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Background Few studies have been conducted on patterns of recurrence after resection for distal cholangiocarcinoma (DCC). The aim of this study was to investigate the incidence and pattern of recurrence after resection of DCC, and to evaluate prognostic factors for time to recurrence and recurrence-free survival (RFS). Methods Patients who underwent pancreatoduodenectomy with curative intent for DCC between 2001 and 2010 at one of 30 hospitals in Japan were reviewed retrospectively, with special attention to recurrence patterns. The Cox proportional hazards model was used for multivariable analysis. Results In the study interval, 389 patients underwent pancreatoduodenectomy for DCC with R0/M0 status. Recurrence developed in 213 patients (54·8 per cent). The estimated cumulative probability of recurrence was 54·3 per cent at 5 years. An initial locoregional recurrence occurred in 55 patients (14·1 per cent) and initial distant recurrence in 168 (43·2 per cent), most commonly in the liver. Isolated initial locoregional recurrence occurred in 45 patients (11·6 per cent). Independent prognostic factors for time to recurrence and RFS were perineural invasion (P = 0·001 and P = 0·009 respectively), pancreatic invasion (both P < 0·001) and lymph node metastasis (both P < 0·001). RFS worsened as the number of risk factors increased: the 5-year RFS rate was 70·6 per cent for patients without any risk factors, 50·3 per cent for patients with one factor, 31·8 per cent for those with two factors, and 13·4 per cent when three factors were present. Conclusion More than half of patients with DCC experienced recurrence after R0 resection, usually within 5 years. Perineural invasion, pancreatic invasion and positive nodal involvement are risk factors for recurrence.

Background Little is known about the value of portal vein (PV) resection in distal cholangiocarcinoma. The aim of this study was to evaluate the clinical significance of PV resection in distal cholangiocarcinoma. Methods Patients who underwent pancreatoduodenectomy (PD) for distal cholangiocarcinoma between 2001 and 2010 at one of 31 hospitals in Japan were reviewed retrospectively with special attention to PV resection. Short- and long-term outcomes were evaluated. Results In the study interval, 453 consecutive patients with distal cholangiocarcinoma underwent PD, of whom 31 (6·8 per cent) had combined PV resection. The duration of surgery (510 versus 427 min; P = 0·005) and incidence of blood transfusion (48 versus 30·7 per cent; P = 0·042) were greater in patients who had PV resection than in those who did not. Postoperative morbidity and mortality were no different in the two groups. Several indices of tumour progression, including high T classification, lymphatic invasion, perineural invasion, pancreatic invasion and lymph node metastasis, were more common in patients who had PV resection. Consequently, the incidence of R1/2 resection was higher in this group (32 versus 11·8 per cent; P = 0·004). Survival among the 31 patients with PV resection was worse than that for the 422 patients without PV resection (15 versus 42·4 per cent at 5 years; P < 0·001). Multivariable analyses revealed that age, blood loss, histological grade, perineural invasion, pancreatic invasion, lymph node metastasis and surgical margin were independent risk factors for overall survival. PV resection was not an independent risk factor. Conclusion PV invasion in distal cholangiocarcinoma is associated with locally advanced disease and several negative prognostic factors. Survival for patients who have PV resection is poor even after curative resection.

It is important to administer appropriate agents to inpatients and outpatients with various conditions. In addition to the preparation and guidance for taking drugs, we should always consider the patient's basic information including age, history of allergy, name of disease, and history of examination. In particular, information on contraindications may have serious effects on patients, and must be checked most strictly. However, it is impossible to do routine work after obtaining all information such as the patient's basic information that are serially changing, drug history frequently revised, and a large volume of information on medication. In this study, we developed a prescription surveillance system. This system facilitates real-time checking of the names of diseases that correspond to contraindications as a rule, drug interactions, and administration to elderly patients and pregnant women on attached documents for medicines, utilizing prescription orders, injection orders, and disease name orders. This system facilitates efficient and accurate checking even in the following cases: when a prescription involves another department; when several prescriptions on different prescription dates occur; when a combination of an oral agent and an injection is contraindicated; or when an agent that can not be administered due to the patient's disease is prescribed. Therefore, all pharmacists can detect prescriptions involving agents that are contraindicated regardless of job skill. Pharmacists may contribute to higher quality medical practice.

A 64-year-old woman presented with right heart failure caused by a cardiac tumor centered in the free wall of the right ventricle, accompanied by pericardial effusion. A match between the biopsy specimen and tissue removed 4 years earlier resulted in the diagnosis of a cardiac metastasis from a chordoma. Immunohistochemical staining was also useful in establishing the diagnosis. To alleviate the right ventricular outflow obstruction, a palliative operation was planned, resecting the tumor and performing a right ventriculoplasty, which was cancelled due to the extent of infiltration of the tumor, and instead a right atrium to pulmonary artery shunt was attempted using a vascular prosthesis, only to fail due to an inability to maintain blood flow through the prosthesis. Presently there are no definitive treatment options available, and some palliative chemotherapy is being performed. Single cardiac metastases from a chordoma are extremely rare.

The clinicopathologic findings of reversible ampulla-like ventriculogram of the left ventricle were studied in 8 elderly women and one middle-aged man. Their coronary arteriograms were normal, even in the 7 patients who had ST elevation on electrocardiogram. Coronary spasm was positive in only 2 of the 7 patients who received provocation tests. Biopsy specimens revealed focal myocyte injury. Normal coronary arteriograms during ST elevation and the presence of pathologic myocardial lesions were not consistent with a concept of stunned myocardium. The presence of myocardial lesions suggested that focal and disseminated myocardial damage had occurred.

