bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erdheim-Chester Disease: a comprehensive review of the literature
Authors: Mazor Roei D , Manevich-Mazor Mirra , Shoenfeld Yehuda 
Published: September 2013

Abstract
Erdheim-Chester Disease (ECD) is a rare form of non Langerhans' cell histiocytosis. Individuals affected by this disease are typically adults between their 5th and 7th decades of life. Males and females are almost equally affected. The multi systemic form of ECD is associated with significant morbidity, which may arise due to histiocytic infiltration of critical organ systems. Among the more common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, kidneys (retroperitoneum) and skin. The most common presenting symptom of ECD is bone pain. The etiology of ECD is unknown yet thought to be associated with an intense TH1 immune response. It may also be associated with the V600E BRAF mutation, as described in as many as half of the patients in recent studies. Bilateral symmetric increased tracer uptake on 99mTc bone scintigraphy affecting the periarticular regions of the long bones is highly suggestive of ECD. However, definite diagnosis of ECD is established only once CD68(+), CD1a(−) histiocytes are identified within a biopsy specimen. At present, this obscure ailment embodies numerous challenges to medical science. Given its rarity, it is diagnostically elusive and requires a high level of clinical suspicion. Therapeutically, it is of limited alternatives. Currently, interferon-α is the most extensively studied agent in the treatment of ECD and serves as the first line of treatment. Treatment with other agents is based on anecdotal case reports and on the basis of biological rationale. Nevertheless, cladribine (2CDA), anakinra and vemurafenib are currently advocated as promising second line treatments for patients whose response to interferon-α is unsatisfactory. Overall, the 5 year survival of ECD is 68%. Herein, the authors mustered and brought about a panoramic consolidation of all the relevant facts regarding ECD. This work highlights the different clinical, radiological and pathological manifestations associated with ECD, the differential diagnoses, the various treatment options and the acknowledged science explaining the disease.
Methodological challenges in monitoring new treatments for rare diseases: lessons from the cryopyrin-associated periodic syndrome registry
Authors: Tilson Hugh , Primatesta Paola , Kim Dennis , Rauer Barbara , Hawkins Philip N , Hoffman Hal M , Kuemmerle-Deschner Jasmin , van der Poll Tom , Walker Ulrich A 
Published: September 2013

Abstract

Background
The Cryopyrin-Associated Periodic Syndromes (CAPS) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS), and Neonatal Onset Multisystem Inflammatory Disease (NOMID). Canakinumab is a monoclonal antibody directed against IL-1 beta and approved for CAPS patients but requires post-approval monitoring due to low and short exposures during the licensing process. Creative approaches to observational methodology are needed, harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring.

Methods
A web-based registry was set up to collect information on long-term safety and effectiveness of canakinumab for CAPS.

Results
Starting in November 2009, this registry enrolled 241 patients in 43 centers and 13 countries by December 31, 2012. One-third of the enrolled population was aged < 18; the overall population is evenly divided by gender. Enrolment is ongoing for children.

Conclusions
Innovative therapies in orphan diseases require post-approval structures to enable in depth understanding of safety and natural history of disease. The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow-up. Broad international practice-based recruitment and web-based data collection are practical.
Metformin decreases the incidence of ovarian hyperstimulation syndrome: an experimental study
Authors: Elia Evelin M , Quintana Ramiro , Carrere Carlos , Bazzano María V , Rey-Valzacchi Gastón , Paz Dante A , Pustovrh María C 
Published: September 2013

Abstract

Background
In assisted reproduction cycles, gonadotropins are administered to obtain a greater number of oocytes. A majority of patients do not have an adverse response; however, approximately 3-6% develop ovarian hyperstimulation syndrome (OHSS). Metformin reduces the risk of OHSS but little is known about the possible effects and mechanisms of action involved.

Objective
To evaluate whether metformin attenuates some of the ovarian adverse effects caused by OHSS and to study the mechanisms involved.

Material and methods
A rat OHSS model was used to investigate the effects of metformin administration. Ovarian histology and follicle counting were performed in ovarian sections stained with Masson trichrome. Vascular permeability was measured by the release of intravenously injected Evans Blue dye (EB). VEGF levels were measured by commercially immunosorbent assay kit. COX-2 protein expression was evaluated by western blot and NOS levels were analyses by immunohistochemistry.

Results
Animals of the OHSS group showed similar physiopathology characteristics to the human syndrome: increased body weight, elevated progesterone and estradiol levels (P<0.001), increased number of corpora lutea (P<0.001), higher ovarian VEGF levels and vascular permeability (P<0.001 and P<0.01); and treatment with metformin prevented this effect (OHSS+M group; P<0.05). The vasoactive factors: COX-2 and NOS were increased in the ovaries of the OHSS group (P<0.05 and P<0.01) and metformin normalized their expression (P<0.05); suggesting that metformin has a role preventing the increased in vascular permeability caused by the syndrome.

