Microscopic mechanism for shear thickening of non-Brownian suspensions.

We propose a simple model, supported by contact-dynamics simulations as well as rheology and friction measurements, that links the transition from continuous to discontinuous shear thickening in dense granular pastes to distinct lubrication regimes in the particle contacts. We identify a local Sommerfeld number that determines the transition from Newtonian to shear-thickening flows, and then show that the suspension's volume fraction and the boundary lubrication friction coefficient control the nature of the shear-thickening transition, both in simulations and experiments.

Dying Like a Dog.

Discussion surrounding the terminal care of an individual hospice patient. This includes the patient's reflections, his dissatisfaction, from his perspective, with inadequate end-of-life care, and his thoughts on assisted suicide. The author also discusses the spiritual aspects of this unusual encounter.

Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer.

PURPOSE: Randomized trials in fluorouracil (FU)-refractory colorectal cancer demonstrate significant survival advantages for patients receiving irinotecan. We prospectively compared the efficacy and tolerability of two irinotecan regimens (once a week for 4 weeks followed by a 2-week rest period [weekly] v once every 3 weeks) in such patients. PATIENTS AND METHODS: This multicenter, open-label, phase III study randomly assigned patients in a 1:2 ratio to irinotecan given either weekly (125 mg/m(2)) or once every 3 weeks (350 mg/m(2), or 300 mg/m(2) in patients who were >/= 70 years of age, who had Eastern Cooperative Oncology Group performance status equal to 2, or who had prior pelvic irradiation). RESULTS: With median follow-up of 15.8 months, there was no significant difference in 1-year survival (46% v 41%, respectively; P =.42), median survival (9.9 v 9.9 months, respectively; P =.43), or median time to progression (4.0 v 3.0 months, respectively; P =.54) between the two regimens. Grade 3/4 diarrhea occurred in 36% of patients treated weekly and in 19% of those treated once every 3 weeks (P =.002). Grade 3/4 neutropenia occurred in 29% of patients treated weekly and 34% of those treated once every 3 weeks (P =.35). Treatment-related mortality occurred in five patients (5.3%) receiving irinotecan weekly and three patients (1.6%) given therapy once every 3 weeks (P =.12). Global quality of life was not statistically different between treatment groups. CONCLUSION: Irinotecan schedules of weekly and of once every 3 weeks demonstrated similar efficacy and quality of life in patients with FU-refractory, metastatic colorectal cancer. The regimen of once every 3 weeks was associated with a significantly lower incidence of severe diarrhea.

Multicenter, randomized trial for stage IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by maintenance weekly paclitaxel or observation.

PURPOSE: To explore the efficacy and safety of three regimens of weekly paclitaxel plus carboplatin as initial therapy and the feasibility of subsequent maintenance therapy versus observation in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Four hundred one patients were randomly assigned to one of the following arms: arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (area under the curve [AUC] = 6) on day 1; arm 2, paclitaxel 100 mg/m2 and carboplatin (AUC = 2) weekly for 3 of 4 weeks; or arm 3, paclitaxel 150 mg/m2 cycle 1 and 100 mg/m2 cycle 2 and carboplatin (AUC = 2) weekly for 6 of 8 weeks. Patients who responded (n = 130) at week 16 were randomly assigned to either weekly paclitaxel therapy (70 mg/m2, 3 of 4 weeks; n = 65) or observation (n = 65). RESULTS: For the 390 assessable patients, the objective response rates observed with initial therapy were 32% for arm 1, 24% for arm 2, and 18% for arm 3. The median time to progression and median survival times were 30 and 49 weeks for arm 1, 21 and 31 weeks for arm 2, and 27 and 40 weeks for arm 3, respectively. The 1-year survival rates were 47% for arm 1, 31% for arm 2, and 41% for arm 3. CONCLUSION: Arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (AUC = 6) administered on day 1, demonstrates the most favorable therapeutic index in patients with advanced NSCLC.

Phase I trial of gemcitabine, administered as a standard and constant dose-rate infusion, in combination with paclitaxel in patients with advanced solid tumors (LOA-2).

