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A case-controlled collaborative study on the intravesical administration of Adriamycin in the presence or absence of verapamil, a calcium-channel blocker, as chemotherapy of superficial bladder cancer was carried out at two universities, Okayama and Kagoshima, and their affiliated hospitals. Although little is known about the expression of P-glycoprotein in superficial bladder cancer, it may be a cause of multidrug resistance (MDR). Verapamil was used as an inhibitor of P-glycoprotein. Arm A consisted of Adriamycin given at 50 mg/50 ml saline, and arm B constituted Adriamycin given at 50 mg/40 ml saline plus 5 ampules (10 ml) of injectable verapamil. The drugs were instilled into the bladder for 3 consecutive days in each of 3 consecutive weeks for a total of 9 instillations. No significant difference in antitumor effects was observed between arm A and arm B. Recurrent tumors responded better than did primary tumors to both arm-A and arm-B treatments (P = 0.012). In both treatment arms, significant differences (P = 0.031) in the response rate were found between tumors with diameters of less than 1 cm and those measuring 1-3 cm in diameter. Although the number of evaluable patients was limited, recurrent subjects who had previously received Adriamycin instillations responded in both treatment arms.

Human T-cell leukemia virus type I (HTLV-I) genome is believed to encode its own protease, although the protease has not yet been detected. To identify the HTLV-I protease, an in-frame gag (3' portion)-prt region was expressed in Escherichia coli. The 14-kDa product was detected using antisera against a synthetic peptide mimicking the fragment of HTLV-I protease, although the molecular weight of the primary translational product was 27,000. A cell extract had a proteolytic activity to cleave a synthetic peptide substrate containing the cleavage site of gag p19/p24 at the correct site in vitro. Replacement of the putative active site Asp-64 with Gly abolished both in vivo processing activity and in vitro proteolytic activity. These results suggest that the 14-kDa product is the mature enzymatically active HTLV-I protease generated through posttranslational autoprocessing in E. coli.

Sialyl dimeric Le(x) antigen was expressed in significant portion of transitional cell carcinoma of the human urinary bladder, but not in the normal uroepithelial tissue. Primary tumors with weak or no expression of the antigen scarcely metastasized to lymph nodes, whereas tumors with high levels of antigen expression metastasized frequently. Metastatic lymph nodes expressed the antigen in most cases. Sialyl dimeric Le(x) antigen was mainly located on 60 and 42 KDa glycoproteins. Since a group of cell adhesion molecules, called LECCAMs, recognize a portion of the antigen, the above results strongly suggest that a LECCAM on the surface of host cells recognizes the carbohydrate structure on the glycoprotein, leading to promotion of metastasis.

Human T-cell leukemia virus type I (HTLV-I) protease has been purified to homogeneity from a strain of recombinant Escherichia coli. The protease was expressed as a larger precursor, which was autoprocessed to form a mature protease. Protein chemical analyses revealed the coding sequence of mature protease, which agreed with the putative sequence predicted from the sequence of bovine leukemia virus protease. The purified protease processed the natural substrate gag precursor (p53) to form gag p19 and gag p24. The protease activity was inhibited by pepstatin A. These results provide direct evidence that this protease belongs to the aspartic protease family and has an activity consistent with the protease in HTLV-I virion.

This report describes the concomitant occurrence of a somatostatin-rich duodenal carcinoid, a medullary thyroid carcinoma and a diffuse adrenal medullary hyperplasia in a patient with von Recklinghausen's disease. A 50-year-old Japanese man died from lung metastasis of a malignant schwannoma. In addition to extensive viscero-cutaneous neurofibromatosis, two different types of neuroendocrine tumors were found in the duodenum and thyroid gland at autopsy. The duodenal tumor, which was located in the second portion, showed the histologic appearance of a carcinoid tumor with glandular differentiation and psammoma-bodies. Immunohistochemically the tumor cells were intensely positive for somatostatin. The thyroid tumor was composed of nests of tumor cells arranged in an endocrine pattern, and showed immunoreactivity for calcitonin. A review of the literature revealed no previously reported case of concomitant occurrence of duodenal somatostatinoma and medullary thyroid carcinoma in a single patient with von Recklinghausen's disease. Morphometric analysis of adrenal glands disclosed the presence of diffuse medullary hyperplasia. Thus, the present case exhibited a similarity in some respects with multiple endocrine neoplasia (MEN) syndrome, Type IIa or IIb.

