The Three Rs of Animal Research: What they Mean for the Institutional Animal Care and Use Committee and Why.

The Institutional Animal Care and Use Committee (IACUC) is entrusted with assessing the ethics of proposed projects prior to approval of animal research. The role of the IACUC is detailed in legislation and binding rules, which are in turn inspired by the Three Rs: the principles of Replacement, Reduction, and Refinement. However, these principles are poorly defined. Although this provides the IACUC leeway in assessing a proposed project, it also affords little guidance. Our goal is to provide procedural and philosophical clarity to the IACUC without mandating a particular outcome. To do this, we analyze the underlying logic of the Three Rs and conclude that the Three Rs accord animals moral standing, though not necessarily "rights" in the philosophical sense. We suggest that the Rs are hierarchical, such that Replacement, which can totally eliminate harm, should be considered prior to Reduction, which decreases the number of animals harmed, with Refinement being considered last. We also identify the need for a hitherto implicit fourth R: Reject, which allows the IACUC to refuse permission for a project which does not promise sufficient benefit to offset the pain and distress likely to be caused by the proposed research.

Genetic characterization of the prion protein gene in camels (Camelus) with comments on the evolutionary history of prion disease in Cetartiodactyla.

Transmissible spongiform encephalopathies (TSEs) are a fatal neurogenerative disease that include Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE), and several others as well as the recently described camel prion disease (CPD). CPD originally was documented in 3.1% of camels examined during an antemortem slaughterhouse inspection in the Ouargla region of Algeria. Of three individuals confirmed for CPD, two were sequenced for the exon 3 of the prion protein gene (PRNP) and were identical to sequences previously reported for Camelus dromedarius. Given that other TSEs, such as BSE, are known to be capable of cross-species transmission and that there is household consumption of meat and milk from Camelus, regulations to ensure camel and human health should be a One Health priority in exporting countries. Although the interspecies transmissibility of CPD currently is unknown, genotypic characterization of Camelus PRNP may be used for predictability of predisposition and potential susceptibility to CPD. Herein, eight breeds of dromedary camels from a previous genetic (mitochondrial DNA and microsatellites) and morphological study were genotyped for PRNP and compared to genotypes from CPD-positive Algerian camels. Sequence data from PRNP indicated that Ethiopian camels possessed 100% sequence identity to CPD-positive camels from Algeria. In addition, the camel PRNP genotype is unique compared to other members of the Orders Cetartiodactyla and Perissodactyla and provides an in-depth phylogenetic analysis of families within Cetartiodactyla and Perissodactyla that was used to infer the evolutionary history of the PRNP gene.

Going Wild in the City-Animal Feralization and Its Impacts on Biodiversity in Urban Environments.

Domestication describes a range of changes to wild species as they are increasingly brought under human selection and husbandry. Feralization is the process whereby a species leaves the human sphere and undergoes increasing natural selection in a wild context, which may or may not be geographically adjacent to where the originator wild species evolved prior to domestication. Distinguishing between domestic, feral, and wild species can be difficult, since some populations of so-called "wild species" are at least partly descended from domesticated "populations" (e.g., junglefowl, European wild sheep) and because transitions in both directions are gradual rather than abrupt. In urban settings, prior selection for coexistence with humans provides particular benefit for a domestic organism that undergoes feralization. One risk is that such taxa can become invasive not just at the site of release/escape but far away. As humanity becomes increasingly urban and pristine environments rapidly diminish, we believe that feralized populations also hold conservation value.

Challenges and solutions to biodiversity conservation in arid lands.