BACKGROUND: Epstein's syndrome is defined as a subtype of Alport's syndrome, and is distinguished from the other subtypes by accompanying macrothrombocytopenia. Mutations in collagen IV genes are known to be involved in the pathogenesis of typical Alport's syndrome. However, the presence of an underlying genetic defect has not been demonstrated in Epstein's syndrome. AIM: To clarify the involvement of collagen IV in Epstein's syndrome. METHODS: The distribution of the alpha(IV) chain was studied in renal specimens obtained from three patients with Epstein's syndrome using chain specific monoclonal antibodies and an antigen retrieval procedure. RESULTS: The patients showed a normal distribution of alpha(IV) chains: alpha 1(IV) and alpha 2(IV) were expressed ubiquitously, whereas expression of alpha 3(IV) through to alpha 6(IV) chains was limited to the glomerular basement membrane, Bowman's capsular basement membrane, and/or a portion of the tubular basement membrane. CONCLUSIONS: These results suggest that genes other than those encoding alpha(IV) chains are responsible for the pathogenesis of Epstein's syndrome.

Porphyromonas gingivalis is a periodontal pathogen whose fimbriae are classified into six genotypes (types I-V and Ib) based on the diversity of the fimA genes encoding the fimbrial subunits. Accumulated evidence suggests that P. gingivalis strains with type II fimbriae are more virulent as compared to those with other types. However, it is unknown if strong virulence is uniformly conserved among clones with type II fimbriae. In the present study, we compared infectious inflammatory changes in clinical isolates of P. gingivalis with type II fimbriae using a mouse abscess model to examine their pathogenic heterogeneity and heterogeneity-related factors.Suspensions of nine different clinical isolates with type II fimbriae were subcutaneously injected into female BALB/c mice and inflammatory parameters, such as serum sialic acid concentration, were compared.Many of the type II fimbrial isolates caused severe inflammation in the mice, though some were less causative, as was the control strain ATCC 33277 (type I fimbria strain). These results showed that pathogenic heterogeneity exists among P. gingivalis clones with type II fimbriae. Further, the heterogeneity-related factors of P. gingivalis strains were analyzed and the pathogenic potentials showed positive relationships to gingipain activities and invasive efficiency but not to hydrophobicity or autoaggregation. In addition, invasive efficiency was related to the activities of gingipains that were extracellularly secreted.These results suggest that pathogenic heterogeneity has relationships with the invasive and proteolytic activities of P. gingivalis clones with type II fimbriae.

In nerve root infiltration (NRI) consisting of neural blockage and radiculography, response to the nerve root block has usually been thought to be diagnostically significant. However radiculography has not been statistically evaluated. The purpose of this paper is to assess the value of selective radiculography of patients with group 1 response (typical pain reproduced by needle placement and then relieved by nerve root block) according to Dooley's criteria. We studied selective radiculography in a consecutive series of 88 patients with lumbo-sacral radicular pain who showed group 1 response in NRI. The accuracy of the preoperative nerve root block and radiculography in 88 nerve roots (L5,S1) were correlated with the intraoperative findings. Selective radiculograms were classified into three groups; normal (absence of block), partial block, and complete block. The tilting angle of all nerve roots was measured. We found the symptomatic root at the same level of the nerve root block in all 88 patients. Selective radiculograms showed five normal roots, 15 roots with incomplete block and 63 roots with complete block. Fifteen radiculograms had abnormal tilting angles. The accuracy of radiculography was 84% in the canal zone and 100% in the intra and extraforaminal zones. If the L5 nerve root angle was more than 60(o), an intra or extraforaminal lesion was strongly suggested (P0.01). Radiculography of patients with group 1 response is useful for detecting compressed sites in the symptomatic nerve root, particularly for detecting lesions in the intra and extraforaminal zones.

It has been reported that measles-associated pneumonia is easily complicated with fatal respiratory failure. During the 6 months from January to June 1998, we treated three young patients with measles-associated pneumonia who had previously been healthy. Their chest X-ray and CT examinations revealed mainly interstitial and partially alveolar pneumonia surrounding extensive areas of bronchiolitis. In one patient, respiratory failure was present, and arterial blood gas analysis showed severe hypoxemia. Therefore, this patient was treated with a mechanical ventilator, which dramatically improved the condition. The other two patients received steroid-pulse therapy and improved rapidly. We believed that in measles-associated pneumonia, steroid pulse therapy is to be recommended for the severely ill patient. According to a report by the Japanese Ministry of Health and Welfare, measles-like disease was widespread in Japan in 1991 and occasionally encountered in 1996. But in Yamanashi Prefecture, the disease was prevalent in 1991, 1994 and 1998. The number of patients in our hospital had reflected the prevalence in the prefecture. It is suggested that the measles is a disease of regional prevalence.

A randomized crossover study between azasetron alone and azasetron combined with dexamethasone was performed to investigate the prevention of nausea and vomiting due to chemotherapy including cisplatin in patients with advanced head and neck carcinoma. The results indicated that the combination therapy with dexamethasone was more effective than azasetron alone in preventing nausea on days 1 through 5 after the administration of cisplatin and was significantly superior to azasetron alone on days 2 and 3. In addition, complete response (no vomiting) and the antiemetic and antinausea efficacy of combination therapy with dexamethasone on day 2 was significantly superior compared to azasetron alone. No adverse effect from either antiemetic therapy was observed in this study.

