Bark-Tissue Thickness of Coastal Western Hemlock in British Columbia

Bark-tissue thicknesses of coastal western hemlock are reported. Variation in these characteristics is considered between sites, trees, and height positions. Total bark thickness did not vary significantly with site, averaging 7.4 mm, 12.2 mm, and 12.6 mm for the top, middle, and butt height positions, respectively. However, the relative contribution of the individual tissues to the total thickness did vary with site. The thickness of all bark characteristics varied with height, being least at the top position, but differing very little between middle and butt positions

A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer

Pancreatic cancer is the fifth most common cause of cancer death in the western world and the prognosis for unresectable disease remains poor. Recent advances in conventional chemotherapy and the development of novel ‘molecular’ treatment strategies with different toxicity profiles warrant investigation as combination treatment strategies. This randomised study in pancreatic cancer compares marimastat (orally administered matrix metalloproteinase inhibitor) in combination with gemcitabine to gemcitabine alone. Two hundred and thirty-nine patients with unresectable pancreatic cancer were randomised to receive gemcitabine (1000 mg m−2) in combination with either marimastat or placebo. The primary end-point was survival. Objective tumour response and duration of response, time to treatment failure and disease progression, quality of life and safety were also assessed. There was no significant difference in survival between gemcitabine and marimastat and gemcitabine and placebo (P=0.95 log-rank test). Median survival times were 165.5 and 164 days and 1-year survival was 18% and 17% respectively. There were no significant differences in overall response rates (11 and 16% respectively), progression-free survival (P=0.68 log-rank test) or time to treatment failure (P=0.70 log-rank test) between the treatment arms. The gemcitabine and marimastat combination was well tolerated with only 2.5% of patients withdrawn due to presumed marimastat toxicity. Grade 3 or 4 musculoskeletal toxicities were reported in only 4% of the marimastat treated patients, although 59% of marimastat treated patients reported some musculoskeletal events. The results of this study provide no evidence to support a combination of marimastat with gemcitabine in patients with advanced pancreatic cancer. The combination of marimastat with gemcitabine was well tolerated. Further studies of marimastat as a maintenance treatment following a response or stable disease on gemcitabine may be justified

A phase I and pharmacological study of the matrix metalloproteinase inhibitor BB-3644 in patients with solid tumours.

BB-3644 is an oral, broad-spectrum matrix metalloproteinase inhibitor (MMPI) structurally related to marimastat and BB-94. It is also >10-fold more active than marimastat in inhibiting the processing of cell-bound TNF-alpha. Preclinical studies suggested a favourable toxicity profile when compared to marimastat, and therefore it was selected for clinical evaluation. Patients with advanced solid tumours against which established treatments had failed, or for which no satisfactory treatment exists and of good performance status, were eligible. Treatment consisted of twice daily (bd) oral BB-3644 for 84 days. The initial dose was 5 mg bd, and subsequent cohorts were treated with 10, 20 and 30 mg bd. In all, 22 patients were enrolled. The dose-limiting toxicity (DLT) was musculoskeletal pain. For 28 days of treatment with BB-3644, 20 mg bd was the maximum tolerated dose (MTD), as at 30 mg bd, six of nine patients developed significant musculoskeletal toxicity by day 28. Following chronic oral dosing (>28 days) with BB-3644, three of five patients treated at 10 mg bd developed musculoskeletal DLT by day 84, defining the MTD as 5 mg bd. As dose-limiting musculoskeletal toxicity was encountered at doses of BB-3644 unlikely to provide an advantage over currently available MMPIs, further evaluation is not recommended

Anti-tumour efficacy of capecitabine in a genetically engineered mouse model of pancreatic cancer.

Capecitabine (CAP) is a 5-FU pro-drug approved for the treatment of several cancers and it is used in combination with gemcitabine (GEM) in the treatment of patients with pancreatic adenocarcinoma (PDAC). However, limited pre-clinical data of the effects of CAP in PDAC are available to support the use of the GEMCAP combination in clinic. Therefore, we investigated the pharmacokinetics and the efficacy of CAP as a single agent first and then in combination with GEM to assess the utility of the GEMCAP therapy in clinic. Using a model of spontaneous PDAC occurring in Kras(G12D); p53(R172H); Pdx1-Cre (KPC) mice and subcutaneous allografts of a KPC PDAC-derived cell line (K8484), we showed that CAP achieved tumour concentrations (∼25 µM) of 5-FU in both models, as a single agent, and induced survival similar to GEM in KPC mice, suggesting similar efficacy. In vitro studies performed in K8484 cells as well as in human pancreatic cell lines showed an additive effect of the GEMCAP combination however, it increased toxicity in vivo and no benefit of a tolerable GEMCAP combination was identified in the allograft model when compared to GEM alone. Our work provides pre-clinical evidence of 5-FU delivery to tumours and anti-tumour efficacy following oral CAP administration that was similar to effects of GEM. Nevertheless, the GEMCAP combination does not improve the therapeutic index compared to GEM alone. These data suggest that CAP could be considered as an alternative to GEM in future, rationally designed, combination treatment strategies for advanced pancreatic cancer

Explicit solution for a Gaussian wave packet impinging on a square barrier

The collision of a quantum Gaussian wave packet with a square barrier is solved explicitly in terms of known functions. The obtained formula is suitable for performing fast calculations or asymptotic analysis. It also provides physical insight since the description of different regimes and collision phenomena typically requires only some of the terms.Comment: To be published in J. Phys.

