Phase I first-in-human study of TAK-285, a novel investigational dual HER2/EGFR inhibitor, in cancer patients.

BACKGROUND: This phase I first-in-human study was conducted in Japanese patients to investigate the safety, pharmacokinetics (PKs), and determine the maximum tolerated dose (MTD) of oral TAK-285, a novel dual erbB protein kinase inhibitor that specifically targets human epidermal growth factor receptor (EGFR) and HER2. METHODS: The TAK-285 dose was escalated until MTD was determined. A second patient cohort received TAK-285 at the MTD for at least 4 weeks. RESULTS: In all, 26 patients received TAK-285 at doses ranging from 50 to 400 mg once daily (q.d.) or twice daily (b.i.d.); 20 patients made up the dose escalation cohort and the remaining 6 patients were the repeated administration cohort. TAK-285 was well tolerated. Dose-limiting toxicities noted in two patients who received 400 mg b.i.d. were grade 3 increases in aminotransferases and grade 3 decreased appetite. Consequently, the MTD was determined to be 300 mg b.i.d. Absorption of TAK-285 was rapid after oral dosing, and plasma exposure at steady-state increased in a dose-proportional fashion for doses ranging from 50 to 300 mg b.i.d. A partial response was observed for one patient with parotid cancer who received 300 mg b.i.d. CONCLUSION: The toxicity profile and PK properties of oral TAK-285 warrant further evaluation.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Phase II study of oxaliplatin plus S-1 as first-line treatment for advanced gastric cancer (G-SOX study).

BACKGROUND: The efficacy and safety of oxaliplatin combined with S-1 (SOX regimen) for unresectable advanced or recurrent gastric cancer were investigated. PATIENTS AND METHODS: Oxaliplatin was administered i.v. (100 mg/m(2)) on day 1, while S-1 was administered orally (80 mg/m(2)/day, b.i.d.) for 14 days followed by a 7-day rest. This schedule was repeated every 3 weeks. RESULTS: Among 55 patients enrolled, one patient received oxaliplatin for the other study, and three patients were considered unsuitable against the inclusion criteria. Accordingly, 51 patients were assessable for efficacy. The response rate was 59%, and the disease control rate was 84%. The median progression-free survival time was 6.5 months, the 1-year survival rate was 71%, and the median survival time was 16.5 months. In 54 patients assessed for safety, the major grade 3/4 toxic effects were neutropenia (22%), thrombocytopenia (13%), anemia (9%), anorexia (6%), fatigue (6%), and sensory neuropathy (4%). CONCLUSION: These findings indicate that SOX regimen with oxaliplatin at a dose of 100 mg/m(2) is feasible and shows promising efficacy against advanced gastric cancer.

Particular types of tumor cells have the capacity to convert transforming growth factor beta from a latent to an active form.

We investigated the capacities of various tumor types to generate an active versus latent form of transforming growth factor beta (TGF-beta) in its culture supernatants (SNs). Tumor cell lines were divided into three types depending on the form and magnitude of TGF-beta detected in their culture SNs: some (2 of 7 lines) generated mostly an active form (Type A); others (4 of 7) generated exclusively a latent form (Type B); and the remaining line (1 of 7) produced only marginal levels of active/latent TGF-beta (Type C). When Type A tumor cells were cultured at lower numbers, cultures failed to generate active TGF-beta. However, the addition of Type B tumor cell culture SNs containing only a latent form of TGF-beta resulted in the generation of the potent activity of active TGF-beta. This capacity was observed for another Type A tumor but not for other types (Type B and Type C). An active form of TGF-beta was detected in culture SNs of Type A tumor cells as early as 3-6 h after the addition of Type B tumor culture SNs. The emergence of an active form of TGF-beta was also observed in cultures of Type A tumor cells, the protein synthesis of which was almost completely inhibited by pretreatment with cycloheximide. Moreover, the Type B tumor SN used for the induction of active TGF-beta activity was found to contain latent TGF-beta with an apparent molecular weight of about 200,000. Type A tumor cells were also capable of generating active TGF-beta by the addition of recombinant TGF-beta of latent form with a small molecular weight (about 60,000), although the generation of active TGF-beta was much weaker after the addition of small latent TGF-beta than after the addition of large latent TGF-beta. Taken collectively, these results indicate that particular types of tumor cells have the capacity to generate an active form of TGF-beta and that such capacity can be attributed to their potential to convert TGF-beta from a latent (mainly large type) to an active form.

