed maspin expression, although maspin expression was not detected in normal pancreatic tissue. Furthermore, maspin was expressed in 23 of 24 tumor specimens obtained from pancreatic cancer patients as well as all high-grade precancerous lesions (PanIN3 and intraductal carcinoma extension). In contrast, no expression was observed in normal and low-grade precancerous lesions. Our results show that maspin is a new factor associated with pancreatic cancer. In addition, the detection of maspin in pancreatic tumor tissues and its lack of expression in all normal pancreatic tissues suggests that maspin may be a useful marker of primary human pancreatic cancer.

Association of maspin expression with the malignancy grade and tumor vascularization in breast cancer tissues.

Maspin belongs to a tumor suppressing protein which is usually expressed highly in myoepithelial cells, and is significantly downregulated in breast cancer cells. We focused on identifying the correlation between maspin expression and the clinicopathological features of human breast cancer tissues using immunohistochemistry. There was a significant correlation in that maspin-positive tumor specimens showed a low pathological grade of malignancy, such as a lower infiltration of the tumor into the surrounding tissue and a downregulation of c-erbB2 expression. Moreover, maspin-positive cases showed a significant decrease in tumor vessels positively stained with anti-factor VIII-related antigen antibody. These results suggest that maspin production in myoepithelial cells could downregulate the malignant phenotype of breast cancer.

Development of a new drug delivery system for protein drugs using silicone (II).

In order to achieve a zero-order release of protein drugs, we have developed a new drug delivery system using silicone, which is named the covered-rod-type formulation. Preparation of the covered-rod-type formulation was conducted under mild conditions without heat treatment or the use of organic solvents. The covered-rod-type formulation released human serum albumin (HSA) or interferon (IFN) at a constant rate for 30-100 days in vitro without significant initial burst. When the IFN covered-rod-type formulation was implanted in nude mice, the serum IFN concentration was maintained at a constant level during the period of observation, i.e., 28 days. The covered-rod-type formulation enabled precise control of the release of the protein drugs and would be expected to increase the duration of the drug effect and to reduce the frequency of administration and side effects.

Down regulation of the tumor suppressor gene maspin in breast carcinoma is associated with a higher risk of distant metastasis.

BACKGROUND: Maspin (mammary serpin) is a relatively novel serine protease inhibitor with tumor suppressing function in breast cancer. Maspin expression was found in normal breast epithelial cells, but was decreased during tumor progression. Only a few systematic analyses of this phenomenon have been undertaken so far. In this study we developed specific nested reverse transcription polymerase chain reaction (RT-PCR) conditions for the detection of maspin expression in human breast carcinoma and assessed maspin's association with the clinical behavior of primary breast cancers. METHODS: Tumor specimens obtained from 45 primary breast cancer patients were analyzed for maspin expression by a nested RT-PCR assay. Recurrence free survival was evaluated and correlated to maspin expression. RESULTS: The maspin transcript was detected in 29 (64%) breast cancer specimens whereas no expression was found in 16 (36%) cancer specimens. This expression was unrelated to any of the established prognostic factors. However, 6 out of 8 patients who developed distant metastasis (lymph nodes, lung, liver, bone, pleura) within 3 yr after their initial diagnosis showed no maspin expression of the primary breast cancer (p < 0.05). CONCLUSIONS: The lack of maspin expression in breast cancer seems to be associated with a short disease free survival and supports maspin's function as an indicator of tumor aggressiveness and metastatic potential. Nested RT-PCR is a sensitive method to determine maspin expression in human breast cancer tissue.

Lower number and thinner myelin of large myelinated fibers in human cervical compression radiculopathy.

The authors conducted a morphometric investigation of the histopathological alterations in myelinated fibers (MFs) of the nerve roots of C-6, which showed macroscopic indentation, presumably due to cervical spondylotic radiculopathy. In six cadavers, designated as the radiculopathy group, in which the nerve roots of C-6 showed indentation due to compression on one side (indented side) and the remaining nerve roots (normal side) showed a normal appearance macroscopically, morphometric findings of the nerve roots and the MFs on both the indented and normal sides were evaluated and subjected to blind comparison. Seven cadavers with normal-appearing C-6 nerve roots served as controls. In the control group, there were no differences in the morphometric parameters: that is, total transverse fascicular area, total number of small and large MFs, and relationship between myelin thickness and the radius of the axon between the right and left sides in either the ventral or dorsal roots. There was no evidence found of axonal degeneration, ongoing demyelination, or loss of MFs in either the ventral or dorsal roots in the radiculopathy group on the indented side. However, there were significantly lower numbers of large MFs per root and significantly thinner myelin sheaths relative to axon size on the indented side compared with those on the normal side in both the ventral and dorsal roots. These findings are characteristic alterations of the MFs produced by chronic low-grade compression.

Lymph node metastasis from breast cancer diagnosed by F-18 FDG whole-body PET (case report).

We report a 48-year-old woman with lymph node (LN) metastases from breast cancer in whom diagnosis was difficult by conventional imaging methods but easy by F-18 fluorodeoxyglucose (FDG) PET. She was given a diagnosis of right breast cancer and then underwent modified radical mastectomy in December 1997. During routine CT and US studies in September 1998, a questionable LN measuring 1 cm in diameter was detected in the right supraclavicular region, but a definitive diagnosis of this LN was difficult by these tests. The patient underwent FDG PET test, which showed strong nodular activity (SUV= 7.1) in the right supraclavicular region, indicating a metastatic lesion. Moreover, an unexpected second metastatic LN lesion (SUV= 5.5) in the medial aspect of the right axillary was diagnosed by PET. The PET results were confirmed by pathological examination of the surgical specimens. FDG PET is a useful tool to detect small malignant lesions that are not easily diagnosed by conventional imaging techniques such as CT and US. It is expected that PET test will be feasible at many institutions.

