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Forty-three hemophiliacs with AIDS or ARC received a daily dose of 334 or 500 mg didanosine (2',3'-dideoxyinosine or ddI) orally in 2 divided doses in phase I/II, open-label clinical trial conducted in Japan. Twenty-eight patients completed 6 months of therapy. There was an increase in circulating CD4(+) cells in 19 valuable patients from 91 +/- 25 (mean +/- SE) at entry to 131 +/- 38 at 24 weeks of therapy P = 0.01; Wilcoxon signed rank). Fourteen of 37 patients met the criteria for CD4 rise >/= 50/mm3 rise or >/= 50% increase from entry values) for more than 4 consecutive weeks. Twenty patients were p24 positive at entry. Nine out of the 10 evaluable patients (90%) showed a decline in p24 antigen at weeks 20-24 (P = 0.02). Thirty-five patients had symptoms related to HIV-1 infection at entry. Twenty-seven patients reported improvements in constitutional symptoms during therapy. Nine patients presented with possible drug-related adverse effects, and didanosine was discontinued in 6 patients (one each with edema; abdominal pain with anorexia; hematuria with edema and rash; sense of abdominal distension with anorexia; diarrhea and abdominal pain; and irritability). One patient had a transient increase in serum amylase level to twice the upper limit of normal, but he continued to receive the drug. These data suggest that didanosine was generally well tolerated in hemophiliacs with AIDS or ARC, and its administration correlated with improvement in constitutional symptoms and laboratory findings. The adverse effects of didanosine seen in this population were moderate to mild, and no complications related to hemorrhagic diathesis were observed, although the relative risk of acute pancreatitis in this population (while not seen in the present study to date) requires more study.

These experiments were undertaken to study the effects of cyclosporine A (CsA) on liver regeneration after an isogeneic orthotopic reduced-size hepatic transplantation (RSHT) in rats. Male Wistar rats were treated with or without a daily injection of CsA beginning 24 hr before surgery and were subjected to a 68% partial hepatectomy. A isogeneic orthotopic reduced-size hepatic transplantation was performed in recipient rats pretreated with or without CsA. A daily injection of CsA was continued until the recipient rats were sacrificed. Animals were sacrificed at various time points (12, 24, 36, 48, and 72 hr) postoperatively. The incorporation of bromodeoxyuridine (BrdU) into the DNA of the remnant hepatocytes was evaluated by immunohistochemical staining with a monoclonal antibody against BrdU. CsA (10 mg/kg/day) significantly augmented BrdU incorporation into hepatocytes after hepatectomy. The maximum labeling index (LI) was observed at 24 hr after hepatectomy. In contrast, the maximum LI in the recipient rats not receiving CsA was seen at 36 hr after RSHT, and 10 mg/kg/day of CsA decreased the LI at 36 hr after RSHT. A lower dose of CsA (3 mg/kg/day), however, significantly increased the LI in the recipient rats (P < 0.01), and it reached a peak at 24 hr after RSHT when compared to the transplant recipients not receiving CsA. The time course of the increase in the LI in the transplant recipient rats receiving 3 mg/kg/day of CsA was similar to that observed in the rats after hepatectomy. This dosage improved the delay in the reduced-size hepatic transplant LI reaching its peak.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied and analysed the effects of combination therapy with TAE and PEIT for unresectable HCC. The subjects were 28 patients (21 males, 7 females) with 31 tumors treated in the Department of Surgery, Osaka Teishin Hospital. The patients were divided into four groups on the basis of the tumor size (< 3 cm, 3-5 cm, 5-8 cm, > 8 cm). The therapeutic effect on the tumors was evaluated on the basis of the maximum reduction rate within 3 months after TAE and PEIT. The response rates after treatment were 87.5%, 60.0%, 25.0% and 0% for < 3 cm, 3-5 cm, 5-8 cm, and > 8 cm tumor size, respectively. The 50% survival period was 50.9 months. The 1-, 2-, 3- and 5-year survival rates were 92%, 76%, 52% and 32%, respectively. In the cases of over 8 cm, this combination therapy had no effects on the survival period. The findings of the present study suggest that the combination therapy was useful for the unresectable HCC of under 5 cm in diameter.

