Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial.

PURPOSE: The goal of chemotherapy for metastatic breast cancer (MBC) is to prolong survival and maintain health-related quality of life. This study aimed to evaluate long-term health status of patients with MBC who participated in the phase III randomized SELECT BC trial. METHODS: In the SELECT BC trial, patients were randomly allocated to the S-1 or taxane (paclitaxel or docetaxel) arm. Health status was assessed by EQ-5D at pre-treatment, 3 and 6 months after randomization, and every 6 months thereafter to the extent possible. Least square mean scores were assessed to compare EQ-5D index values between groups. Time to deterioration analysis was also performed by defining the minimally important difference of EQ-5D as 0.05 or 0.1. RESULTS: The number of patients for EQ-5D analysis was 175 and 208 in the taxane and S-1 arms, respectively. Least square mean EQ-5D index values up to 60 months were 0.741 (95 % CI [0.713-0.769]) in the taxane arm and 0.748 [0.722-0.775] in the S-1 arm. The EQ-5D index value during PFS up to 12 months in the S-1 was superior to the corresponding index value in the taxane (0.812 [0.789-0.834] vs. 0.772 [0.751-0.792], P = 0.009). Time to deterioration analysis also revealed that S-1 significantly delayed the deterioration of EQ-5D index value during the period before progression (P = 0.002 and 0.003). CONCLUSIONS: Our findings suggest that the EQ-5D index value was higher in patients treated with S-1 during first-line chemotherapy. Considering non-inferiority of S-1 in terms of OS, obtained quality-adjusted life years may be greater in the S-1 arm.

Choledochocele with obstructive jaundice: a case report and a review of the Japanese literature.

A case of a 57-year-old farmer with a rare type of choledochal cyst (choledochocele; Alonso-Lej's type III) is described. The patient was admitted because of obstructive jaundice and acute biliary infection. Abdominal computed tomography scan showed a cystic lesion in the head of the pancreas, and endoscopic retrograde cholangiopancreatography disclosed cystic dilatation of the terminal portion of the common bile duct. It was suspected that the choledochocele could swell and compress the common bile duct, causing obstructive jaundice and acute cholangitis; therefore, it was surgically resected. We also reviewed 61 cases of choledochocele reported in Japan; the findings were similar to those reported in the English literature.

Immunohistochemical localization and dynamics of paraquat in small intestine, liver and kidney.

Immunohistochemical techniques were used to observe the localization of paraquat in the small intestine, liver and kidney, organs that absorb and eliminate chemicals. Paraquat-poisoned rats were killed 3 h, 12 h, 24 h, 3 days, 7 days and 10 days after intravenous administration of paraquat. Three hours after injection, paraquat was localized in hepatocytes and in the kidney in the epithelial cells of the distal tubule. The amount of paraquat in the liver and kidney increased by 24 h after the administration and thereafter decreased with time, suggesting that paraquat is secreted into bile and urine. In the intestine, 3 h after injection, paraquat was localized in the epithelial cells. The same finding was also made in rats with a cannulated bile duct. Therefore, it is likely that paraquat is secreted into the gut lumen from epithelial cells and that paraquat secreted from liver into the duodenum is reabsorbed into the epithelial cells of the intestine.

An autopsy case of pancreatic duct cell carcinoma associated with ossification.

A case of pancreatic duct cell carcinoma with ossification was reported. A 71-year-old female died of pancreas carcinoma with liver and diffuse lymph node metastasis. Computed tomography (CT) revealed a punctate calcification of the body of the pancreas. At autopsy, the carcinoma occupied almost all of the pancreas, and histological examination revealed a moderately to well-differentiated adenocarcinoma with mucin production in the glands. The whole of the pancreas was examined microscopically by multiple-step sections, and mature ossification was found in the body, corresponding to its CT localization. Around the ossification were found cancer cells with massive mucin in the cytoplasm, capillary proliferation, scattered necrosis and mesenchymal cells, which were thought to be fibroblasts. But neither cartilage nor calcification was found. The pathogenesis of ossification was believed to be associated with metaplastic changes of mesenchymal cells. This is the fourth case of pancreatic carcinoma with ossification, and the second case of pancreatic duct cell carcinoma with mature bone formation to have been reported.

Malignant lymphoma involving the penis following malignant pleural mesothelioma.

A 74-year-old man who had been diagnosed with malignant mesothelioma developed malignant lymphoma of B-cell origin involving the penis. He had a history of occupational exposure to asbestos as a construction worker. The association of malignant mesothelioma with lymphoma is rare, and the possibility of asbestos exposure as a common etiology is discussed. The intense stimulation of B lymphocytes and decreased T lymphocyte activity in asbestos-exposed populations may result in development of B-cell malignancies. Though the relationship between asbestos exposure and malignant mesothelioma is firmly established, the relationship between asbestos exposure and lymphoma remains to be investigated.

Assessment of mutations of Ha- and Ki-ras oncogenes and the p53 suppressor gene in seven malignant mesothelioma patients exposed to asbestos--PCR-SSCP and sequencing analyses of paraffin-embedded primary tumors.

To examine whether malignant mesothelioma due to asbestos has genetic alterations in the Ha- and Ki-ras oncogenes or in the p53 suppressor gene, we analyzed the point mutations of these genes in paraffin-embedded autopsy samples of the primary tumors of malignant mesothelioma in seven asbestos patients who died from malignant mesothelioma. The genetic analysis was conducted by the polymerase chain reaction-single strand comformation polymorphysms (PCR-SSCP) method in all patients, and through the sequencing of deoxyribonucleic acid (DNA) bases in one patient. No genetic alterations were found in exons 1 or 2 of Ha- and Ki-ras oncogenes, or in exons 5 to 9 of the p53 gene, in any of the patients. Further studies on a larger number of patients are required to reach a definite conclusion concerning the genetic effects of asbestos on malignant mesothelioma.

Production of monoclonal antibodies against diquat and its enzyme-linked immunosorbent assay.

Monoclonal antibodies(MoAbs) very specific to diquat (DQ) were produced. An immunogen was synthesized by binding DQ to bovine serum albumin via a diazo-coupled derivative. BALB/c mice were immunized i.p. monthly with 0.25mg of the immunogen for five months. Their spleen cells were fused with P3U1 myeloma cells and hybridoma clones secreting MoAbs were obtained. Two MoAbs were selected and subtyped to be IgM and IgG3. The MoAbs recognized DQ but did not bind to paraquat and other analogues at all. A datum obtained from a clinical sample demonstrates that an enzyme-linked immunosorbent assay system using one of the MoAbs is useful in the practice of toxicological analysis.

Estimating stature from the length of the lumbar part of the spine in Japanese.

In order to estimate the stature from the length of the lumbar part of spine (LLPS), studies were made on Japanese males (n = 42) and females (n = 29) autopsied in our laboratory during 1984-1987. Somatometry was performed on the stature and LLPS in centimetres, the latter being measured from the upper edge of the first lumbar vertebral body, to the promonitorium, along the anterior surface of the spine. LLPS were 19.9 +/- 1.19 cm in males and 18.6 +/- 0.84 cm in females (mean +/- S.D.). The regression equations calculated were as follows: stature in males = LLPS x 3.23 + 101.7; stature in females = LLPS x 2.31 + 110.8. The standard errors of estimate were 6.16 cm in males and 4.05 cm in females. This method is useful for estimating the stature of severely burned or mutilated bodies which have no limbs.

Immunohistochemical localization of paraquat in lung and brain.

In order to observe the localization and dynamics of paraquat in lung and brain, immunohistochemical approaches were conducted by using animals. Experimental paraquat-poisoned rats were sacrificed 3 hours, 12 hours, 24 hours, 3 days, 7 days and 10 days after intravenous administration of paraquat (5 mg/kg). In lung tissues, paraquat was localized in histiocytes, walls of blood vessels and bronchiolar epithelial cells from 3 hours to 10 days after the paraquat exposure, and interstitial pulmonary fibrosis was being developed with time. On the other hand, in brain tissues, paraquat was localized only in capillary walls and glial cells but not observed in nerve cells 10 days after the administration of paraquat.

[A case of CEA and CA19-9 producing recurrent transitional cell carcinoma in an Indiana pouch after total cystectomy].

A 73-year-old female with transitional cell carcinoma (TCC) of the bladder underwent total cystectomy and Indiana pouch replacement in April, 1992. Histological examination revealed grade 3 TCC. In February 1995, she complained of gross hematuria. Intravenous pyelography (IVP) revealed a right non-functional kidney and filling defect in the Indiana pouch. We suspected colon cancer in the Indiana pouch because the levels of serum carcino-embryonic antigen (CEA) and CA19-9 were elevated. Endoscopic biopsy of intrapouch tumor was done. Pathological examination revealed grade 2 TCC. In July 1995, right nephroureterectomy with resection of Indiana pouch was performed and the surgical specimen revealed renal pelvic and ureteral cancer, grade 2 TCC. The levels of serum CEA and CA19-9 returned to the normal range 21 days after the operation. CEA and CA19-9 histochemical stain of renal pelvic and ureteral cancer were positive. Also CEA-, CA19-9-positive cells were detected in the specimens of the bladder tumor from the total cystectomy performed in 1992. This rare case is discussed and the literature is reviewed.

[An autopsy case of corticobasal degeneration mimicking frontal Pick's disease].

A pathologically proven case of corticobasal degeneration (CBD) with marked psychiatric symptoms was reported. A 59-year-old female was admitted to our hospital in October 1989 because of her "forgetfulness". Her abnormal behavior began in August 1989, and she had no psychiatric signs before that time. On this admission she was diagnosed to have panhypopituitarism due to Sheehan syndrome. Cortisone and levothyroxine were administered, but her mental symptoms deteriorated. Strange behaviors such as buying same materials every day and wandering around all day long fully dressed with all of her jewels were observed. She could not perform her housework after March 1991. She was in a bed ridden state after 1992 and died in March 1993, at the age of 62. The total duration of her illness was 3 years and 7 months. Her clinical course resembled frontal Pick's disease. At autopsy advanced gastric cancer without metastasis and infarct of the pituitary gland were found. The weight of the brain was 987g and atrophy of the bilateral frontal lobes was evident on macroscopical examination. Neuronal loss, proliferation of the glia, and spongy state were observed in the superficial layer of the frontal cerebral cortex. Widespread appearance of ballooned neurones was also observed in the deep layers of the frontal cerebral cortex. Neuronal loss and gliosis were found in the striatum, pallidum, thalamus, and substantia nigra. There was neither senile plaques nor Pick bodies. Numerous argyrophilic threads were found by Gallyas-Braak method and all these pathological findings were compatible with the previously reported cases of CBD. Although CBD is considered as predominantly a motor disorder, there are a few reports of pathologically proven cases of CBD mimicking Pick's disease. These cases suggest clinical diversity of CBD and further investigations are essential to establish the disease entity of CBD and Pick's disease.

[Hodgkin's disease associated with Tolosa-Hunt syndrome].

A thirty-eight-year-old man developed gradually progressing right retro-orbital pain, diplopia on the left lateral gaze, and left ptosis. On examination paresthesia was present on the first division of right trigeminal nerve. Orbital venography revealed obstruction of right superior orbital vein on the entering portion to the cavernous sinus. A daily administration of 30 mg of prednisolone resulted in a rapid improvement of the symptoms. Diagnosis of Tolosa-Hunt syndrome was made on the basis of neurological symptoms, roentgenographic findings and responsiveness to prednisolone. One year later, weakness of right leg accompanied with left cervical and axillary lymphadenopathy was developed. A biopsy specimen of cervical lymph node was identical with the Hodgkin's disease, lymphocyte predominance type. He was treated with COPP regimen; lymphadenopathy decreased in size. We reported a rare case of Hodgkin's disease preceded by Tolosa-hunt syndrome which might be caused by the extranodal lesions.

[An autopsy case of atypical hanging: were arteries and air passage obstructed?].

A housewife hanged herself with her left foot on a washstand and her right foot above the floor. The ligature mark encircled once horizontally at the height of the laryngeal prominence (horizontal part), crossed at the front of the neck, rose to the posterior regions of the mandibular angles and extended upward to the preauricular regions (ascending part). Petechial haemorrhage was in the conjunctivae and froth was in the air passage. Vertebral arteries are not obstructed by the compression of the horizontal part (Brinkmann et al., 1981). Vertebral arteries are possibly not obstructed by the traction of the ascending part (experiment on our own necks). An air passage is not obstructed by the compression of the horizontal part (Langreuter, 1886; Strassmann, 1922). Obstruction of an air passage by typical hanging is removed by putting the bent head to upright position (Langreuter, 1886). From these experimental observations we clarified that in our case the vertebral arteries and air passage had very possibly not been obstructed by the hanging while 70-80% of her body weight, i.e. 40-45 kg, had loaded on the neck. The force to obstruct the arteries and air passage by hanging, which has been quoted in texts and articles in Japan, is absolutely due to the value for "typical" hanging.

Production and characterization of antibodies reactive with leukotoxin.