[New CT program simulating kidney displacement during retroperitoneal laparoscopic nephrectomy].

A total of 12 patients with malignant localized renal or ureteral neoplasms underwent multi-slice computed tomography. Imaging data were sent to the dedicated workstation to create volume rendering and virtual laparoscopic images of the kidney which was displaced ventrally with retroperitoneal balloon. These findings were compared with video images obtained during retroperitoneal laparoscopic nephrectomy. The kidney displacement simulator depicted all renal arteries (100% sensitivity) and 13 of 14 renal veins (93% sensitivity). Hilar anatomy, including the tumor, major vessels and their relationships were visualized as in the actual laparoscopic views. The desired portions of major vessels as well as the left adrenal and gonadal veins visualized with this system completely corresponded with the actual laparoscopic images during surgery. The kidney displacement simulator is useful to foresee desired portions of major vessels and branched small vessels such as the adrenal or gonadal veins in advance of surgery. It is thus able to guide surgeons and reduce operative risks and possible complications.

Significance of tryptophan residues in the D-domain of the fibrin molecule in fibrin polymer formation.

The modification of fibrin monomer with H2O2 caused reduction of the association activity of fibrin monomer. The association activity was not reduced even by modification of approx. 16 out of the total 64 tryptophan residues in the fibrin molecule; it was then abolished by further modification of the following several residues. Fragment D obtained by proteolysis of fibrinogen with plasmin, inhibited the association activity of fibrin monomer and the modification of approx. six out of the total 21 tryptophan residues in the fragment led to the complete loss of the inhibitory effect. It was concluded from these studies that about six tryptophan residues in the D-domain of fibrin are important for the association of fibrin monomer.

Functional consequences of tryptophan modification in human fibrinogen.

When human fibrinogen was modified with H2O2, inter- and intra-molecular cross-links of fibrinogen were formed, accompanied with oxidation of tryptophan, methionine and tyrosine residues. These cross-links may be closely associated with oxidation of tryptophan residues. The polymerization activity of fibrinogen with thrombin was decreased markedly by this modification. Modification of tryptophan residues in fibrinogen was also performed with 2-hydroxy-5-nitrobenzyl bromide. Modification of two out of a total 78 tryptophan residues in the molecule with the reagent led to the intensification (1.7 times) of the polymerization activity with thrombin and further modification of the next two residues led to complete loss of the polymerization activity. The first two tryptophan residues to be modified are in Fragment D, and the next two occur in Fragment E.

Uracil-tegafur in gastric carcinoma: a comprehensive review.

PURPOSE: The second-generation oral anticancer agent UFT, a combination of uracil and tegafur (TGF), results in a higher fluorouracil (5-FU) concentration in the tumor tissues than is achieved by TGF or comparable doses of intravenous 5-fluorouracil. UFT has been extensively studied in Japan and has been in use in the Orient for many years, particularly for patients with gastric carcinoma. UFT has recently entered extensive investigations in North America and Europe. METHODS: Relevant studies that have chronicled the establishment of UFT, its mechanism of action, preclinical toxicology, human pharmacokinetics, phase I studies, and activity against gastric carcinoma are described in detail. RESULTS: The uracil in UFT slows degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD), which results in sustained concentrations of 5-FU in blood and tumor tissues. UFT is well tolerated, but such toxic effects as nausea, vomiting, and diarrhea are dose- and schedule-dependent. In phase I pharmacokinetic studies, UFT given orally on a 28-day schedule resulted in blood concentrations comparable to those following low-dose continuous intravenous infusion of 5-FU. In patients with gastric carcinoma, UFT alone has a response rate of approximately 20%. In the adjuvant setting, UFT plus mitomycin appears superior to TGF plus mitomycin. In Japan, UFT is part of the standard adjuvant chemotherapy for gastric carcinoma. CONCLUSION: UFT is one of the first second-generation oral 5-FU prodrugs under investigation in North America and Europe. The literature suggests UFT is well tolerated and has cellular pharmacokinetic superiority over the first-generation 5-FU prodrug TGF. UFT has a more favorable toxicity profile than intravenous 5-FU. The issues of efficacy, patient convenience, and quality of life need to be studied in controlled randomized trials.

