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Objective: The study objective was to report early outcomes of integrating Hypotension Prediction Index–guided hemodynamic management within a cardiac enhanced recovery pathway on total initial ventilation hours and length of stay in the intensive care unit. Methods: A multicenter, historical control, observational analysis of implementation of a hemodynamic management tool within enhanced recovery pathways was conducted by identifying cardiac surgery cases from 3 sites during 2 time periods, August 1 to December 31, 2019 (preprogram), and April 1 to August 31, 2021 (program). Reoperations, emergency (salvage), or cases requiring mechanical assist were excluded. Data were extracted from electronic medical records and chart reviews. Two primary outcome variables were length of stay in the intensive care unit (using Society of Thoracic Surgeons definitions) and acute kidney injury (using modified Kidney Disease Improving Global Outcomes criteria). One secondary outcome variable, total initial ventilation hours, used Society of Thoracic Surgeons definitions. Differences in length of stay in the intensive care unit and total ventilation time were analyzed using Kruskal–Wallis and stepwise multiple linear regression. Acute kidney injury stage used chi-square and stepwise cumulative logistic regression. Results: A total of 1404 cases (795 preprogram; 609 program) were identified. Overall reductions of 6.8 and 4.4 hours in intensive care unit length of stay (P = .08) and ventilation time (P = .03) were found, respectively. No significant association between proportion of patients identified with acute kidney injury by stage and period was found. Conclusions: Adding artificial intelligence–guided hemodynamic management to cardiac enhanced recovery pathways resulted in associated reduced time in the intensive care unit for patients undergoing nonemergency cardiac surgery across institutions in a real-world setting.

Wildfires in forests globally have become more frequent and intense because of changes in climate and human management. Shrub layer fuels allow fire to spread vertically to forest canopy, creating high-intensity fires. Our research provides a deep-time perspective on shrub fuel loads in fire-prone southeastern Australia. Comparing 2833 records for vegetation cover, past climate, biomass burning, and human population size across different phases of human occupation, we demonstrated that Indigenous population expansion and cultural fire use resulted in a 50% reduction in shrub cover, from approximately 30% from the early to mid-Holocene (12 to 6 thousand years ago) to 15% during the late to mid-Holocene (6 to 1 thousand years ago). Since the start of British colonization to the present, shrub cover has increased to the highest ever recorded (mean of 35% land cover), increasing the risk of high-intensity fires.

This Data in Brief paper comprises dataset obtained for sediment cores collected from Lake Selina, located in the West Coast Range of Tasmania, Australia. Datasets include radiocarbon and optically stimulated luminescence age estimates, elemental composition, beryllium isotopes, magnetic properties and the paleomagnetic record measured on the cores assigned as TAS1402 (Location: Tasmania, Year: 2014, Site number: 02). The multi-proxy dataset was used to develop a chronostratigraphy for the 5.5 m and 270,000 year old record. See Lisé-Pronovost et al. (2021) (10.1016/j.quageo.2021.101152) for interpretation and discussion. The data presented in this study serve as an archive for future studies focusing on Earth system dynamics and the timeline and linkages of environmental changes across Tasmania, the Southern Hemisphere and at a global scale., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2022 The Author(s). Published by Elsevier Inc.)

The environmental crises currently gripping the Earth have been codified in a new proposed geological epoch: the Anthropocene. This epoch, according to the Anthropocene Working Group, began in the mid-20th century and reflects the "great acceleration" that began with industrialization in Europe [J. Zalasiewicz et al., Anthropocene 19, 55-60 (2017)]. Ironically, European ideals of protecting a pristine "wilderness," free from the damaging role of humans, is still often heralded as the antidote to this human-induced crisis [J. E. M. Watson et al., Nature , 563, 27-30 (2018)]. Despite decades of critical engagement by Indigenous and non-Indigenous observers, large international nongovernmental organizations, philanthropists, global institutions, and nation-states continue to uphold the notion of pristine landscapes as wilderness in conservation ideals and practices. In doing so, dominant global conservation policy and public perceptions still fail to recognize that Indigenous and local peoples have long valued, used, and shaped "high-value" biodiverse landscapes. Moreover, the exclusion of people from many of these places under the guise of wilderness protection has degraded their ecological condition and is hastening the demise of a number of highly valued systems. Rather than denying Indigenous and local peoples' agency, access rights, and knowledge in conserving their territories, we draw upon a series of case studies to argue that wilderness is an inappropriate and dehumanizing construct, and that Indigenous and community conservation areas must be legally recognized and supported to enable socially just, empowering, and sustainable conservation across scale., Competing Interests: The authors declare no competing interest.

Indigenous people play an integral role in shaping natural environments, and the disruption to Indigenous land management practices has profound effects on the biosphere. Here, we use pollen, charcoal and dendrochronological analyses to demonstrate that the Australian landscape at the time of British invasion in the 18th century was a heavily constructed one-the product of millennia of active maintenance by Aboriginal Australians. Focusing on the Surrey Hills, Tasmania, our results reveal how the removal of Indigenous burning regimes following British invasion instigated a process of ecological succession and the encroachment of cool temperate rainforest (i.e. later-stage vegetation communities) into grasslands of conservation significance. This research provides empirical evidence to challenge the long-standing portrayal of Indigenous Australians as low-impact 'hunter-gatherers' and highlights the relevance and critical value of Indigenous fire management in this era of heightened bushfire risk and biodiversity loss.

Mining causes extensive damage to aquatic ecosystems via acidification, heavy metal pollution, sediment loading, and Ca decline. Yet little is known about the effects of mining on freshwater systems in the Southern Hemisphere. A case in point is the region of western Tasmania, Australia, an area extensively mined in the 19th century, resulting in severe environmental contamination. In order to assess the impacts of mining on aquatic ecosystems in this region, we present a multiproxy investigation of the lacustrine sediments from Owen Tarn, Tasmania. This study includes a combination of radiometric dating ( 14 C and 210 Pb), sediment geochemistry (XRF and ICP-MS), pollen, charcoal and diatoms. Generalised additive mixed models were used to test if changes in the aquatic ecosystem can be explained by other covariates. Results from this record found four key impact phases: (1) Pre-mining, (2) Early mining, (3) Intense mining, and (4) Post-mining. Before mining, low heavy metal concentrations, slow sedimentation, low fire activity, and high biomass indicate pre-impact conditions. The aquatic environment at this time was oligotrophic and dystrophic with sufficient light availability, typical of western Tasmanian lakes during the Holocene. Prosperous mining resulted in increased burning, a decrease in landscape biomass and an increase in sedimentation resulting in decreased light availability of the aquatic environment. Extensive mining at Mount Lyell in the 1930s resulted in peak heavy metal pollutants (Pb, Cu and Co) and a further increase in inorganic inputs resulted in a disturbed low light lake environment (dominated by Hantzschia amphioxys and Pinnularia divergentissima). Following the closure of the Mount Lyell Co. in 1994 CE, Ca declined to below pre-mining levels resulting in a new diatom assemblage and deformed diatom valves. Therefore, the Owen Tarn record demonstrates severe sediment pollution and continued impacts of mining long after mining has stopped at Mt. Lyell Mining Co., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: There is a growing need to improve patient education for nonsurgical fracture care in children. A Quick Response (QR) code was used as an alternative method to provide cast care instructions in our outpatient fracture clinic. We evaluated satisfaction and examined the convenience and impact this might have on the child's casting experience., Methods: A prospective study was conducted in which QR codes were embedded in the casting of nonsurgical pediatric fractures in 88 children. The number of times the QR code was scanned, who scanned the code, treatment satisfaction, cast-related issues, and whether scan helped prevent a call to the treating physician were recorded., Results: Google Analytics showed the QR code was scanned an average of 1.6 times by 60 participants with most scans done by a parent (65%). Seventy-nine participants (89.9%) found it useful to have the QR code on their cast, and 65 (73.9%) were "very satisfied" with the convenience of the QR code and 37 stated that the information they found kept them from contacting the physician., Discussion: We demonstrated that the use of QR codes for nonsurgical pediatric fracture care has a high level of satisfaction and may reduce calls to the treating physician.

Purpose: Nitrate (NO3-), through its conversion to nitrite (NO2-) and nitric oxide, has been shown to increase exercise tolerance in healthy younger adults and older diseased patients. Nitrate's effect in well-trained middle to older-aged adults has not been studied. Therefore, the purpose of this investigation was to examine the effects of a NO3- rich beverage on submaximal constant work rate exercise time in well-trained middle to older-aged adults., Methods: This was a randomized controlled cross-over trial with 15 well-trained middle to older-aged adults, 41-64 year-old, who received one of two treatments (NO3- rich beverage then placebo or placebo then NO3- rich beverage), after which an exercise test at 75 percent of the subject's maximal work rate was completed., Results: The NO3- rich beverage increased plasma NO3- and NO2- levels by 260 μM and 0.47 μM, respectively (p<0.001). Exercise time was not significantly different (p = 0.31) between the NO3- rich versus placebo conditions (1130±151 vs 1060±132 sec, respectively). Changes in exercise time between the two conditions ranged from a 55% improvement to a 40% decrease with the NO3- rich beverage. Oxygen consumption and rating of perceived exertion were not significantly different between the two conditions., Conclusion: In middle to older-aged well-trained adults, NO3- supplementation has non-significant, albeit highly variable, effects on exercise tolerance. ClinicalTrials.gov Identifier: NCT03371966., Competing Interests: This work was supported by a grant from Isagenix International LLC, Gilbert, AZ awarded to MJB. MJB, GDM, DBK-S and SB received funding from Isagenix LLC to conduct the study. Contents of the manuscript are the sole responsibility of the authors. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The funding source had no involvement with the study design, data collection, data analysis and interpretation or the decision to submit this work for publication. The results of the study are presented clearly, honestly, and without fabrication, falsification or inappropriate data manipulation. Dr. Kim-Shapiro is co-inventor on a patent related to the use of nitrite for cardiovascular conditions, and owns stock in and serves on the scientific advisory board for Beverage Operations LLC, which has licensed Wake Forest University intellectual properties and thus has a financial interest in Beverage Operations LLC. None of the other authors have any financial, non-financial, professional or personal competing interests to declare.