Objectives: we determined the incidence and specific markers of postoperative delirium in elderly patients with chronic lower limb ischaemia. Patients and methods: since April, 1995, 110 patients aged 60 years or older (mean: 71.6±6.6 years) who underwent bypass surgery were assessed regarding aetiological factors of delirium: age, sex, dementia, body-mass index, hypertension, diabetes, cerebral disease, laboratory test results, severity of limb ischaemia, type of arterial occlusion, operative time, and blood transfusion. Results: discriminant analysis showed statistical significance in the following five variables: age ≥70 years; critical limb ischaemia (and/or ankle pressure

To clarify pathological features of dilated form of hypertrophic cardiomyopathy (d-HCM), 14 autopsied hearts with d-HCM were studied. Prognosis of 23 cases with dHCM confirmed by myocardial biopsy specimens were evaluated. Pathological study revealed marked myocardial fibrosis(14/14), moderate to severe disarray(14/14), fibro-fatty degeneration of the outer layer of the left ventricle(13/14) and sclerosis of the intramural coronary arteries(mild, 5; moderate, 4). Degeneration of LV outer layer is an unique pathology in patients with d-HCM. Prognosis of 23 patients with d-HCM is longer than usually supposed(Ten-year-survival rate from the initial symptoms: 78%).

We report a case of spontaneous hepatocellular adenoma with marked cystic degeneration in the non-cirrhotic liver. A 36 year-old Japanese woman with neither history of liver diseases nor use of oral contraceptives and steroids, complained of a 6 kg weight loss over 6 months. Barium meal study revealed an extramural compression along the fornix of the stomach. Abdominal ultrasonography (UC) and computed tomography (CT) demonstrated a mass in the left lateral segment of the liver that measured 11.6x9.5 cm with cystic lesions. Laboratory data on admission showed no significant findings. Celiac angiography revealed a hyper-vascular mass. Surgical exploration revealed a soft mass arising and protruding from the left lateral segment of the liver. Partial resection of the left lateral segment was performed. Histologically, the tumor was surrounded by a thin fibrous pseudocapsule. The neoplastic cells resembling normal hepatocytes around the tumor were large, pale and arranged in thick, irregular cords. Neither mitotic figures nor foci of dysplasia were present. The central portions of the tumor showed marked cystic degeneration. The tumor was histologically diagnosed as hepatocellular adenoma (HCA). HCA with cystic degeneration has been rarely reported.

Endothelin-1, a potent vasoconstrictive peptide, is known to modulate changes in local circulation. Additionally, hepatocyte growth factor, a potent mitogen for hepatocytes, is increased in various liver diseases. The present study examined changes in serum endothelin-1 and hepatocyte growth factor levels in patients with obstructive jaundice before and after percutaneous transhepatic cholangio drainage.Endothelin-1 and hepatocyte growth factor levels were measured by enzyme-linked immunosorbent assay using sera from 16 patients with obstructive jaundice before and after percutaneous transhepatic cholangio drainage.Serum endothelin-1 levels decreased rapidly in the good bilirubin decrease group after biliary drainage. Endothelin-1 levels decreased 1 week after drainage but then increased gradually in the worse bilirubin decrease group. Serum hepatocyte growth factor levels decreased gradually after biliary drainage, and were higher in the worse bilirubin decrease group than in the good bilirubin decrease group throughout the study.These results suggest that endothelin-1 may be associated with the microcirculatory disturbance in obstructive jaundice and prolonged cholestasis. Measurement of hepatocyte growth factor levels in patients with obstructive jaundice before percutaneous transhepatic cholangio drainage may be an early clinical predictor of the subsequent rate of decrease of the serum bilirubin concentration.

Using restriction landmark genomic scanning (RLGS) methods, 21 samples of human meningioma were analyzed. We found 3 alterations in the genomic DNAs of tumor samples located on chromosomes 5, 14 and 17 which appear to be common to the meningothelial subtype. Two other separate genetic abnormalities located on chromosomes 9-12 and 20 are apparently associated with atypical meningiomas. In addition, the neurofibromatosis type 2 gene is apparently involved in more than half of the tumor samples. There appear to be both common and type-specific genetic mutations associated with the formation and progression of human meningiomas.

We investigated whether or not hepatocyte growth factor increases in portal serum via an endocrine mode after partial hepatectomy in humans.Portal blood was sampled through a catheter inserted through the umbilical vein to the portal trunk during surgery in 17 patients. Serum human hepatocyte growth factor levels were determined by enzyme-linked immunosorbent assay.Human hepatocyte growth factor levels were higher in portal than in peripheral serum throughout the study. Portal and peripheral serum human hepatocyte growth factor levels without complications increased rapidly and reached a maximum level 1 day after partial hepatectomy. The maximal level of portal and peripheral serum human hepatocyte growth factor was 1.20 and 1.00 ng/ml, respectively. In the case of hepatic failure after partial hepatectomy, portal and peripheral serum human hepatocyte growth factor levels markedly increased and reached 9.31 ng/ml and 6.78 ng/ml 2 days before death, respectively.These results suggest that hepatocyte growth factor increases in portal serum via an endocrine mode after partial hepatectomy in humans. Furthermore, measurement of the portal and peripheral serum human hepatocyte growth factor levels may be useful for the clinical evaluation of patients with post-operative hepatic failure.

We conducted a dose-escalation study with a fixed dose of intraperitoneal cisplatin and G-CSF support of carboplatin using the Calvert formula in epithelial ovarian cancer. Twenty-five patients were entered in this study. On day 1, carboplatin was administered intravenously at target AUCs of 4, 5, 6, and 7. On day 2, cisplatin was given i.p. in 70 mg/m2. G-CSF, 50 microgram/m2, was administered subcutaneously from day 7 to 16. Cycles were scheduled to be delivered every four weeks. A total of 85 cycles were administered. The maximum tolerated dose was AUC 7 mg/ml x min of carboplatin. The overall response rate was 80% (12/15). The combination in this regimen is feasible, and a phase II study of this regimen is warranted.