Phase 1/11 study of bi-weekly irinotecan plus cisplatin in the treatment of advanced gastric cancer.

OBJECTIVES: To conduct a phase I/II study of irinotecan with cisplatin to establish a recommended dose, and assess the safety, efficacy and feasibility of this regimen in unresectable advanced or recurrent gastric cancer. PATIENTS AND METHODS: In the phase I portion of the study, patients received a fixed dose of cisplatin (30 mg/m2) with escalating doses of irinotecan, ranging from 30 mg/m2 to 70 mg/m2, on days 1 and 15. In the phase II portion of the study, 40 patients were evaluated for response and safety at the recommended dose. RESULTS: Eighteen patients were enrolled in the phase I study. Dose-limiting toxicity (diarrhea and neutropenia) appeared at the irinotecan dose of 70 mg/m2. Therefore, the recommended irinotecan dose was 60 mg/m2. In the phase II study, 40 patients received cisplatin (30 mg/m2) plus irinotecan (60 mg/m2). Twenty-five out of 40 patients had received prior chemotherapy. The median number of cycles was 3.5. The response rate was 32.5% (13/40) overall, and 53.3% (8/15) in patients without prior chemotherapy. The median time to tumor progression (TTP) was 162 days. The median survival time was 288 days. Four patients (10%) developed grade 4 neutropenia and 3 patients (7.5%) developed grade 4 anemia. The only observed non-hematological toxicity at grade 3 or higher was diarrhea, seen in 2.5% (1/40) of the patients. CONCLUSION: Bi-weekly administration of irinotecan and cisplatin is safe and active for the management of unresectable advanced or recurrent gastric cancer.

Combined therapy of deoxyspergualin and plasmapheresis: a useful treatment for antibody-mediated acute rejection after kidney transplantation.

Antibody-mediated acute rejection (AbAR) is one of the primary causes of graft impairment in kidney transplant recipients. Deoxyspergualin (DSG), which displays an antiproliferative action against antigen-stimulated B cells inhibiting antibody production, may be effective to rescue AbAR in combination with plasmapheresis by suppressing antibody production and elimination. In the present study, we report our experience with DSG/plasmapheresis therapy for the treatment of AbAR. Five kidney transplant patients experienced a steroid-resistant acute rejection requiring dialysis followed by an AbAR that was confirmed by biopsy and flow cytometry crossmatch (FCXM) results. DSG was administration at 3 mg/kg per day for 10 days with plasmapheresis reduce antidonor antibody. Treatment outcome, effectiveness, and adverse events were examined; in two cases sequential FCXM examinations were performed to evaluate antibody status. All five patients received DSG/plasmapheresis therapy. The number of plasmapheresis treatments ranged from 1 to 9 according to treatment outcomes. Four patients recovered graft function following treatment; whereas one showed no response to the treatment, and the graft was lost. No serious side effects or infections were observed during or after treatment. Monitoring of sequential FCXM correlated with the clinical course. AbAR shows a worse prognosis than cellular rejection. It is refractory to conventional antirejection therapy. In the present study, DSG/plasmapheresis therapy was effective in four of five patients (80%) with AbAR. It may be considered the first choice of treatment for cases of acute humoral rejection.

Recent developments in oral chemotherapy options for gastric carcinoma.