The association of macrophage infiltration with orthotopic rat liver transplant rejection was studied in the ACI(RT1a) to the LEW(RT1(1)) rat combination, using immunohistochemical staining with several monoclonal antibodies at different time points. LEW recipients of ACI liver transplants experienced severe acute rejection, with a mean survival of 10.2 +/- 0.7 days. An indirect immunoperoxidase technique on cryostat sections of the liver grafts was used to determine the localization of macrophages infiltrating the grafts as defined by specific rat anti-macrophage monoclonal antibodies designated TRPM-3 and KI-M2R. In addition, the monoclonal antibodies MRC OX3 and MRC OX6 were used to detect the macrophages that expressed Ia antigens. MRC OX3 binds only with the host LEW Ia antigens, but MRC OX6 binds with both host LEW and donor ACI Ia antigens. OX3+ and OX6+ macrophages were seen in the periportal area of the hepatic allograft on Day 5; thereafter, the number of these cells increased in the periportal and pericentral areas as well as in the sinusoidal lumens. A large number of TRPM-3+ cells were also seen at the periportal area in the hepatic allograft on Day 5, whereas there was no increase in the number of KI-M2R+ cells. In addition, most of the infiltrating mononuclear cells were OX3+. These findings suggest that a large number of TRPM-3+ macrophages of recipient origin migrate into the hepatic allograft soon after transplantation. A progressive relative increase in host TRPM-3+ macrophages is a characteristic feature of ongoing first-set rejection in the rat hepatic allograft.

Macrophage subpopulations infiltrating the grafts of ACI(RT1a) to LEW(RT1(1)) orthotopic rat liver transplants treated with or without immunosuppressive therapy were studied using immunohistochemical staining. LEW recipients of ACI liver transplants experienced severe acute graft rejection, with a mean survival of only 10.2 +/- 0.7 days. An indirect immunoperoxidase technique on cryostat sections of the liver grafts was used to determine the localization of macrophage subpopulations infiltrating the grafts, as defined by specific anti-rat macrophage monoclonal antibodies, designated TRPM-1 (pan-macrophage), TRPM-3 (activated macrophage) and Ki-M2R (tissue macrophage). TRPM-1+ or TRPM-3+ cells gradually increased on days 5 and 7 in the untreated hepatic allografts, whereas no significant changes in the number of these cells were observed in the isografts. Treatment with cyclosporine (CsA) greatly decreased the number of these two different types of cells infiltrating the hepatic allografts, compared to the untreated hepatic allografts or the isografts. The time course of the accumulation of these cells in the allografts treated with CsA showed a similar pattern; the cells increased gradually by day 5 and thereafter decreased. This pattern is different from that observed in the untreated allografts or in the isografts. There was no significant difference in the number of Ki-M2R+ cells between the untreated hepatic allografts and the isografts. However, the number of the Ki-M2R+ cells in the hepatic allografts treated with CsA was much less than that of either the untreated allografts or the isografts. These findings suggest that a progressive relative increase in host TRPM-3+ macrophage is a characteristic feature of ongoing first-set rejection in the rat hepatic allograft.2+ allograft, even when compared with the isografts.

HIV-1 strains were isolated from three patients treated with AZT and from three patients not treated with AZT. Progenomes of HIV-1 RT gene were amplified by PCR and cloned to M13mp18 vecter. Four amino acid mutations in RT gene (Asp67, Lys70, Thr215, Lys219) associated with resistance to AZT were analysed. All of the 14 clones obtained from the three patients with AZT therapy had mutations at codon 215 (Thr-->Tyr or Phe). Some of the 14 clones also had other mutations at codon 67 (Asp-->Asn or Ser), codon 70 (Lys-->Arg) and codon 219 (Lys-->Glu). All of 18 clones obtained from the patients not treated with AZT have no mutation at any codon mentioned above.

A human adenocarcinoma cell line designated as GAC-1, was established from ascites of the 56-year old male patient with rapidly progressive gastric cancer. The doubling time was about 18.5 hours in vitro, and cell cycle analysis using flow cytometry showed marked increase of S phase (46.1%). Immunohistochemical demonstration of GAC-1 cells revealed positive staining of TGF-alpha, EGF, EGF-R, FN-R, laminin and negative staining of fibronectin. Histogram of them indicated aneuploidy with modal number 57 and they formed tumors in nude mice.