The major purposes of this study were to determine the maximally tolerated dose (MTD), dose-limiting toxicity (DLT), toxicity profile, and antitumor activity of gemcitabine and paclitaxel combination therapy when administered to patients with advanced solid tumors, using two infusion schedules of each agent. Paclitaxel was administered on day 1, followed by gemcitabine, and gemcitabine alone was administered on day 8, of each 21-day treatment course. In the initial phase of the trial, paclitaxel was administered during 3 hours and gemcitabine during 30 minutes (schedule A). After the MTD was determined on this schedule, patients were then treated with paclitaxel during 1 hour and gemcitabine at a fixed dose-rate of 10 mg/m(2)/min (schedule B). Forty-six patients were treated with 176 courses at 7 dose levels. The MTD for schedule A was 1,300 mg/m(2) and 200 mg/m(2) and for schedule B was 1,000 mg/m(2) and 200 mg/m(2) for gemcitabine and paclitaxel, respectively. The DLT for schedule A was neutropenia and for schedule B was neutropenia and thrombocytopenia. Nonhematologic toxicity was relatively mild. Gemcitabine and paclitaxel, using both schedules of administration in the current trial, is a promising chemotherapeutic regimen.

Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer.

PURPOSE: To compare the efficacy and safety of weekly paclitaxel in combination with carboplatin administered every 4 weeks to the standard regimen of paclitaxel and carboplatin administered every 3 weeks for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Four hundred forty-four patients with previously untreated stage IIIB/IV NSCLC were randomly assigned to either arm 1 (n = 223), paclitaxel 100 mg/m(2) weekly for 3 of 4 weeks with carboplatin area under the curve (AUC) = 6 mg/mL x min on day 1 of each 4 week cycle, or arm 2 (n = 221), paclitaxel 225 mg/m(2) and carboplatin AUC = 6 on day 1 of each 3-week cycle. After four cycles of therapy, patients in both treatment arms were eligible to continue weekly paclitaxel (70 mg/m(2), 3 of 4 weeks) as maintenance therapy until unacceptable toxicity or disease progression. RESULTS: The objective response rate was 27.6% for arm 1 and 19.2% for arm 2. Median time to progression (TTP) was 18.4 and median survival (MS) was 38.6 weeks for arm 1. For arm 2, the median TTP and MS were 16.7 weeks and 42.9 weeks respectively. Grade 3/4 anemia was more common with arm 1, although grade 2/3 neuropathy and arthralgia were less common. The remainder of the toxicities were similar between the two arms. CONCLUSION: All efficacy parameters were similar between the two treatment arms. The favorable nonhematologic toxicity profile of arm 1 makes this an alternative treatment option for patients with advanced NSCLC.

Comparison of outcomes for elderly patients treated with weekly paclitaxel in combination with carboplatin versus the standard 3-weekly paclitaxel and carboplatin for advanced nonsmall cell lung cancer.

BACKGROUND: The purpose of this study was to compare the outcomes between elderly (aged > or = 70 years) patients treated with paclitaxel on a weekly basis and with carboplatin (every 4 weeks) versus the standard 3-weekly regimen of carboplatin and paclitaxel for first-line therapy of advanced nonsmall cell lung cancer. METHODS: Of the 444 patients enrolled, 136 (31%) were aged > or = 70 years. Seventy-two patients were randomized to the weekly schedule (paclitaxel, 100 mg/m(2) weekly for 3 of 4 weeks; carboplatin, area under the curve [AUC] = 6 mg/mL.min on Day 1 every 4 weeks), and 64 patients were randomized to the standard schedule (paclitaxel, 225 mg/m(2); carboplatin, AUC = 6 mg/mL.min on Day 1 every 21 days). Patients with stable disease or objective response after 4 cycles of therapy were eligible for maintenance therapy with weekly paclitaxel (70 mg/m(2), 3 of 4 weeks). RESULTS: The response rate for elderly patients was 26% on the weekly regimen and 19% on the standard schedule. The median survival duration for the weekly and the standard schedules was 37 weeks and 31 weeks, respectively. The 1-year survival rates were similar at 31% and 33%. Grade 3 to 4 anemia was more common on the weekly schedule (16% vs 6%), whereas grade 3 neuropathy was less common (5.5% vs 9.5%). Nausea and emesis were also less frequent on the weekly schedule. CONCLUSIONS: Efficacy was similar between the weekly regimen and the standard regimen of carboplatin and paclitaxel for elderly patients with advanced NSCLC and may be advantageous based on its favorable tolerability profile.

