Understanding quality of life issues in patients with advanced melanoma: Phase 1 and 2 in the development of the EORTC advanced melanoma module.

AIMS: We aimed to develop a European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) module tailored for patients with advanced (resectable or unresectable stage III/IV) melanoma receiving immune checkpoint inhibitors or targeted therapy. METHODS: Following the EORTC QoL Group module development guidelines, we conducted phases 1 and 2 of the development process. In phase 1, we generated a list of health-related (HR)QoL issues through a systematic literature review and semi-structured interviews with healthcare professionals (HCPs) and patients with advanced melanoma. In phase 2, these issues were converted into questionnaire items to create the preliminary module. RESULTS: Phase 1: we retrieved 8006 articles for the literature review, of which 35 were deemed relevant, resulting in 84 HRQoL issues being extracted to create the initial issue list. Semi-structured interviews with 18 HCPs and 28 patients with advanced melanoma resulted in 28 issues being added to the initial issue list. Following EORTC module development criteria, 26 issues were removed, and two issues were added after review by patient advocates. Phase 2: To ensure uniformity and avoid duplication, 16 issues were consolidated into eight items. Additionally, an independent expert contributed one new item, resulting in a preliminary module comprising 80 HRQoL items. CONCLUSION: We identified a range of HRQoL issues (dry skin, xerostomia, and arthralgia) relevant to patients with stage III/IV melanoma. Future module development phases will refine the questionnaire. Once completed, this module will enable standardized assessment of HRQoL in patients with (locally) advanced melanoma.

Patient-reported outcome measures for physical function in cancer patients: content comparison of the EORTC CAT Core, EORTC QLQ-C30, SF-36, FACT-G, and PROMIS measures using the International Classification of Functioning, Disability and Health.

BACKGROUND: Patient-reported physical function (PF) is a key endpoint in cancer clinical trials. Using complex statistical methods, common metrics have been developed to compare scores from different patient-reported outcome (PRO) measures, but such methods do not account for possible differences in questionnaire content. Therefore, the aim of our study was a content comparison of frequently used PRO measures for PF in cancer patients. METHODS: Relying on the framework of the International Classification of Functioning, Disability and Health (ICF) we categorized the item content of the physical domains of the following measures: EORTC CAT Core, EORTC QLQ-C30, SF-36, PROMIS Cancer Item Bank for Physical Function, PROMIS Short Form for Physical Function 20a, and the FACT-G. Item content was linked to ICF categories by two independent reviewers. RESULTS: The 118 items investigated were assigned to 3 components ('d - Activities and Participation', 'b - Body Functions', and 'e - Environmental Factors') and 11 first-level ICF categories. All PF items of the EORTC measures but one were assigned to the first-level ICF categories 'd4 - Mobility' and 'd5 - Self-care', all within the component 'd - Activities and Participation'. The SF-36 additionally included item content related to 'd9 - Community, social and civic life' and the PROMIS Short Form for Physical Function 20a also included content related to 'd6 - domestic life'. The PROMIS Cancer Item Bank (v1.1) covered, in addition, two first-level categories within the component 'b - Body Functions'. The FACT-G Physical Well-being scale was found to be the most diverse scale with item content partly not covered by the ICF framework. DISCUSSION: Our results provide information about conceptual differences between common PRO measures for the assessment of PF in cancer patients. Our results complement quantitative information on psychometric characteristics of these measures and provide a better understanding of the possibilities of establishing common metrics.

The current use of the EORTC QLQ-NMIBC24 and QLQ-BLM30 questionnaires for the assessment of health-related quality of life in bladder cancer patients: a systematic review.

PURPOSE: Investigating the use of the EORTC bladder cancer (BC) modules by evaluating: (a) study contexts/designs; (b) languages/countries in which the modules were administered; (c) their acceptance by patients/investigators; and (d) their psychometric properties. METHODS: A systematic review was performed with studies from 1998 until 20/10/2021 in five databases. Articles/conference abstracts using the EORTC-QLQBLM30 (muscle invasive BC) and the EORTC-QLQNMIBC24 (previously referred to as QLQ-BLS24; non-muscle invasive BC) were included. Two authors independently screened titles/abstracts/full-texts and performed data extraction. RESULTS: A total of 76 eligible studies were identified. Most studies included the BLM30 (n = 53), were in a urological surgery context (n = 41) and were cross-sectional (n = 35) or prospective (n = 30) in design. The BC modules were administered in 14 languages across 19 countries. Missing data were low-moderate for all non-sex related questions (< 1% to 15%). Sex-related questions had higher rates of missing data (ranging from 6.9% to 84%). Most investigators did not use all scales of the questionnaires. One validation study for the original BLS24 led to the development of the NMIBC24, which adopted a new scale structure for which good structural validity was confirmed (n = 3). Good reliability and validity was shown for the NMIBC24 module, except for malaise and bloating/flatulence scales. Psychometric evidence for BLM30 is lacking. CONCLUSION: These results provide insight into how the EORTC BC quality of life modules could be further improved. Current work is ongoing to update the modules and to determine if the two modules can be combined into a single questionnaire that works well in both the NMIBC and MIBC settings.

Feasibility and safety of cangrelor in patients with suboptimal P2Y12 inhibition undergoing percutaneous coronary intervention: rationale of the Dutch Cangrelor Registry.

BACKGROUND: Despite the advances of potent oral P2Y12 inhibitors, their onset of action is delayed, which might have a negative impact on clinical outcome in patients undergoing percutaneous coronary intervention (PCI). Trials conducted in the United States of America have identified cangrelor as a potent and rapid-acting intravenous P2Y12 inhibitor, which has the potential of reducing ischemic events in these patients without an increase in the bleeding. As cangrelor is rarely used in The Netherlands, we conducted a nationwide registry to provide an insight into the use of cangrelor in the management of patients with suboptimal platelet inhibition undergoing (primary) PCI (the Dutch Cangrelor Registry). STUDY DESIGN: The Cangrelor Registry is a prospective, observational, multicenter, single-arm registry with cangrelor administered pre-PCI in: (1) P2Y12 naive patients with ad-hoc PCI, (2) patients with STEMI/NSTEMI with suboptimal P2Y12 inhibition including (3) stable resuscitated/defibrillated patients with out-of-hospital cardiac arrest (OHCA) due to acute ischemia and (4) STEMI/NSTEMI patients with a high thrombotic burden. Primary endpoint is 48 h Net Adverse Clinical Events (NACE), which is a composite endpoint of all-cause death, recurrent myocardial infarction (MI), target vessel revascularization (TVR), stroke, stent thrombosis (ST) and BARC 2-3-5 bleeding. The Dutch Cangrelor Registry will assess the feasibility and safety of cangrelor in patients with suboptimal P2Y12 inhibition undergoing (primary) PCI in the setting of acute coronary syndrome (ACS) and stable coronary artery disease (CAD) in the Netherlands.

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Health-related predictors of cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: The relationship between comorbid disease and health service use and risk of cancer of unknown primary site (CUP) is uncertain. METHODS: A prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. Baseline questionnaire data were linked to cancer registration, health service records 4-27 months prior to diagnosis, and mortality data. We compared individuals with incident registry-notified CUP (n = 327; 90% C80) to two sets of randomly selected controls (3:1): (i) incident metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In fully adjusted models incorporating sociodemographic and lifestyle factors, people with cancer registry-notified CUP were more likely to have fair compared with excellent self-rated overall health (OR 1.78, 95% CI 1.01-3.14) and less likely to self-report anxiety (OR 0.48, 95% CI 0.24-0.97) than those registered with metastatic cancer of known primary. Compared to general cohort population controls, people registered with CUP were more likely to have poor rather than excellent self-rated overall health (OR 6.22, 95% CI 1.35-28.6), less likely to self-report anxiety (OR 0.28, 95% CI 0.12-0.63), and more likely to have a history of diabetes (OR 1.89, 95% CI 1.15-3.10) or cancer (OR 1.62, 95% CI 1.03-2.57). Neither tertiary nor community-based health service use independently predicted CUP risk. CONCLUSION: Low self-rated health may be a flag for undiagnosed cancer, and an investigation of its clinical utility in primary care appears warranted.

Demographic, social and lifestyle risk factors for cancer registry-notified cancer of unknown primary site (CUP).

BACKGROUND: Little is known about the risk factors for cancer of unknown primary site (CUP). We examined the demographic, social and lifestyle risk factors for CUP in a prospective cohort of 266,724 people aged 45 years and over in New South Wales, Australia. METHODS: Baseline questionnaire data were linked to cancer registration, hospitalisation, emergency department admission, and mortality data. We compared individuals with incident cancer registry-notified CUP (n = 327) to two sets of controls randomly selected (3:1) using incidence density sampling with replacement: (i) incident cancer registry-notified metastatic cancer of known primary site (n = 977) and (ii) general cohort population (n = 981). We used conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In a fully adjusted model incorporating self-rated overall health and comorbidity, people diagnosed with CUP were more likely to be older (OR 1.05, 95% CI 1.04-1.07 per year) and more likely to have low educational attainment (OR 1.77, 95% CI 1.24-2.53) than those diagnosed with metastatic cancer of known primary. Similarly, compared to general cohort population controls, people diagnosed with CUP were older (OR 1.10, 95% CI 1.08-1.12 per year), of low educational attainment (OR 1.69, 95% CI 1.08-2.64), and current (OR 3.42, 95% CI 1.81-6.47) or former (OR 1.95, 95% CI 1.33-2.86) smokers. CONCLUSION: The consistent association with educational attainment suggests low health literacy may play a role in CUP diagnosis. These findings highlight the need to develop strategies to achieve earlier identification of diagnostically challenging malignancies in people with low health literacy.

Evaluation of motion correction for clinical dynamic contrast enhanced MRI of the liver.

Motion correction of 4D dynamic contrast enhanced MRI (DCE-MRI) series is required for diagnostic evaluation of liver lesions. The registration, however, is a challenging task, owing to rapid changes in image appearance. In this study, two different registration approaches are compared; a conventional pairwise method applying mutual information as metric and a groupwise method applying a principal component analysis based metric, introduced by Huizinga et al (2016). The pairwise method transforms the individual 3D images one by one to a reference image, whereas the groupwise registration method computes the metric on all the images simultaneously, exploiting the temporal information, and transforms all 3D images to a common space. The performance of the two registration methods was evaluated using 70 clinical 4D DCE-MRI series with the focus on the liver. The evaluation was based on the smoothness of the time intensity curves in lesions, lesion volume change after deformation and the smoothness of spatial deformation. Furthermore, the visual quality of subtraction images (pre-contrast image subtracted from the post contrast images) before and after registration was rated by two observers. Both registration methods improved the alignment of the DCE-MRI images in comparison to the non-corrected series. Furthermore, the groupwise method achieved better temporal alignment with smoother spatial deformations than the pairwise method. The quality of the subtraction images was graded satisfactory in 32% of the cases without registration and in 77% and 80% of the cases after pairwise and groupwise registration, respectively. In conclusion, the groupwise registration method outperforms the pairwise registration method and achieves clinically satisfying results. Registration leads to improved subtraction images.

Macrophage-mediated gliadin degradation and concomitant IL-27 production drive IL-10- and IFN-γ-secreting Tr1-like-cell differentiation in a murine model for gluten tolerance.

Celiac disease is caused by inflammatory T-cell responses against the insoluble dietary protein gliadin. We have shown that, in humanized mice, oral tolerance to deamidated chymotrypsin-digested gliadin (CT-TG2-gliadin) is driven by tolerogenic interferon (IFN)-γ- and interleukin (IL)-10-secreting type 1 regulatory T-like cells (Tr1-like cells) generated in the spleen but not in the mesenteric lymph nodes. We aimed to uncover the mechanisms underlying gliadin-specific Tr1-like-cell differentiation and hypothesized that proteolytic gliadin degradation by splenic macrophages is a decisive step in this process. In vivo depletion of macrophages caused reduced differentiation of splenic IFN-γ- and IL-10-producing Tr1-like cells after CT-TG2-gliadin but not gliadin peptide feed. Splenic macrophages, rather than dendritic cells, constitutively expressed increased mRNA levels of the endopeptidase Cathepsin D; macrophage depletion significantly reduced splenic Cathepsin D expression in vivo and Cathepsin D efficiently degraded recombinant γ-gliadin in vitro. In response to CT-TG2-gliadin uptake, macrophages enhanced the expression of Il27p28, a cytokine that favored differentiation of gliadin-specific Tr1-like cells in vitro, and was previously reported to increase Cathepsin D activity. Conversely, IL-27 neutralization in vivo inhibited splenic IFN-γ- and IL-10-secreting Tr1-like-cell differentiation after CT-TG2-gliadin feed. Our data infer that endopeptidase mediated gliadin degradation by macrophages and concomitant IL-27 production drive differentiation of splenic gliadin-specific Tr1-like cells.

Effects of clopidogrel therapy on whole blood platelet aggregation, the Plateletworks® assay and coagulation parameters in cats with asymptomatic hypertrophic cardiomyopathy: a pilot study.

BACKGROUND: Although scientific evidence is limited, clopidogrel is frequently used as prophylaxis for arterial thromboembolism in cats with hypertrophic cardiomyopathy (HCM). OBJECTIVES: Evaluating effects of clopidogrel therapy in asymptomatic cats with HCM on (1) conventional whole blood aggregation (WBA), (2) alternative platelet aggregation assessed with tubes of the Plateletworks® assay and (3) standard coagulation parameters. ANIMALS AND METHODS: Prospective, randomized, double-blind, placebo-controlled pilot study. Fourteen asymptomatic HCM cats were randomly allocated to receive placebo (n = 5) or clopidogrel (18.75 mg/cat q24h, n = 9) as part of a larger study. Aggregation responses (to 20 µM adenosine diphosphate (ADP) and 10 µg/ml collagen) in WBA and the Plateletworks® assay and standard coagulation parameters were evaluated at baseline and after seven days of therapy. RESULTS: Clopidogrel therapy significantly reduced aggregation responses to ADP and collagen in the Plateletworks® agonists tubes (ADP and collagen: P < 0.001), but did not significantly reduce aggregation responses to ADP and collagen in the WBA technique (ADP: P = 0.07, collagen: P = 0.30). Clopidogrel therapy did not show a significant effect on prothrombin time, activated partial thromboplastin time, antithrombin, D-dimers and fibrinogen concentrations. CONCLUSION AND CLINICAL IMPORTANCE: Clopidogrel therapy at a dose of 18.75 mg/cat q24h for seven days causes a significant decrease in in vitro platelet aggregation evaluated with the Plateletworks® assay, without affecting standard coagulation parameters in cats with asymptomatic HCM.

[Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension]. / Ballonpulmonalisangioplastiek voor chronische trombo-embolische pulmonale hypertensie.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by an elevated average blood pressure in the pulmonary artery (≥ 25 mmHg). This increase is secondary to fibrous organization of thromboembolic obstructions in the pulmonary arteries. CTEPH is associated with significant morbidity and mortality due to right-sided heart failure and ventilation-perfusion discrepancy. Therapy is aimed at normalising pulmonary artery pressure, and pulmonary endarterectomy is usually the treatment of first choice. When surgery is not possible because of peripheral disease localisation or comorbidity, percutaneous balloon pulmonary angioplasty (BPA) can be used. BPA is associated with improvements in functional status and haemodynamic profile. Initially procedural complications often occurred, but improvements in procedural technique have ensured that BPA is used increasingly worldwide. In this article, we discuss the history, procedural aspects and outcomes of BPA, and present our first experiences with BPA in a patient with CTEPH.

Mouth opening in patients irradiated for head and neck cancer: a prospective repeated measures study.

OBJECTIVES: Aims of this prospective cohort study were (1) to analyze the course of mouth opening up to 48months post-radiotherapy (RT), (2) to assess risk factors predicting decrease in mouth opening, and (3) to develop a multivariable prediction model for change in mouth opening in a large sample of patients irradiated for head and neck cancer. MATERIALS AND METHODS: Mouth opening was measured prior to RT (baseline) and at 6, 12, 18, 24, 36, and 48months post-RT. The primary outcome variable was mouth opening. Potential risk factors were entered into a linear mixed model analysis (manual backward-stepwise elimination) to create a multivariable prediction model. The interaction terms between time and risk factors that were significantly related to mouth opening were explored. RESULTS: The study population consisted of 641 patients: 70.4% male, mean age at baseline 62.3years (sd 12.5). Primary tumors were predominantly located in the oro- and nasopharynx (25.3%) and oral cavity (20.6%). Mean mouth opening at baseline was 38.7mm (sd 10.8). Six months post-RT, mean mouth opening was smallest, 36.7mm (sd 10.0). In the linear mixed model analysis, mouth opening was statistically predicted by the location of the tumor, natural logarithm of time post-RT in months (Ln (months)), gender, baseline mouth opening, and baseline age. All main effects interacted with Ln (months). CONCLUSION: The mean mouth opening decreased slightly over time. Mouth opening was predicted by tumor location, time, gender, baseline mouth opening, and age. The model can be used to predict mouth opening.

Systematic review of the surgical strategies of adenocarcinomas of the gastroesophageal junction.

INTRODUCTION: The optimal surgical treatment of patients with adenocarcinoma of the gastroesophageal junction has not been established yet. OBJECTIVE: To evaluate the surgical strategies to treat adenocarcinoma of the gastroesophageal junction. METHODS: Databases Pubmed, Cochrane, and Embase were searched for "adenocarcinoma of the gastroesophageal junction" AND ("surgery" OR "esophagectomy" OR "gastrectomy") or its synonyms or abbreviations. Only comparative studies that evaluated gastrectomy versus esophagectomy were included. RESULTS: In total 10 cohort studies comparing esophagectomy versus gastrectomy fulfilled the quality criteria. The R0 resection rates varied between 72-93% for esophagectomy and 62%-93% for gastrectomy. Morbidity was 33-39% after esophagectomy versus 11-54% after gastrectomy. The 30-day mortality ranged between 1.0-2.3 after esophagectomy and 1.8-2.7% after gastrectomy. At 6 months after surgery, health-related quality of life was higher after total gastrectomy than after esophagectomy. The 5-year survival rates varied between 30-42% for esophagectomy and 18-38% for gastrectomy, but were not significantly different. CONCLUSION: No clear oncologic benefit of either esophagectomy or gastrectomy in patients with adenomacarcinoma of gastroesophageal junction could be observed. However, gastrectomy seems to be accompanied with better quality of life. Future research should preferably consist of a multicenter RCT comparing esophagectomy and gastrectomy for adenocarcinomas of the gastroesophageal junction.

Survival after cutaneous melanoma in kidney transplant recipients: a population-based matched cohort study.

Transplant recipients are at elevated risk of melanoma and may have poorer outcomes than nontransplant recipients. We conducted a national, population-based, matched cohort study of Australian kidney transplant recipients and randomly selected members of the general population matched for age, sex, state and year of diagnosis with invasive cutaneous melanoma (1982-2003). Melanoma histopathological characteristics were extracted from cancer registry notifications and death data were obtained from the National Death Index (1982-2011). Histopathology was compared using conditional logistic regression and overall survival analyzed using Cox proportional hazard models. Compared to melanomas in nontransplant recipients (n = 202), melanomas in transplant recipients (n = 75) had a higher Clark's level (p = 0.007) and higher American Joint Committee on Cancer pathologic stage (p = 0.002), but not Breslow thickness (p = 0.11). Posttransplant melanoma conferred higher risk of death (adjusted hazard ratio 4.26, 95% CI 2.71-6.72, p < 0.001) after adjustment for the matching variables, pathologic stage, histological type and anatomic site. This was not explained by transplantation alone. Melanomas in transplant recipients are more invasive than those in nonrecipients. More aggressive tumor behavior is also supported by a markedly poorer outcome. Treatment algorithms developed for the general population with melanoma may not apply to transplant recipients. A review of patient education and skin cancer screening guidelines is warranted.

Mannitol is essential for the development of stress-resistant ascospores in Neosartorya fischeri (Aspergillus fischeri).

The polyol mannitol is one of the main compatible solutes in Neosartorya fischeri and accumulates in conidia and ascospores. Here, it is shown that biosynthesis of mannitol in N. fischeri mainly depends on mannitol 1-phosphate dehydrogenase (MpdA). Reporter studies and qPCR analysis demonstrated that mpdA is moderately expressed in vegetative hyphae and conidiophores, while it is highly expressed during development of ascospores. Deletion of mpdA reduced mannitol in whole cultures as much as 85% of the wild type, while trehalose levels had increased more than 4-fold. Decreased mannitol accumulation had no effect on mycelial growth irrespective of heat- or oxidative stress. Notably, conidia of the ΔmpdA strain had higher mannitol and lower trehalose levels. They were more sensitive to heat stress. The most distinct phenotype of mpdA deletion was the absence of full development of ascospores. Formation of cleistothecia, and asci was not affected. The ascus cell wall, however, did not dissolve and asci contained incompletely formed or aborted ascospores. Addition of the Mpd inhibitor nitrophenide to the wild type strain also resulted in disturbed ascospore formation. Taken together, these results show that mannitol has a role in sexual development of N. fischeri and in stress resistance of conidia.

Patient tailored resection planning in patients undergoing liver surgery for colorectal liver metastases; how and why should you do it?

BACKGROUND: A systematic preoperative evaluation to determine the individual resection strategy in patients with colorectal liver metastases (CRLM) was assessed as to its clinical value. PATIENTS AND METHODS: From 2009 to 2011, 75 patients with CRLM who were scheduled for surgery were prospectively included and received an additional preoperative systematic evaluation in the presence of a hepatobiliary radiologist and the hepatobiliary surgeon scheduled to perform the surgery. The following items were assessed in a standardized manner: lesion detection and characterization, presence of extrahepatic disease, vascular anatomy, and resection strategy. Intraoperative findings and histopathological results were prospectively recorded. RESULTS: Five out of 75 patients were not considered to be eligible for surgery due to additional findings, such as additional metastases or extrahepatic disease. Sensitivity and specificity for detection of individual CRLM were 80.9% (95% CI 75.7-86.1%) and 69.1% (95% CI 59.1-79.1%), respectively. Radical resections were performed in 87.1%. There was one futile laparotomy (1.4%). CONCLUSION: In patients with colorectal liver metastases, standardized preoperative work-up, with subsequent planning of an individualized resection in a jointed meeting of a hepatobiliary radiologist and the surgeon who will perform the operation, leads to a high level of radical resections and a low number of futile laparotomies.

Identification and characterization of a novel adenovirus in the cloacal bursa of gulls.

Several viruses of the family of Adenoviridae are associated with disease in birds. Here we report the detection of a novel adenovirus in the cloacal bursa of herring gulls (Larus argentatus) and lesser black-backed gulls (Larus fuscus) that were found dead in the Netherlands in 2001. Histopathological analysis of the cloacal bursa revealed cytomegaly and karyomegaly with basophilic intranuclear inclusions typical for adenovirus infection. The presence of an adenovirus was confirmed by electron microscopy. By random PCR in combination with deep sequencing, sequences were detected that had the best hit with known adenoviruses. Phylogenetic analysis of complete coding sequences of the hexon, penton and polymerase genes indicates that this novel virus, tentatively named Gull adenovirus, belongs to the genus Aviadenovirus. The present study demonstrates that birds of the Laridae family are infected by family-specific adenoviruses that differ from known adenoviruses in other bird species.

Longitudinal study of hormonal and physical development in young twins.

CONTEXT AND OBJECTIVE: Information on the correlation of normative reproductive hormone levels with physical development (Tanner stages) during puberty and on the influences of genes and environment on variation in these hormones and Tanner stages is limited. DESIGN, SETTING, AND PARTICIPANTS: One hundred twelve healthy 9-year-old twin pairs (n = 224) took part in a longitudinal study, of which 89 pairs participated again at age 12 years (n = 178). MAIN OUTCOME MEASURES: Morning urinary LH, FSH, estradiol, and salivary testosterone levels, determined by competitive immunoassays, were measured. Tanner stages were determined through physical examination. RESULTS: Over the 3-year interval, all hormone levels showed a 2- to 9-fold increase. LH and FSH at age 9 years predicted sex-specific Tanner stages at age 12 years in both boys and girls. Most of the associations between hormone levels at age 9 years and physical development at 12 years were explained by genetic influences. FSH in 9-year-old boys correlated with all hormone levels and Tanner stages at age 12 years. Moderate to high heritability estimates were found for hormone levels at both ages and in both sexes. In girls a shift from environmental (age 9 years) to genetic influences (age 12 years) was found for estradiol and pubic hair development, and for breast development a shift in the opposite direction was seen. CONCLUSIONS: During development LH and FSH (and testosterone in boys) levels predict secondary sexual characteristics in boys and girls 3 years later. These correlations are largely due to genes that are involved in both early pubertal hormone levels and subsequent physical development.

Focal nodular hyperplasia: hepatobiliary enhancement patterns on gadoxetic-acid contrast-enhanced MRI.

OBJECTIVES: To assess the range of hepatobiliary enhancement patterns of focal nodular hyperplasia (FNH) after gadoxetic-acid injection, and to correlate these patterns to specific histological features. MATERIALS AND METHODS: FNH lesions, imaged with Gadoxetic-acid-enhanced MRI, with either typical imaging findings on T1, T2 and dynamic-enhanced sequences or histologically proven, were evaluated for hepatobiliary enhancement patterns and categorized as homogeneously hyperintense, inhomogeneously hyperintense, iso-intense, or hypo-intense-with-ring. Available histological specimens of FNHs (surgical resection or histological biopsy), were re-evaluated to correlate histological features with observed enhancement patterns. RESULTS: 26 FNHs in 20 patients were included; histology was available in six lesions (four resections, two biopsies). The following distribution of enhancement patterns was observed: 10/26 homogeneously hyperintense, 4/26 inhomogeneously hyperintense, 5/26 iso-intense, 6/26 hypointense-with-ring, and 1/26 hypointense, but without enhancing ring. The following histological features associated with gadoxetic-acid uptake were identified: number and type of bile-ducts (pre-existent bile-ducts, proliferation, and metaplasia), extent of fibrosis, the presence of inflammation and extent of vascular proliferation. CONCLUSION: FNH lesions can be categorized into different hepatobiliary enhancement patterns on Gadoxetic-acid-enhanced MRI, which appear to be associated with histological differences in number and type of bile-ducts, and varying the presence of fibrous tissue, inflammation, and vascularization.