A single intravenous injection of 1 ml freshly heparinized donor blood seven days before transplantation significantly prolonged the survival of subsequent donor-specific hepatic allografts in the fully allogeneic ACI(RT1a-to-LEW(RT1l)) rat combination. The time course of cell-mediated lympholysis was studied in this animal model. The activity of CML in lymphocytes infiltrating into the hepatic allograft (CML-G) and in the spleen (CML-S) was determined by measuring % lysis of donor Con A blast cervical lymph node cells. Preoperative DST resulted in an increased activity of CML-S with a peak (31.6%, E/T = 150) on day 7. This increased CML-S activity after DST rapidly declined during the first days following hepatic transplantation. The activities of both CML-S and CML-G then increased after transplantation and reached peaks on days 15 (48%, E/T = 150) and 20 (2.57%, E/T = 75), respectively. These were much higher than the peak values of CML-S (11.2%, E/T = 150) on day 7 and CML-G (19.5%, E/T = 75) on day 6 in untreated controls and were followed by a subsequent gradual decrease in those activities to preoperative levels by day 113 posttransplant. Phenotypic analysis of lymphocytes infiltrating grafts in DST-treated hosts demonstrated that the CD4/CD8 ratio remained relatively constant (less than 1.0). While the ratio in control grafts increased and reached a peak (2.17) on day 9. Histological examination revealed that mononuclear cell infiltration of grafts reached a peak on day 9 in both DST-treated hosts and controls. This mononuclear cell accumulation gradually subsided in DST-enhanced grafts. The mitotic index of graft hepatocytes reached a peak on day 15 in DST-treated hosts and on day 7 in control. The evidence of prolonged survival of hepatic grafts in recipients pretreated with DST, despite the presence of cytotoxic T cells with increased CML activity in vitro, suggests that effector cytotoxic cell activity may not be necessary for rat liver allograft rejection and that there may be limitations in measuring host cytotoxic activity simply by CML assays.

The effect of total-body irradiation of the donor on hepatic allograft survival was studied in the rat, with ACI(RT1a) as the donor and LEW(RT1(1)) as the recipient. LEW recipients of ACI liver transplants experienced severe acute rejection, with a mean survival of only 10.2 +/- 0.3 days. The doses of irradiation were 450, 750, and 1000 rads administered 24 hr prior to harvesting or subsequent transplantation. TBI with a dose of 750 rads significantly prolonged the survival of the hepatic allograft to 30.3 +/- 1.7 days, without concomitant immunosuppression. However, neither 450 rads nor 1000 rads of TBI resulted in successful suppression of graft rejection. TBI appeared to have a beneficial effect on hepatic allograft survival and to have no deleterious effect on isograft survival, suggesting a possible modulation of the immunogenicity of the donor organ. Although the cause of this beneficial effect is not clear, TBI with a dose of 750 rads 24 hr prior to organ harvest seems to be optimal to eliminate-antigen presenting cells in the donor organs.

In this study, we analyzed 149 surgical cases of colorectal cancer between January 1983 and August 1989. Thirteen cases (8.7 percent) of colorectal primary cancer associated with extracolonic primary malignancy of 14 lesions and 10 cases (6.7 percent) of multiple primary colorectal cancers were included. Among the 14 lesions of extracolonic primary malignancy, there were 6 gastric carcinomas, 2 endometrial carcinomas, 2 urinary bladder carcinomas, and one each in the esophagus, liver, bile duct and jejunum. The second tumor was not detected preoperatively in 3 of 4 cases of synchronous multiple primary colorectal carcinoma. A curative resection was done in 10 (77 percent) out of 13 cases of colorectal cancer associated with extracolonic malignancy, while 7 (88 percent) out of 8 cases of multiple colorectal cancers had a curative resection. Nine patients (69 percent) with colorectal cancer associated with extracolonic malignancy were disease-free for 2 months to 14 years. Seven patients (88 percent) with multiple colorectal cancers were disease-free for one to 22 years. We recommend, therefore, that in any patient with colorectal cancer, the entire large bowel should be thoroughly searched for any other primary tumors, by taking the existence of extracolonic tumors into account. A curative resection should be performed, and the follow-up period should be life-long.

