The STAMPEDE2 Trial: a Site Survey of Current Patterns of Care, Access to Imaging and Treatment of Metastatic Prostate Cancer.

AIMS: The forthcoming STAMPEDE2 trial has three comparisons in metastatic hormone-sensitive prostate cancer. We aim to determine clinical practices among STAMPEDE trial investigators for access to imaging and therapeutic choices and explore their interest in participation in STAMPEDE2. MATERIALS AND METHODS: The survey was developed and distributed online to 120 UK STAMPEDE trial sites. Recipients were invited to complete the survey between 16 and 30 May 2022. The survey consisted of 30 questions in five sections on access to stereotactic ablative body radiotherapy (SABR), 177lutetium-prostate-specific membrane antigen-617 (177Lu-PSMA-617), choice of systemic therapies and use of positron emission tomography/computerised tomography and whole-body magnetic resonance imaging. RESULTS: From 58/120 (48%) sites, 64 respondents completed the survey: 55/64 (86%) respondents were interested to participate in SABR, 44/64 (69%) in 177Lu-PSMA-617 and 56/64 (87.5%) in niraparib with abiraterone comparisons; 45/64 (70%) respondents had access to bone, spine and lymph node metastases SABR delivery and 7/64 (11%) to 177Lu-PSMA-617. In addition to androgen deprivation therapy, 60/64 (94%) respondents used androgen receptor signalling inhibitors and 46/64 (72%) used docetaxel; 29/64 (45%) respondents would consider triplet therapy with androgen deprivation therapy, androgen receptor signalling inhibitors and docetaxel. Positron emission tomography/computerised tomography was available to 62/64 (97%) respondents and requested by 45/64 (70%) respondents for disease uncertainty on conventional imaging and 39/64 (61%) at disease relapse. Whole-body magnetic resonance imaging was available to 24/64 (38%) respondents and requested by 13/64 (20%) respondents in highly selected patients. In low-volume disease, 38/64 (59%) respondents requested scans at baseline and disease relapse. In high-volume disease, 29/64 (45%) respondents requested scans at baseline, best response (at prostate-specific antigen nadir) and disease relapse; 54/64 (84%) respondents requested computerised tomography and bone scan for best response assessment. CONCLUSION: There is noteworthy disparity in clinical practice across current study sites, however most have expressed an interest in participation in the forthcoming STAMPEDE2 trial.

Species sensitivity distributions: data and model choice.

Species sensitivity distributions (SSDs) are increasingly incorporated into ecological risk assessment procedures. Although these new techniques offer a more transparent approach to risk assessment they demand more and superior quality data. Issues of data quantity and quality are especially important for marine datasets that tend to be smaller (and have fewer standard test methods) when compared with freshwater data. An additional source of uncertainty when using SSDs is appropriate selection from the range of methods used in their construction. We show through examples the influence of data quantity, data quality, and choice of model. We then show how regulatory decisions may be affected by these factors.

Hidden implications of clumps and masses.

In a recent study on the spawn of the common frog (Rana temporaria) surveyed over several breeding sites, a significant linear relationship (p < 0.001) was found to exist between the number of spawn 'clumps' making up a bouyant spawn 'mass' and the area of the mass visible from above the water surface (Griffiths and Raper, 1994). An open question exists, as to why such a strong linear relationship is to be found. Using elementary physics, I suggest some factors which may underly the observed linearity and how it may reveal characteristics other than size of a breeding population. A follow-up experiment is outlined to test for these in the field and some ecological implications are discussed.

Seasonal synchronicity and stage-specific life cycles: Topp's beetles revisited.

In his study on Catops nigricans (Coleoptera: Leiodidae), Topp (W. Topp, Selection for an optimal monovoltine life-cycle in an unpredictable environment: Studies on the beetle C. nigricans Spence. Oecologia 84: 134-141 (1990).) observed that the times of eclosion and oviposition of a population of this European beetle are tightly synchronized to the local seasonal environment. Topp proposed that the key mechanism producing such synchrony is the developmental response that individuals exhibit to seasonal fluctuations of temperature and light at discrete stages of their life cycle. Here, an individual-level model of the C. nigricans life cycle is constructed and parameterized with the complete set of Topp's stage-specific development data. Seasonal variations of temperature and light are replicated by sinusoidal functions of time. Simulations are carried out to investigate the temporal behavior of lineages (generated from an arbitrary cohort) exposed to these periodic environmental variations over several generations. Our results support the hypothesis that stage-specific development in a periodic environment produces a powerful mechanism by which life-cycle synchronization can occur.

