Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor ...receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers.
Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively.
Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1-20%), with a median progression-free survival of 2 months (95% CI: 2-3), and median overall survival of 6 months (95% CI: 3-8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash.
Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.
The loss of expression of the transcription factor GATA3 in breast tumors has been linked to aggressive tumor development and poor patient survival. In the present work, we address potential roles ...for GATA3 in breast tumor lung metastasis and progression. Using an aggressive breast cancer cell line, which metastasizes specifically to the lung, we show that GATA3 expression results in reduced tumor outgrowth in the mammary fat pad and lower lung metastatic burden in nude mice. Specifically, GATA3 expression inhibits breast cancer cell expansion inside the lung parenchyma. This phenotype correlates with the ability of GATA3 to negatively regulate the expression of several genes that promote breast cancer lung metastasis (ID1/-3, KRTHB1, LY6E and RARRES3). Conversely, the expression of genes encoding known inhibitors of lung metastasis (DLC1 (deleted in liver cancer 1) and PAEP (progestagen-associated endometrial protein)) is upregulated by GATA3. These data correlate with microarray data from human breast cancer patients, showing a strong correlation between high GATA3 expression and absence of metastases specifically to the lungs. We conclude that GATA3 inhibits primary breast tumor outgrowth and reduces lung metastatic burden by regulating key genes involved in metastatic breast tumor progression.
Photosynthetic production of organic matter by microscopic oceanic phytoplankton fuels ocean ecosystems and contributes roughly half of the Earth's net primary production. For 13years, the ...Sea-viewing Wide Field-of-view Sensor (SeaWiFS) mission provided the first consistent, synoptic observations of global ocean ecosystems. Changes in the surface chlorophyll concentration, the primary biological property retrieved from SeaWiFS, have traditionally been used as a metric for phytoplankton abundance and its distribution largely reflects patterns in vertical nutrient transport. On regional to global scales, chlorophyll concentrations covary with sea surface temperature (SST) because SST changes reflect light and nutrient conditions. However, the ocean may be too complex to be well characterized using a single index such as the chlorophyll concentration. A semi-analytical bio-optical algorithm is used to help interpret regional to global SeaWiFS chlorophyll observations from using three independent, well-validated ocean color data products; the chlorophyll a concentration, absorption by CDM and particulate backscattering. First, we show that observed long-term, global-scale trends in standard chlorophyll retrievals are likely compromised by coincident changes in CDM. Second, we partition the chlorophyll signal into a component due to phytoplankton biomass changes and a component caused by physiological adjustments in intracellular chlorophyll concentrations to changes in mixed layer light levels. We show that biomass changes dominate chlorophyll signals for the high latitude seas and where persistent vertical upwelling is known to occur, while physiological processes dominate chlorophyll variability over much of the tropical and subtropical oceans. The SeaWiFS data set demonstrates complexity in the interpretation of changes in regional to global phytoplankton distributions and illustrates limitations for the assessment of phytoplankton dynamics using chlorophyll retrievals alone.
•Evaluation of the SeaWiFS climate data record of chlorophyll concentrations.•Colored dissolved organic matter obfuscates the empirical retrieval of chlorophyll.•Global trends and patterns depend on the choice of bio-optical model used.•Chlorophyll changes reflects both phytoplankton biomass and physiological changes.•The SeaWiFS mission laid out a blueprint for future satellite ocean color missions.
Summary
Background
Paediatric cutaneous lupus erythematosus (CLE) is uncommon and inadequately described in the literature. Similar to adults, children with CLE develop LE‐specific and/or ...LE‐nonspecific skin findings. Similarities and differences in demographics and clinical course between paediatric and adult CLE have not been sufficiently described.
Objectives
To detail the demographic and clinical features of paediatric CLE and compare these findings with those reported in the adult literature.
Methods
A retrospective chart review was performed of 53 children seen in a paediatric dermatology clinic with cutaneous manifestations of LE.
Results
Patients presented with all five major subtypes of CLE, with some notable differences from adult CLE and previously published reports of paediatric CLE. Progression from discoid LE to systemic LE (SLE) did not occur in our cohort. Patients with subacute CLE were more likely than adults to have lesions below the waist as well as concomitant SLE. Sex distribution for CLE in our study was equal prior to puberty and female predominant in post‐pubertal patients.
Conclusions
Children with CLE have variable clinical presentations and progression to SLE that may be different from adult disease. Specifically, children with acute and subacute CLE may be more likely than adults to have systemic disease; therefore, patients with these subtypes should be monitored closely for evidence of SLE. Study limitations included small patient numbers that may limit the ability to generalize these data and relatively short follow‐up intervals.
What's already known about this topic?
The demographics and clinical course differ between cutaneous lupus erythematosus (CLE) subtypes in adults.
Patterns in the demographics and disease course of systemic lupus erythematosus (SLE) differ between children and adults.
The female to male ratio of SLE is equal until puberty and then becomes female predominant.
What does this study add?
The demographics and clinical course also differ between CLE subtypes in children.
Patterns in the demographics and disease course of CLE differ between children and adults.
The female to male ratio of CLE is equal until puberty and then becomes female predominant.
Children are more prone than adults to develop CLE subtypes that are more strongly associated with systemic disease.
The aim of this study was to compare the results of computed tomography (CT) and positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (FDG) for lymph node staging in patients with ...carcinoma of the cervix and to evaluate the relationship of the imaging findings to prognosis.
We retrospectively compared the results of CT lymph node staging and whole-body FDG-PET in 101 consecutive patients with carcinoma of the cervix. Patients were treated with standard irradiation and chemotherapy (as clinically indicated) and observed at 3-month intervals for a median of 15.4 months (range, 2.5 to 30 months). Progression-free survival was evaluated by the Kaplan-Meier method.
CT demonstrated abnormally enlarged pelvic lymph nodes in 20 (20%) and para-aortic lymph nodes in seven (7%) of the 101 patients. PET demonstrated abnormal FDG uptake in pelvic lymph nodes in 67 (67%), in para-aortic lymph nodes in 21 (21%), and in supraclavicular lymph node in eight (8%). The 2-year progression-free survival, based solely on para-aortic lymph node status, was 64% in CT-negative and PET-negative patients, 18% in CT-negative and PET-positive patients, and 14% in CT-positive and PET-positive patients (P <.0001). A multivariate analysis demonstrated that the most significant prognostic factor for progression-free survival was the presence of positive para-aortic lymph nodes as detected by PET imaging (P =.025).
This study demonstrates that FDG-PET detects abnormal lymph node regions more often than does CT and that the findings on PET are a better predictor of survival than those of CT in patients with carcinoma of the cervix.
Cerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically ...assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome.
Intracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities.
By study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections.
The arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral.
Summary
Background
Morphoea is a rare fibrosing disease of the skin and subcutaneous tissue with an unpredictable disease course, running the spectrum from mild skin involvement to severe ...disfigurement or extracutaneous complications.
Objectives
Our objective was to describe the natural history of paediatric morphoea and determine patient variables that were associated with severe disease.
Patients and methods
We conducted a retrospective chart review of patients with morphoea seen in one paediatric hospital system. Information about demographics, clinical characteristics, disease course and treatment were collected. Statistical analysis was performed using appropriate univariate tests and a multivariable model.
Results
One hundred and fourteen patients met study inclusion criteria. The female : male ratio was 2·6 : 1, and the median age of onset was 7 years old. There were 55 patients (48%) with linear morphoea, 38 patients (33%) with circumscribed morphoea, 12 patients (11%) with generalized morphoea, and nine patients (8%) with mixed morphoea. Neurological symptoms and joint involvement were present in 27 subjects (24%). Extracutaneous manifestations occurred in 38% of subjects with linear morphoea, compared with 15% with generalized morphoea and 3% with circumscribed morphoea (P = 0·0001). Thirty‐six per cent of children with disease onset prior to 10 years of age and 5% of children with disease onset after 10 years of age had extracutaneous manifestations (P = 0·0002). Both linear morphoea and early‐onset disease were significantly associated with extracutaneous involvement in a multivariable model.
Conclusions
Children with linear morphoea and disease onset before 10 years of age should be monitored closely for extracutaneous manifestations and need early treatment with systemic medications to prevent disease complications.
What's already known about this topic?
Paediatric morphoea has an unpredictable disease course with self‐limited mild disease in some children and unremitting severely disfiguring disease in others.
What does this study add?
Linear morphoea and age of onset < 10 years of age are significantly associated with extracutaneous manifestations.
Children with linear morphoea and onset of disease prior to 10 years of age should be treated with systemic therapy to prevent neurological and joint complications.
The purpose of this study was to investigate whether positron emission tomography (PET) with the glucose analog (18)Ffluorodeoxyglucose (FDG) and the estrogen analog 16 alpha-(18)Ffluoroestradiol-17 ...beta (FES), performed before and after treatment with tamoxifen, could be used to detect hormone-induced changes in tumor metabolism (metabolic flare) and changes in available levels of estrogen receptor (ER). In addition, we investigated whether these PET findings would predict hormonally responsive breast cancer.
Forty women with biopsy-proved advanced ER-positive (ER(+)) breast cancer underwent PET with FDG and FES before and 7 to 10 days after initiation of tamoxifen therapy; 70 lesions were evaluated. Tumor FDG and FES uptake were assessed semiquantitatively by the standardized uptake value (SUV) method. The PET results were correlated with response to hormonal therapy.
In the responders, the tumor FDG uptake increased after tamoxifen by 28.4% +/- 23.3% (mean +/- SD); only five of these patients had evidence of a clinical flare reaction. In nonresponders, there was no significant change in tumor FDG uptake from baseline (mean change, 10.1% +/- 16.2%; P =.0002 v responders). Lesions of responders had higher baseline FES uptake (SUV, 4.3 +/- 2.4) than those of nonresponders (SUV, 1.8 +/- 1.3; P =.0007). All patients had evidence of blockade of the tumor ERs 7 to 10 days after initiation of tamoxifen therapy; however, the degree of ER blockade was greater in the responders (mean percentage decrease, 54.8% +/- 14.2%) than in the nonresponders (mean percentage decrease, 19.4% +/- 17.3%; P =.0003).
The functional status of tumor ERs can be characterized in vivo by PET with FDG and FES. The results of PET are predictive of responsiveness to tamoxifen therapy in patients with advanced ER(+) breast cancer.
Phytoplankton photosynthesis links global ocean biology and climate-driven fluctuations in the physical environment. These interactions are largely expressed through changes in phytoplankton ...physiology, but physiological status has proven extremely challenging to characterize globally. Phytoplankton fluorescence does provide a rich source of physiological information long exploited in laboratory and field studies, and is now observed from space. Here we evaluate the physiological underpinnings of global variations in satellite-based phytoplankton chlorophyll fluorescence. The three dominant factors influencing fluorescence distributions are chlorophyll concentration, pigment packaging effects on light absorption, and light-dependent energy-quenching processes. After accounting for these three factors, resultant global distributions of quenching-corrected fluorescence quantum yields reveal a striking consistency with anticipated patterns of iron availability. High fluorescence quantum yields are typically found in low iron waters, while low quantum yields dominate regions where other environmental factors are most limiting to phytoplankton growth. Specific properties of photosynthetic membranes are discussed that provide a mechanistic view linking iron stress to satellite-detected fluorescence. Our results present satellite-based fluorescence as a valuable tool for evaluating nutrient stress predictions in ocean ecosystem models and give the first synoptic observational evidence that iron plays an important role in seasonal phytoplankton dynamics of the Indian Ocean. Satellite fluorescence may also provide a path for monitoring climate-phytoplankton physiology interactions and improving descriptions of phytoplankton light use efficiencies in ocean productivity models.
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