Climate change is affecting the distribution of species and the functioning of ecosystems. For species that are slow growing and poorly dispersed, climate change can force a lag between the distributions of species and the geographic distributions of their climatic envelopes, exposing species to the risk of extinction. Climate also governs the resilience of species and ecosystems to disturbance, such as wildfire. Here we use species distribution modelling and palaeoecology to assess and test the impact of vegetation-climate disequilibrium on the resilience of an endangered fire-sensitive rainforest community to fires. First, we modelled the probability of occurrence of Athrotaxis spp. and Nothofagus gunnii rainforest in Tasmania (hereon "montane rainforest") as a function of climate. We then analysed three pollen and charcoal records spanning the last 7,500 cal year BP from within both high (n = 1) and low (n = 2) probability of occurrence areas. Our study indicates that climatic change between 3,000 and 4,000 cal year bp induced a disequilibrium between montane rainforests and climate that drove a loss of resilience of these communities. Current and future climate change are likely to shift the geographic distribution of the climatic envelopes of this plant community further, suggesting that current high-resilience locations will face a reduction in resilience. Coupled with the forecast of increasing fire activity in southern temperate regions, this heralds a significant threat to this and other slow growing, poorly dispersed and fire sensitive forest systems that are common in the southern mid to high latitudes., (© 2019 John Wiley & Sons Ltd.)

This study investigated metal contamination from historical mining in lakes in the Tasmanian Wilderness World Heritage Area (TWWHA) and surrounding region. The largest increase in sedimentation and metal contamination occurred ca. 1930 when open-cut mining commenced and new mining technology was introduced into the region. The geochemical signal of lake sediments changed from reflecting the underlying geology and lithology to that reflecting mining activities. The HYSPLIT air particle trajectory model explains metal distribution in the lakes, with those in the northwest region closest to the mines having the highest metal contamination. Lake metal concentrations since mining activities commenced are in the order: Owen Tarn > Basin Lake > Perched Lake > Lake Dove > Lake Dobson > Lake Cygnus, with Perched Lake and Lakes Dove, Dobson and Cygnus in the TWWHA. Metal contamination affected centres up to 130 km down-wind of mining sites. Enrichment factors (EF) for Pb, Cu, As and Cd are >1 for all lakes, with Owen Tarn and Basin Lake having very high EFs for Cu and Pb (98 and 91, respectively). Pb, Cu, As and Cd concentrations are above the Australia/New Zealand lower sediment guidelines, with Pb, Cu and As above the high guidelines in Owen Tarn and Basin Lake. This study demonstrated the legacy of metal contamination in the TWWHA by mining activities and the consequences of a lack of execution of environmental regulations by past governments in Tasmania., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma., Experimental Design: After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), beta 2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry., Results: The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and beta 2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P < or = 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P < 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P < 0.001) were independent prognostic markers for death from ovarian carcinoma., Conclusion: The negative effect of APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.

Background: Interleukin-8 (IL-8) is a proangiogenic cytokine that is overexpressed in many human cancers. We investigated the clinical and biologic significance of IL-8 in ovarian carcinoma using human samples and orthotopic mouse models., Methods: Tumor expression of IL-8 was assessed by immunohistochemistry among ovarian cancer patients (n = 102) with available clinical and survival data. We examined the effect of IL-8 gene silencing with small interfering RNAs incorporated into neutral liposomes (siRNA-DOPCs), alone and in combination with docetaxel, on in vivo tumor growth, angiogenesis (microvessel density), and tumor cell proliferation in mice (n = 10 per treatment group) bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) and taxane-resistant (SKOV3ip2.TR) ovarian tumors. All statistical tests were two-sided., Results: Of the 102 cancer specimens, 43 (42%) had high IL-8 expression and 59 (58%) had low or no IL-8 expression; high IL-8 expression was associated with advanced tumor stage (P = .019), high tumor grade (P = .031), and worse survival (median survival for patients with high vs low IL-8 expression: 1.62 vs 3.79 years; P < .001). Compared with empty liposomes, IL-8 siRNA-DOPC reduced the mean tumor weight by 32% (95% confidence interval [CI] = 14% to 50%; P = .03) and 52% (95% CI = 27% to 78%; P = .03) in the HeyA8 and SKOV3ip1 mouse models, respectively. In all three mouse models, treatment with IL-8 siRNA-DOPC plus the taxane docetaxel reduced tumor growth the most compared with empty liposomes (77% to 98% reduction in tumor growth; P < .01 for all). In the HeyA8 and SKOV3ip1 models, tumors from mice treated with IL-8 siRNA-DOPC alone had lower microvessel density than tumors from mice treated with empty liposomes (HeyA8: 34% lower, 95% CI = 32% to 36% lower [P = .002]; SKOV3ip1: 39% lower, 95% CI = 34% to 44% lower [P = .007]). Compared with empty liposomes, IL-8 siRNA-DOPC plus docetaxel reduced tumor cell proliferation by 35% (95% CI = 25% to 44%; P < .001) and 38% (95% CI = 28% to 48%; P < .001) in the HeyA8 and SKOV3ip1 models, respectively., Conclusions: Increased IL-8 expression is associated with poor clinical outcome in human ovarian carcinoma, and IL-8 gene silencing decreases tumor growth through antiangiogenic mechanisms.

Background: EphA2 is overexpressed in the majority of ovarian cancers and predicts poor clinical outcome. Based on EphA2's emerging role in angiogenesis, we hypothesized that tumors overexpressing EphA2 demonstrate greater microvessel density (MVD) and matrix metalloproteinase (MMP) expression., Methods: After Institutional Review Board (IRB) approval, 77 invasive epithelial ovarian tumors were analyzed for CD31, EphA2, MMP-2, MMP-9, and MT1-MMP expression., Results: The median age of the patients was 59 years (range, 34-83). EphA2 was overexpressed in 76% of tumors and was associated with advanced-stage disease (P < .001) and high-grade histology (P = .04). MVD was stratified into high (>12.7 vessels/high-power field [HPF]) versus low (

The EphA2 tyrosine kinase receptor is frequently overexpressed in ovarian cancer and this feature is predictive of poor clinical outcome. Preclinical investigation has also linked EphA2 with p53. In our present study, we examined EphA2 and p53 status (both expression and full-length mutation status) in 6 ovarian cell lines and 79 human ovarian cancers to determine potential associations. EphA2 was overexpressed in 80% of ovarian cancer cell lines and in 75% of clinical specimens. In particular, high levels of EphA2 occurred in 91% of tumors with p53 null mutations compared to 68% in tumors with wild-type or missense mutations (p=0.027). EphA2 expression did not relate to critical versus non-critical site missense p53 mutations or the location of mutations on specific p53 exons. We also demonstrated that while EphA2 and p53 can provide independent information regarding clinical status, the combination of EphA2 and p53 status can predict poor clinical outcome. In particular, the combination of EphA2 overexpression and p53 null status was associated with decreased overall patient survival and related to increased incidence of ascites and distant metastasis. Taken together, these data indicate a complex relationship between EphA2 and p53 that appears to regulate EphA2 expression and clinical outcome.

Objectives: To characterize the clinical characteristics, therapeutic options, and potential outcomes in patients diagnosed with malignant mixed mullerian tumor (MMMT) of the uterine cervix., Methods: Five women ranging in age from 25 to 66 (mean 49.6 years) were diagnosed with MMMT of the cervix and treated at the University of Iowa Hospitals and Clinics between 1986 and 2001. Data were retrospectively analyzed from available charts and pathological reports with particular attention to patient demographics, presenting symptoms, treatment, and follow-up., Results: Abnormal vaginal bleeding was a common presenting symptom in all but one patient, in whom an abnormal screening Pap smear was the primary reason for referral. FIGO disease staging at initial diagnosis included two patients with stage IB1 (ages 29 and 66 years), two patients with stage IB2 (ages 25 and 64 years), and one patient with stage IVB (age 64 years) MMMT of the cervix. Organ-confined, early stage lesions (stages IB1 and IB2) responded well to regimens of either surgery alone or surgery plus radiation therapy, with no evidence of recurrent disease at last follow-up 28, 35, 42, and 65 months later, respectively. The lone patient with advanced stage IVB disease, however, was unresponsive to both external beam radiation therapy and ifosfamide chemotherapy, and succumbed to disease within 5 months., Conclusions: Cervical MMMT is an uncommon disease, but long-term survival is possible in organ-confined early stage disease with primary therapy.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is activated by integrin clustering. There are limited data regarding the functional role of FAK in ovarian cancer migration and invasion. In the current study, FAK expression was evaluated in ovarian cell lines (nontransformed and cancer), 12 benign ovarian samples, and in 79 invasive epithelial ovarian cancers. All three ovarian cancer cell lines overexpressed FAK compared to the nontransformed cells. The dominant-negative construct called FAK-related nonkinase (FRNK) was introduced into two ovarian cancer cell lines (SKOV3 and 222). FRNK promoted FAK dephosphorylation without changing total FAK levels in these cell lines. Furthermore, FRNK decreased the in vitro invasive ability of ovarian cancer cells by 56 to 85% and decreased migration by 52 to 68%. FRNK-transfected cells also displayed poor cell spreading. Immunohistochemical analysis revealed that the surface epithelium from all benign ovarian samples had weak FAK expression. In contrast, 68% of invasive ovarian cancers overexpressed FAK. FAK overexpression was significantly associated with high tumor stage, high tumor grade, positive lymph nodes and presence of distant metastasis (all P values <0.05). FAK overexpression was also associated with shorter overall survival (P = 0.008). Multivariate analysis revealed that FAK overexpression and residual disease >1 cm were independent predictors of poor survival. These data indicate that FAK is overexpressed in most invasive ovarian cancers and plays a functionally significant role in ovarian cancer migration and invasion. Thus, FAK may be an important therapeutic target in ovarian carcinoma.

Purpose: EphA2 (epithelial cell kinase) is a transmembrane receptor tyrosine kinase that has been implicated in oncogenesis. There are no published data regarding the role of EphA2 in ovarian carcinoma, which is the focus of the present study., Experimental Design: Nontransformed (HIO-180) and ovarian cancer (EG, 222, SKOV3, and A2780-PAR) cell lines were evaluated for EphA2 by Western blot analysis. Five benign ovarian masses, 10 ovarian tumors of low malignant potential, and 79 invasive ovarian carcinomas were also evaluated for EphA2 expression by immunohistochemistry. All samples were scored in a blinded fashion. Univariate and multivariate analyses were used to determine significant associations between EphA2 expression and clinicopathological variables., Results: By Western blot analysis, EG, 222, and SKOV3 cell lines overexpressed EphA2, whereas A2780-PAR and HIO-180 had low to absent EphA2 expression. All of the benign tumors had low or absent EphA2 expression. Among the invasive ovarian carcinomas examined (mean age of patients was 59.2 years), 60 (75.9%) tumors overexpressed EphA2 and the other 19 tumors had negative or minimal EphA2 expression. There was no association of EphA2 overexpression with ascites, likelihood of nodal positivity, pathological subtype, and optimum surgical cytoreduction (residual tumor <1 cm). However, EphA2 overexpression was significantly associated with higher tumor grade (P = 0.02) and advanced stage of disease (P = 0.001). The median survival for patients with tumor EphA2 overexpression was significantly shorter (median, 3.1 years; P = 0.004); the median survival for patients with low or absent EphA2 tumor expression was at least 12 years and has not yet been reached. In multivariate analysis using the Cox proportional hazards model, only volume of residual disease (P < 0.04) and EphA2 overexpression (P < 0.01) were significant and independent predictors of survival., Conclusions: EphA2 overexpression is predictive of aggressive ovarian cancer behavior and may be an important therapeutic target.

Juvenile granulosa cell tumor (JGCT) of the ovary, if diagnosed at an early stage, has a favorable prognosis. Recurrences are uncommon but typically occur within the first year. The patient presented here was treated with a left oophorectomy after initial presentation. Tumor recurrence in the left adnexa, diagnosed 48 months later, was treated with cytoreductive surgery followed by chemotherapy; she remains disease free 19 months after this recurrence. Late recurrences of JGCT can occur and continued close surveillance is recommended.

Objective: We previously demonstrated that aggressive ovarian cancer cells are able to display in vitro vasculogenic mimicry, which is reflected by their ability to form vasculogenic-like networks in 3-dimensional cultures and to express vascular cell-associated markers. The goal of this study was to examine the functional role of specific matrix metalloproteinases in the formation of vasculogenic-like networks and extracellular matrix remodeling in vitro. We also investigated the clinical relevance of matrix metalloproteinase-2 and -9 and membrane type 1-matrix metalloproteinase in human ovarian cancers with evidence of tumor cell-lined vasculature., Study Design: Ovarian cancer cells (A2780-PAR, SKOV3, and EG) were seeded onto separate 3-dimensional cultures that contained either Matrigel or type I collagen, in the absence of endothelial cells or fibroblasts. These cultures were treated with either chemically modified tetracycline-3 (general matrix metalloproteinase inhibitor), recombinant tissue inhibitor of metalloproteinase-1 or -2, or function-blocking antibodies to matrix metalloproteinase-2 or -9 or membrane type 1-matrix metalloproteinase. In addition, 78 invasive epithelial ovarian cancers were evaluated for expression of matrix metalloproteinase-2 and -9 and membrane type 1-matrix metalloproteinase and correlated with various clinical parameters., Results: The aggressive ovarian cancer cells (SKOV3 and EG) were able to form in vitro vasculogenic-like networks and contract 3-dimensional collagen I gels, whereas the poorly aggressive A2780-PAR cell line did not. Chemically modified tetracycline-3 completely blocked the network formation. Blocking antibodies to matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase inhibited the formation of the vasculogenic-like networks and collagen gel contraction, but the antibody to matrix metalloproteinase-9 had no effect on network formation and minimal effect on gel contraction. Treatment of 3-dimensional cultures with tissue inhibitor of metalloproteinase-2 retarded the network formation and only small, partially developed structures were noted that did not form network connections. Tissue inhibitor of metalloproteinase-1 had no appreciable effect on the extent or efficiency of network formation. Human invasive ovarian cancers with evidence of tumor cell-lined vasculature were significantly more likely to have strong epithelial and stromal matrix metalloproteinase-2 and -9 and membrane type 1-matrix metalloproteinase expression (all probability values were <.05)., Conclusion: Matrix metalloproteinase-2 and membrane type 1-matrix metalloproteinase appear to play a key role in the development of vasculogenic-like networks and matrix remodeling by aggressive ovarian cancer cells. Human ovarian cancers with matrix metalloproteinase overexpression are more likely to have tumor cell-lined vasculature. These results may offer new insights for consideration in ovarian cancer treatment strategies.

Objective: To review the role of transarterial renal embolization in our unit, assessing the indications, tolerability and efficacy of this technique for treating renal cell carcinoma (RCC)., Patients and Methods: Thirty patients undergoing transarterial embolization between 1991 and 1999 were identified and 25 case notes analysed retrospectively., Results: Most patients (14 of 25) presented with less advanced (stage I-III) RCC who were unable or unwilling to undergo radical surgery; the remainder (11) presented with advanced (stage IV) disease. The embolizing agent was ethanol, usually combined with stainless steel coils (85% of cases). Procedural pain and fever was controlled successfully. The median hospital stay associated with the procedure was 4 days. At the time of analysis six of 11 stage IV and 11 of 14 stage I-III patients were alive (median follow-up 27 and 39 months, respectively). Symptoms from the primary tumour were well controlled. Overall, 17 of 25 (68%) of patients reported no problems while three (12%) required brief hospital admission for treatment of persistent haematuria. Fourteen patients were subsequently re-staged; the primary tumour in two had increased, in seven remained unchanged and in five it decreased. No patients without metastases developed them and metastases in two patients regressed., Conclusion: Transarterial embolization is associated with minimal morbidity and complications, and subsequent symptom control is good. The effect of palliative embolization on RCC progression is unknown and requires prospective investigation. Presently, there is no role for cytoreductive embolization; it should be included as a treatment option in clinical trials evaluating such options in patients with metastatic RCC.

Vasculogenic mimicry reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature; such has been demonstrated in aggressive ovarian carcinoma. This study measured the clinical significance of tumor cell-lined vasculature in ovarian carcinomas (n=77), which was detected in 23 (29.8%) tumors. The data show that tumor cell-lined vasculature was associated with aggressive tumor features and with shorter overall survival (p<0.001). Cox proportional hazards model revealed that tumor cell-lined vasculature (p=0.002) was independently associated with poor survival. This is the first study demonstrating the clinical implications of tumor cell-lined vasculature in ovarian carcinoma.

Maspin is a noninhibitory member of the serpin family that is down-regulated in breast carcinoma but overexpressed in pancreatic carcinoma. There are no published data regarding the role of maspin in ovarian carcinoma, which is the focus of the present study. Ovarian cell lines (normal and cancer) and tumors (80 invasive, 14 benign, and 10 low malignant potential) were evaluated for maspin expression and localization. Normal ovarian surface epithelial cells had low levels of maspin. Two of four ovarian cancer cell lines (OVCAR3 and SKOV3) expressed maspin, whereas the cell line EG had weak expression, and 222 had no detectable maspin. Subcellular fractionation studies revealed that the two maspin-positive ovarian cancer cell lines contained maspin in both the nuclear and cytosolic compartments. Wild-type maspin was transfected into the aggressive ovarian cancer cell lines SKOV3 and 222. The in vitro invasive activity of the maspin-transfected cell lines was 44-68% lower than respective controls. The histopathology analysis revealed that among the ovarian tumors examined, 57 (71%) were ranked positive for maspin. Thirty (37%) of the invasive tumors overexpressed maspin. Invasive cancers were more likely to have predominantly cytoplasmic staining compared with benign and low-malignant-potential tumors. Maspin overexpression was significantly associated with a high tumor grade (P = 0.004), the presence of ascites (P = 0.02), a lower likelihood of optimal surgical cytoreduction (P = 0.04), and a shorter duration of overall survival (median survival, 6.33 versus 2.67 years; P = 0.003). The Cox proportional hazards multivariate model revealed that maspin overexpression and high stage were independent predictors of survival. Thus, maspin was found to be overexpressed in a substantial proportion of ovarian tumors, which may serve as an adverse prognostic factor; however, its localization may provide new clues as to its activity and function. These paradoxical results may offer new insights regarding the role of maspin in ovarian cancer progression that may also impact diagnosis and treatment strategies.

During embryogenesis, the formation and remodeling of primary vascular networks occur by vasculogenesis and angiogenesis. Recently, the term "vasculogenic mimicry" was introduced by our laboratory and collaborators to reflect the embryonic-like ability of aggressive, but not nonaggressive, tumor cells to form a pattern of vasculogenic-like networks in three-dimensional culture, with concomitant expression of vascular-associated cell markers. We reviewed research on the ability of invasive ovarian carcinoma cells to engage in molecular vasculogenic mimicry reflected by their plasticity. In addition, we reviewed in vivo evidence regarding the presence of tumor cell-lined vasculature in aggressive ovarian carcinoma and other cancers, which may serve as the correlate to in vitro vasculogenic mimicry. These results may offer new insights and molecular markers for consideration in ovarian cancer diagnosis and treatment strategies based on molecular vascular mimicry by aggressive tumor cells.

Objective: To assess the 2-year symptomatic and urodynamic results of a prospective randomized trial of interstitial radiofrequency therapy of the prostate (IRFT) vs transurethral resection of the prostate (TURP)., Patients and Methods: Patients with lower urinary tract symptoms (LUTS) and urodynamic evidence of bladder outlet obstruction (BOO) were randomized to undergo IRFT or TURP and were followed up using the International Prostate Symptom Score (IPSS) and urodynamic assessment for 2 years., Results: At 2 years there was a clinically relevant reduction in the IPSS in the IRFT (20 to 9) and TURP groups (22 to 4). There was also a statistically significant reduction in the detrusor pressure at maximum urinary flow in both groups, but the reduction in the IRFT group was probably not sufficient to explain the observed symptomatic improvements solely from a reduction in BOO., Conclusion: IRFT can produce a sustained improvement in LUTS for at least 2 years. However, such improvements are unlikely to be entirely the result of a reduction in BOO. The effects of radiofrequency energy may, at least partly, be independent of any thermal effect and depend instead on neuromodulation of lower urinary tract nerves.

A 47-year-old man presented to the otolaryngologist with a 7-year history of a mass of the cheek. Fine-needle aspiration revealed foci of spindled cells admixed with abundant fat and myxoid material. A diagnosis of spindle cell lipoma was rendered on the resected specimen. The cytologic findings of spindle cell lipoma of the parotid gland as seen by fine-needle aspiration are presented along with the histologic correlates.