Wavelengths effective in induction of malignant melanoma.

It is generally agreed that sunlight exposure is one of the etiologic agents in malignant melanoma of fair-skinned individuals. However, the wavelengths responsible for tumorigenesis are not known, although DNA is assumed to be the target because individuals defective in the repair of UV damage to DNA are several thousandfold more prone to the disease than the average population. Heavily pigmented backcross hybrids of the genus Xiphophorus (platyfish and swordtails) are very sensitive to melanoma induction by single exposures to UV. We irradiated groups of five 6-day-old fish with narrow wavelength bands at 302, 313, 365, 405, and 436 nm and scored the irradiated animals for melanomas 4 months later. We used several exposures at each wavelength to obtain estimates of the sensitivity for melanoma induction as a function of exposure and wavelength. The action spectrum (sensitivity per incident photon as a function of wavelength) for melanoma induction shows appreciable sensitivity at 365, 405, and probably 436 nm, suggesting that wavelengths not absorbed directly in DNA are effective in induction. We interpret the results as indicating that light energy absorbed in melanin is effective in inducing melanomas in this animal model and that, in natural sunlight, 90-95% of melanoma induction may be attributed to wavelengths > 320 nm--the UV-A and visible spectral regions.

DNA damage, photorepair, and survival in fish and human cells exposed to UV radiation.

The effect of various wavelengths of UVB radiation on the induction of cyclobutane pyrimidine dimers in fish cells and human fibroblasts and the repair of these lesions were studied using an UV-endonuclease to measure dimers (endonuclease sensitive sites) by sedimentation of radioactive DNA, by gel electrophoresis of unlabeled DNA, and by cell survival. The data show that fish cells have an efficient photoreactivation system at wavelength > 304 nm that reverses cytotoxicity and dimer formation after exposure to filtered sunlamp irradiation of a shorter wavelength (lambda > 290 nm). Shorter wavelengths in UVB (> 304 nm) are more effective in photoreversal than longer ones (> 320 nm). As a consequence, 50-85% of dimers induced by these wavelengths in fish are photoreactivated while they are being formed. A major cytotoxicological lesion is the cyclobutane pyrimidine dimers. Cultured human fibroblasts do not possess such a repair system. These results indicate that sunlamp irradiation has wavelengths that both damage and repair DNA.

Confrontation naming in the elderly: the Build-up Picture Test as an aid to differentiating normals from subjects with dementia.

This paper reports the results of a study in which the Build-up Picture Test (BUPT) was given to three groups of elderly subjects with 15 subjects in each group: independent, dependent and those with probable senile dementia of the Alzheimer type (SDAT). The BUPT is a task designed to combine confrontation and generative naming, incorporating priming, cueing and latency aspects to facilitate responses. It involves presentation of degraded line drawings of objects, built up in stages to black and white photographs of the objects. Results showed the scores by the probable SDAT subjects to be highly significant at the 1.00 level (P = 0.0000). Analysis of scores showed better than expected responses from the probable SDAT subjects to representations of familiar objects with simple outline shapes. The implications for differential diagnosis are discussed.

Animal model for ultraviolet radiation-induced melanoma: platyfish-swordtail hybrid.

Sunlight exposure is strongly indicated as one of the important etiologic agents in human cutaneous malignant melanoma. However, because of the absence of good animal models, it has not been possible to estimate the wavelengths or wavelength regions involved. We have developed a useful animal model from crosses and backcrosses of platyfish (Xiphophorus maculatus) and swordtails (Xiphophorus helleri). Two strains of these fish are susceptible to invasive melanoma induction by exposure to filtered radiation from sunlamps in the wavelength ranges lambda greater than 290 nm and lambda greater than 304 nm. Multiple exposures on 5-20 consecutive days beginning on day 5 after birth or a single exposure of approximately 200 J/(m2.day) of lambda greater than 304 nm result in a tumor prevalence of 20% to 40% at 4 months of age compared with a background rate of 12% in one strain and 2% in another. Exposure of the fish to visible light after UV exposure reduces the prevalence to background. The melanomas are similar in many respects to mammalian melanomas, as judged by light and electron microscopy. The genetics of the crosses determined by others and the high sensitivity of the hybrids to melanoma induction indicate that the UV radiation probably inactivates the one tumor repressor gene (or a small number of tumor repressor genes) in the hybrid fish. The small size of the animals and their high susceptibility to melanoma induction make them ideal for action spectroscopy.

Established cell lines from nonmammalian vertebrates: models for DNA repair studies.

Several established cell lines from different classes of vertebrates were assayed for the presence of O6-methylguanine acceptor protein. This protein is instrumental in removing adducts from DNA caused by exposure to alkylating agents. Cultured cells had levels of acceptor protein activity within the range found in fresh tissues from animals in the same class. We suggest that cells from lower vertebrates are satisfactory in vitro models for studies of this DNA repair function.

Presence of O6-methylguanine acceptor protein in the tissues of different classes of vertebrates and invertebrates.

We have measured the ability of extracts of tissues from several species of mammals, birds, reptiles, amphibia and fish to demethylate adducts of O6-methylguanine in exogenous DNA by transfer of the methyl group to an acceptor protein. Our study also encompassed tissues from a smaller number of invertebrates, from arthropods, molluscs and annelids. The vertebrate tissues used were liver, brain, spleen and kidney. In the case of the invertebrates we sampled liver, neural tissue, gonads, digestive tract and hepatopancreas. There was no consistent change in the amount of acceptor activity per unit of protein or DNA going from cold-blooded to warm-blooded vertebrates. Liver invariably had the highest amount; this finding was not unexpected since metabolic processes in the liver are high, and good cellular protective mechanism important. Inter-class comparisons within the vertebrates are highly speculative, and hindered by the fact that there is little information on carcinogenesis in animals other than rodents and humans. O6-methylguanine acceptor activity was found in all the invertebrate tissues tested. The amounts were variable, 0.003-0.0051 fmol/micrograms cellular DNA, but the values fell within the range of those found in the tissues of vertebrates.

Levels of O6-methylguanine acceptor protein in tissues of rats and their relationship to carcinogenicity and aging.

N-nitroso compounds react with cellular DNA to produce various damaging adducts, one of the more important being O6-alkylguanine. DNA restoration is accomplished by transfer of the alkyl group to a cysteine residue of an acceptor protein. The levels of acceptor activity were compared in several tissues from well-fed and dietary-restricted inbred SD rats 30-1,194 days of age. Striking and consistent differences were found in the levels of acceptor activity in different tissues from both groups; these levels corresponded to their sensitivity to tumorigenesis by alkylating agents. Acceptor activity levels were highest in the liver and somewhat less in the spleen; there were significantly lower levels in brain and kidney. The random loss with time in the integrity of DNA may cause alterations in cellular function or limit cellular proliferation, thus leading to senescence and death. DNA repair processes may alter the rate of accumulation of damage, thereby affecting potential longevity. There were no significant age-associated changes in the ability of cells from either dietary group to remove DNA adducts and there was no evidence of alterations in the acceptor protein with age that would compromise its functional activity.

Routine focal mollusciciding after chemotherapy to control Schistosoma mansoni in Cul de Sac valley, Saint Lucia.

Concluding results of a 10-year schistosomiasis control programme in Cul de Sac valley, Saint Lucia, are described. After an area-wide mollusciciding campaign (1970-75), and a surveillance/treatment programme supplemented with selective population chemotherapy in 1975 and 1976, prevalence rates of Schistosoma mansoni were reduced to low levels. To prevent a resurgence of transmission a cost effective routine focal mollusciciding programme, suitable for public health implementation was evaluated from 1977 to 1981. Streams and main collector drains in banana fields, considered to be potential S. mansoni transmission sites, were treated every four weeks with Bayluscide 6076 emulsifiable concentrate (Clonitralide). Snail populations were effectively controlled in the treated areas but large numbers were present where no treatment was given. Only 0 X 06% of sentinel snails became infected. Prevalence of infection in the human population remained low (over-all 5%) and intensity of infection at a level not normally associated with schistosomal disease. Since control started 10 years earlier the level of potential contamination has fallen by 92% in high transmission areas. The four-year programme cost US+12,909 of which 54% was for molluscicide, 27% for labour and 19% for transport, equipment and sundries. The average annual cost per head of population was US+0 X 46.

Value of individual household water supplies in the maintenance phase of a schistosomiasis control programme in Saint-Lucia, after chemotherapy.

