The role of cytotoxic chemotherapy in the management of aggressive and malignant pituitary tumors

Pituitary tumors are mostly benign lesions, although 5-35% are locally invasive. A small number exhibit a more aggressive course, infiltrating dura, bone and sinuses, and are designated highly aggressive. However, the presence of metastases separate from the pituitary in the central nervous system or at a distance is necessary to designate pituitary tumors as carcinomas, i.e. truly malignant. When conventional therapeutic modalities fail, systemic chemotherapy remains the last option. We report seven such patients, three with highly aggressive and four with malignant pituitary tumors (n=4) four women; median age, 32 yr; range, 23-48 yr), who received one or more courses of chemotherapy with lomustine and 5-fluorouracil (median, two courses; range, one to six courses). Three patients with systemic metastatic disease had a shorter survival (median, 5 months; range, 1-14 months) than the one patient with central nervous system metastases alone (10 yr). A patient with an aggressive nonmetastatic prolactinoma who initially responded to chemotherapy died from another nondisease-associated cause. Two patients, one with an aggressive and one with a metastatic tumor, achieved symptomatic improvement with a median duration of 6 months. A hormonal reduction greater than 50% was observed in two of seven patients; only one patient who had an aggressive tumor obtained an objective tumor response. The median survival from the time of initiation of chemotherapy in patients with malignant tumors ranged from 3-65 months. Two patients with malignant tumors developed disease progression while receiving chemotherapy; no patient with extracranial metastases showed a response. Treatment was well tolerated, with minimal individual side-effects. Three patients with no response to initial treatment received different chemotherapeutic regimens with no additional response. All patients with metastatic malignant tumors eventually died. Treatment with cytotoxic chemotherapy is noncurative, and current experience is limited. Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression. The combination of lomustine/5-fluorouracil proved easy to administer with minimal toxicity, although the response rate was only 14%. Until a more specific treatment is found, an optimal chemotherapeutic regimen needs to be established.     

Potentiation and inhibition of nicotinic acetylcholine receptors by spermine in the TE671 human muscle cell line

Nicotinic acetylcholine receptors (nAChR) of the TE671 cell line were investigated using whole-cell and membrane patch recording techniques. At negative holding potentials (VH), pulses of acetylcholine (ACh) elicited whole-cell inward currents that rapidly desensitized. The EC50 value for ACh at VH = -60 mV was 7.8 microM. The ACh-induced current reversed at approximately 0 mV. Desensitization of nAChR by ACh was biphasic and reversible within approximately 20 sec. Spermine (1-100 microM) potentiated responses to ACh (10 microM - 1 mM) by reducing the rate of onset of desensitization; potentiation was inhibited by arcaine (10-100 microM). Spermine (1 mM) noncompetitively antagonized the AChinduced current. Antagonism by 1 to 5 mM spermine was voltage-dependent, increasing with negative VH. In 100 microM arcaine, this antagonism was shown to contain a voltage-independent component. Spermine (10 mM) increased the EC50 values for ACh, suggesting that at this concentration the polyamine is also a competitive antagonist. Single channel openings elicited during application of ACh to outside-out patches had a conductance of 47 pS at VH = -60 mV. At 10 and 100 microM, spermine increased channel open probability (po), but at 1 mM spermine, po was not significantly different from controls. The single channel conductance for ACh was unaffected by 10 and 100 microM spermine, but was decreased by 1 mM spermine. Spermine promoted the occurrence of approximately 27 pS openings. It is proposed that spermine acts at an excitatory modulatory site similar to that present on N-methyl-D-aspartate receptors and at least three inhibitory sites on nAChR of TE671 cells.     

VITAMIN B1 AND RIBOFLAVIN IN BREWING

Vitamin B₁ has been determined in a large number of beers by the fermentation method of Schultz, Atkin and Frey which has not previously been applied to worts and beers. In general, the highest amounts were found in beers of high original gravity and in those made almost entirely from malt. Well-attenuated and unprimed beers give the highest ratio, units of B1: calories. During the brew the malt, almost the sole source of vitamin B₁, yields up the vitamin to the wort, which in its turn loses most of it to the yeast. Most of the vitamin B₁ results have been confirmed by the thiochrome method involving an entirely different principle, whilst the general validity of both methods was further confirmed by animal feedings tests. Determination of Riboflavin (vitamin B₂) by the microbiological method of Snell and Strong has led to the following conclusions:—Riboflavin is formed during germination of barley and in growing yeast. Most of the riboflavin of the malt passes into the wort during mashing and sparging and remains in the beer, the yeast not taking out any appreciable quantity. The number of microgrms. of riboflavin per 100 ml. of beer, in general, exceeds somewhat the number of degrees of original gravity.     

Designing to Facilitate Browsing: A Look Back at the Hyperties Workstation Browser

Since browsing hypertext can present a formidable cognitive challenge, user interface design plays a major role in determining acceptability. In the Unix workstation version of Hyperties, a research-oriented prototype, we focussed on design features that facilitate browsing. We first give a general overview of Hyperties and its markup language. Customizable documents can be generated by the conditional text feature that enables dynamic and selective display of text and graphics. In addition we present: — an innovative solution to link identification: pop-out graphical buttons of arbitrary shape.

— application of pie menus to permit low cognitive load actions that reduce the distraction of common actions, such as page turning or window selection.

— multiple window selection strategies that reduce clutter and housekeeping effort. We preferred piles-of-tiles, in which standard-sized windows were arranged in a consistent pattern on the display and actions could be done rapidly, allowing users to concentrate on the contents.