A monoclonal antibody, TAK-B1, was produced by immunization of BALB/c mice with mammary carcinoma induced in inbred Sprague-Dawley rats by treatment with 7,12-dimethylbenz[a]anthracene. TAK-B1 reacted with ovary-independent mammary carcinoma cells which had been transformed from ovary-dependent mammary carcinoma cells, but did not react with original mammary carcinoma cells or with cells from mammary glands exhibiting fibrocystic changes or normal mammary glands. However, TAK-B1 reacted not only with basal cells of the epidermis and epithelial cells of the bottom portion of crypts of the small intestine in adult rats, but also with basal cells of epidermis in skin and mesenchymal cells around developing hair follicles in fetuses. We therefore classify TAK-B1 as an ovary-independent rat mammary tumor-associated antigen. Immunoelectron microscopic examinations revealed that the antigen recognized by TAK-B1 was localized in the cell surface membrane of ovary-independent mammary carcinoma cells. Immunoprecipitation assay revealed that the antigen recognized by TAK-B1 was composed of M 220,000 protein and four other minor proteins.

A case of paraganglioma of the cauda equina is reported. The patient was a 55-year-old Japanese woman who complained of lower back pain and gradual weakening of the left lower extremity, she was diagnosed as having a spinal cord tumor, and the tumor was removed surgically. Histologically, the tumor was encapsulated, and consisted of solid nests of large, polyhedral epithelioid cells with abundant eosinophilic cytoplasm. The nests were separated from each other by a thin fibrovascular stroma. Grimelius staining revealed neurosecretory granules in the cytoplasm of the tumor cells. This was further confirmed by electron microscopic observation. The tumor cells were immunohistochemically positive for neuron-specific enolase (NSE), but negative for glial fibrillary acidic protein (GFAP). On the basis of the histologic, immunohistochemical and electron microscopic features of the tumor cells, the tumor was diagnosed as paraganglioma. The cauda equina is a rare location for this type of tumor, and only a limited number of cases have been reported.

The efficacy of three kinds of fluid such as isotonic sodium chloride (0.9% NaCl), hypertonic sodium chloride (7.5% NaCl) and iso-oncotic (3% in saline) albumin solutions to maintain the hemodynamics was investigated in rats with superior mesenteric artery occlusion (SMAO) shock. Three kinds of fluid were infused so as to maintain the mean arterial pressure within 70% of the control values. Animals in the control group without fluid therapy died within three hours because of shock. Three regimens could maintain the mean arterial blood pressure over three hours. The hypertonic crystalloid solution was effective in the early period of SMAO shock to regain the blood pressure by infusing a small volume. An excessively large amount of volume was required in the group infused with an isotonic crystalloid, providing inadequate tissue perfusion. The iso-oncotic colloid produced a stable circulatory status with minimum changes in tissue perfusion.

Patients with human T-cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) sometimes have accompanying voiding disturbances. We performed clinical surveys and urodynamic examinations on 25 untreated patients with HAM. Although 4 cases (16%) were entirely aware of urinary symptoms, the onset of urinary symptoms preceded other pyramidal symptoms in 6 cases (24%). All cases suffered from dysuria. The cause of dysuria was thought mainly to be detrusor external sphincter dyssynergia, but in some cases an underactive detrusor and poor opening of the bladder neck at voiding were also the causes of dysuria. There was a tendency for urinary dysfunction to become worse as the primary disease progresses. Patients with HAM must be carefully followed up by urologists in order to prevent deterioration of the urinary tract.

An autopsy case of hemolytic uremic syndrome after treatment with antineoplastic agents for advanced gastric carcinoma is reported. A 70 year-old woman underwent partial gastrectomy for gastric carcinoma on April 16, 1987 (P0H0S2N4, Stage IV). She was treated with Mitomycin C (MMC), UFT, OK-432 and PSK as post operative chemotherapy. Total doses were 60 mg of MMC, 33.9 g of UFT, 55 KE of OK-432 and (507 g) of PSK. She suffered from occult blood in urine in September 1987, thrombocytopenia and anemia in October, edema and hypertension in November and died due to acute renal failure and pulmonary failure on December 5, 1987. It seemed that the cause of death was hemolytic uremic syndrome induced by antineoplastic agents.