The strategic goals of the United Nations and the Aichi Targets for biodiversity conservation have not been met. Instead, biodiversity has continued to rapidly decrease, especially in developing countries. Setting a new global biodiversity framework requires clarifying future priorities and strategies to bridge challenges and provide representative solutions. Hyper-arid, arid, and semi-arid lands (herein, arid lands) form about one third of the Earth's terrestrial surface. Arid lands contain unique biological and cultural diversity, and biodiversity loss in arid lands can have a disproportionate impact on these ecosystems due to low redundancy and a high risk of trophic cascades. They contain unique biological and cultural diversity and host many endemic species, including wild relatives of key crop plants. Yet extensive agriculture, unsustainable use, and global climate change are causing an irrecoverable damage to arid lands, with far-reaching consequences to the species, ground-water resources, ecosystem productivity, and ultimately the communities' dependant on these systems. However, adequate research and effective policies to protect arid land biodiversity and sustainability are lacking because a large proportion of arid areas are in developing countries, and the unique diversity in these systems is frequently overlooked. Developing new priorities for global arid lands and mechanisms to prevent unsustainable development must become part of public discourse and form the basis for conservation efforts. The current situation demands the combined efforts of researchers, practitioners, policymakers, and local communities to adopt a socio-ecological approach for achieving sustainable development (SDGs) in arid lands. Applying these initiatives globally is imperative to conserve arid lands biodiversity and the critical ecological services they provide for future generations. This perspective provides a framework for conserving biodiversity in arid lands for all stakeholders that will have a tangible impact on sustainable development, nature, and human well-being.

Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial.

PURPOSE: Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS: Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS: Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS (P = .10) or OS (P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION: In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

Forecasting the risk of brown tree snake dispersal from Guam: a mixed transport-establishment model.

The brown tree snake (Boiga irregularis) is a devastating invader that has ecologically and economically affected Guam and is poised to disperse further. Interdiction efforts are being conducted on Guam and some of the potential receiving sites, but no tools exist for evaluating the potential for snake incursion; thus, the amount of effort that should be invested in protecting particular sites is unknown. We devised a model that predicts the relative risk of establishment of the brown tree snake (BTS) at a given site. To calculate overall risk, we incorporated in the model information on the likelihood of an organism entering the transportation system, avoiding detection, surviving to arrive at another location, and establishing at the receiving end. On the basis of documented rates of snake arrival at receiving sites, the model produced realistic predictions of invasion risk. Model outputs can thus be used to prioritize interdiction efforts to focus on especially vulnerable receiving locations. We provide examples of the utility of the model in evaluating the impacts of changes in transportation parameters. Finally, the model can be used to evaluate the impacts that BTS establishment at an additional site and that creation of a new source of snakes would have. The use of qualitative inputs allows the model to be adapted by substituting data on other invasive species or transportation systems.

On piecewise models and species-area patterns.

AIM: Area thresholds, at which the form of the species-area relationship (SAR) changes abruptly, have played an important role in the theoretical framework of conservation biogeography and biodiversity research. The application of piecewise regressions has been advocated as a rigorous statistical technique to identify such thresholds within SARs, but a large variety of piecewise models remains untested. We explore the prevalence and number of thresholds in SARs and examine whether the currently widely used method for detecting the small island effect (SIE) is robust. LOCATION: Global. TAXON: We consider all multicellular taxa based on the criteria of datasets selection. METHODS: We apply 15 regression models, including linear regression and piecewise regressions with two and three segments to 68 global island datasets that are sourced from the literature. RESULTS: The number of area thresholds in SARs varied among groups and correlated positively with area range of a studied system. Under the AIC or AICc criterion, three-segment piecewise models were more prevalent, whereas under the BIC criterion, two-segment piecewise models were more prevalent. From the results of Aegean Sea isopods, West Indies herpetofauna, and Australian Islands mammals, we found evidence that the traditional criteria for detection of SIEs are not robust. MAIN CONCLUSIONS: Our study demonstrates that (a) to detect an SIE, the comparison should use as many models as possible, including not only variants with and without a left-horizontal part, but also those with two and more segments; (b) naive use of the traditional two-segment piecewise regressions may cause poor estimations of both slope and breakpoint values; (c) the number of thresholds increases with the area range of a studied system; (d) conservation biologists and applied ecologists should determine the number of area thresholds when estimating the precise species-area patterns and making management strategies in fragmented landscapes.

Dosimetric and radiobiological investigation of permanent implant prostate brachytherapy based on Monte Carlo calculations.

