Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T.

BACKGROUND: Sipuleucel-T has demonstrated improved overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This analysis examined the effect of sipuleucel-T on time to disease-related pain (TDRP) and time to first use of opioid analgesics (TFOA) in mCRPC using data pooled from three randomized phase III studies in men with asymptomatic or minimally symptomatic mCRPC (D9901 (NCT00005947), D9902A (NCT01133704), D9902B (IMPACT; NCT00065442)). METHODS: Four-hundred and twenty-eight asymptomatic patients were analyzed for TDRP; 737 patients were analyzed for TFOA. Pain status was collected using logs adjudicated by blinded, independent reviewers. Opioid use for cancer-related pain was identified from medically reviewed reports of concomitant medication. Disease-related pain was defined as pain post enrollment. TDRP and TFOA were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: Treatment with sipuleucel-T was not associated with a significant difference in TDRP (hazard ratio (HR)=0.819; 95% confidence interval (CI): 0.616-1.089; P=0.170; median TDRP 5.6 months for sipuleucel-T and 5.3 months for control, respectively), although 39.3% of sipuleucel-T-treated patients and 18.9% of control patients were pain-free at 12 months. However, there was a significant delay in TFOA with sipuleucel-T (HR=0.755; 95% CI: 0.579-0.985; P=0.038). Median TFOA for sipuleucel-T was 12.6, and 9.7 months for control, with 50.6% and 43.1% opioid-free at 12 months, respectively. Kaplan-Meier curves for both end points began to diverge at 6 months. CONCLUSIONS: Sipuleucel-T was associated with longer TFOA but not significantly longer TDRP. Both end points demonstrated evidence of a delayed treatment effect, consistent with an active immunotherapy.

An easily built diffuse illumination system effective at both very low and moderate magnifications, for observing in situ stained slides.

Effective study of in situ stained sections often requires illumination that is difficult to achieve with commonly used research microscopes. One must be able to switch quickly and conveniently from the very lowest to moderate magnifications. At all magnifications contrast due to light scatter must be minimized, so that the weak staining that signifies low gene expression can be observed reliably. For the lowest power objectives (e.g., 1.25x or 2x) many microscopes require that the condenser be removed to illuminate the full field of view. This is not only very inconvenient when switching magnifications, but without a condenser the low numerical aperture of the illuminating light beam results in unwanted contrast due to light scatter. We have devised a simple system that diffusely illuminates the full field of view of the lowest power objective (1.25x) and has high enough numerical aperture for use with the 25x and 40x objectives. A key feature is the use of a large diameter ring light (internal diameter 5.8 cm), placed on the microscope base, to illuminate a large diameter diffuser placed just below the slide.

Wilkinson support calculated with exact probabilities: an example using Floricaula/LEAFY amino acid sequences that compares three hypotheses involving gene gain/loss in seed plants.

This paper describes a method for quantifying the extent to which a character supports a hypothesized monophyletic group. The basic idea was first proposed by Wilkinson in 1998; hence, we call it Wilkinson support. A character provides Wilkinson support if it could have changed state on the branch leading to the hypothesized monophyletic group without requiring any extra steps in an evolutionary tree. We describe a method to determine the exact probability that a character would provide Wilkinson support for a random group of the same size as the hypothesized monophyletic group. A character's weight is defined as the negative natural log of this probability. The sum over all characters of these weights in a data set is a measure of total weighted support. We exemplify this method using 30 Floricaula/LEAFY amino acid sequences. One copy of this gene occurs in angiosperms, but two copies occur in the other four seed plant groups. Angiosperms could have been primitively single-copy or could have lost either of the two paralogs. These possibilities correspond to three hypotheses of monophyly. We use total weighted Wilkinson support to evaluate these three hypotheses, and all three are shown to be significantly different from random as individual hypothesized monophyletic groups. Comparing these three hypotheses for total weighted support reveals that one has much more support than do the other two. This hypothesis favors the "mostly-male" theory of flowering-plant origins.

Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer.

PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti-prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies. RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of >/= 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of >/= 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea. CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.

Stage II nonseminomatous testis cancer: the roles of primary and adjuvant chemotherapy.

Historically, a retroperitoneal lymph node dissection (RPLND) has been the primary treatment of stage II nonseminomatous germ cell tumor (NSGCT) patients, whereas chemotherapy has been used in the adjuvant setting. Increasing evidence of the efficacy of chemotherapy has led to additional treatment possibilities for stage II patients. Both chemotherapy and RPLND have a role in the primary therapy of stage II NSGCT, and both modalities can be used as secondary adjunctive therapy. Management of these patients now requires a renewed emphasis on risk stratification and on the integration of patient preferences into the management algorithm.

PATHMASTER: modelling differential diagnosis as "dynamic competition" between systematic analysis and disease-directed deduction.

PATHMASTER is an expert system under development to assist in teaching histopathologic differential diagnosis. The system incorporates two "orthogonal" representations of the knowledge required to perform differential diagnosis. One representation groups histopathologic features around the anatomic structures of liver tissue, the second representation groups the features around the diseases in which they occur. Using these two representations, PATHMASTER models the process of diagnosis as a "dynamic competition" between systematic analysis and disease-directed deduction. By varying two parameters of PATHMASTER's underlying mathematical model, the interplay between these factors can be varied.

Evidence for arginine as the endogenous precursor of necines in heliotropium.

In pyrrolizidine alkaloid-bearing Heliotropium angiospermum and H. indicum shoots exposed, in the light, to (14)C-labeled CO(2) for 44 hours, the incorporation of (14)C into 1,2-epoxy-1-hydroxymethylpyrrolizidine and retronecine amounted to 0.23 and 0.15%, respectively, of the total carbon assimilated. Treatment of the shoots with alpha-dl-difluoromethylornithine, the specific ornithine decarboxylase inhibitor, at 1 to 2 millimolar had no effect on (14)C incorporation into the necines. In contrast, alpha-dl-difluoromethylarginine, the specific arginine decarboxylase inhibitor, prevented the incorporation of (14)C into the necines of both species; the inhibitor did not affect the absolute incorporation of (14)C from exogenous [1,4-(14)C] putrescine in either species. Thus, arginine is the only apparent endogenous precursor of the putrescine channeled into pyrrolizidines, at least in these two Heliotropium species that exhibited a relatively much higher in vitro activity of arginine decarboxylase than of ornithine decarboxylase. However, within 28 hours after administration, not only exogenous l-[5-(14)C]arginine, but also exogenous l-[5-(14)C]ornithine exhibited significant incorporation of their label into the necines, incorporation that could be partially prevented by both inhibitors. Neither inhibitor affected the rates of (14)C-labeled CO(2) assimilation, transformation of labeled assimilates into ethanol-insoluble compounds, or the very high degree of conversion of the introduced amino acids into other compounds. Methodology related to alkaloid biosynthetic studies is discussed.

Birefringent objects visualized by circular polarization microscopy.

In the standard polarizing microscope, birefringent material appears bright only if its optic axis is oblique to the axes of the polarizer and analyzer filters; consequently, an object may be visualized as several disconnected bright regions. This confusing appearance is avoided if the crossed plane polarizers of the conventional microscope are replaced by circular polarizers of opposite handedness. All orientations of the optic axis in the focal plane then become equivalent; objects generally appear uniformly bright. Ordinary microscopes are easily modified to use this technic with readily available components.

Appearance of vegetation in ultraviolet light: absorbing flowers, reflecting backgrounds.

Flowers that uniformly absorb ultraviolet light may contrast strikingly with a bright ultraviolet-reflecting background, such as densely hairy or glaucous foliage, white soils, or the sky. Shadows will not resemble these flowers if the appearance of each in visible light is also considered. Examples are shown from Mexican heliotropiums and Michigan dune plants.