Between 1970 and 1975, the incidence of new Schistosoma mansoni infections was reduced in 5 villages after each household was provided with its individual water supply and community laundry shower units were made available. In 1975, 1976, and 1977 chemotherapy with oxamniquine was offered to persons found to be infected. Transmission was reduced further and remained at a low level for the next 4 years, with no sign of an increase in spite of the reservoir of infection remaining after therapy and a poor level of sanitation in the villages.Thus, properly maintained water supplies appear to be effective in maintaining transmission at a low level during the maintenance phase of a schistosomiasis control programme, after chemotherapy. Sporadic new infections must be anticipated among children, but these will probably be of low intensity and associated with minimal morbidity.

Evaluation of chemotherapy in the control of Schistosoma mansoni in Marquis Valley, Saint Lucia. I. Results in humans.

Hycanthone at a dose of 2.5 mg kg body weight was given in 1973 and 1974 to persons found by a sedimentation concentration technique to be excreting Schistosoma mansoni eggs. In a further two campaigns oxamniquine was used (15 mg/kg body weight). The last treatment was given after the 1976 survey and stools of children were re-examined annually but not further treatment was planned. In six villages prevalence remained low, at 4%, 4 years later, in two it increased to 10%, and in two others after 3 years it was 23% and further treatment was offered. Factors affecting renewed transmission and the rate prevalence builds up were investigated and found to be low attendance rate for treatment, greater use of the river water and, possibly, infected immigrants. But if prevalence builds up slowly, retreatment may be necessary only every 3-4 years at an estimated annual cost of 40 cents per person protected.

Routine focal mollusciciding after chemotherapy to control Schistosoma mansoni in Cul de Sac valley, St. Lucia

Concluding results of a ten year schistosomiasis control programme in Cul de Sac valley, St. Lucia, are described. After an area wide mollusciciding campaign (1970-1975), and a surveillance/treatment programme supplemented with selective population chemotherapy in 1975 and 1976, prevelence rates of Schistosoma mansoni were reduced to low levels. To prevent a resurgence of transmission a cost effective routine focal mollusciciding programme, suitable for public health implementation was evaluated from 1977 to 1981. Streams and main collector drains in banana fields, considered to be potential S. mansoni transmission sites, were treated every four weeks with Bayluscide 6076 emulsifiable concentrate (Clonitralide). Snail populations were effectively controlled in the treated areas but large numbers were present where no treatment was given. Only 0.06 percent of sentinel snails became infected. Prevalence of infection in the human population remained low (over-all 5 percent) and intensity of infection at a level not normally associated with schistosomal disease. Since control started ten years earlier the level of potential contamination has fallen by 92 percent in high transmisssion areas. The four year programme cost US$12,909, of which 54 percent was for molluscicide, 27 percent for labour and 19 percent for transport, equipment and sundries. The average annual cost per head of population was US$0.46

Reduction in transmission of Schistosoma mansoni by a four-year focal mollusciciding programme against Biomphalaria glabrata in Saint Lucia.

The effect of transmission of Schistosoma mansoni of a focal snail control programme was investigated over four years amongst approximately 1250 people living in five communities in the steep-sided Soufriere river valley, St. Lucia, West Indies. Bayer 6076 was applied from constant flow drip cans to 12 stream sections at a target dose of 8 mg/litre clonitralide every four weeks. Only proven and potential transmission sites were treated; marsh habitats, where Biomphalaria glabrata were widespread, were ignored. In the stream snail numbers were reduced by 94% in the first year and by 100% thereafter. Incidence of new S. mansoni infections amongst children fell from 18% in the last year before control to 6% and 9% after three and four years respectively. Amongst children and adults in the four years of control the conversion/reversion ratio declined leading to a lowering of the over-all prevalence from 40% to 22%. Parasitologically the results were similar to those of a previously evaluated area-wide mollusciciding programme. The mean annual cost per person protected was US $2.60. This figure is atypically high because the topography of the area severely limited the population size.

Reduction in transmission of Schistosoma mansoni by a four-year focal mollusciciding programme against Biomphalaria glabrata in St. Lucia

The effect on transmission of Schistosoma mansoni of a focal snail control programme was investigatsd over four years amongst approximately 1250 people living in 5 communities in the steep-sided Soufriere river valley, St. Lucia, West Indies. Bayer 6076 was applied from constant flow drip cans to 12 stream sections at a target dose of 8mg/litre clonitralide every four weeks. Only proven and potential transmission sites were treated (AU)