PURPOSE: Permanent implant prostate brachytherapy plays an important role in prostate cancer treatment, but dose evaluations typically follow the water-based TG-43 formalism, ignoring patient anatomy and interseed attenuation. The purpose of this study is to investigate advanced TG-186 model-based dose calculations via retrospective dosimetric and radiobiological analysis for a new patient cohort. METHODS AND MATERIALS: A cohort of 155 patients treated with permanent implant prostate brachytherapy from The Ottawa Hospital Cancer Centre is considered. Monte Carlo (MC) dose calculations are performed using tissue-based virtual patient models. Dose-volume histogram (DVH) metrics (target, organs at risk) are extracted from 3D dose distributions and compared with those from calculations under TG-43 assumptions (TG43). Equivalent uniform biologically effective dose and tumor control probability are calculated. RESULTS: For the target, D90 (V100) is 136.7 ± 20.6 Gy (85.8% ± 7.8%) for TG43 and 132.8 ± 20.1 Gy (84.1% ± 8.2%) for MC; D90 is 3.0% ± 1.1% lower for MC than TG43. For organs at risk, MC D1cc = 104.4 ± 27.4 Gy (TG43: 106.3 ± 28.3 Gy) for rectum and 80.8 ± 29.7 Gy (TG43: 78.4 ± 28.4 Gy) for bladder; D1cc = 185.9 ± 30.2 Gy (TG43: 191.1 ± 32.0 Gy) for urethra. Equivalent uniform biologically effective dose and tumor control probability are generally lower when evaluated using MC doses. The largest dosimetric and radiobiological discrepancies between TG43 and MC are for patients with intraprostatic calcifications, for whom there are low doses (cold spots) in the vicinity of calcifications within the target, identified with MC but not TG43. CONCLUSIONS: DVH metrics and radiobiological indices evaluated with TG43 are systematically inaccurate by upward of several percent compared with MC patient-specific models. Mean cohort DVH metrics and their MC:TG43 variances are sensitive to patient cohort and clinical practice, underlining the importance of further retrospective MC studies toward widespread clinical adoption of advanced model-based dose calculations.

The sprightly little sphaerodactyl: Systematics and biogeography of the Puerto Rican dwarf geckos Sphaerodactylus (Gekkota, Sphaerodactylidae).

Studies of the Caribbean herpetofauna (amphibians and reptiles) have made significant contributions to our knowledge of evolutionary patterns and processes. A prerequisite for these studies are accurate taxonomies and robust phylogenetic hypotheses. One notable Caribbean radiation lacking such data are dwarf geckos of the genus Sphaerodactylus. Systematics of the Puerto Rican Sphaerodactylus have been turbulent since the initial species descriptions and no molecular phylogenies exist that include complete or near-complete taxon sampling. Here, we combine a multi-locus molecular phylogeny with extensive morphological information to investigate the current diversity of Sphaerodactylus geckos from the Puerto Rican Bank, with a large number of species from Hispaniola as an outgroup. In particular, we focus our efforts on resolving the taxonomy of the Sphaerodactylus macrolepis Günther species complex. We find S. macrolepis sensu lato (currently two nominal species with nine subspecies) is made up of at least four diagnosable species within two clades: (1) the sister species Sphaerodactylus macrolepis sensu stricto from the Virgin Islands (including St. Croix) and Culebra, and S. parvus King from islands in the northern Lesser Antilles; and (2) all other Sphaerodactylus macrolepis subspecies from Puerto Rico, Vieques, and Culebra. We resurrect Sphaerodactylus grandisquamis Stejneger from synonymy to refer to all subspecies from Puerto Rico and elevate the subspecies Sphaerodactylus inigoi Thomas Schwartz for geckos from Vieques and western Culebra. The resulting phylogeny and revised taxonomy will be a useful tool for subsequent research into Sphaerodactylus conservation and evolution.

Improving interactions between animal rights groups and conservation biologists.