During development, the formation and remodeling of primary vascular networks occurs by vasculogenesis and angiogenesis. Recently, the term "vasculogenic mimicry" has been used by our laboratory and collaborators to reflect the embryonic-like ability of aggressive, but not nonaggressive, melanoma tumor cells to form a pattern of matrix-rich networks (containing channels) surrounding spheroids of tumor cells in three-dimensional culture, concomitant with their expression of vascular cell markers. Ovarian cancer is usually diagnosed as advanced stage disease in most patients when widespread metastases have already been established within the peritoneal cavity. In this study, we explored whether invasive ovarian carcinoma cells could engage in molecular vasculogenic mimicry reflected by their plasticity, compared with their normal cell counterparts. The data revealed that the invasive ovarian cancer cells, but not normal ovarian surface epithelial cells, formed patterned networks containing solid and hollow matrix channels when grown in three-dimensional cultures containing Matrigel or type I collagen, in the absence of endothelial cells or fibroblasts. Immunohistochemical analysis showed that matrix metalloproteinases (MMP)-1, -2, and -9, and MT1-MMP were discretely localized to these networks, and the formation of the networks was inhibited by treatment with MMP inhibitors. Furthermore, the RNase protection assay revealed the expression of multiple vascular cell-associated markers by the invasive ovarian cancer cells. In patient tumor sections from high-stage, high-grade ovarian cancers, 7 to 10% of channels containing red blood cells were lined by tumor cells. By comparison, all vascular areas in benign tumors and low-stage cancers were endothelial lined. These results may offer new insights and molecular markers for consideration in ovarian cancer diagnosis and treatment strategies based on molecular vascular mimicry by aggressive tumor cells.

Objective: To assess the safety and effectiveness of transurethral resection of the prostate (TURP) in patients over 80 years old., Patients and Methods: The records of all patients over 80 years old undergoing TURP at one institution over a 3.5-year period were studied retrospectively., Results: 31% of patients underwent TURP for symptoms and 68% for urinary retention. The early complication rate was 41%. The late complication rate was 22%. There were no deaths within 30 days of surgery. Of all patients, 80% were satisfied with the outcome of their operation. Of all patients with retention, 80% were able to void with small residual volumes by 6 weeks after operation., Conclusions: Although TURP in the over 80-year-old male is associated with significant morbidity, it is an effective treatment for urinary symptoms or retention. The majority of patients are able to void afterwards and are satisfied with the outcome of their surgery.

Objective: To evaluate the accuracy and use of fine-needle aspiration (FNA) cytology for the diagnosis of renal masses because with the improved quality and increasing use of ultrasonography and computed tomography (CT), asymptomatic renal masses, particularly small (< 5 cm) tumours, are being discovered more frequently., Patients and Methods: Between 1995 and 1997, 49 patients (mean age 67.5 years, range 42-88, 34 men and 14 women) underwent FNA of a solid or complex cystic mass under radiological guidance. All masses were further evaluated and staged by CT. Solid masses were divided according to size (< 5 cm and >/= 5 cm). Patients were followed up to the determination of a final diagnosis on tissue histology, after nephrectomy where possible., Results: Thirty-six patients had histologically confirmed carcinoma at nephrectomy, and nine had presumed carcinoma (four unfit for surgery, five with advanced malignancy). The remaining four patients had benign diagnoses. FNA produced insufficient sample in eight cases (16%). The sensitivity was 89% for large (>/= 5 cm) solid masses, 64% for small (< 5 cm) solid masses and 50% for complex cysts., Conclusion: FNA does not contribute to the diagnosis of malignancy in large (> 5 cm) masses, as good radiological imaging is nearly always diagnostic. For smaller (< 5 cm) masses and complex cysts, FNA can occasionally confirm malignancy, but lack of diagnostic yield and low sensitivity means that FNA is unreliable as a diagnostic tool and will rarely help in the routine management of these patients.

We report the case of a woman who presented with obstruction and urosepsis of her left kidney secondary to small cystine calculi. The calculi could not be seen on initial plain abdominal X-ray. However, following percutaneous nephrostogram the calculi became more radio-dense and visible on later X-rays. Experimental enhancement of calculi has been described before but not in man. We presume that the contrast medium was adsorbed by the calculus to increase the radio-density. Further investigation of this phenomenon could prove useful in the management of complex radiolucent calculi.

Objective: To validate a new urodynamic technique to assess detrusor function in patients presenting with acute urinary retention, using the balloon channel of their Foley catheter (transballoon cystometry), and to use the technique to assess patients presenting in acute retention., Patients and Methods: The technique of transballoon cystometry is described and validated in vitro using a specially constructed water manometer, and in vivo on five patients who had a suprapubic catheter in addition to the urethral Foley catheter. Fifty-two patients presenting in acute retention underwent transballoon cystometry one week after catheterization; they were divided according to their clinical presentation into uncomplicated acute retention (41 patients) and acute-on-chronic retention (11 patients). The results from transballoon cystometry were compared between these groups., Results: The pressure recorded through the balloon channel was equal to that recorded through the lumen of the catheter, both in vitro and in vivo. Patients with acute-on-chronic retention had a larger volume at first sensation, a larger maximum cystometric capacity, higher end-filling pressure and lower maximum detrusor pressure during isometric contraction than patients in uncomplicated retention., Conclusion: Transballoon cystometry is accurate and easy to perform. The clinical distinction between uncomplicated acute retention and acute-on-chronic retention was supported by the urodynamic data. This test could be used before surgery to identify patients with detrusor failure.

