High-Field Nuclear Magnetic Resonance Studies Reveal New Structural Landscape of Sulfur-Vulcanized Natural Rubber.

Despite intensive research efforts over the past 3 decades, the structural analysis of sulfur-vulcanized natural rubber (NR) remains challenging owing to the complexity and low population of its sulfur moieties. Herein, solid vulcanized NR samples and NR samples reacted with sulfur and other reactants in an organic solvent were analyzed by solid-state NMR with fast magic-angle spinning and solution NMR, respectively. The present high-field two-dimensional NMR analysis revealed six novel sulfur moieties in these samples, including cyclic sulfides, cyclic di/polysulfides, and crosslinked structures with a vinylidene group. While previous studies reported a variety of sulfur-crosslinked structures in NR, our analysis identified only two dominant types of crosslinked structures that matched those reported previously. Our NMR assignments for the crosslinked structures were inconsistent to a large extent with those presented in the previous studies; thus, in the current work, the crosslinked structures were reassigned using the new data. Based on quantitative NMR analysis, this study also provides the first tangible evidence that cyclic rather than crosslinked sulfides can be the dominant sulfur moieties in vulcanized NR. These results may drastically alter the previously established structural landscape of sulfur-vulcanized NR.

Splenomegaly in FOLFOX-naïve stage IV or recurrent colorectal cancer patients due to chemotherapy-associated hepatotoxicity can be predicted by the aspartate aminotransferase to platelet ratio before chemotherapy.

BACKGROUND: Chemotherapy-associated hepatotoxicity is a common cause of postoperative complications after major hepatectomy. Splenomegaly may indicate portal hypertension due to chemotherapy. To identify chemotherapy-naïve patients with liver damage, the splenic volume (SV) and aspartate aminotransferase to platelet ratio (APR) were investigated. METHODS: Seventy-one patients receiving FOLFIRI, FOLFOX, or FOLFOX plus bevacizumab as first-line chemotherapy were included in this study. The SV measurement was performed by helical computed tomography volumetry, and the SV index (SVI) was calculated during 6 cycles of chemotherapy. The APR was used as an indicator of liver injury and the APR index (APRI) was calculated. RESULTS: The SVI and APRI were significantly higher in the FOLFOX group than in the FOLFIRI group. In the FOLFOX group, the maximum APR during FOLFOX administration was significantly higher in the subjects with SVI ≥ +30% than in those with SVI < +30% (p < 0.01). The incidences of grade 3 or 4 adverse events and grade 2 or greater histopathological sinusoidal injury were significantly higher in the SVI ≥ +30% than in the SVI < +30% group. Interestingly, the SVI was significantly higher in the group with APR ≥ 0.17 before FOLFOX than in the subjects with an APR < 0.17 before FOLFOX (p < 0.05). CONCLUSION: Splenomegaly due to FOLFOX-associated hepatotoxicity can be predicted if the APR before FOLFOX is 0.17 or higher.

Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases.

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappa B ligand (RANKL), suppresses bone resorption. This open-label, multicenter, phase 1 study evaluated the safety, pharmacodynamics, and pharmacokinetics of denosumab in Japanese women with breast cancer-related bone metastases. Patients (n = 18; median age, 57 years) received a single subcutaneous injection of denosumab 60 mg or 180 mg or three doses of denosumab 180 mg on days 1, 29, and 57 (every 4 weeks) and were followed for > or = 141 days. No major safety concerns related to denosumab were noted in any cohort. All patients experienced at least 1 adverse event (AE); most were mild (grade < or = 2). One patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment-related; other treatment-related AE were grade < or = 2. No antidenosumab antibodies or clinically significant changes in laboratory findings, vital signs, or electrocardiograms were observed. Pharmacokinetics were approximately dose-linear. Denosumab caused rapid, substantial, and sustained suppression of urinary N-telopeptide corrected for creatinine (uNTx/Cr) across all doses; at day 85, the median change from baseline uNTx/Cr ranged from -61.9% to -90.8%. No dose-limiting toxicity was observed at any dosage. Coupled with pharmacokinetic and pharmacodynamic data, these results were consistent with those observed in non-Japanese populations.

Multicenter Phase II study of cetuximab plus irinotecan in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines.

OBJECTIVE: Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. We evaluated the efficacy and safety of cetuximab in combination with irinotecan in patients with metastatic colorectal cancer (CRC) refractory to irinotecan, oxaliplatin and fluoropyrimidines. METHODS: Cetuximab was administered initially at a dose of 400 mg/m(2) followed by weekly infusions at 250 mg/m(2). Irinotecan was administered either weekly at a dose of 100 mg/m(2) or every 2 weeks at 150 mg/m(2). RESULTS: Between October 2005 and February 2006, 39 consecutive patients were enrolled. The response and disease control rates (complete or partial response, or stable disease) were 30.8% (95% CI, 17.0-47.6) and 64.1% (95% CI, 47.2-78.8), respectively. With a median follow-up of 14.4 months, median time to progression was 4.1 months (95% CI, 2.7-5.1) and median survival time was 8.8 months (95% CI, 5.9-12.8). Patients (5.1%) developed Grade 3 acne-like rash. CONCLUSIONS: Combination therapy of cetuximab and irinotecan is effective and well-tolerated in patients with metastatic CRC refractory to irinotecan, oxaliplatin and fluoropyrimidines.

[Adjuvant chemotherapy of premenopausal breast cancer with LH-RH analogue for ovarian protection--a case report].

We report a case in which the LH-RH analogue, goserelin acetate was administered to a 26-year-old female patient diagnosed with premenopausal breast cancer and concurrently receiving anthracycline-based adjuvant chemotherapy for ovarian protection. After radical operation, pathological diagnosis showed that adjuvant chemotherapy was indicated. As she hoped for childbirth, at first goserelin was injected twice and then adjuvant chemotherapy was undergone concurrently with goserelin acetate for ovarian protection. The adjuvant chemotherapy consisted of 4 cycles of every four week intravenous dripinjection of adriamycin 50 mg/m2 and cyclophosphamide 500 mg/m2. The chemotherapy and goserelin acetate were completed at the same time. Menstruation recovered about two months after the finish of adjuvant therapy and was well-regulated after recovery. It is suggested that goserelin combined adjuvant chemotherapy for premenopausal breast cancer may be useful for ovarian protection.

Phase I study of combination therapy with irinotecan, leucovorin, and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for advanced colorectal cancer in Japanese patients.

BACKGROUND: Irinotecan, leucovorin, and bolus and continuous-infusion 5-fluorouracil administered every two weeks (FOLFIRI regimen) is active in patients with metastatic colorectal cancer. However, the efficacy and toxicity of this regimen in Japanese patients with metastatic colorectal cancer remain unknown. PATIENTS AND METHODS: We investigated the maximum tolerated dose, dose-limiting toxicity, and recommended dose at Step 1. Twenty-one patients with metastatic colorectal cancer were enrolled in Step 1. At the five dose levels, fixed doses of bolus 5-fluorouracil (400 mg/m(2)) and leucovorin (200 mg/m(2)) were administered in combination with escalating doses of irinotecan from 120-180 mg/m(2) with 46-h continuous infusion of 5-fluorouracil 2000-3000 mg/m(2) every two weeks. In Step 2, an additional 24 patients received the recommended doses determined in Step 1, and safety and antitumor efficacy were evaluated in terms of tumor response. RESULTS: No dose-limiting toxicities were observed at dose levels 1-4. Four out of eight patients experienced a dose-limiting toxicity at level 5; therefore, this level was considered the maximum tolerated dose. Consequently, the recommended doses were determined to be 180 mg/m(2) of irinotecan and 2,400 mg/m(2) of 5-fluorouracil in continuous i.v. infusion. At this level (FOLFIRI-180), National Cancer Institute common terminology criteria grade 3-4 neutropenia, leukopenia, and vomiting were common but manageable. Other hematological and non-hematological toxicities were mild. Seven out of 23 response-assessable patients achieved an objective response (response rate=30%). CONCLUSION: This FOLFIRI-180 regimen is manageable and effective in Japanese patients with metastatic colorectal cancer.

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer.