     

The Inventory Approach to Urban Growth Boundaries

In this article, we argue that insights can be gained by analyzing the use of urban growth boundaries (UGBs) for urban growth management as an inventory problem. The analysis provides three useful insights. First, it shows that where UGBs are employed, too much emphasis is placed on whether UGBs contain sufficient land to accommodate 20 years of growth and too little is placed on how frequently, how much, or under what circumstances UGBs should be expanded. Second, it shows that where market factors are used, they have been used inappropriately to increase the size of UGBs immediately after expansion, when they should be used to influence the size of UGBs immediately before expansion. Third, it shows that UGBs are likely to work better if expansions occur not after an arbitrary period of time, but when the supply—or the price—of land reaches some critical threshold. We conclude by asserting that the use of UGBs should not be governed by arbitrary rules of thumb, because such rules do not stand up to critical examination, they preclude adaptation to local situations, and they prevent experimentation.     

Planning a City through ‘Dialogue’: Deliberative Policy-making in Action in Western Australia

Deliberative policy-making is an alternative method of generating new planning strategies based on the public deliberation of citizens and stakeholders. Four ideals of deliberative policy-making espoused by deliberative democracy theorists are identified. Using this framework the ‘Dialogue with the City’ process undertaken by the Western Australian Government to develop the Network City spatial planning strategy for the Perth metropolitan region is examined. While this process went further than most towards realising the ideals of deliberative policy-making, the Government was not able to fully achieve the ideals of inclusive decision-making, equitable decision-making, deliberation toward the common good and consensus decision-making. It is most likely that the deliberative approach to policy-making does not represent a new model for governing; rather, these participation techniques constitute a more sophisticated model for involving citizens and stakeholders in planning.

     

Decision rules for determining terrestrial movement and the consequences for filtering high-resolution global positioning system tracks: a case study using the African lion (Panthera leo)

The combined use of global positioning system (GPS) technology and motion sensors within the discipline of movement ecology has increased over recent years. This is particularly the case for instrumented wildlife, with many studies now opting to record parameters at high (infra-second) sampling frequencies. However, the detail with which GPS loggers can elucidate fine-scale movement depends on the precision and accuracy of fixes, with accuracy being affected by signal reception. We hypothesized that animal behaviour was the main factor affecting fix inaccuracy, with inherent GPS positional noise (jitter) being most apparent during GPS fixes for non-moving locations, thereby producing disproportionate error during rest periods. A movement-verified filtering (MVF) protocol was constructed to compare GPS-derived speed data with dynamic body acceleration, to provide a computationally quick method for identifying genuine travelling movement. This method was tested on 11 free-ranging lions (Panthera leo) fitted with collar-mounted GPS units and tri-axial motion sensors recording at 1 and 40 Hz, respectively. The findings support the hypothesis and show that distance moved estimates were, on average, overestimated by greater than 80% prior to GPS screening. We present the conceptual and mathematical protocols for screening fix inaccuracy within high-resolution GPS datasets and demonstrate the importance that MVF has for avoiding inaccurate and biased estimates of movement.     

Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy

Stereotactic body radiotherapy (SBRT) is known to induce important immunologic changes within the tumor microenvironment (TME). However, little is known regarding the early immune responses within the TME in the first few weeks following SBRT. Therefore, we used the canine spontaneous tumor model to investigate TME responses to SBRT, and how local injection of immune modulatory antibodies to OX40 and TLR 3/9 agonists might modify those responses. Pet dogs with spontaneous cancers (melanoma, carcinoma, sarcoma, n = 6 per group) were randomized to treatment with either SBRT or SBRT combined with local immunotherapy. Serial tumor biopsies and serum samples were analyzed for immunologic responses. SBRT alone resulted at two weeks after treatment in increased tumor densities of CD3+ T cells, FoxP3+ Tregs, and CD204+ macrophages, and increased expression of genes associated with immunosuppression. The addition of OX40/TLR3/9 immunotherapy to SBRT resulted in local depletion of Tregs and tumor macrophages and reduced Treg-associated gene expression (FoxP3), suppressed macrophage-associated gene expression (IL-8), and suppressed exhausted T cell-associated gene expression (CTLA4). Increased concentrations of IL-7, IL-15, and IL-18 were observed in serum of animals treated with SBRT and immunotherapy, compared to animals treated with SBRT. A paradoxical decrease in the density of effector CD3+ T cells was observed in tumor tissues that received combined SBRT and immunotherapy as compared to animals treated with SBRT only. In summary, these results obtained in a spontaneous large animal cancer model indicate that addition of OX40/TLR immunotherapy to SBRT modifies important immunological effects both locally and systemically.     

Dynamic equalization during charging of serial energy storageelements

A technique is described that equalizes the amount of charge in a serial string of energy-storage cells during charging by using DC-to-DC converters to divert portions of the charging current past selected cells (or groups of cells). When no converters are operating, the charging current through the string is equal to that of the charging source. As the string charges, one cell eventually reaches a threshold voltage V_A. At threshold, a shunt converter is activated to divert current around the cell, thus maintaining it at V_A. The diverted current extracts energy, which is returned to the charging bus and appears as an additional charging current to the source. This positive feedback increases the current available for charging the string and allows the least charged cells, or cells of larger capacity, to be charged at higher rates than available directly from the source. During discharging, the converters across the remaining cells supply energy to the bus, while the converter across the open cell maintains a constant terminal voltage. The maximum current gain of the system is equal to the number of converters used in the system