The optimal time of intravenous lidocaine for attenuation of pressor responses to laryngoscopy and endotracheal intubation was evaluated in fifty adult patients and the correlation between plasma lidocaine level and its clinical effects were also studied. The plasma lidocaine levels were highest 0.5 min after administration of lidocaine 1.5 mg.kg(-1) intravenously. However, endotracheal intubation 0.5 min after lidocaine administration caused significant increase in mean arterial pressure (MAP) and heart rate (HR). Mean arterial pressure and HR increased with endotracheal intubation following 1, 2 and 3 min after lidocaine administration, but the magnitude of increase was not statistically significant. There were no significant differences in MAP changes among these three groups. It was concluded that the plasma lidocaine levels did not correlate with its suppressive effect on circulatory responses due to laryngoscopy and endotracheal intubation. Laryngoscopy and endotracheal intubation should be carried out at least 1 min after intravenous lidocaine administration.

Nitrates and calcium channel blockers are frequently administered during cardiac surgery. We simultaneously measured femoral arterial pressure and radial arterial pressure to investigate whether nitrates, in conjunction with calcium channel blockers, would influence the central-to-peripheral arterial pressure gradient. Combined nitroglycerin and nicardipine infusion during cardiac surgery involving coronary artery bypass grafting or valve replacement resulted in a significant increase above baseline levels in the femoral-to-radial arterial pressure gradient at 60 min after cardiopulmonary bypass. In control patients there was no significant increase in the femoral-to-radial arterial pressure gradient at 60 min after completion of cardiopulmonary bypass. A subsequent study in patients given nitroglycerin and nicardipine identified that the difference in the systolic arterial pressure between femoral and radial arteries was observed 15, 60, and 120 min after completion of cardiopulmonary bypass. However, there was no difference in the mean arterial pressure between femoral and radial arteries throughout the same period. We conclude that combined infusion of nitroglycerin and nicardipine, a new calcium channel blocker, intensifies the magnitude and duration of the femoral-to-radial arterial pressure gradient after cardiopulmonary bypass.

The purpose of this trial was to minimize local inflammation caused by intravesical instillation of antitumor agents, especially Adriamycin, in the treatment of bladder tumor. Tranexamic acid was chosen as the solvent vehicle for Adriamycin and IV bolus injection of an antiallergic drug, Stronger neo-minophagen C, was given at the time of each instillation. Of 81 cases scheduled for Adriamycin instillation therapy, nine cases (11.1%) dropped out due to severe bladder inflammation, while 17 other cases (21%) experienced local side-effects which were tolerated. Of 62 evaluable cases in whom more than eight instillations were performed, complete regression was observed in six cases (9.7%) and partial regression in 20 cases (32.3%).

In a series of investigation to elucidate the roles of chemical substances in the atrophic process of nephron in chronic pyelonephritis (CPN), two protease inhibitors (PI) and enterobacterial antigen were examined by immunofluorescence (IF). Alpha-antitrypsin (alpha 1AT) was always found in the sclerotic glomerular tuft (GT) and along the thickened Bowman's capsule (BC) as well as the thickened tubular basement membrane (TBM) in every atrophic nephron of CPN. Antithrombin III (AT III) was always found along the inside of thickened TBM in every atrophic nephron, but not found in the sclerotic GT nor along the thickened BC. No enterobacterial antigen was present in the sclerotic GT, thickened BC, and thickened TBM. Therefore, alpha 1AT and AT III seem to play significant roles in the process of atrophy of nephrons as a different factor from the persistence of enterobacterial antigen which has been considered to be one of the progressive factors of CPN. At III was easily dissociated from the thickened TBM after the incubation in warm (37 degrees C) 0.01 M phosphate buffered saline of various pH (pH 4.0, pH 7.2 or pH 10.0) and cold (4 degrees C) or warm (37 degrees C) 0.75 M hydrazine solutions of the same pH, while alpha 1AT was not dissociated from the atrophic nephrons after the incubation in all solutions. These results may imply different processes of deposition between the two PI in the atrophic nephrons.