Among 44 patients with hepatocellular carcinoma (HCC), combination treatment with both transhepatic arterial embolization (TAE) and ethanol injection therapy (EIT) was performed in 10 patients. Only two had tumors measuring less than 3 cm in diameter. In all, eight patients had solitary tumors and two had multiple tumors. The tumor was classified as stage I in one patient, stage II in six subjects, stage III in two patients, and stage IV in one subject prior to TAE, but one stage II case was changed to stage III after laparotomy. The clinical stage was I in two patients, II in six subjects and III in two patients. Five patients with tumors of stages I and II achieved either a complete response (CR) or partial response (PR). However, three patients with tumors of stages III and IV showed progressive disease (PD). Thus, the response rate (CR+PR) was 50%. For tumor stages I and II, the 1-, 2-, and 3-year survival values were 100%, 100%, and 83%, respectively. For tumor stages III and IV, the 1- and 2-year survival values were 75% and 25%, respectively. Combination treatment of HCC appears to be efficacious for tumor stages I and II.

A 36-year-old man with anemia due to gastrointestinal bleeding, diagnosed to have a leiomyoma of the duodenum, is described. The conventional barium meal study and gastroendoscopy were useful for diagnosing the lesion. More invasive radiological methods, such as abdominal angiography and technetium-99m scintigraphy failed to detect the tumor. Early diagnosis and resection of the tumor would result in a good prognosis.

Nine patients with multiple metastases including liver from breast cancer were treated with transarterial chemoembolization through hepatic artery using 40-50 mg of 4'-epi-adriamycin and Lipiodol, followed by 800-1,200 mg/day of medroxyprogesterone acetate. Of 9 patients thus treated, there were 4 partial response (44%), 2 no change and 3 progressive disease. Duration of disease control ranged from 4 to 46 months (mean 24.5 months). Seven out of 9 patients died within 6 to 37 months (mean 15.3 months) after diagnosis of liver metastases. The 3- and 5-year survival rates were 45% and 11%, respectively. We conclude that this therapy is a useful treatment modality for controlling liver metastases of breast cancer.

Temporal bone findings in two infants demonstrating congenital aural atresia with microtia were presented focusing mainly on the external and middle ears. These two cases were proved to have chromosome aberration that is, 13-15 trisomy and extra chromosome in group G individually. Temporal bones showed the multiple anomalies through the external, middle and internal ears. The external canals were filled with connective tissue in one case and with bony plate in the other to form aural atresia. There were no development of the tubotympanic recess in a case of 13-15 trisomy. The oval window area in both cases was poorly developed resulting in a connective tissue fissure in the lateral wall of the vestibule except for one ear, while the round windows were normally formed in all ears. The facial nerves showed an abnormal running course without forming the geniculate ganglion and the horizontal segment. These findings indicate that the structures derived from the second branchial arch might be more deeply involved than the first one in the congenital aural atresia.

We studied the histopathologic features of the temporal bones in a human embryo with unilateral aural atresia. The developmental stage of the embryo was at stage 22 in the Carnegie system, and the estimated ovulation age was 8 weeks. There were severe hypoplastic changes in Meckel's and Reichert's arch cartilages without differentiation of the auditory ossicles, hypoplasia of the tubotympanic recess, and resultant abnormal passing of the facial nerve in the affected ear. Abnormal lateral extension of the cartilaginous otic capsule replaced a posterior half of the middle ear region and seemed to form the so-called atresia plate. The external and middle ears of the unaffected side and the bilateral inner ears were morphologically normal. These findings might explain some parts of the complicated mechanism in the development of middle ear anomalies encountered in surgery for congenital aural atresia.

Clinical effect and excretion into wound exudate of a new semisynthetic cephalosporin cefroxadine (CXD), were studied. CXD was given in 25 cases of surgical infections; 6 cases of wound infection, 9 cases of abscess, 9 cases of infected atheroma and 1 case of furuncle. CXD was orally administered in daily dose of 750 to 1,500 mg. Clinical results were excellent in 1 case, good in 18 cases, fair in 3 cases and poor in 3 cases. The overall clinical efficacy rate was 76.0%. Clinical efficacy classified by diagnosis was 66.7% in wound infection, 66.7% in abscess, 88.9% in infected atheroma, and 100% in furuncle. Side effects were not observed in all cases among 25 patients in CXD trials. Studies of excretion into wound exudate of CXD were performed in 1 postoperative case of mamma carcinoma after oral administration of 500 mg of CXD. The concentration of CXD in exudate was 1.12 micrograms/ml in 2 hours, 3.48 micrograms/ml in 3 hours, 4.13 micrograms/ml in 4 hours, 5.56 micrograms/ml in 5 hours and 4.41 micrograms/ml in 6 hours after administration, which was observed that CXD was excreted in wound exudate in high concentration.

A case of a stromal sarcoma of the breast that developed after augmentation mammoplasty is presented. A 55-year-old woman, who had received mammoplasty twenty years earlier, was referred to our hospital due to a mass in her left breast. A diagnosis of myxoid sarcoma was determined by an incisional biopsy and a radical mastectomy was performed. A pathological specimen, however, revealed the mass to be a stromal sarcoma because of its metaplastic heterogeneous elements, such as bone, cartilage, and muscle. We also present previous cases, and discuss the matter of diagnosis and therapy.

Considerable amounts of immunoreactive pancreatic secretory trypsin inhibitor were detected in lung, stomach, liver, pancreas, kidney, small intestine and ovary. Immunoreactive pancreatic secretory trypsin inhibitor content of surgically removed gastric mucosa was approximately seven times higher than that of gastric mucosa obtained at autopsy. The reduction in PSTI-immunoreactivity seen in a tissue extract of fresh gastric mucosa on 24 hours' incubation represented 9% of the original immunoreactivity in 10 mM Tris-HCl buffer, pH 7.4, at 37 degrees C. While, there was a more than 80% reduction in immunoreactivity on 12 hours' incubation at 37 degrees C at pH 4.0 or under more acidic conditions.

Three cases of persistent bilateral sensorineural hearing loss following Mycoplasma pneumoniae (MP) infection are reported. These cases were characterized by highly elevated MP complement fixation titer and cold hemagglutinin titer. All the patients had bilateral acute otitis media with a moderate to high degree of mixed hearing loss in the early stage following primary atypical pneumonia (PAP).

Intra-arterial infusion chemotherapy of adriamycin (ADM) was performed in 31 cases with locally advanced breast cancer. The overall response rate for ADM was as high as 71% (22/31) in the primary lesions and histological response rate was obtained in 54.8% (17/31). Five-year survival rates for patients with stage IIIa, IIIb and IV breast cancer were 100%, 37.5% and 40.0%, respectively, compared with 63.8%, 35.7% and 12.5%, respectively, for 80 cases of control group. Although there was no correlation between local response rate and longer survival time, a more favorable prognosis seems possible with this treatment compared with other forms of therapy.

Twenty-six of 31 seriously injured patients (84%) showed a marked elevation of serum pancreatic secretory trypsin inhibitor (PSTI) to more than twice the initial level within the first 2 weeks after admission. Serum PSTI rose from the second or third post-traumatic day and reached the maximum at day 5.8 on average. In uneventful cases, it returned to the level on admission within 2 weeks. The maximum serum PSTI in these patients was significantly correlated with the severity of the injury as judged at the time of admission, indicating that the elevation of serum PSTI in these patients was related to the extent of initial damage. In contrast, serum PSTI in patients with serious complications remained at high level even at 2 weeks after trauma, and it was not correlated with the initial severity of the injury.

Histopathological findings in the temporal bone are described in a newborn infant, diagnosed as having Potter's syndrome. The infant has severely malformed low-set ears bilaterally and a small lower jaw; autopsy findings showed bilateral renal agenesis and pulmonary hypoplasia. The temporal bone indicated the deformities of the inner ear, classified as Mondini-type, complicated by extensive deformities to the external ear and middle ear, including absence of auditory ossicles, atresia of the oval window, abnormal course of the facial nerve, and hypoplastic external auditory canal. The cochlear membranous labyrinth showed nearly normal form in the upper turn, but severe hypoplasia in the basal turn, which was an unusual cochlear anomaly.