Takayasu aortitis is a chronic inflammatory vasculitis characterised by stenosis or obliteration of large and medium sized arteries. Although coronary arteries are affected in approximately 10% of cases, most of the lesions are luminal narrowing, and coronary aneurysm formation is extremely rare. A case is described of giant aneurysm of the left main coronary artery complicated with Takayasu aortitis in a 46 year old Japanese woman who was followed until her death at age 71. Pronounced intimal proliferation and adventitial fibrous thickening of the involved arterial wall usually induce constriction or occlusion at the orifice of the main branch of the aorta in Takayasu aortitis. However, systemic hypertension, which resulted from renovascular stenoses in this case, is likely to have enlarged the vessel lumen before replacement of medial and adventitial fibrosis after extensive destruction of medial elastic fibres in the left main coronary artery. Moreover, associations such as autoimmune hepatitis, chronic thyroiditis, and Sjögren syndrome strongly suggests that Takayasu aortitis may be an autoimmune disease. Keywords: giant coronary aneurysm; Takayasu aortitis; renovascular hypertension; autoimmune disorders

Mitral valve aneurysm is defined as a localized protrusion of the valve with a different radius from that of the remaining portion of the valve. The medical records and pathological findings of seven patients with mitral valve aneurysm [aged 48-69 years (mean 64), 4 males] and the pathological findings of other 29 Japanese cases were reviewed. All seven patients were diagnosed pathologically as infective endocarditis, but two patients had no documentation of clinical symptoms suggestive of infective endocarditis (latent infective endocarditis). The underlying lesion of the heart was aortic valve disease and/or fibrosal degeneration of the mitral valve. Only 29 of 36 Japanese case reports stated a precise description of the valve pathology. Of these 29 cases, 23 were associated with infective endocarditis, two with rheumatic valvular disease with fusion and/or shrinkage of the chordae tendineae, three with mitral valve prolapse or myxomatous degeneration of the mitral valve, and one with aortitis syndrome. Neovascularization was described in eight cases. Neovascularization with thick wall should be considered as post-inflammatory vascularization. This review indicates that patients with latent infective endocarditis and mitral valve aneurysm should be considered as potential candidates for valve surgery.

The effects of weekly subcutaneous recombinant human erythropoietin (r-hEPO) administration on anemia during chemotherapy including cisplatin and 5-fluorouracil in patients with head and neck carcinomas were examined. Weekly subcutaneous r-hEPO administration in cancer patients has not been investigated previously. Patients were treated with r-hEPO 100 IU/kg (2 patients), 200 IU/kg (6 patients), or 400 IU/kg (5 patients), or placebo, and effectiveness was evaluated by monitoring hemoglobin concentration changes after administration for 8 weeks. Hemoglobin concentrations in all 3 r-hEPO dosage groups were higher than that in the control group during chemotherapy. All r-hEPO doses produced improvements in the anemia induced by chemotherapy; however, the 400 IU/kg dose was most effective. The requirement for blood transfusions decreased in patients receiving r-hEPO therapy, and no significant side-effects were associated with r-hEPO administration. These results suggest that chemotherapy-induced anemia can be prevented by weekly subcutaneous r-hEPO administration.

We evaluated in 7 eyes the mobility of a newly designed orbital implant made of hydroxyapatite. This orbital implant has a screw peg and is covered with a piece of sclera from the enucleated eye of the patient. The implant was well tolerated and there were no cases of proptosis during the follow-up of 1.8 +/- 0.6 years. Assuming the mobility of a healthy eye as 100%, photographic analysis showed the mobility of the anterior orbit to be 92.6% in adduction, 85.9% in abduction, 84.9% in supraduction, and 90.9% in infraduction. The mean tugging weight of the implant was, when measured by a strain gauge, 344.2 +/- 29.2 g in adduction and 327.6 +/- 33.4 g in abduction. These values corresponded to 90.4 +/- 4.4% and 89.5 +/- 5.3% respectively of those in a healthy eye. The presence of the orbital implant did not affect the electrooculogram as compared to a healthy eye. Cinematic studies using magnetic resonance imaging (MRI) showed that the constriction and extension of the extraocular muscles, which were sewn onto the orbital implant, matched that of a healthy eye.

To characterize the American College of Rheumatology core set of disease activity measures for rheumatoid arthritis (RA) clinical trials (ACR core set measures) and the ACR definition of improvement of RA (ACR improvement definition), we studied 42 Japanese patients with active RA who were treated with DMARDs including mizoribine. Each patient's disease activity was assessed at the time of enrollment to the study and after 24 weeks using the ACR core set measures as well as the physical global assessment through the conventional measures. Twenty-five (60%) patients were discerned as showing improved by physicians through the conventional measures. This decision appeared to be based on improvement in Lansbury activity index (LAI) and C-reactive protein (CRP) value. Twelve of the 25 "improved" patients satisfied the ACR improvement definition. The 12 patients showed significant improvement in "outcome" measures including patients assessments of pain, disease activity, and physical function, compared to the 30 patients not satisfying the ACR definition. However, no significant differences were observed between these two groups in "process" measures including LAI, tender joint count, swallen joint count, or CRP value. In conclusion, the ACR core set measures including both process and outcome measures have potential to reflect clinical important changes on "real life" of patients with RA.