Docetaxel and epirubicin as first-line treatment for patients with metastatic breast cancer: a Minnie Pearl Cancer Research Network Phase II trial.

BACKGROUND: Taxanes and anthracyclines are the two most active classes of cytotoxic agents in the treatment of patients with metastatic breast cancer. Epirubicin, a doxorubicin analog, has shown modest toxicity advantages when compared to the parent compound. In this Phase II trial, we evaluated the activity and toxicity of a docetaxel/epirubicin combination. METHODS: Thirty patients with previously untreated metastatic breast cancer were treated with docetaxel 60 mg/m2 one-hour IV infusion and epirubicin 90 mg/m2 IV bolus; both drugs were repeated at 21-day intervals. Patients were evaluated for response after 2 courses of treatment; responding and stable patients continued treatment for a total of 6 courses. RESULTS: Fifteen patients (50 percent) had objective response to treatment; an additional 20 percent of patients had stable disease of more then 6 months duration. The median and 2-year progression-free survivals were 12 months and 34 percent, respectively. Median and 2-year overall survivals were 18 months and 42 percent, respectively. Myelosuppression was the most common Grade 3/4 toxicity, and 2 patients in this trial (6 percent) had treatment-related mortality associated with severe sepsis. CONCLUSION: The results of this Phase II trial confirm previous observations regarding the efficacy and toxicity profile of the docetaxel/epirubicin combination. This combination has activity similar to other taxane/anthracycline combinations used in the first-line treatment of metastatic breast cancer.

Treatment of elderly non-small cell lung cancer patients with three different schedules of weekly paclitaxel in combination with carboplatin: subanalysis of a randomized trial.

BACKGROUND: Administration of paclitaxel on a weekly schedule in combination with carboplatin is associated with a lower incidence of neuropathy and myelosuppression. The authors conducted subgroup analysis of their randomized phase II study of three different schedules of weekly paclitaxel with carboplatin to determine the efficacy of each regimen in elderly patients (aged > or = 70 years) with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC were randomized to one of three different weekly paclitaxel/carboplatin regimens. After four cycles of chemotherapy, those with objective response or stable disease were randomized to weekly paclitaxel or observation as maintenance therapy. Four hundred three patients were enrolled in the study, of whom 111 (28%) were aged 70 years or older. RESULTS: The treatment regimen of weekly paclitaxel (100 mg/m for 3 of 4 weeks) and carboplatin (area under the curve = 6 mg/ml/min once every 4 weeks) (arm 1) was associated with the best therapeutic index overall. The median survival and 1-year survival rates were 11.3 months and 50% for patients in the > or =70 years cohort versus 11.2 months and 46% for the <70 years cohort in arm 1. Efficacy results were comparable between the two groups in the other arms as well. Grade 4 neutropenia and febrile neutropenia occurred in 13.6% and 2.3% in the > or =70 years cohort compared with 4.5% and 1.1% in the <70 years cohort in arm 1. CONCLUSION: The weekly regimen of paclitaxel administered in combination with carboplatin is tolerated well by elderly NSCLC patients and has comparable efficacy with younger patients.

Multicenter Phase II study of estramustine phosphate plus weekly paclitaxel in patients with androgen-independent prostate carcinoma.

BACKGROUND: The current study determined the efficacy and toxicity of weekly paclitaxel in combination with estramustine phosphate (EMP) in patients with androgen-independent prostate carcinoma (AIPC). METHODS: Patients with progressive AIPC received 90 mg/m2 paclitaxel by 1-hour intravenous infusion weekly for 3 weeks, followed by a 1-week treatment rest. Patients received 140 mg EMP orally 3 times daily on the day before, the day of, and the day after paclitaxel administration. Patients received 1 mg warfarin daily to prevent thromboembolism. RESULTS: Sixty-six patients with progressive AIPC received treatment at 29 centers. Forty-two percent of patients had a 50% decline in prostate-specific antigen (PSA; 95% confidence interval [CI], 30-54%). For 26 patients with bidimensionally measurable disease, the objective response rate was 15% (95% CI, 1-30%). The median time to disease progression was 6.3 months, and the median time to PSA progression was 11.4 months. The median survival period was 15.6 months. Grade 3-4 toxicities were uncommon and included thromboembolism (8%), anemia (3%), neutropenia (3%), and peripheral neuropathy (2%). There was one treatment-related death. CONCLUSIONS: This regimen of EMP plus weekly paclitaxel was an active and well tolerated treatment for patients with AIPC.

Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-FU and radiation therapy in locoregional esophageal cancer: final results of a Minnie Pearl Cancer Research Network phase II trial.

PURPOSE: This phase II study was designed to determine the feasibility, toxicity, and therapeutic efficacy of a novel outpatient combined-modality preoperative regimen in patients with localized esophageal cancer. PATIENTS AND METHODS: One hundred twenty-nine eligible patients with previously untreated, potentially resectable, clinical stage I-III carcinoma of the esophagus were treated between July 1995 and July 1999. Combined-modality treatment included: paclitaxel, 200 mg/m2, 1-hour i.v. infusion, days 1 and 22; carboplatin, an area under the concentration time curve 6.0 i.v., days 1 and 22; 5-fluorouracil, 225 mg/m2/day, continuous i.v. infusion, days 1-42; and radiation therapy, 45 Gy, 1.8-Gy single daily fractions 5 days weekly, beginning day 1. All patients underwent surgical resection 4-8 weeks after completion of the preoperative therapy. RESULTS: One hundred twenty-three patients (95%) completed preoperative therapy, 105 patients (81%) underwent attempted resection, and 96 patients (74%) had definitive resection. A pathological complete response was achieved in 47 of 123 evaluable patients (38%); an additional 30 patients (24%) had only microscopic residual tumor. With a median follow-up of 45 months, the median survival is 22 months (95% CI = 15-32 months), with actuarial 1-, 2-, and 3-year survivals of 71%, 47%, and 41%, respectively. The most frequent grade 3/4 toxicities of the neoadjuvant program were leukopenia (73%) and esophagitis (43%). Although 73 patients (57%) required brief hospitalizations during preoperative therapy, there were no treatment-related deaths, and 94% of patients remained candidates for resection after the completion of treatment. Six patients (6%) died after surgery. CONCLUSIONS: This novel combined-modality regimen is highly active in the treatment of locoregional esophageal cancer, producing an actuarial 3-year survival of 41%. Although this preoperative regimen produced moderate acute toxicity, there were no treatment-related deaths and the large majority of patients were able to undergo subsequent esophageal resection. These results, obtained in a community-based setting and involving multiple surgeons, radiation oncologists, and medical oncologists, compare favorably with those of previous single-center and multicenter results. Further evaluation of novel combined-modality programs is warranted, as is the incorporation of epidermal growth factor receptor antagonists or other targeted agents.

A Phase II trial of topotecan and gemcitabine in patients with previously treated, advanced nonsmall cell lung carcinoma.

BACKGROUND: Multiple trials have been performed to evaluate second-line clinical chemotherapy in patients with advanced nonsmall cell lung carcinoma (NSCLC). However, no single agent or combination has demonstrated superior activity. METHODS: Patients with advanced NSCLC who had already received one chemotherapeutic regimen were treated with topotecan (0.75 mg/m(2) over 30 minutes, Days 1-5) and gemcitabine (400 mg/m(2) over 30 minutes, Days 1 and 5) every 21 days. RESULTS: Of 35 patients who were treated, 4 (11%) achieved a partial responses and 8 (23%) hadstable disease for at least four courses of treatment. The response rate for patients with refractory disease (progressing during frontline chemotherapy) was 18% (3 of 17) with 18% having stable disease for at least four courses of treatment. The median survival of the entire group was 7 months (range, 1.5-44 months) and 20% (7 of 35) of patients were alive 1 year from the initiation of topotecan and gemcitabine treatment. Patients with refractory disease had a median survival of 4(1/2) months, with 6-month and 1-year survival rates of 47% and 18%, respectively. During Course 1, five patients (14%) developed Grade IV neutropenia and three patients (9%) developed Grade IV thrombocytopenia. Nonhematologic toxicity was relatively mild, with one patient developing Grade III side effects (fatigue) and eight patients (23%) developing Grade II nonhematologic side effects. CONCLUSIONS: The combination of topotecan and gemcitabine demonstrated antitumor activity with a modest side effect profile in patients with advanced, previously treated NSCLC.