Sclerotic processes of glomeruli in chronic pyelonephritis (CPN) and chronic diffuse proliferative glomerulonephritis (CDPGN) were investigated in a lectin binding study in connection with an immunofluorescent examination of protease inhibitor deposition. Ulex europaeus agglutinin-I (UEA-I), which is specific to a certain terminal alpha-L-fucosyl residue of glycoconjugates, specifically labelled intact endothelia of glomerular capillaries, peritubular capillaries and blood vessels in human kidneys. Segmental or global loss of the UEA-I binding with glomerular capillaries was observed in the sclerotic areas where alpha 1-antitrypsin (alpha 1AT) deposits were always detected in the glomeruli with segmental or global sclerosis of CPN. This high correlation between loss of UEA-I binding and alpha 1AT deposition was also observed in the affected glomeruli of CDPGN. In considering glomerular sclerosis, it is significant that loss of UEA-I binding and alpha 1AT deposition are common to both CPN and CDPGN, although their original etiologies are quite different.

We examined whether a combined use of UFT with interferon against human KDR-1 strain cells was effective or not. KDR-1 strain derived from the patient with renal cell carcinoma was transplanted into nude mice. When the tumor grew large enough, the mice were divided into 4 groups. The group consisted of 1) oral use of 5% Acasia as a control, 2) oral administration of UFT, 3) combined use of UFT and IFN-alpha, 4) intraperitoneal injection of IFN. Each group was treated continuously for 16 days. Antitumor effect was not observed in group 2 and 4, but observed in group 3. The concentration of UFT in the tumor tissue did not show any differences between combination and UFT groups. Therefore, there is no evidence to prove that IFN-alpha makes UFT level higher. Antitumor effect was observed histopathologically in the combined regimen group, although a mechanism of synergistic effect is still unknown.

The accumulation of oxygen free radicals is reported to occur in the organs subjected to temporary ischemia followed by reperfusion, resulting in the fatal outcome of the animals. The effects of human SOD, a representative scavenger of oxygen free radicals, on the survival rates were investigated in the rats with temporary splanchnic ischemia. The temporary ischemia was induced by the occlusion of anterior mesenteric and celiac arteries for 30 min under anesthesia. Prior and after treatment with 2 mg/100 g of human SOD, iv or sc, produced significant improvements in survival rates. Human SOD, cloned from human placenta DNA and expressed in microorganisms, has extreme homogeneity. The results suggest the possible introduction of human SOD into clinical field as an effective scavenger of oxygen free radicals.

Since 1975 parasitism by the filarial worm has not existed in Japan. However, patients still present with filarial chyluria because the condition is one of the late manifestations of filariasis. From 1952 to 1973 renal pelvic instillation therapy, and surgical stripping and interruption of renal pedicle lymphatics were done in 217 and 383 patients, respectively, in the urology clinic of our and affiliated hospitals. Chyluria ceased immediately after instillation therapy in 129 of the 217 patients (59.4 per cent) but recurred in half of the cases. The short-term results of the surgical procedure were excellent. Chyluria ceased in 375 of the 383 patients (97.9 per cent) and diminished in 5 (1.3 per cent). Of 160 operated patients followed for more than 2 years recurrence of chyluria at contralateral and undetermined sites was observed in 41 (25.6 per cent).

Distribution of laminin on the surface of teratocarcinoma-derived parietal endoderm cells was studied by immuno-histochemical staining of the fixed specimen using affinity-purified anti-laminin antibody. Laminin was distributed on the basal surface of the cells, while treatment either with colchicine or with cytochalasin D (CD) resulted in a severely polarized distribution; laminin was seen only at one end of the cell. Treatment with both the reagents did not cause the severe polarization. Receptors for lectins and cell surface villi were polarized by treatment with CD but not by treatment with colchicine. These results suggest that laminin--or its cell surface receptor--is linked to both microfilament and microtubules and that the mode of transmembrane control for laminin is different from certain other cell surface components of the cells.

Antibacterial activities of imipenem (MK-0787), cefazolin (CEZ), cefmenoxime (CMX) and cefoperazone (CPZ) were measured by using an agar dilution method against 243 strains of bacteria isolated from the patients with urinary tract infections. The MIC80 of MK-0787 against S. epidermidis, E. faecalis, E. coli, K. pneumoniae, E. cloacae, S. marcescens, P. mirabilis, P. vulgaris and P. aeruginosa was less than or equal to 0.10, 3.13, less than or equal to 0.10, 0.20, 0.78, 1.56, 3.13, 3.13 and 6.25 micrograms/ml, respectively. MK-0787 was more active than CEZ, CMX and CPZ against all bacterial species except Proteus spp. Imipenem/cilastatin sodium (MK-0787/MK-0791) 500 mg/500 mg two times a day for 5 days was given to 31 cases of chronic complicated urinary tract infections and a case of acute prostatitis. Overall clinical effectiveness rate judged by the criteria proposed by the Japanese UTI committee in 22 cases of chronic complicated urinary tract infection treated with MK-0787/MK-0791 was evaluated to be 86% including excellent in 6 cases, moderate in 13 cases and poor in 3 cases. As side effects, 2 cases encountered eruption or anorexia. Abnormal laboratory findings were observed in 6 cases.