Invasive species are often considered to be a major threat to biodiversity, leading conservation biologists to often recommend their complete eradication. Animal rights groups typically categorically oppose killing animals, and their opposition has brought eradication attempts of gray squirrels in northern Italy (Europe) and mute swans in Vermont to a halt. As a result native red squirrels may disappear from Europe and ecosystem-wide impacts are expected to be caused by the swan. In contrast, cooperation between managers and animal rights groups has resulted in a successful control program for feral pigs in Fort Worth, Texas (U.S.A.). The philosophical differences between animal rights and conservation biologists' views make cooperation seem unlikely, yet documented cases of cooperation have been beneficial for both groups. We recommend that managers dealing with invasive species should consult with social scientists and ethicists to gain a better understanding of the implications of some of their policy decisions. In addition, we recommend that animal rights groups do more to support alternatives to lethal control, which are often excluded by economic limitations. Prevention of arrival of invasive species via application of the precautionary principle may be an especially productive avenue for such collaboration because it fits the goals and values of both groups.

Morphometric and genetic variation in 8 breeds of Ethiopian camels (Camelus dromedarius).

Dromedary camels (Camelus dromedarius) are a domesticated and closely guarded economic staple of indigenous people located throughout Ethiopian territorial states. Seventeen morphometric variables were examined to determine intraspecific variation among 8 pastoralist-designated breeds of camels. Additionally, DNA sequences from mitochondrial cytochrome-b gene and genotyping of 6 nuclear microsatellite loci were examined to assess genetic diversity and phylogenetic relationship of Ethiopian camels. Examination of 525 individuals revealed significant morphometric differentiation in Afar as compared with the remaining 7 breeds. Analysis of cytochrome-b sequences failed to recover monophyletic groups associated with pastoralist-recognized breeds. Analysis of 6 microsatellite loci from 104 individuals depicted no resolution of distinct genetic lineages in accordance to geographical or designated breeds. Overall, separation of 2 ecotypes based on the morphometric data was supported; however, genetic analysis of cytochrome-b and microsatellite data failed to support any unique genetic lineage or statistically significant population structure.

Mature results of the Ottawa phase II study of intermittent androgen-suppression therapy in prostate cancer: clinical predictors of outcome.

PURPOSE: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). METHODS AND MATERIALS: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. RESULTS: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. CONCLUSIONS: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs.

Feasibility study of using MOSFET detectors for in vivo dosimetry during permanent low-dose-rate prostate implants.

PURPOSE: To investigate the feasibility of using new micro-MOSFET detectors for QA and in vivo dosimetry of the urethra during transperineal interstitial permanent prostate implants (TIPPB). METHODS AND MATERIALS: This study involves measurements for several patients who have undergone the implant procedure with iodine-125 seeds. A new micro-MOSFET detector is used as a tool for in vivo measurement of the initial dose rate within the urethra. MOSFETs are calibrated using a single special order calibration seed. The angular response is investigated in a 100 kVp X-ray beam. RESULTS: micro-MOSFETs are found to have a calibration factor of 0.03 cGy/mV for low energy X-rays and a high isotropic response (within 2.5%). Prostate volume and shape changes during TIPPB due to edema caused by the trauma of needle insertion, making it difficult to achieve the planned implant geometry and hence the desired dose distribution. MOSFET measurements help us to evaluate the overall quality of the implant, by analyzing the maximum dose received by urethra, the prostate base coverage, the length of the prostatic urethra that is irradiated, and the apex coverage. CONCLUSIONS: We demonstrate that ease of use, quick calibration and the instantaneous reading of accumulated dose make micro-MOSFETs feasible for in vivo dosimetry during TIPPB.

Detecting the small island effect and nestedness of herpetofauna of the West Indies.

To detect the small island effect (SIE) and nestedness patterns of herpetofauna of the West Indies, we derived and updated data on the presence/absence of herpetofauna in this region from recently published reviews. We applied regression-based analyses, including linear regression and piecewise regressions with two and three segments, to detect the SIE and then used the Akaike's information criterion (AIC) as a criterion to select the best model. We used the NODF (a nestedness metric based on overlap and decreasing fill) to quantify nestedness and employed two null models to determine significance. Moreover, a random sampling effort was made to infer about the degree of nestedness at portions of the entire community. We found piecewise regression with three segments performed best, suggesting the species-area relationships possess three different patterns that resulted from two area thresholds: a first one, delimiting the SIE, and a second one, delimiting evolutionary processes. We also found that taxa with lower resource requirement, higher dispersal ability, and stronger adaptation to the environment generally displayed lower corresponding threshold values, indicating superior taxonomic groups could earlier end the SIE period and start in situ speciation as the increase of island size. Moreover, the traditional two-segment piecewise regression method may cause poor estimations for both slope and threshold value of the SIE. Therefore, we suggest previous SIE detection works that conducted by two-segment piecewise regression method, ignoring the possibility of three segments, need to be reanalyzed. Antinestedness occurred in the entire system, whereas high degree of nestedness could still occur in portions within the region. Nestedness may still be applicable to conservation planning at portions even if it is antinested at the regional scale. However, nestedness may not be applicable to conservation planning at the regional scale even if nestedness does exist among sampling islands from a portion.

Species-area relationships and additive partitioning of diversity of native and nonnative herpetofauna of the West Indies.

To evaluate the regional biogeographical patterns of West Indian native and nonnative herpetofauna, we derived and updated data on the presence/absence of all herpetofauna in this region from the recently published reviews. We divided the records into 24 taxonomic groups and classified each species as native or nonnative at each locality. For each taxonomic group and in aggregate, we then assessed the following: (1) multiple species-area relationship (SAR) models; (2) C- and Z-values, typically interpreted to represent insularity or dispersal ability; and (3) the average diversity of islands, among-island heterogeneity, γ-diversity, and the contribution of area effect toward explaining among-island heterogeneity using additive diversity partitioning approach. We found the following: (1) SARs were best modeled using the Cumulative Weibull and Lomolino relationships; (2) the Cumulative Weibull and Lomolino regressions displayed both convex and sigmoid curves; and (3) the Cumulative Weibull regressions were more conservative than Lomolino at displaying sigmoid curves within the range of island size studied. The Z-value of all herpetofauna was overestimated by Darlington (Zoogeography: The geographic distribution of animals, John Wiley, New York, 1957), and Z-values were ranked: (1) native > nonnative; (2) reptiles > amphibians; (3) snake > lizard > frog > turtle > crocodilian; and (4) increased from lower- to higher-level taxonomic groups. Additive diversity partitioning showed that area had a weaker effect on explaining the among-island heterogeneity for nonnative species than for native species. Our findings imply that the flexibility of Cumulative Weibull and Lomolino has been underappreciated in the literature. Z-value is an average of different slopes from different scales and could be artificially overestimated due to oversampling islands of intermediate to large size. Lower extinction rate, higher colonization, and more in situ speciation could contribute to high richness of native species on large islands, enlarging area effect on explaining the between-island heterogeneity for native species, whereas economic isolation on large islands could decrease the predicted richness, lowering the area effect for nonnative species. For most of the small islands less affected by human activities, extinction and dispersal limitation are the primary processes producing low species richness pattern, which decreases the overall average diversity with a large among-island heterogeneity corresponding to the high value of this region as a biodiversity hotspot.

The Evolution of Search Modes: Ecological versus Phylogenetic Perspectives.

Both theoretical and empirical studies, many of them on lizards, suggest that foraging behaviors often take one of two forms, sometimes called "modes": active search or sedentary ambush. I tested this by expanding the database on lizard foraging behaviors and testing for the existence of modality in this much larger database. My findings did not support the validity of some previous analyses. Greatly expanded lizard data did not show a bimodal distribution of foraging behaviors. Phylogeny, however, was a strong predictor of behavior. One clade, Autarchoglossa, was characterized by a wide range of foraging behaviors, but closely related species tended to exhibit similar behaviors. Two other clades, Iguania and Gekkota, retain the ancestral sedentary behavior. This phylogenetic trend, combined with phylogenetically biased sampling, may have been responsible for the appearance of bimodality in previous studies. Thus, bimodality of search modes is rejected. Some previous generalizations regarding correlates of foraging "mode" need to be reevaluated in this light.

Correlating the degree of needle trauma during prostate brachytherapy and the development of acute urinary toxicity.

PURPOSE: To determine if there is an association between the degree of prostate trauma during prostate brachytherapy and development of acute urinary toxicity. METHODS AND MATERIALS: In a consecutive prospective cohort of permanent (125)I prostate brachytherapy patients, the number of times each needle was repositioned was tracked, and the dosimetry plans were used to determine the number of times needles within 1 cm of the urethra were manipulated. Additionally, prostate volume, total number of needles, number of needles/prostate volume, and the number of periurethral needle manipulations/prostate volume were determined. The need for catheterization beyond 24 hours and the Radiation Therapy Oncology Group (RTOG) urinary toxicity score at 4 weeks were recorded. The independent samples t test was used to search for a correlation between these parameters and the recorded toxicity scores. RESULTS: Twenty-eight consecutive implant patients were evaluated in the study. Median (range) values were as follows: prostate volume 35 cc ( range, 15-51 cc), number of needles per patient 32 (range, 21-41), number of needle manipulations per patient 94.5 ( range, 55-147), and number of periurethral needle manipulations 42 (range, 17-65). The only significant association between urinary toxicity and these variables was for the number of periurethral needle manipulations (p = 0.025). CONCLUSIONS: These data provide evidence that needle prostate trauma during brachytherapy contributes to acute urinary toxicity.

Report of a multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer.

PURPOSE: To evaluate the effect of 3 months vs. 8 months of neoadjuvant hormonal therapy before conventional dose radiotherapy (RT) on disease-free survival using prostate-specific antigen PSA and biopsies as end points for clinically localized prostate cancer. METHODS AND MATERIALS: Between February 1995 and June 2001, 378 men were randomized to either 3 or 8 months of flutamide and goserelin before conventional-dose RT (66 Gy) at four participating centers. The median patient age was 72 years (range, 50-84 years). The stage distribution was 17% T1c, 35% T2a, 34% T2b-T2c, 13% T3-T4. The Gleason score (GS) was < or =6 in 51%, 7 in 38%, and 8-10 in 11%. The median baseline PSA level was 9.7 ng/mL (range, 1.3-189 ng/mL). Of the 378 men, 26% were low risk (Stage T1c-T2a, GS < or =6, PSA <10 ng/mL), 43% were intermediate risk (Stage T2b or GS 7 or PSA 10-20 ng/mL), and 31% were high risk (Stage T3 or GS 8-10 or PSA >20 ng/mL). The two arms were balanced in terms of age, GS, T stage, risk group, and presenting PSA level. The median follow-up was 44 months (range, 10-84 months), and 361 patients were available for evaluation. RESULTS: The 8-month arm achieved a lower PSA level before starting RT (0.37 vs. 0.74 ng/mL, p < or =0.001) and had a greater downsizing of the prostate (mean volume 26.6 cm(3) vs. 30.5 cm(3), p < or =0.001). However, the actuarial freedom from failure rate (biochemical by American Society for Therapeutic Radiology and Oncology definition, local or distant) for the 3-month vs. 8-month arms at 3 years was 66% vs. 68% and by 5 years was 61% vs. 62%, respectively (p = 0.36). No statistically significant difference was noted in the types of failure between the two arms (crude final status): biochemical, 22.2% vs. 22.3%; local, 10.2% vs. 6.5%; and distant, 3.4% vs. 4.4% (p = 0.61). Two-year post-RT biopsies were done in 57% (n = 205). Negative biopsies were obtained in 68% of the 3-month and 77% of the 8-month patients; 18% and 14% had indeterminate biopsies and 14% and 9% were positive for residual cancer (p = 0.34) in the two arms, respectively. The median PSA level for nonfailing patients was 0.50 ng/mL in both the 3-months and 8-month arms. A suggestion of improvement was found in the 8-month arm for disease-free survival at 5 years for high-risk patients (39% vs. 52%) but did not achieve statistical significance. CONCLUSION: A longer period of neoadjuvant hormonal therapy before standard-dose RT does not appear to confer a benefit in terms of disease-free survival or to alter failure patterns. Failure was delayed in the 8-month arm, but this advantage was lost by 5 years of follow-up. A suggestion of benefit was noted with a longer period of hormonal therapy for high-risk patients.

Radiotherapy for localized prostate cancer: assessment of results by systematic biopsy and PSA.

This study attempted to determine the failure pattern after radiotherapy for localized prostate cancer using systematic biopsies and serum PSA in assessment of outcome. Between July 1987 and February 1993, 226 patients treated with radical external beam radiotherapy were followed prospectively with systematic transrectal ultrasound-guided biopsies and serum PSA. Four hundred and ten transrectal ultrasound-guided biopsies were performed with 4-7 samples (usually six) per session. Stage distribution was T1b: 32, T1c: 11, T2a: 45, T2b: 62, T3: 50, T4: 6. Median follow-up was 41 months. The rate of positive biopsies continued to decrease over time, reaching a nadir of 30.5% at 30 months post radiotherapy. Local failures have occurred in 17% (38/226) overall, or 13% of T1b, 0% of T1c, 13% of T2a, 20% of T2b and 21% of T3-4. Six additional patients (2.5%) have had biochemical failure and 34 (15%) have biopsy-only failure. Forty seven patients initially showing residual tumor on post radiotherapy biopsies (median time 18 months), demonstrated late tumor clearance, achieving negative biopsies at a median time of 28 months. Median nadir PSA in patients with no evidence of disease (NED) at last follow-up was 0.5 ng/mL, achieved at 24 months post radiotherapy. For patients with delayed tumor clearance, the median nadir PSA was 0.6 ng.mL at 27 months. For those with local failure it was 1.6 ng.mL at 16 months and for all failures, 1.8 ng/mL at 13 months. Systematic prostate biopsies show that tumor clearance after radiotherapy may take up to 30 months. Histologic tumor clearance parallels the fall in serum PSA. Serum PSA nadirs earlier and at a higher value in patients destined to fail.

Wheel-well and cargo compartment temperatures of large aircraft in flight: implications for stowaways.

BACKGROUND: Desperate people sometimes risk journeys as stowaways in aircraft wheel-wells. Some of them survive, despite the risks of being crushed by retracting landing gear, falling when the gear deploys for landing, or experiencing severe hypoxia and hypobaria in-flight. This study evaluates the level of hypothermia to which stowaways in aircraft may be exposed. METHODS: Miniature dataloggers were used to record in-flight temperatures in aircraft wheel-wells and cargo compartments. Temperatures were measured for front and side wheel-wells (FW and SW, respectively) on 36 flights by C-130 aircraft (mean duration 3.3 h, mean cruise altitude 5588 m (18,333 ft)) and 11 flights by C-141 aircraft (6.7 h and 10,744 m (35,250 ft)). RESULTS: Mean minimum temperatures for the C-130 remained above freezing and averaged 5.1 degrees C for FW and 11.9 degrees C for SW. The higher, longer C-141 flights produced temperatures below freezing with mean minimum temperatures of -18.0 degrees C for FW and -12.4 degrees C for SW. In general, temperatures in wheel-wells remained about 20 degrees C above outside air temperature (OAT) at all altitudes. This increase reflects the fact that wheel-wells are closed spaces within the aircraft body, in addition to which they contain sources of heat such as hydraulic lines and electrical equipment. Cargo compartment minimum temperature was relatively high (mean = 18.6 degrees C for commercial airline). A search of the medical literature and lay press produced information on 46 incidents of people found in wheel-wells after landing where there was no evidence of trauma. The 15 survivors had stowed away on relatively short flights (mean = 4.8 h, maximum = 10 h) compared with fatalities (mean = 7.5 h, range = 3-12 h). CONCLUSIONS: Temperatures in wheel-wells during short flights may sustain life. Long flights add severe hypothermia to acute hypoxia and hypobaria as potentially fatal environmental factors faced by wheel-well stowaways.