Symphalangism (two phalanges) in the digits of the Japanese foot.

We report here an investigation into the number of phalanges of the 2nd to 5th toes in a Japanese population. The number of phalanges in each of these toes is normally three, distal, middle and proximal. However, occasionally only two phalanges are observed. In this condition, known as symphalangism, the middle and distal phalanges are fused (synarthrosis of the distal interphalangeal joint). The incidence of symphalangism in the 488 feet was found to be 72.5% in the 5th toe, 11.9% in the 4th toe, 0.8% in the 3rd toe, and 0.0% in the 2nd toe. No left-to-right or sex differences were observed. The reported overall incidence of symphalangism in the 5th toe of the foot in the Japanese population (74.7%) is significantly higher than that in the European population (40.2%). In the present sample, the incidence of symphalangism of the 4th toe (11.9%) was significantly higher than that in Japanese population samples previously studied (4.2%).

[Japanese anatomical terminology (nomina anatomica japonica) from the educational view point (1)--sune and nezumi].

A few considerations on two Japanese anatomical terms, sune (the anterior part of the leg or the shin in medical terminology) and nezumi (the rat) from the anatomical point of view are made. Japanese words generally have two readings. For example, sune which means the anterior part of the leg, may be read as sune and kei. But kei has two other meanings, the neck and the road. Sune is used more for the anterior part of the leg than kei, especially in classes for beginners of the anatomical course. Nezumi means rat, but is also read as so. Because kei means road, and kan means canal, sokeikan means the rat's tubular passageway, namely, the descent of testis (Descensus testis). In Japanese anatomical terminology the passage of the testis through the inguinal canal is considered similar to a rat going through a passageway. The work sokeikan is better than the English anatomical term inguinal canal which means only the canal in the root of the groin. In Japanese, two words, fukurahagi and komura are used for the posterior part of the leg.

The foot shape of school girls and female farm workers in northern Kyushu.

This is an anthropometric study of the foot shape of 23 school girls of Northern Kyushu. They live in Kitakyushu City and its suburbs. Their parents are descendants of people of Fukuoka Prefecture. While there was no significant difference regarding the foot-length among these school girls and the other two groups of farm workers who lived in the rural areas of Northern Kyushu about two decades ago, these school girls had the narrowest feet with the smallest foot-index (a ratio of the foot-breadth to the foot-length) and the tallest stature. These physical features may be considered to be the result of the urban life and the differences of generation.

A statistical study on anatomical variation in the origin of the Japanese pectoralis minor muscle.

The origin of the pectoralis minor muscle of Japanese was studied in the dissection practice for medical students in our school of medicine and the incidence of the variation of the origin of this muscle was statistically studied and compared with that of American whites and American negroes. The most frequent types in Japanese were type 2-5 (the pectoralis minor muscle arising from the 2nd, 3rd, 4th and 5th ribs) in males and 2-4 in females on both thoracic sides. Type 2-4 in Japanese females was the most frequent among these three ethnological groups.

Stature, sitting height and relative sitting height of female northern Kyushuites.

Stature, sitting height and relative sitting height (a ratio of sitting height to stature) of 318 high school girls of 17 years of age in Kitakyushu City were studied. They consisted of groups over a three-year period; 1973, 1980 and 1984. There are statistically no significant changes in the stature, in the sitting height, and in the relative sitting height among these three groups. The relative sitting height of these three groups is about 54%, which is about the same as among the Chinese, Eskimos, American-Indians and the Hokkaido-Ainu.

[Pharmacokinetic studies of a new oral cephem T-2588. Pharmacokinetics in gastrectomized volunteers and the renal excretory system in healthy volunteers].

According to the result of the pharmacokinetic examination of T-2588 (esterified prodrug of T-2525) administered to adult male volunteers who have undergone gastrectomy, it appears that the absorption of T-2588 is delayed in the hypoacidity or the anacidity and also the excretion ratio of T-2525A (an inactive metabolite of T-2525) showed a tendency to become higher in these subjects. Again, according to the result of the pharmacokinetic examination of T-2588 when it was administered together with probenecid to normal healthy volunteers, it appears that the T-2525 is excreted from the kidneys not only into the glomerular filtration but also partly through renal tubules.

[Clinical experience of intra-arterial chemotherapy for liver metastases of breast cancer patients].

The aim of this study was to evaluate retrospectively the effect of intra-arterial chemotherapy for liver metastases of breast cancer patients. Eleven patients treated between August 1991 and July 1997 at Keio University Hospital, Tokyo, Japan, were the subjects for this study. The duration of disease-free periods after the operation ranged from 9 to 78 months (median 27 months). The site of the recurrence was the liver alone in 6 cases, and the liver and lung in 1 case, bone in 1 case, lymph nodes in 2 cases, and a local region, in 1 case. The main drugs were adriamycin (ADM) and 5-fluorouracil (5-FU), administered in a single injection or continuously via an indwelling catheter in the hepatic artery. This method had a 36% response rate, including PR in 4 cases, NC in 3 cases and PD in 4 cases. The survival duration was 1 to 19 months (median 14 months) following this treatment, and 3 to 49 months (median 17 months) after the recognition of the recurrence. The only side effects of Grade 3 or 4 were leucocytopenia or granulocytopenia and nausea. These results suggest that intra-arterial chemotherapy for liver metastases of breast cancer patients may be an effective method for the control of liver metastases with minor side effects. However, further study may be necessary to establish methods to manage the indwelling catheter and to control patients with multiple metastases of the other organs, to improve the prognosis for recurrent breast cancer patients.