Analytic results for Gaussian wave packets in four model systems: I. Visualization of the kinetic energy

Using Gaussian wave packet solutions, we examine how the kinetic energy is distributed in time-dependent solutions of the Schrodinger equation corresponding to the cases of a free particle, a particle undergoing uniform acceleration, a particle in a harmonic oscillator potential, and a system corresponding to an unstable equilibrium. We find, for specific choices of initial parameters, that as much as 90% of the kinetic energy can be localized (at least conceptually) in the `front half' of such Gaussian wave packets, and we visualize these effects.Comment: 22 pages, RevTeX, four .eps figures, to appear in Found. Phys. Lett. Vol. 17, Dec. 200

Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial

This randomised, double-blind, placebo-controlled study was designed to evaluate the ability of the orally administered matrix metalloproteinase inhibitor, marimastat, to prolong survival in patients with non-resectable gastric and gastro-oesophageal adenocarcinoma. Three hundred and sixty-nine patients with histological proof of adenocarcinoma, who had received no more than a single regimen of 5-fluorouracil-based chemotherapy, were randomised to receive either marimastat (10 mg b.d.) or placebo. Patients were treated for as long as was tolerable. The primary endpoint was overall survival with secondary endpoints of time to disease progression and quality of life. At the point of protocol-defined study completion (85% mortality in the placebo arm) there was a modest difference in survival in the intention-to-treat population in favour of marimastat (P=0.07 log-rank test, hazard ratio=1.23 (95% confidence interval 0.98–1.55)). This survival benefit was maintained over a further 2 years of follow-up (P=0.024, hazard ratio=1.27 (1.03–1.57)). The median survival was 138 days for placebo and 160 days for marimastat, with 2-year survival of 3% and 9% respectively. A significant survival benefit was identified at study completion in the pre-defined sub-group of 123 patients who had received prior chemotherapy (P=0.045, hazard ratio=1.53 (1.00–2.34)). This benefit increased with 2 years additional follow-up (P=0.006, hazard ratio=1.68 (1.16–2.44)), with 2-year survival of 5% and 18% respectively. Progression-free survival was also significantly longer for patients receiving marimastat compared to placebo (P=0.009, hazard ratio=1.32 (1.07–1.63)). Marimastat treatment was associated with the development of musculoskeletal pain and inflammation. Events of anaemia, abdominal pain, jaundice and weight loss were more common in the placebo arm. This is one of the first demonstrations of a therapeutic benefit for a matrix metalloproteinase inhibitor in cancer patients. The greatest benefit was observed in patients who had previously received chemotherapy. A further randomised study of marimastat in these patients is warranted

Modelling prognostic factors in advanced pancreatic cancer

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer

Lipid Profiles of American Collegiate Football Athletes in Response to Fall Preseason Camp

Recent studies show former football athletes, especially football linemen, to be at increased cardiovascular disease risk. However, the lipid profiles of American NCAA Football Bowl Subdivision (FBS) players in response to sport participation are currently unknown. PURPOSE: To quantify the effects of participation in fall preseason football training camp on the blood lipid profiles in NCAA FBS athletes. METHODS: Seated venous blood samples were drawn in the morning after an overnight fast from 51 football players (age = 20 ± 2 yr, weight = 232.8 ± 40.8 lb, height = 73.9 ± 2.6 in) and analyzed for total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-cholesterol (HLD-C), and triglyceride (TG). Samples were obtained on two separate occasions corresponding to the beginning of fall preseason football camp, and again 16 days later near the end. Data were analyzed by paired t-test. RESULTS: See table, values are means ± SD, * = p ≤ 0.001. Measurement Time Lipid and Lipoprotein Concentrations (mg/dL) TC LDL-C HDL-C TG TC:HDL Ratio Beginning 158 ± 34 90 ± 24 54 ± 15 117 ± 50 3.02 ± 0.70 End 151 ± 35 92 ± 28 47 ± 11* 86 ± 41* 3.32 ± 0.84* CONCLUSION: Participation in fall preseason training camp significantly alters the traditional lipid profiles of Collegiate FBS athletes. These lipid changes suggest a proinflammatory state with high energy utilization, and are consistent with the hypothesis that LDL-C is necessary for the structural repair of damaged tissue

Raltitrexed–eloxatin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status (PS) and are candidate for further treatment. Patients >18 years, PS ⩾50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-containing chemotherapy, and progression-free survival (PFS) <12 months received a combination of raltitrexed (3 mg m−2) and oxaliplatin (130 mg m−2) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade >2 toxicity was: neutropenia in five patients (12%), thrombocytopenia, liver and vomiting in three (7%), fatigue in two (5%). In total, 10 patients (24%) yielded a partial response, 11 a stable disease. Progression-free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS >6 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed–oxaliplatin regimen may constitute a treatment opportunity in gemcitabine-resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment