Metals in urban soils of Europe: A systematic review.

Metal contamination of soils is widespread across Europe and is of great concern as it may impact food production, the supply of drinking water and human health (European Environment Agency, 2014; Panagos et al., 2013). Most research to date on soil metal contamination has focussed on agricultural soils (Tóth et al., 2016a). Current knowledge of the extent of urban soil metal contamination in Europe, however, is limited, especially for soils in recreational areas, which is particularly concerning as these areas may have a high footfall. Here, we conducted a systematic analysis of metal contamination in European urban soils based on 174 peer-reviewed studies spanning 143 urban sites and 29 European countries. The results show that reporting of data on urban soil metals is highly heterogeneous across the study area. Over half of all studies are from only five countries (Italy, Spain, UK, Poland and Serbia) and no data are available for 14 other European countries. The metals that most commonly exceed national safety thresholds are Pb, Zn, Cu, Cr and Ni. Elevated levels of these metals are usually attributed to anthropogenic sources, primarily traffic and industry. Some 22 % of urban sites studied show anthropogenic enrichment; this phenomenon is most common in Italy, Serbia and Finland. In contrast, 44 % of urban sites studied show geogenic metal enrichment; this is most common in Italy, the UK and Serbia. The dataset is subject to a sample size bias, whereby soil metal enrichment is identified more frequently in regions with more data. Future studies should focus on key knowledge gaps, such as urban soils in locations with current or historical heavy industrialisation and locations in central and eastern Europe. Study methods should be standardised to facilitate comparison of soil metal data from different studies and European safety thresholds should be identified for key elements.

Radical Resection in Entero-Pancreatic Neuroendocrine Tumors: Recurrence-Free Survival Rate and Definition of a Risk Score for Recurrence.

BACKGROUND: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date. OBJECTIVE: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence. PATIENTS AND METHODS: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model. RESULTS: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01). CONCLUSIONS: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs.

Decoding the Evolution of Melanin in Vertebrates.

Melanins are widespread pigments in vertebrates, with important roles in visual signaling, UV protection, and homeostasis. Fossil evidence of melanin and melanin-bearing organelles - melanosomes - in ancient vertebrates may illuminate the evolution of melanin and its functions, but macroevolutionary trends are poorly resolved. Here, we integrate fossil data with current understanding of melanin function, biochemistry, and genetics. Mapping key genes onto phenotypic attributes of fossil vertebrates identifies potential genomic controls on melanin evolution. Taxonomic trends in the anatomical location, geometry, and chemistry of vertebrate melanosomes are linked to the evolution of endothermy. These shifts in melanin biology suggest fundamental links between melanization and vertebrate ecology. Tissue-specific and taxonomic trends in melanin chemistry support evidence for evolutionary tradeoffs between function and cytotoxicity.

Outcomes in patients ≥ 80 years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy.

Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80 years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan-Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80 years. Of patients < 80 and ≥ 80 years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80 years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients ≥ 80 years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80 years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80 years. Of patients ≥ 80 years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07 months (95% CI 8.89-11.08) and 10.10 months (95% CI 6.30-12.30) in patients < 80 and ≥ 80 years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.

Trade-off between pulse rate and radiation dose during modified barium swallow examination: what is the reality?

AIM: To evaluate the effect of modification of dose mode and frame rate on patient radiation dose during modified barium swallow (MBS) examinations. MATERIALS AND METHODS: A retrospective review was undertaken of consecutive MBS examinations performed over 6 months in the inpatient setting. Patients were divided into two cohorts: pre-implementation of the MBS Impairment Profile (MBSImP; low rate, normal dose) and post-implementation (high rate, low dose). Prior to implementation, pulse rate and dose testing were performed on multiple phantoms. RESULTS: Four hundred and forty-nine patients were included in the pre-implementation cohort and 378 in the post-implementation cohort. Phantom dose testing demonstrated no significant difference in dose on either phantom between low rate/normal dose and high rate/low dose modes. Prior to MBS standardisation, the mean radiation dose was 5.86 (±4.35) mGy. Following standardisation, the mean radiation dose was 4.72 (±3.77) mGy (p<0.0001). The mean fluoroscopy time for MBS prior to standardisation was 83.8 (±44.4) seconds and the mean fluoroscopy time for MBS after standardisation was 82.3 (±39.8) seconds (p=0.62). The dose rate for MBS prior to standardisation was 4.35 (±2.42) and the dose rate for MBS after standardisation was 3.55 (±2.41) mGy/s (p<0.0001). CONCLUSION: Adjustments made to lower the dose mode and the increase in fluoroscopy frame rate decreased the patient radiation dose and did not increase fluoroscopy time.

Urgent need for consensus: international survey of clinical practice exploring use of platinum-etoposide chemotherapy for advanced extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC).

BACKGROUND: Platinum-etoposide (PE) chemotherapy (CH) is a globally established combination for extra-pulmonary high grade neuroendocrine carcinoma (EP-G3-NEC); the optimal schedule has not been established. METHODS: An international survey was designed, and completed by clinicians with an expertise in the field to assess consistency in clinical practice. RESULTS: Seventy-five replies were received (June-Nov'17). A minority of physicians (13; 17.6%) did not take Ki-67 or morphology (9; 12.0%) into consideration for selection of CH. Most (72; 96.0%) selected PE-CH as first-line treatment for EP-G3-NEC. CH schedules varied: cisplatin-based (37/71; 52.1%), carboplatin-based (34/71; 47.9%); intravenous etoposide (64/71; 90.1%), oral etoposide (7/71; 9.9%). Choice of second-line CH depended on time to progression on PE-based first-line: if > 6 months, re-challenge with PE was the preferred choice (34; 45.9%); if < 6 months, alternative combinations such as fluoropyrimidine/irinotecan (21; 29.2%) or temozolomide/capecitabine (22; 30.6%) were used. CONCLUSION: Significant variation in PE regimen employed exists. Standardising clinical practice would facilitate clinical trial development.

Diffusion-weighted MRI as a screening tool for hepatocellular carcinoma in cirrhotic livers: correlation with explant data-a pilot study.

OBJECTIVE: The purpose of this study was to compare the sensitivity and specificity of diffusion-weighted liver MRI alone with complete, multiphasic gadoteridol-enhanced MRI for the detection of hepatocellular carcinoma in cirrhotic patients before liver transplant. MATERIALS AND METHODS: This single institution retrospective study was performed after IRB approval and was HIPAA compliant. MRI scans of 37 patients who underwent liver transplant were evaluated and findings correlated with liver explant (36) or biopsy (1). All MRI scans were obtained within six months of explant. MRI from 17 patients with liver lesions by report at imaging subsequently proven to be HCC at pathology and 20 controls without liver lesions by imaging and pathology were reviewed in random order on the radiology PACS by three independent readers blinded to the MRI reports and pathology reports in two separate sittings. First, only the diffusion-weighted images (DWI) were interpreted. Second, the complete multiphasic MRI exam with DWI was reviewed. A consensus read was obtained by two separate radiologists who had access to the patients' explant data in order to map lesions. Reader-specific and pooled classification was assessed using sensitivity, specificity, positive predictive value, and negative predictive values and corresponding 95% confidence intervals (CI) for both DWI and complete MRI examination readings compared to pathology. McNemar's test and Kappa coefficient were used to assess differences (agreement) in DWI and complete examination readings. RESULTS: A total of 37 patients have been studied (25M 12F age range 21-70). Averaged results of the three independent readers demonstrated a sensitivity of 78% (95% CI 65-89%) and specificity of 88% (95% CI 77-95%) for DWI alone for detection of liver lesions, with a positive predictive value of 85% (95% CI 72-94%) and a negative predictive value of 83% (95% CI 71-91%). Review of the complete MRI exam showed a sensitivity of 90% (95% CI 76-97%) and a specificity of 82% (95% CI 66-92%) with a positive predictive value of 83% (95% CI 69-93%) and a negative predictive value of 89% (95% CI 74-97%). McNemar's agreement test revealed no significant difference between the DWI and complete multiphasic interpretations (p = 0.3458), with simple Kappa coefficient of 0.6716 (95% CI 0.5332-0.8110). Lesions identified on DWI ranged in size from 1.5 to 5 cm. Detection of lesions was decreased in the presence of artifact from motion, large ascites, and technical issues. CONCLUSION: Diffusion-weighted MRI has NPV and PPV comparable to complete multiphasic MRI examination for liver lesion detection in cirrhotic patients and may have a role in screening.

Identification of clinical biomarkers for patients with advanced hepatocellular carcinoma receiving sorafenib.

BACKGROUND: Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers. METHODS: Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively. RESULTS: Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8-5.2) and 6.5 (95 % CI 4.9-8.01) months, respectively. Child-Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5-12.4) compared with 4.1 (95 % CI 2.7-5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2-0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006). CONCLUSION(S): The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.

Prognostic factors for disease relapse in patients with neuroendocrine tumours who underwent curative surgery.

AIM: Surgery is the only modality of cure in patients diagnosed with neuroendocrine tumours (NETs). The aim of this study was to identify prognostic factors associated with disease relapse in patients with NETs treated by potentially-curative surgery. METHODS: Sequential patients registered in The Christie European NET Society (ENETS) Centre of Excellence, with grade (G)1 or G2 NETs who had undergone curative surgery (February 2002-June 2014) were included. Investigated prognostic factors for relapse were: age, gender, TNM stage, tumour-localisation, functionality, genetic predisposition, presence of multiple NETs, second malignancy, grade (Ki-67-based), presence of vascular and/or perineural invasion, necrosis, surgical margin (R0/R1), Eastern Cooperative Oncology Group performance status and Adult Comorbidity Evaluation co-morbidity score. RESULTS: One hundred and eighty-eight patients were identified [median age of 60 years (range 16-89)]. With a median follow-up of 2.6 years, 43 relapses occurred. The estimated median relapse-free survival (RFS) for the entire cohort was 8.0 years (95% confidence interval [CI] 5.9-10.0 years). In univariate analysis, primary NET location (p = 0.01), ENETS T-(HR-1.4; 95%-CI 1.0-2.0, p = 0.026), N-(HR-2.0, 95%-CI 1.1-3.9, p = 0.026) and M-stage (HR-2.6, 95%-CI 1.1-6.3, p = 0.052), grade (Ki-67%-based) (HR-2.5; 95%-CI 1.4-4.7; p = 0.003) and perineural invasion (HR-2.1; 95%-CI 1.1-3.9; p = 0.029) were prognostic for relapse. Factors remaining significant after multivariable analysis were tumour size (HR-1.67; 95%-CI 1.04-2.70; p = 0.03), nodal involvement (HR-2.61; 95%-CI 1.17-5.83; p = 0.013) and Ki-67 at the time of diagnosis (HR-1.93; 95%-CI 1.24-3.0; p = 0.002). CONCLUSION: Size of tumour, lymph node involvement and Ki-67 were independent prognostic factors for relapse after potentially curative surgery in NET.

Prognostic factors for progression-free and overall survival in advanced biliary tract cancer.

BACKGROUND: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease. METHODS: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset. RESULTS: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]. CONCLUSION: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers.

Using the Neptune project to benefit Australian aquatic animal health research.

Diseases of aquatic animals have had, and continue to have, a significant impact on aquatic animal health. In Australia, where fisheries and aquaculture are important industries, aquatic species have been subject to serious disease outbreaks, including pilchard herpesvirus, the cause of one of the largest wild fish kills ever recorded. At the same time, there is a consensus that Australia's parasite fauna are largely unknown, and that aquatic animal health information is difficult to access. Managing aquatic animal diseases is challenging because they may be entirely new, their hosts may be new to aquaculture, and specialist expertise and basic diagnostic tools may be lacking or absent. The Neptune project was created in response to these challenges, and it aims to increase awareness of aquatic animal diseases, improve disease management, and promote communication between aquatic animal health professionals in Australia. The project consists of an online database, a digital microscopy platform containing a whole-slide image library, a community space, and online communications technology. The database contains aquatic animal health information from published papers, government reports, and other sources, while the library contains slides of key diseases both endemic and exotic to Australia. These assets make Neptune a powerful resource for researchers, students, and biosecurity officials.

Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer.

BACKGROUND: Biliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis. PATIENTS AND METHODS: Baseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model. RESULTS: Eight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ⩽ 2. A NLR ⩾ 3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ⩾ 3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ⩾ 3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06-1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR-1.26, 95% CI; 1.02-1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR-1.70, 95% CI; 1.10-2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04-2.44, P = 0.048). CONCLUSION: Baseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials.

The role of disease severity in influencing body mass index in people with haemophilia: a single-institutional cross-sectional study.

The aim of this study was to evaluate the effect of haemophilia disease severity and potential intermediaries on body mass index (BMI) in patients with haemophilia. A secondary analysis of a cross-sectional study of 88 adults with haemophilia was undertaken. On bivariate analysis, persons with severe haemophilia had 9.8% lower BMI (95% CI -17.1, -3.0) than persons with non-severe haemophilia. The effect of haemophilia severity on BMI varied significantly by human immunodeficiency virus (HIV) status. Among HIV-positive subjects, haemophilia severity was not associated with BMI (+5.0%, 95% CI -22.4, 41.9). Among HIV-negative subjects, severe haemophilia was associated with 15.1% lower BMI (95% CI, -23.6, -5.7). Older (>41 years) HIV-negative subjects with severe haemophilia had a BMI that was 24.8% lower (95% CI -39.1, -7.0) than those with non-severe haemophilia. No statistically significant association was detected between BMI and severe vs. non-severe haemophilia for younger HIV-negative subjects. Although joint disease, as measured by the World Federation of Hemophilia (WFH) joint score, did not influence the association between haemophilia disease severity and BMI, adjustment for the atrophy component of the WFH score reduced the association between haemophilia severity and BMI by 39.1-69.9%. This suggested that muscle atrophy mediated at least part of the relationship between haemophilia severity and BMI. Haemophilia disease severity is associated with BMI and appears to be mediated by muscle atrophy of surrounding joints. This association appears to be modified by HIV status and possibly age.

Evidence for extensive cryptic speciation in trematodes of butterflyfishes (Chaetodontidae) of the tropical Indo-West Pacific.

Molecular data from the cytochrome c oxidase subunit I (cox1) mitochondrial DNA gene and the second internal transcribed spacer (ITS2) nuclear rDNA region were used to test the current morphologically-based taxonomic hypothesis regarding species of Monorchiidae (Hurleytrematoides) from chaetodontid and tetraodontid fishes from six sites in the tropical Indo-West Pacific (TIWP): Heron and Lizard Islands off the Great Barrier Reef (GBR, Australia), Moorea (French Polynesia), New Caledonia, Ningaloo Reef (Australia) and Palau. The 16 morphospecies analysed differed from each other by a minimum of 55bp (9.1%) over the mitochondrial cox1 and 8bp (1.6%) over the ITS2 DNA regions. For two species, Hurleytrematoides loi and Hurleytrematoides sasali, specimens from the same host species in sympatry differed at levels comparable to those between pairs of distinct morphospecies for both cox1 and ITS2 sequences. We take this as evidence of the presence of combinations of cryptic species; however, we do not propose new species for these taxa because we lack identified morphological voucher specimens. For seven species, Hurleytrematoides coronatum, Hurleytrematoides deblocki, Hurleytrematoides faliexae, H. loi, Hurleytrematoides morandi, H. sasali and Hurleytrematoides sp. A, samples from some combinations of localities had base pair differences that were equal to or greater than differences between some pairs of distinct morphospecies for one or both cox1 and ITS2 sequences. For three species, H. coronatum, H. loi and H. morandi, one haplotype differed from every other haplotype by more than the morphospecies benchmark. In these cases morphological specimens could not be distinguished by morphology. These data suggest extensive cryptic richness in this genus. For the present we refrain from dividing any of the morphospecies. This is because there is a continuum of levels of intra- and interspecific genetic variation in this system, so that distinguishing the two would be largely arbitrary.

Coarse particulate matter and airborne endotoxin within wood stove homes.

Emissions from indoor biomass burning are a major public health concern in developing areas of the world. Less is known about indoor air quality, particularly airborne endotoxin, in homes burning biomass fuel in residential wood stoves in higher income countries. A filter-based sampler was used to evaluate wintertime indoor coarse particulate matter (PM10₋2.5) and airborne endotoxin (EU/m³, EU/mg) concentrations in 50 homes using wood stoves as their primary source of heat in western Montana. We investigated number of residents, number of pets, dampness (humidity), and frequency of wood stove usage as potential predictors of indoor airborne endotoxin concentrations. Two 48-h sampling events per home revealed a mean winter PM10₋2.5 concentration (± s.d.) of 12.9 (± 8.6) µg/m³, while PM2.5 concentrations averaged 32.3 (± 32.6) µg/m³. Endotoxin concentrations measured from PM10₋2.5 filter samples were 9.2 (± 12.4) EU/m³ and 1010 (± 1524) EU/mg. PM10₋2.5 and PM2.5 were significantly correlated in wood stove homes (r = 0.36, P < 0.05). The presence of pets in the homes was associated with PM10₋2.5 but not with endotoxin concentrations. Importantly, none of the other measured home characteristics was a strong predictor of airborne endotoxin, including frequency of residential wood stove usage.

A phase I/II prospective, single arm trial of gefitinib, trastuzumab, and docetaxel in patients with stage IV HER-2 positive metastatic breast cancer.

Inhibition of the HER-2 pathway via the monoclonal antibody trastuzumab has had a major impact in treatment of HER-2 positive breast cancer, but de novo or acquired resistance may reduce its effectiveness. The known interplay between the epidermal growth factor receptor (EGFR) and HER-2 receptors and pathways creates a rationale for combined anti-EGFR and anti-HER-2 therapy in HER-2 positive metastatic breast cancer (MBC), and toxicities associated with the use of multiple chemotherapeutic agents together with biological therapies may also be reduced. We conducted a prospective, single arm, phase I/II trial to determine the efficacy and toxicity of the combination of trastuzumab with the EGFR inhibitor gefitinib and docetaxel, in patients with HER-2 positive MBC. The maximum tolerated dose (MTD) was determined in the phase I portion. The primary end point of the phase II portion was progression-free survival (PFS). Immunohistochemical analysis of biomarker expression of the PKA-related proteins cAMP response element-binding protein (CREB), phospho-CREB and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) plus t-DARPP (the truncated isoform of DARPP-32); PTEN; p-p70 S6K; and EGFR was conducted on tissue from metastatic sites. Nine patients were treated in the phase I portion of the study and 22 in the phase II portion. The MTD was gefitinib 250 mg on days 2-14, trastuzumab 6 mg/kg, and docetaxel 60 mg/m(2) every 21 days. For the 29 patients treated at the MTD, median PFS was 12.7 months, with complete and partial response rates of 18 and 46%, and a stable disease rate of 29%. No statistically significant correlation was found between response and expression of any biomarkers. We conclude that the combination of gefitinib, trastuzumab, and docetaxel is feasible and effective. Expression of the biomarkers examined did not predict outcome in this sample of HER-2 overexpressing metastatic breast cancer.

Monorchiids (Platyhelminthes: Digenea) of chaetodontid fishes (Perciformes): biogeographical patterns in the tropical Indo-West Pacific.

Species richness and biogeography of the monorchiid genus Hurleytrematoides was studied by the examination of 2834 individuals of 45 species of Chaetodontidae at six major sites in the tropical Indo-West Pacific: Heron Island, Lizard Island, Ningaloo (Western Australia), Palau, New Caledonia and Moorea (French Polynesia). In total, 18 species were distributed among six sites; descriptions are provided for eight new species: H. boucheti n. sp., H. combesi n. sp., H. deblocki n. sp., H. dollfusi n. sp., H. euzeti n. sp., H. kulbickii n. sp., H. pasteuri n. sp., and H. planesi n. sp. Overall richness ranged from zero to five Hurleytrematoides species per chaetodontid species. Seven Hurleytrematoides species were found at only one locality and eleven were found at multiple localities. Only one species, H. morandi, was found at all localities. Individual localities had between six (Moorea) and 10 (Heron Island) species; we attribute Moorea's depauperate parasite fauna to its isolation and distance from the Indo-Philippine centre of biological diversity. Using cluster analysis of 18 species of Hurleytrematoides and 45 species of chaetodontids sampled in the Indo-West Pacific, we show that the localities on the Great Barrier Reef (Heron Island and Lizard Island) and New Caledonia have the most similar chaetodontid and parasite fauna of any locality pairs. Cluster analysis results also show that the similarity of the chaetodontid assemblages at five of the six localities is relatively high and that Ningaloo has the most distinct fauna. Similarity values based on sharing of species of Hurleytrematoides are generally lower than those for their hosts; Moorea, Ningaloo and Palau all have low similarity to New Caledonia and Great Barrier Reef sites. We attribute these distinctions to the differential dispersal capability of the fish and their parasites. Chaetodontids have long-lived mobile pelagic larvae, the dispersal of which would be most affected by prominent biogeographical barriers, such as that between the Indian and Pacific Oceans. In contrast, monorchiids have no obvious dispersal stage, and vast distances have the capacity to act as effective barriers to dispersal. We conclude that the present distributions of species of Hurleytrematoides in the Indo-Pacific are driven by historical opportunity and capacity to disperse, and that some disjunct distributions are sculpted by stochasticity.