Objective: To evaluate in a prospective study the efficacy of interstitial radiofrequency therapy (IRFT) of the prostate in relieving acute urinary retention in patients with benign prostatic hyperplasia., Patients and Methods: Twenty-seven patients presenting in acute urinary retention who failed at least one trial of voiding one week after presentation were treated with IRFT of the prostate. During the 6-month follow-up, the International Prostate Symptom Score (IPSS), urinary flow rate, post-void residual volume (PVR) and serum creatinine were determined and changes in erectile and ejaculatory functions recorded. The treatment was considered successful if the patient resumed normal voiding, without compromising renal function and without troublesome lower urinary tract symptoms necessitating further treatment., Results: Of the 26 evaluable patients, 77% resumed normal voiding. At 6 months after treatment, the mean (SD) IPSS had decreased from 15.0 (8.3) to 8 (5.4), the PVR from 950 (203) to 88 (60) mL and the maximum flow rate was 10.5 (4.36) mL/s., Conclusion: IRFT of the prostate is a safe and effective treatment, at least in the short-term, for relieving acute urinary retention in patients with benign prostatic hyperplasia. The longer term follow-up is continuing.

Objective: To carry out a prospective randomized trial comparing interstitial radiofrequency therapy (IRFT) with transurethral resection of the prostate (TURP) in the treatment of bladder outlet obstruction (BOO) caused by benign prostatic hyperplasia., Patients and Methods: The change in detrusor pressure at maximum flow (PdetQmax) was chosen as the primary measure of outcome but the symptom score, Qmax and residual volume were also measured. Patients with urodynamic evidence of BOO were randomized to receive IRFT (n = 25) or TURP (n = 25); the urodynamics were repeated 6 months after treatment., Results: There was a statistically significant reduction in PdetQmax at 6 months for TURP (P < 0.001) and IRFT (P < 0.01) although the change seen in the latter group was probably not clinically relevant. Nevertheless, a clinically relevant reduction in symptom score occurred in both groups. Both techniques were associated with a low morbidity., Conclusion: IRFT is a cheap and safe technique which may be useful in the treatment of lower urinary tract symptoms in certain groups of patients in whom symptomatic improvement is a priority rather than objective outcome. The underlying mechanism for this symptomatic improvement is at present unclear.

Background: The concept of estrogen withdrawal by an aromatase inhibitor in the treatment of benign prostatic hyperplasia (BPH) was assessed in a prospective, randomized, double-blind, placebo-controlled multicenter trial., Methods: Two hundred and ninety-two patients with clinical symptoms of BPH were randomly allocated to one of the following treatments for 48 weeks: placebo or the selective aromatase inhibitor, atamestane, at a daily dose of 100 mg or 300 mg. Both doses of atamestane significantly reduced serum concentrations of estradiol and estrone, and produced a slight, dose-dependent, counter-regulatory increase in peripheral androgen concentration., Results: Clinical symptoms improved during treatment in all three groups. Even after 48 weeks, the effect of active treatment did not exceed the effect seen with placebo. Overall tolerance of 100 mg atamestane was excellent, but 300 mg showed a slightly increased incidence of side effects compared with placebo., Conclusions: The conclusion from this study is that the reduction in estrogen concentration using the selective aromatase inhibitor atamestane has no effect on clinically established BPH.

Purpose: We assessed the feasibility of using interstitial radiofrequency therapy for benign prostatic hyperplasia (BPH) in 50 patients., Materials and Methods: Therapy was given using a standard diathermy unit as the radiofrequency generator and a disposable needle electrode. The main outcome measure was improvement in symptoms assessed by symptom scores., Results: Patients with bothersome symptoms or acute retention showed clinically significant improvements in symptom score, while those with chronic retention did not. There were no serious complications., Conclusions: Interstitial radiofrequency therapy may be effective for symptomatic BPH. Further studies with long-term objective data are under way to assess its role in the management of BPH.

Objective: To compare the analgesic efficacy of a single 30 mg intramuscular dose of ketorolac with that of intramuscular pethidine 100 mg, in a double-blind, parallel-group investigation of patients presenting with pain suggestive of renal colic., Patients and Methods: Seventy-six patients (17 women, 15 men; mean age 45.2 years, range 20-80) were allocated by means of a pre-determined randomization schedule to receive ketorolac and 78 patients (20 women, 58 men; mean age 42.1, years range 18-70) to receive pethidine. Data from eight patients in the ketorolac group and six in the pethidine group were excluded from the efficacy analyses because of protocol violations. The severity of each patient's pain was assessed on a four-point verbal rating scale (VRS) and a 10 cm visual analogue scale at pre-dose and at 15 min intervals for the first hour post dosing. The time to first administration of rescue analgesic, up to 24 h following dosing with the study medication, was recorded. Adverse events were elicited by general questioning., Results: Eighty-eight per cent of patients in each treatment group had improved according to the VRS of pain severity 1 h after dosing; the summed pain intensity differences up to 1 h were statistically significantly different in favour of ketorolac (P < 0.05). Fifty-six per cent of patients who were receiving ketorolac required rescue analgesia during the study period compared with 74% receiving pethidine. The incidences of adverse events were lower in the ketorolac group (28%) than the pethidine group (51%)., Conclusion: Ketorolac can be considered a viable alternative to pethidine for the treatment of renal colic.