The surgical results and postoperative management of 90 patients with hepatocellular carcinoma (HCC) who underwent hepatectomy were reviewed, and clinical factors relating to HCC were analyzed to determine what type of HCC responds best to hepatectomy. The patients consisted of 69 men and 21 women. Serum anti-hepatitis C virus was positive in 76.9% of patients and hepatitis B surface antigen was positive in 18.9%. The operative procedures consisted of right lobectomy in six patients, left lobectomy in seven, right hepatic segmentectomy in eight, left lateral segmentectomy in 13, two adjoining subsegmentectomy in 17, subsegmentectomy in 29, and partial hepatectomy in 10. Liver cirrhosis was confirmed histopathologically in 63 patients. There were two operative deaths and two other in-hospital deaths. During the follow-up period, HCC recurred in 64 of the remaining 86 patients at the following sites: liver in 56 patients (87.5%), bones in four (6.3%), lymph nodes in three (4.7%), and lung in one (1.6%). Transcatheter arterial chemoembolization was performed in 22 of the patients with recurrence, transcatheter arterial chemoembolization in combination with percutaneous ethanol injection was performed in 14, hepatectomy was performed in six, and irradiation with Linac x-rays was performed in eight. The cumulative 3- and 5-year survival rates were 63.8% and 37.8%, respectively. Univariate and multivariate analyses of factors influencing survival disclosed that having a single HCC nodule of up to a maximal diameter of 4.0 cm, an absence of intrahepatic metastasis, and a functional liver reserve estimated as clinical stage I contributed significantly and independently to increasing the survival rate.

The occurrence of concealed infection or "natural remission" in infective endocarditis was investigated microscopically in 35 consecutive patients (36 valves) with infective endocarditis (between April 1987 and May 1995). Four patients were considered as having concealed or silent infective endocarditis. Preoperative diagnosis of these patients was mitral valve prolapse, rheumatic aortic valve stenosis with insufficiency, aortic valve prolapse and hypertrophic cardiomyopathy, respectively. These patients did not present with any clinical signs of infective endocarditis such as cardiac murmur and ventricular dysfunction. Histological examination of the excised valves revealed valvular perforation, small round cell infiltration, neovascularization, remnants of vascular smooth muscle cells, and organizing vegetations. These findings are consistent with the histological findings of infective endocarditis. Latent infective endocarditis may be present without inflammatory manifestation.

Deoxyribonucleic acid (DNA) synthesis of mesenchymal cells in the diseased valve tissue of patients with rheumatic and non-rheumatic valve diseases were compared. Surgically resected mitral valves from eight rheumatic and eight non-rheumatic patients in their 40s were examined immunohistochemically to estimate the activity of the various mesenchymal cells by cell cycle analysis, using monoclonal antibodies to cyclin E, A, B1, p53, and b cl-2 after routine tissue fixation, paraffin embedding and sectioning. Cyclin B1-positive fibrocytes and fibroblasts of the spongiosa and fibrosa were observed in all non-rheumatic cases, whereas some lymphocytes in the perivascular area were cyclin B1-, p53- and b cl-2-positive in rheumatic cases. The distinct qualitative difference in the mesenchymal cells of valve tissue between rheumatic and non-rheumatic etiologies suggests a different mode of valve pathology.

We examined the postoperative swallowing function of 12 tongue and oral floor cancer patients reconstructed with a recto-abdominal myocutaneous free flap after glossectomy. On the basis of the resection site, the present cases were classified into either anterior type or lateral type. Subjective evaluation of postoperative swallowing function was obtained from self-reports from patients. The movement of the reconstructed tissue was evaluated videofluorographically during swallowing, by tracking the movement of two small pellets temporarily attached to the anterior and central portions of the reconstructed tongue. The trajectory of the two pellets and the selected point of the hyoid bone were recorded together with the distance between the plate and the tongue dorsum, and between the posterior pharyngeal wall and the tongue base. Using a personal computer, a quantitative study of the video images was performed. The results were summarized as follows. 1) The movement pattern of the reconstructed tissue was generally saccadic rather than smooth. It was suggested that the swallowing pattern of the patients was different to that of normal controls. 2) Postoperative swallowing function was poorer in cases of the anterior type when compared to the lateral type. 3) In general, cases which showed relatively wide movement range appeared to achieve subjectively satisfactory swallowing function.

To determine the spectrum of mutations of the COL4A5 gene encoding type IV collagen among Japanese Alport syndrome (AS) patients, 60 unrelated patients (47 males and 13 females) from all over the country were recruited. Screening for mutations in all the exons (1 to 51) of the COL4A5 gene was carried out by PCR-SSCP analysis. A mobility shift was observed in 22 of 60 patients, and their genomic DNA were analyzed by the direct sequence method and using cloned ssDNA. Nine of these had missense mutations in the collagenous domain (in exons 39, 37, 31, 29, 28, 27, 21, 20, 19). Eight of these mutations were observed in a codon of glycine residue. Two were altered to arginine, two to valine, two to glutamic acid and two to aspartic acid. The other missense mutation was a change from isoleucine to serine in a interruption region. Five patients had small size base deletions and one had a 4 bp insertion resulting in frameshift (in exons 49, 41, 19, 14, 13). Three had a splice site mutation (in exons 49, 47, 27). One had a nonsense mutation (in exon 17). These mutations seemed to be pathogenic, but the phenotype, which includes extrarenal manifestations, can vary with respect to both expression and severity. The remaining mutations were three silent ones (in exons 19, 39, 46). In addition, major gene rearrangement seemed to be rare in Japanese AS patients.

Underlying pathologic disorders of infected valves were analyzed in 36 consecutive patients with infective endocarditis (from April 1987 to May 1995) of 18 aortic, 11 mitral and 8 prosthetic valves. Among 29 cases of native valve endocarditis, 27 had known organic changes [aortic valve prolapse 8, bicuspid aortic valve 4, annuloaortic ectasia 1, mitral valve prolapse 9 (including 2 cases associated with hypertrophic cardiomyopathy), looping chordae 1, rheumatic heart disease 4]. However, the remaining two cases had unknown etiology. Histological examination of these two aortic valves revealed proliferation of small vessels and remnants of vascular smooth muscle cells, suggesting postinflammatory valve prolapse. Five cases with definite pathology had no clinical signs of infection. The preponderance of surgically resected valves with infective endocarditis in Japan is non-rheumatic in origin.