The incidence of carcinoma of the stomach is low in the United States, Canada, and Australia but is a significant health problem in Asia, South America, Eastern Europe, and countries of the previous Soviet Union. For patients with advanced disease, chemotherapy remains palliative. With the increasing emphasis on patients' quality of life, convenience, and cost containment, oral chemotherapy has come into increasing focus. We review oral chemotherapy agents for use in patients with advanced gastric carcinoma. Etoposide, given intravenously, has modest activity in gastric carcinoma. We studied oral etoposide, which was administered to 28 patients at the starting dose of 50 mg/m2/day for 21 days followed by a 7-day rest period. Five patients achieved a partial response and 4 patients achieved a minor response. The drug was well tolerated. Common toxicities included myelosuppression, alopecia, and nausea. Oral etoposide thus shows evidence of modest activity against gastric carcinoma. In Japan, considerable advances have been made in the oral chemotherapy of gastric carcinoma. The second generation fluorouracil prodrug tegafur/uracil (UFT) has been extensively evaluated in Japan, Korea, and Spain. Data predominantly from Japan indicate that tegafur/uracil has a response rate of approximately 20% in treatment naive patients with advanced gastric carcinoma. When combined with other active agents, tegafur/uracil has a response rate of more than 30% in these patients. The available data also suggest that tegafur/uracil is well tolerated and that patient acceptance is high. In conclusion, future clinical research is likely to focus on the development of convenient outpatient regimens with efficacy equal to that of intravenous regimens.

Ph1-positive acute lymphoblastic leukemia associated with an isochromosome 17q.

We report a patient with Ph1-positive acute lymphoblastic leukemia (ALL) having i(17q) in whom bony lesions were the initial clinical manifestation. The patient was a 53-year-old male who began to have pains in his left hip early in March 1985. Relevant findings on admission included: WBC 21,300/microliters; blast cells 73.5%; peripheral blood blast cells, peroxidase (-), PAS (-) and esterase (-); cytoimmunologic markers, Ia(+) cells 49.1%, CD10(+) cells 67.1%, CD20(+) cells 75.1%; positivity for TdT, and Ph1(+); and i(17q) upon chromosomal analysis. These findings led to a diagnosis of ALL with Ph1(+),i(17q). This case seems to represent an exceedingly rare instance of Ph1(+),i(17q) ALL in which the differential diagnosis between blast transformation of CML and Ph1(+) ALL was initially difficult to make.

Retroperitoneal schwannoma.

A case of retroperitoneal benign schwannoma is presented; in addition, 133 cases of retroperitoneal schwannoma reported in Japanese literature are studied. In our series 66 per cent of the cases were found to be cystic. Therefore, the cystic change may be one of the preoperative features of schwannomas, because other types of retroperitoneal tumor do not frequently form cysts. Furthermore, the necessity of postoperative electron microscopy for accurate histologic diagnosis is discussed.

True histiocytic lymphoma.

An 86-year-old man had true histiocytic lymphoma of the skin. Diagnosis was established by the following findings: (1) typical histological features, (2) lack of receptors on tumor cells for immunological surface markers, and (3) active phagocytic function. Electron microscopic studies indicated cytoplasmic multivesicular bodies in the tumor cells. Multivesicular bodies have been reported in histiocytic proliferative disorders and may be of diagnostic value in cases of true histiocytic lymphoma.

Immunohistochemical expression of vascular endothelial growth factor can predict response to 5-fluorouracil and cisplatin in patients with gastric adenocarcinoma.

The combination of 5-fluorouracil (5-FU) and cisplatin is used most commonly for gastric carcinoma. Recent studies have indicated that vascular endothelial growth factor (VEGF) is related to drug delivery through angiogenesis and vascular permeability. In this study, we evaluated the efficacy and toxicity of continuous infusion of 5-FU and low dose cisplatin infusion as first-line treatment in patients with unresectable gastric adenocarcinoma. We also examined the relationship between chemotherapy response and immunohistochemical expression of VEGF in the biopsy samples of gastric primary. All 30 patients enrolled in this study were assessable for response, adverse reactions, and VEGF expression. The regimen consisted of 5-FU (350 mg/m2/day every day by continuous venous infusion) and low dose cisplatin (7 mg/m2/day by drip infusion over 1 h on days 1-5 every week). This treatment was repeated weekly for 3 consecutive weeks. Four weeks after the second cycle, mesurable lesions were estimated for response. An overall response rate was 46.7% (14/30). Patients with intestinal histologic type (10/12) and good performance status ([PS], 13/18) showed good response rate (83.3%, and 72.2%, respectively) compared to patients with diffuse histologic type (4/18) and poor PS [(1/12) 22.2%, and 8. 3%, respectively]. The response rate of VEGF-positive cases and VEGF-negative cases was 75% (12/16), and 16.7% (2/14), respectively. Multivarite analysis revealed that VEGF-positive and good PS had a significant impact on chemotherapy response in this treatment. The most common garde 3 or higher toxicities were myelosuppression (30%) and diarrhea (13.3%). Continuous infusion of 5-FU and low dose cisplatin infusion is an effective treatment for patients with unresectable gastric carcinoma, and VEGF expression may be a useful predictor of chemotherapy response in this regimen.