IFN-beta was more active than recombinant interferon-alpha (rIFN-alpha) and interferon-gamma (rIFN-gamma) in a human renal cell carcinoma transplanted in nude mice. In 3 out of 5 mice, the tumor completely disappeared and viable tumor cells were not observed at a daily dose of 5 x 10(5) U/mouse. Combination with anti-asialo GM1 antibody did not influence the tumor growth inhibition by IFN-beta. Mononuclear cells around damaged cancer cells were found not to be macrophages. Although the role of mononuclear cells remained unknown, the antitumor activity of IFN-beta seemed to depend on its direct cellular action. IFN-beta may be a useful agent in some renal cell carcinomas.

Effects of continuous prostaglandin E1 (PGE1) infusion 0.03 micrograms.kg-1.min-1 on hemodynamics, body temperature and urine output during cardiopulmonary bypass (CPB) were studied. Systemic vascular resistance was kept significantly lower in PGE1 administration group than control group. Differences between core and peripheral temperature decreased faster in the PGE1 administration group than the control group. Mean arterial pressure was stable at 40mmHg during CPB in the PGE1 group and 60mmHg in the control group. However, there were no significant differences in urine output between the PGE1 administration group (10.8ml.kg-1.h-1) and the control group (9.4ml.kg-1.h-1). This study indicates that continuous PGE1 infusion (0.03 micrograms.kg-1.min-1) is a method of choice for vasodilation and improvement of peripheral perfusion during hypothermia of CPB.

Post-shunt subdural hematoma was found in two patients with hydrocephalus due to subarachnoid hemorrhage. The first case was a 46-year-old man with two episodes of subarachnoid hemorrhage from anterior communicating aneurysm. Two weeks after neck-clipping for the aneurysm, a ventriculo-peritoneal shunt with Pudenz's system was performed since hydrocephalus with moderately increased pressure had been found. He did well for one month, then soon after mild head injury, disorientation and right hemiparesis developed. Cerebral angiogram revealed avascular space in the left parietotemporal region. After the ligation of the shunt tube, subdural hematoma was removed. The symptoms improved in two weeks. The second case was a 62-year-old man with an aneurysm at the trifurcation of the right middle cerebral artery. One month after successful clipping of the aneurysm, he received a ventriculoperitoneal shunt with Pudenz's system for normal pressur hydrocephalus. One and a half years after the operations he hit his head against the ground during his convulsive seizure. Since then, disorientation, urinary incontinence and gait disturbance appeared. After cerebral angiogram, the subdural hematoma was removed and the shunt tube was ligated. He became free of these symptoms in two weeks. The cerebrospinal fluid shunt is recommended for hydrocephalus induced by subarachnoid hemorrhage, but careful follow-up is necessary since these patients might develop post-shunt subdural hematoma, especially after head trauma as shown in our cases.

The functional status of cerebrospinal fluid shunting systems provided with flushing devices has commonly been assessed by the response of the flushing device to digital compression and a review of the clinical status of the patient. In order to study the reliability of the response of the flushing device as an indicator to shunt function, 47 hydrocephalic children with implanted shunts were studied. In 40% of these children, the flushing device was pumping well at the time of shunt obstruction, and in 50% it was not, although the patient's clinical status was perfectly normal. Accordingly, we conclude that the flushing device is a very poor indicator of shunt functioning.

We have experienced with 50 cases of parasellar tumors, four cases of which had persistent thirst, polydipsia, polyuria, and reversible temporary hyponatremia secondary to hypernatriuresis. The mechanism of the syndrome in these four cases could not be explained by either that of the syndrome of hypernatremia or of the so-called SIADH. We tentatively named this syndrome as "CEREBRAL POLYURIC HYPONATREMIA" and the criteria of this syndrome as as follows: 1) persistent thirst, polydipsia polyuria, 2) reversible temporary hyponatremia secondary to hypernatriuresis, 3) exception of the following items--administration of uretic drugs, renal and adrenal dysfunction, hyperglycemia, hyperlipemia, overadministration of water, and poor administration of NaCl. The mechanism of this syndrome is presumed as follows: 1) compression by a tumor or surgical attack to the anterior hypothalamus, 2) disturbance of the mechanism of ADH secret-on, 3) extrasecretion of natriuretic factor possibly produced in the anterior hypthalamus, and 4) preservation of the thirst center.

Measurement of MICs of PC-904, CBPC and GM against 135 strains of Pseudomonas aeruginosa isolated from patients with urinary tract infections was performed. Susceptibility to PC-904 of Pseudomonas aeruginosa was found to be 3 approximately 7 times more sensitive than that to CBPC and as same as that to GM with inoculum size of 10(8)/ml and 10(6)/ml. Serum level of PC-904 reached a peak of 38.5 microgram/ml 15 minutes after 0.5 g intravenous administration. Urinary recovery rate unit 6 hours after the administration was 12.5%. Overall clinical efficacy of 6 cases of acute simple cystitis and 3 cases of chronic complicated cystitis was judged to be 83.3% and 33.3% respectively by a criterion proposed by the UTI Committee in Japan.

Twelve cases of G.I. tract bleeding, treated in the Department of Neurosurgery, Kobe University School of Medicine, were analyzed with the special reference to clinical data before the episode of G.I. tract bleeding. These 12 cases consist of 10 cases of aneurysm, 1 of metastatic brain tumor, and 1 of chronic subdural hematoma. The anterior communicating artery has the majority in the case of aneurysm by 50 per cent. In each case, C.B.C., bleeding time, coagulation time, serum electrolytes, serum glucose, glucosuria, steroid administration, blood pressure, hyperthermia, and water balance were reviewed retrospectively. Only serum glucose showed the specific abnormality with the average of 135 mg/dl (Hoffman method) before the episode of G.I. tract bleeding among them. In 1931, Cushing reported the clinical case of G.I. tract bleeding with intracranial disease and also experimental G.I. tract bleeding, in which discussion he concluded only parasympathetic nerve system has the involvement in the mechanism. In 1952, French, however, certified also the involvement of sympathetic nerve system in G.I. tract bleeding with the experimental results. In addition to this report, many experimental works under the standpoint of hypothalamus involvement in stress ulcer were undertaken. On the other hand, hyperglycemia and glycosuria in the stress have been reported as the results of clinical and experimental works. In 1971, Frohman concluded that only ventromedial nuclei has relation to the control of glycogen metabolism in hypothalamus from his experimental results. We concluded that this hyperglycemia before the evidence of G.I. tract bleeding due to the involvements of hypothalamus or other parts of C.N.S. in the neurosurgical disease is one clinical sign of the stimualtion to sympathetic nerve system that also can be a cause of G.I. tract bleeding, and this hyperglycemia before the evidence of G.I. tract bleeding should be paid attention as a warning datum.

Between April, 1984 and March, 1985 in 14 centers, 33 patients with prostatic cancer of our 14 centers were randomized to subcutaneously receive either 125, 250, or 500 micrograms/day of ICI 118,630, an LH-RH analogue, for 12 weeks, and the clinical efficacy, safety and endocrinal effects of the drug by dose were examined. An objective partial response was obtained in 44.4% of the 125 micrograms-treated group, in 50.0% of the 250 micrograms-treated group, and 42.9% of the 500 micrograms-treated group, showing no significant difference between the groups. General subjective response rates in these three groups were respectively 75.0%, 62.5%, and 85.7%, not differing from each other significantly. No significant difference was observed in endocrinal effect which was seen in 58.3%, 66.7%, and 100% of 125 micrograms, 250 micrograms, and 500 micrograms groups, respectively. Medical castration was attained in 4.1 +/- 2.0 weeks on average. Adverse reactions observed included fever up to 37 degrees C in 1 of the 13 (7.3%) patients treated with 125 micrograms, and hot feeling at the injection site and flare in 1 of the 8 (12.5%) patients treated with 500 micrograms, which were all mild. These patients responded to further ICI 118,630 therapy without requiring any treatment for the adverse reactions.