The most important factor to reduce late restenosis following directional coronary atherectomy is the technical provision of the largest luminal diameter as possible. However, the safety of deep arterial resection and the resulting arterial perforation or late aneurysm formation is questionable. This study examined the frequency of coronary artery aneurysm formation in patients treated by directional coronary atherectomy. Ninety-eight patients with 123 lesions were analyzed by quantitative angiographic and histologic data. Coronary aneurysms (ratio of dilated vessel segment to the adjacent reference segment1.2:1) occurred in seven patients (seven lesions: 5.7%). Specimens were categorized by the deepest layer retrieved. Forty lesions (32.5%) were treated by resection of the intima alone, 65 (52.8%) by resection of the medial tissues and 18 (14.6%) received resections of the adventitial tissues including fatty tissues in three lesions. Late coronary aneurysms occurred often in lesions with resection of adventitial tissue (38.9%) and occurred in all three lesions with resections of fatty tissues. Six coronary aneurysms occurred in the left anterior descending artery (six in segs. 6, 7), and one aneurysm in the left circumflex artery. Among the target lesions in which coronary artery aneurysms were formed, six lesions were primary lesions and one lesion was a restenotic lesion after percutaneous transluminal coronary angioplasty. Statistically, patients with coronary artery aneurysms frequently have associated hypertension (p = 0.02) but rarely diabetes mellitus (p = 0.05). Lesions with late aneurysms had significantly high specimen weight (p = 0.01) and a trend to lower postprocedure % diameter (p = 0.20). There was no significant preprocedural angiographic predictor of aneurysms such as minimal lumen diameter or reference vessel diameter.

Clinical significance of IgG phospholipid-dependent anti-beta 2-glycoprotein I (beta 2-GPI) antibodies in patients with antiphospholipid syndrome (APS) was studied. The subjects consisted of 14 patients with primary APS (PAPS) and 32 with secondary APS based on SLE. IgG phospholipid-dependent anti-beta 2-GPI antibodies were examined by ELISA. Incidences of malar rash, arthritis, renal disorder, leucopenia, immunological disorder, and hypocomplementemia were significantly less frequent in patients with PAPS than in those with secondary APS based on SLE. However, sustained positive reactions of IgG anticardiolipin antibodies were found in 86% of patients with PAPS. Frequency of IgG phospholipid-dependent anti-beta 2-GPI antibodies was significantly higher in patients with PAPS (100%) than in those with secondary APS (34%). Moreover, titer of IgG phospholipid-dependent anti-beta 2-GPI antibodies was significantly higher in patients with PAPS than in those with secondary APS. These data indicated that IgG phospholipid-dependent anti-beta 2-GPI antibodies are useful for identifying a subset in patients with APS as well as for studying the mechanism of thrombotic events in these patients.

The growth fraction of childhood acute leukemia was evaluated by the immunostaining with the monoclonal antibody "Ki-67", which reacts with a nuclear antigen in proliferating cells. Ki-67 labeling rates (the percentage of Ki-67 positive cells in the total cells analyzed) greatly varied from patient to patient (0.0% approximately 49.2%). The mean value of the Ki-67 labeling rates was significantly higher in ALL than in ANLL (23.6% vs 5.6%, p0.001). In ALL, the Ki-67 labeling rates correlated with the proportion of S-phase cells determined by DNA flow cytometry (FCM) (r = 0.82) High Ki-67 labeling rates were preferably seen in ALL with favorable prognostic factors, although the correlation was not statistically significant. These results suggest that Ki-67 labeling rates reflect the differences in proliferative activity of bone marrow blast cells in childhood acute leukemia and is useful to determine the treatment schedule of cycle specific drugs.

A prospective study for detecting minimal residual disease (MRD) was conducted on children with acute lymphoblastic leukemia (ALL). Thirty-nine patients (38 B-lineage ALL, one T-ALL) with TCR delta rearrangements could be followed for 21 to 44 months (mean 30.9 months) excluding four patients who died. One hundred and ninety four bone marrow (BM) samples and 13 peripheral blood stem cell (PBSC) grafts were available for detection of MRD. Initially 34 cases were treated prospectively according to the CCLSG risk-stratified protocols for ALL (ALL874 or ALL911), and five cases according to the other protocols. Conventional chemotherapy was replaced by autologous PBSC transplantation (PBSCT) in five patients, by allogenic BM transplantation (BMT) in one patient, or suspended in another patient. Twenty-nine of 32 children in whom conventional chemotherapy could be continued without interruption remain in complete remission (CR). In 24 of the 29 patients MRD became undetectable within 12 months of their diagnosis. In five cases, BM samples obtained during maintenance therapy exhibited residual leukemia cells, and yet none of them relapsed (mean follow-up period 28.6 months). Our results thus indicate that intensive maintenance therapy for patients with PCR-positive results during consolidation therapy may prevent subsequent relapse. Nine events of relapse were diagnosed in eight patients (five BM, two isolated central nervous system (CNS), one combined BM and CNS, one isolated skin relapse). An increase or a re-emergence of MRD was detected in BM samples obtained from patients prior to BM relapse, but one patient remained in CR despite reappearance of leukemic cells following a PCR-negative status. Monitoring of MRD failed to predict isolated CNS or skin relapse. PBSCT allows high-dose cytoreduction therapy for patients with refractory neoplasia. In our study, leukemic cells were identified in eight of 13 PBSC grafts harvested from five patients. Three of four children who received PBSC grafts containing leukemic cells relapsed within 6 months after PBSCT. Monitoring of MRD as part of quality control of PBSC grafts may ultimately contribute to improvements in PBSCT procedures.

The mechanisms of cardiac involvement in systemic lupus erythematosus (SLE) were studied using immunohistochemical staining of endomyocardial biopsy specimens from 14 patients with SLE and normal coronary arteriograms. All 14 specimens showed mild interstitial edema, 11 showed mild cardiac fibrosis, and another two cases showed moderate cardiac fibrosis with myocardial derangements. Four specimens showed moderate cell infiltration in the interstitium. Area of fibrosis, diameter of myocardium and area of interstitial edema were increased in the SLE patients compared to the control cases. Immunofluorescence showed IgG and fibrinogen deposition in the membrane of cardiac myocytes and in the interstitium. Immunohistochemistry found no B lymphocytes in any of the seven SLE cases. T lymphocytes were observed in all seven SLE cases, and OKT 8 lymphocytes were increased significantly in the interstitial tissue as compared with OKT 4 lymphocytes. At endomyocardial biopsy, all 14 patients were receiving corticosteroid therapy and had low activity disease. The results suggest that cardiac tissue damage was associated with immunological abnormalities and might progress silently under conditions in which the disease activity was suppressed by corticosteroid therapy.

A questionnaire survey of blood donors at Santa Cruz General Hospital, Bolivia, showed that while there were no seropositive cases of syphilis, HBsAg, and HIV, the prevalence of Chagas' disease was very high (23%) among the 225 blood donors who responded to this questionnaire. Actual cases of Chagasic seropositive blood being used for blood transfusion were seen, including the urgent need for a program for Chagas' disease in Bolivia. From the results of this study, it is recommended that for blood donors from South American countries, the presence/absence of Chagas' disease should be confirmed.

We analysed the clinical presentation, treatment and outcome of our own 36 cases of posterior circulation dissecting aneurysms (DA) and discussed the surgical indications and procedures regarding posterior fossa DA. Twenty one cases were male, 15 cases were female. Their mean age was 54 +/- 14 years. Clinical manifestations were subarachnoid haemorrhage (SAH) in 14 cases (39%) and ischaemic attacks in 22 cases (61%). Three of 14 SAH cases had rebleeding in the acute stage. Angiographic findings were aneurysmal dilatation in 16 cases, retention of contrast medium in 12 cases, string sign in 9 cases, double lumen in 4 cases, pearl and string sign in 3 cases, and occlusion of parent artery in 2 cases. Surgical treatment was performed on nineteen cases (53%). The operation was carried out in the acute stage on the SAH group; in the subacute or chronic stage on the ischaemic group. The surgical procedure was the proximal ligation, trapping and removal of DA with or without revascularization of the parent artery. 84% of the surgically managed patients and 71% of the nonsurgical cases had a favourable outcome (good recovery or moderate disability). Poor prognosis was revealed from the rebleeding and primary neurological stage. We recommend surgical treatment in the acute stage on the SAH group. On the ischaemic group surgical treatment in the subacute or chronic stage is recommended, if the DA has the risk of rupture or progression of the dissection.

A randomized controlled clinical trial was conducted to compare the use of farmorubicin (FARM) and adriamycin (ADR) in Lipiodol transcatheter arterial chemoembolization (L-TAE) as a treatment of hepatocellular carcinoma. In all, 192 hospitals participated, and 415 patients were enrolled in the study during the period from October 1989 through December 1990, and their data were collected. The patients were randomly allocated to group A (FARM) or group B (ADR) by a central telephone registration. Several clinical characteristics were slightly worse in group A than in group B, but there was no statistically significant difference. The actual doses of FARM and ADR were 72 mg/body and 48 mg/body, respectively. Additional treatments, including repeated TAE or surgery, were given to 248 patients. The 1- and 2-year survival rates were 69% and 44% for group A and 74% and 57% for group B, respectively. The difference was marginally significant (P value in the log-rank test, 0.038). When each group of patients was classified into two subgroups, i.e., high-risk and low-risk categories, based on the severity index calculated by the Cox regression model from significant prognostic factors, the ADR subgroup was significantly superior to the FARM subgroup in the low-risk category, but there was no significant difference between the subgroups in the high-risk category. The change in the serum alpha-fetoprotein level, the extent of Lipiodol accumulation in the tumor, and the extent of tumor reduction did not show any significant difference between the groups. At the above-mentioned doses, ADR seemed to have efficacy almost the same as or slightly superior to that of FARM in L-TAE for the treatment of hepatocellular carcinoma.

A 48-year-old woman with malignant lymphoma, who was diagnosed as a hepatitis B virus (HBV) carrier because of positive HBs antigen, was admitted to Chiba Cancer Center Hospital. Complete remission was achieved by two courses of combination chemotherapy, but fulminant hepatitis developed after withdrawal of chemotherapy and she died of hepatic failure. Retrospective analysis of viral DNA disclosed a mutation in the precore region of HBV-DNA in her serum. We consider that the precoremutant virus was associated with the pathogenesis of severe hepatic failure after withdrawal of cytotoxic chemotherapy.

Pancreatic adenocarcinomas are known to have a high incidence of K-ras gene mutations. Differential diagnosis of pancreatic cancer and chronic pancreatitis sometimes presents a clinical dilemma. We recently developed a highly sensitive and specific polymerase chain reaction capable of detecting 3-30 copies of mutant K-ras genes harboring codon 12 single base changes in the presence of 300,000 normal copies. Mutant ras genes were detected in DNA purified from pancreatic juice from all 6 cases of pancreatic adenocarcinoma and 1 case of intraductal papillary neoplasms of the pancreas. In 2 of 6 other cases with pancreatic adenocarcinoma, circulating metastatic cells were detected in DNA purified from peripheral blood. Activated ras genes were not found in pancreatic juice of three control cases (chronic pancreatitis and choledocholithiasis) or in the peripheral blood of two patients with insulinomas. Notable conclusions of this study are that there can be significant levels of shed tumor cells in peripheral blood and an even higher number in pancreatic juice. In addition, two different K-ras mutations were found in some patients.

One hundred and eighty eight children with acute lymphoblastic leukemia (ALL) were treated in a Children's Cancer and Leukemia Study Group high-risk ALL 874 study from April, 1987 to September, 1991. These patients received a four-drug induction regimen followed by the early consolidation regimen, cranial irradiation at 6 months of remission and three years of continuation therapy with rotational administration of four drugs. The patients were randomized into two regimens. In regimen A, the consolidation chemotherapy consisted of the intermediate dose cytosine arabinoside (Ara-C), cyclophosphamide (CPM) plus 6MP, and in regimen B, it consisted of high-dose Ara-C plus CPM. Regimen A was given to 106 patients and 82 patients received regimen B. The complete remission induction rate for regimen A and B was 89.4% (93/104) and 98.7% (78/79), respectively. The 3-year event-free-survival (EFS) rate was 70.6% for regimen A, which was higher than the 56.7% for regimen B. The 3-year EFS rate was 44.4% for the 53 patients with an initial leukocyte countor = 10 x 10(4)/microliters and 72.2% for 132 patients with a leukocyte count10 x 10(4)/microliter. We considered that Ara-C plus L-asp, added to the conventional high-risk ALL 811 protocol, improved the prognosis of the high risk ALL patients. However, further intensive chemotherapy was required for improvement of the outcome of the patients with hyperleukocytosis (or = 10 x 10(4)/microliters).

We synthesized lecithinized superoxide dismutase (PC-SOD), in which a lecithin derivative was covalently bound to recombinant human SOD. We selected PC4-SOD (4 molecules of the lecithin derivative bound to each SOD dimer) and PC10-SOD (10 molecules of the derivative to each SOD dimer) for our study. Both of these PC-SOD retained SOD activity in vitro and showed delayed plasma disappearance in vivo in rats. PC-SOD also had 4 to 20 times higher affinity in vitro for several kinds of cells than that of unmodified SOD. Because Forssman antiserum is known to induce bronchial obstruction in guinea pigs via actions of O2-, we studied the effect of PC-SOD on Forssman antiserum-induced respiratory resistance. Unmodified SOD was ineffective at the doses of 1,000 to 30,000 U/kg, whereas PC-SOD showed a dose-dependent inhibitory effect over the range of 10 to 1,000 U/kg. The ED50 of PC4-SOD and PC10-SOD were 140 and 240 U/kg, respectively, at 30 min after the challenge with Forssman antiserum. These findings suggest that the pharmacological potency of PC-SOD is over 200 times more than that of unmodified SOD, and that PC-SOD may have the potential for various clinical applications.

We described two pediatric patients with acute promyelocytic leukemia (APL) who were successfully induced into complete remission with all-trans retinoic acid (ATRA, 45 mg/m2 per day) after failing on conventional chemotherapy. Initial response was observed as correction of DIC within a week of treatment. Hematologically, initial increase of maturing leukocytes reached a peak peripheral WBC count on the 16th and 20th day, respectively. However, these seemingly differentiated leukocytes retained Auer body and dysplastic features and there was no concomitant recovery of erythroid and megakaryocytic lineages at this point. A sudden drop of leukocyte counts after this peak made a brief period of leukopenia before the complete remission was finally attained morphologically in 4-5 weeks. Thus, remission of APL by ATRA therapy consisted of a two-phase course. In one patient, we observed an increase of histiocytes phagocytizing leukocytes in the marrow during the recovery from leukopenia. It is, therefore, postulated that the two-phase course of recovery may reflect the differentiation of leukemic cells by ATRA and subsequent clearance of senescent cells by the reticuloendothelial system followed by regeneration and differentiation of residual normal hematopoietic stem cells.

A randomized clinical trial comparing L-TAE with Farmorubicin (FARM) and L-TAE with Adriamycin (ADR) in the treatment of hepatocellular carcinoma was conducted from October 1989 through December 1990. In all, 192 hospitals participated in this study and 117 patients were entered. The patients were randomly allocated to group A (L-TAE+FARM) or group B (L-TAE+ADR). There was no significant intergroup difference in background factors. Additional treatment consisting of repeated TAE or surgery was given to 66 patients. Four factors were analyzed in this study: the percentage of reduction in tumor size, the change in the AFP level, lipiodol accumulation, and survival. None of these factors differed significantly between the two groups. The final evaluation of this study will be based on differences in survival after a long-term follow-up. Toxic effects manifested less frequently in group A than in group B, and the decrease in the platelet count in the peripheral blood was significantly lower in group A than in group B. These results suggest that FARM exerts a more favorable effect than does ADR in the treatment of hepatocellular carcinoma.

A randomized, controlled clinical trial comparing the use of lipiodol-transcatheter arterial embolization (L-TAE) in the presence versus the absence of Adriamycin (ADR) for the treatment of hepatocellular carcinoma was conducted from August 1988 through September 1989. In all, 125 Japanese hospitals participated in this study and 289 patients were entered in the trial. The patients were randomly allocated into group A (L-TAE) or group B (L-TAE + ADR) by telephone registration. There was no significant difference in background factors between group A and group B. Additional treatment, including repeated TAE or hepatic resection, was given to 189 patients. Among the four endpoints analyzed, the rate of tumor reduction and lipiodol accumulation in the tumor did not significantly differ between the two groups. The 3-year survival values for groups A and B were 33.6% and 34.9%, respectively; the difference was not significant. The serum alpha-fetoprotein level, however, decreased to a significantly greater extent in the group that received ADR than in the group that did not (P0.05). This result suggests that ADR has some favorable additional effect in L-TAE for the treatment of hepatocellular carcinoma.