[Results of the Burch colposuspension operation for female stress incontinence].

Of 48 patients with radiologically proven cystocele, 13 patients were treated with the Burch colposuspension procedure from October, 1980 to August, 1984 in our clinic. A satisfactory result with good urinary control was obtained in 13 cases and the procedure was a failure in one. Partial or complete urinary retention was evident postoperatively in 8 patients (62%), but all of the patients voided satisfactorily within 4 weeks. Radiological diagnosis of the cystocele and advantage of Burch colposuspension procedure are discussed.

[A case of spontaneous rupture of renal cell carcinoma].

There have been a few reports on the spontaneous rupture of renal cell carcinoma. A 67-year-old female patient complaining of vomiting and severe abdominal pain was referred to our hospital. Plain computerized tomography demonstrated large heterogenous mass in the right retroperitoneum. We suspected the hemorrhagic shock because of the rupture of the right kidney and therefore emergent laparotomy was performed. Simple nephrectomy for the right kidney was performed. A pathological report revealed renal cell carcinoma, granular cell subtype, grade 1, pT3a. The patient has been followed for one year and five months after the operation, there has been no evidence of local recurrence or distant metastasis of cancer. Thirteen cases of spontaneous rupture of renal cell carcinoma in the Japanese literature are reviewed.

[A case of solitary pelvic kidney with vesicoureteral reflux and neurogenic bladder dysfunction].

A case of solitary pelvic kidney with neurogenic bladder dysfunction with vesicoureteral reflux is presented. The patient was a 15-year-old boy with sacral vertebral dysplasia and hare-lip, and he has been complaining of recurrent fever episodes and urinary incontinence since 11 years old. Renal anomaly was confirmed by DIP, CT and angiography, and grade IV vesicoureteral reflux was demonstrated by voiding cystourethrography. On cystometrography, low compliance bladder which had a 70 ml capacity on first desire to void and 90 ml capacity on maximum desire to void was observed. Electromyography of anal sphincter performed with uroflowmetry revealed no relaxation of external sphincter during voiding. To preserve renal function, antireflux surgery was performed by Cohen's method, and a successful result, that is cessation of reflux and no ureteral obstruction, was achieved. After operation, periodic transcutaneous electrical stimulation were applied to the pudendal nerve, as a result bladder capacity increased to 150 ml and dysuria with incontinence improved.

[A case of invasive squamous carcinoma of the urinary bladder perforated intraperitoneally after intra-arterial chemotherapy].

We report a case of invasive squamous cell carcinoma of the urinary bladder, which was perforated intraperitoneally after intra-arterial chemotherapy. The patient was a 67-year-old woman complaining of macrohematuria and body weight loss. After thorough examination, the diagnosis of clinical stage C of squamous cell carcinoma of urinary bladder was made. At first, balloon occluded intra-arterial infusion with 80 mg, cis-dichlorodiamine platinum 10 mg mitomycin C and 1 mg vincristine was performed, followed by radiotherapy and 15 mg bleomycin injection. On the 5th day, the patient fell into shock with abdominal expansion, and bladder perforation into peritoneal cavity was confirmed by rapid cystography. Emergency cystohysterectomy and drainage were performed. Resected bladder had a large defect on its posterior wall, and tumor had fallen into severe necrosis. Since January, 1986 we performed balloon occluded intra-arterial infusion of antineoplastic drugs for 3 other cases. We obtained a partial response for 2 of these cases. The outcome of intra-arterial chemotherapy in our hospital is also reported.

A case of retroperitoneal ganglioneuroma.

We describe a rare case of a primary retroperitoneal ganglioneuroma that was found accidentally during preoperative examinations conducted due to a suspicion of ovarian cancer. Computerized tomography was not able to differentiate the retroperitoneal mass from an adrenal tumor. We diagnosed the retroperitoneal tumor by means of selective adrenal angiography.