A sensitive radioimmunoassay was developed for the determination of leukotoxin (9: 10-epoxy-12-octadecenoic acid), which was reported to exist in human burned skin and neutrophils, and was regarded as a toxic and/or defensive substance in living beings. The leukotoxin was conjugated with bovine serum albumin by means of the mixed anhydride technique as immunogen and rabbits were immunized over 4 months. According to a titration test of antiserum, forty-fold diluted antiserum was found to bind approximately 50% of about 4,000 dpm of methylated leukotoxin labeled with [14C] carbon. The detection limit of leukotoxin was at least as low as 5 ng in this radioimmunoassay by use of a polyetylene glycol precipitation method. This antiserum had a strong specificity to leukotoxin and no cross-reactivity with the other analogs tested.

[Advantages and disadvantages of the intraarterial chemotherapy using a reservoir as postoperative adjuvant therapy for hepatocellular carcinoma].

We conducted a retrospective study on the efficacy and disadvantages of intraarterial chemotherapy using a reservoir (ICUR), as postoperative adjuvant therapy for hepatocellular carcinoma (HCC). One hundred and seventy HCC patients who underwent hepatectomy since 1987 to 1992 in our institute were enrolled in this study. Ninety-two patients were postoperatively treated with ICUR (group R), and seventy-eight patients without it (group N). There were no significant differences between the two groups in the preoperative evaluations of the characteristics of patients, tumors, and operative procedures. Although statistical significances were not found, disease-free rates within 1 year and cumulative survival rates appeared to be higher in group R than in group N. Patency of the catheter of reservoirs at one and two years were maintained in 80.3 and 44.1% of the patients, respectively. HCC recurred after an occlusion of the reservoir in 18 patients. In four out of these 18 patients, transcatheter arterial embolization (TAE) for recurrent tumors was not feasible, because of occlusion of the hepatic artery. TAEs for recurrent lesions would have been impossible in about 10% of all patients treated with ICUR. Thus, both the advantages and disadvantages should be taken into consideration on the indication of ICUR, and the maintainance of the catheter is important for successful ICUR.

[Synthesized leukotoxin: its biological activity and establishment of radioimmunoassay].

Leukotoxin, 9: 10-epoxy-12-octadecenoic acid, was reported to exist in human burned skin and neutrophils, and to have toxic effects in experimental animals and antifungal effects against rice blast disease. Leukotoxin was regarded as a toxic and/or defensive substance in living beings. The author synthesized leukotoxin from linoleic acid with peracetic acid and purified practically by thin layer chromatography. The leukotoxin synthesized was injected into guinea pigs intravenously and caused a systemic convulsion of the animal body and cardiac arrest. The leukotoxin synthesized, on the other hand, was conjugated with bovine serum albumin (BSA) by means of the mixed anhydride technique and immunized in rabbits. After immunization of leukotoxin conjugated with BSA over 4 months, the author succeeded in producing anti-leukotoxin antiserum for the first time. According to a titration test of antiserum, sixty-folds diluted antiserum was found to bind approximately 50% of methylated leukotoxin labeled with carbon 14. And unlabeled leukotoxin was detected at least 5 ng in this radioimmunoassay by use of polyethylene glycol precipitation. This antiserum had a strong specificity to leukotoxin and no cross-reactivity to the other analogs tested. The role of leukotoxin in living creatures had not been clarified yet. Therefore both the leukotoxin synthesized by this simple procedure and the anti-leukotoxin antibodies would aid the study of the mechanism of its biological activities and its histochemical investigations.

Determination of dimethyl sulphide in blood and adipose tissue by headspace gas analysis.

A method for the headspace analysis of dimethyl sulphide in blood and adipose tissue has been established. Blood (0.2 ml) or adipose tissue (0.5 g) with added dimethyl sulphide was sealed in a 10-ml vial using PTFE sheet to prevent escape of dimethyl sulphide from the headspace. Equilibration was performed at 60 degrees C for 4 h, and 20 microliters of gaseous phase sampled from the headspace was subjected to gas chromatography (with flame photometric detection). Calibration curves were prepared for the two samples. Linearity was observed in the range from 5-10 micrograms to 2 mg.

Development and characterization of monoclonal antibodies reactive with paraquat.

A set of three anti-paraquat monoclonal antibodies(MoAbs), named APM-1, APM-2 and APM-3, has been isolated. In order to evaluate the ability of these MoAbs to recognize various kinds of bipyridyl herbicides and similar congeners of paraquat, a competition enzyme-linked immunosorbent assay (ELISA) using avidin-biotin complex (ABC) was developed. All three antibodies strongly recognized paraquat and slightly did the other analogs. These three MoAbs are therefore advantageous to a toxicological study of paraquat and of its localization in tissues.