BACKGROUND: Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents. METHODS: Nineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m2 dose of CDDP. RESULTS: In the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18 mg/m2, with CDDP 3 mg/m2, to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16 mg/m2 with CDDP, 3 mg/m2. In the phase II part of the study, the response rate was 25.0%; five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%). CONCLUSION: The RD was determined to be TXL 14 mg/m2, with CDDP 3 mg/m2.

Retrospective analysis of clinical results and predictors of response in chemo-naive patients with advanced gastric cancer treated with S-1, an oral fluoropyrimidine derivative, as single-agent chemotherapy.

BACKGROUND: Despite the fact that there are only a few reports of phase II studies, S-1 is widely used in single-agent or combination therapies for patients with advanced gastric cancer in Japan. We retrospectively analyzed the effectiveness of S-1 as single-agent chemotherapy for patients with advanced gastric cancer. METHODS: A total of 119 patients with advanced or recurrent gastric cancer were treated with S-1 as first-line monochemotherapy from September 1999 to March 2003 at the National Cancer Center Hospital. S-1 was administered orally twice daily, at a standard dose of 80 mg/m2 per day for 28 days, followed by a 14-day rest. RESULTS: One hundred and eleven patients were analyzed retrospectively. The overall response rate was 26.1% (29/111; 95% confidence interval [CI], 17.8% to 34.1%). Median time to progression and median overall survival were 141 days (95% CI, 108 to 175 days) and 378 days (95% CI, 310 to 447 days), respectively. The response rate of ascites, according to the Japanese classification of gastric carcinoma, was 36.8% (14/38; 95% CI, 25.4% to 56.6%). Among all of the pretreatment variables examined, hemoglobin level and the presence of lymph node metastasis were related to the response. CONCLUSION: Single-agent chemotherapy of S-1 for chemo-naive patients with advanced gastric cancer was modestly effective and well-tolerated in the outpatient setting.

Phase I/II study of irinotecan, 5-fluorouracil, and l-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer.

BACKGROUND: A combination of irinotecan 125 mg/m2, 5-fluorouracil (5-FU) 500 mg/m2, and leucovorin (LV) 20 mg/m2 (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen. METHODS: Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100 mg/m2 was given intravenously over the course of 90 min on day 1, followed by l-LV 10 mg/m2, and then 5-FU. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100 mg/m2 and the dose of 5-FU in the original Saltz regimen was 500 mg/m2. RESULTS: One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2. CONCLUSION. Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100 mg/m2, 5-FU 500 mg/m2, and l-LV 10 mg/m2.

Phase I study of irinotecan and S-1 combination therapy in patients with metastatic gastric cancer.

BACKGROUND: Irinotecan plus intravenous 5-fluorouracil with leucovorin is effective against gastrointestinal cancer. S-1 is an oral fluoropyrimidine derivative combining tegafur with the modulators 5-chloro-2,4-dihydroxypyrimidine (a potent dihydropyrimidine dehydrogenase inhibitor), and potassium oxonate (an orotate phosphoribosyl transferase inhibitor), in a molar ratio of 1 : 0.4 : 1. S-1 has a high response rate, of about 40%, in advanced gastric cancer. A phase I study was conducted to assess the maximum tolerated dose and the recommended dose of the combination of irinotecan and S-1. METHODS: Irinotecan was given intravenously over the course of 90 min on day 1 and S-1 was given orally from days 1 to 14 of a 21-day cycle. The dose of S-1 was 80 mg/m2 per day, given in two divided doses. The dose of irinotecan was escalated in a stepwise fashion from 100 mg/m2 (level 1; n = 3), to 125 mg/m2 (level 2; n = 3), and 150 mg/m2 (level 3; n = 6). RESULTS: Dose-limiting toxicity did not occur during cycle 1, and the recommended dose for phase II studies was determined to be level 3, which was associated with grade 3 diarrhea in one patient, and with refusal to continue treatment because of prolonged fatigue in two patients. Grade 3 neutropenia developed in one of three patients at level 1 and level 2, and in two of six during cycle 1 of level 3. The recommended dose was determined to be 150 mg/m2 of irinotecan on day 1 and 80 mg/m2 per day of S-1 on days 1 to 14 of a 21-day cycle. Five of seven patients with measurable lesions had a partial response. CONCLUSIONS: A combination of irinotecan and S-1 can be recommended for further phase II studies in patients with gastric cancer.