Conclusion
Metformin has a beneficial effect preventing OHSS by reducing the increase in: body weight, circulating progesterone and estradiol and vascular permeability. These effects of metformin are mediated by inhibiting the increased of the vasoactive molecules: VEGF, COX-2 and partially NOS. Molecules that are increased in OHSS and are responsible for a variety of the symptoms related to OHSS.
Evaluation of serum Amphiregulin levels in breast cancer patients and cancer-free controls
Authors: Peterson Esther A , Pectasides Eirini , Shabbeer Shabana , Wiechmann Lisa , Sparano Joseph A , Kenny Paraic A 
Published: September 2013

Abstract

Background
Expression of the Epidermal Growth Factor Receptor ligand, Amphiregulin, has been associated with estrogen receptor positive breast cancer. As Amphiregulin is proteolytically released from the surface of breast cancer cells, we investigated the levels of Amphiregulin in the serum of breast cancer patients and cancer-free women to evaluate its potential utility as a breast cancer biomarker.

Findings
Serum Amphiregulin levels were quantified by ELISA from 125 cancer-free women and 114 breast cancer patients. No significant association between serum Amphiregulin levels and breast cancer status was detected at two cut-points evaluated.

Conclusions
Measurement of serum Amphiregulin levels lacks the necessary sensitivity and specificity for breast cancer screening in the general population.
Accessory renal arteries in a Caribbean population: a computed tomography based study
Authors: Johnson Peter B , Cawich Shamir O , Shah Sundeep D , Aiken William , McGregor Roy G , Brown Hilary , Gardner Michael T 
Published: September 2013

Abstract

Introduction
The commonest variation to the classic anatomic description of renal arterial supply is the presence of accessory renal arteries. The incidence varies widely according to ethnicity. There is no data on the prevalence of these anomalies in persons of Caribbean ethnicity.

Methods
All CT scans done over two years from July 1, 2010 to June 30, 2012 were retrospectively evaluated. The anatomy of the renal arterial supply was reported from these studies and the anatomy of accessory renal arteries was documented.

Results
There were 302 CT scans evaluated and accessory renal arteries were present in 109/302 (36.1%) CT scans, 95% confidence interval 30.6%, 41.4%. There were 71/309 (23.5%) patients with accessory arteries on the left and 54/309 (17.9%) had them on the right (p 0.087). Of these, 16 (14.7%) patients had bilateral accessory renal arteries present. The most common origin for the accessory arteries was the abdominal aorta in 108 (99.1%) cases and in 1 case the accessory artery arose from the coeliac trunk. There were 80 left sided accessory renal arteries: 17 (21.3%) upper polar and 27 (33.8%) lower polar arteries. Of 62 right sided accessory arteries, 14 (22.6%) were upper polar and 26 (42%) were lower polar arteries.

Conclusion
This is the first population-based report of anatomic anomalies in renal arterial supply in a Caribbean population. These are important findings that may affect vascular and urologic procedures on persons of Caribbean ethnicity.
The potential impact of adding genetic markers to clinical parameters in managing high-risk prostate cancer patients
Authors: Alvarez-Cubero Maria Jesus , Martinez-Gonzalez Luis Javier , Vazquez-Alonso Fernando , Saiz Maria , Alvarez Juan Carlos , Lorente Jose Antonio , Cozar Jose Manuel 
Published: September 2013

Abstract

Purpose
High-risk prostate cancer is a potentially lethal disease that is increasing in the diagnosis of prostate cancer patients. Compared to other prostate cancer patients (medium or low risk), management, diagnosis and treatment are not as successful among high-risk patients. Because the genetic characterization of prostate cancer patients is increasing, we aimed to determine whether genetic information in one of the primary associated genes, such as RNASEL (2', 5'-oligoadenylate-dependent RNase L), could be used as a biomarker to improve the quality of life and treatment among high-risk patients. The main objective is to identify genetic variants of RNASEL that could be associated with high-risk prostate cancer to improve the clinical managing of these patients.

Methods
A total of 231 prostate cancer patients were genotyped for 7 variants of RNASEL gene. Clinical information was obtained from medical examinations and genetic analysis (amplification and sequencing 7 variants of RNASEL gene) were performed by the researchers. Data were processed by statistical analysis (Chi square and logistic regression) using SPSS v.15.0.

Results
Comparisons between genotypes and clinical characteristics of patients revealed that individuals with GG in D541E, AA in R462Q and AG in I97L in RNASEL gene were high-risk patients according to the European Urology Guidelines.

Conclusions
Genotyping the RNASEL gene with routine diagnostic techniques could confer a more precise diagnosis of high-risk prostate cancer patients and increase the diagnostic accuracy above the current rate of 70% due to the relation between the genetic variants of RNASEL gene and the risk of this cancer.
Opposite regulatory effects of IFN-β and IL-3 on C-type lectin receptors, antigen uptake, and phagocytosis in human macrophages
Authors: Cardone Marco , Ikeda Kyojiro N , Varano Barbara , Belardelli Filippo , Millefiorini Enrico , Gessani Sandra , Conti Lucia 
Published: September 2013

ABSTRACTCLRs are predominantly expressed in macrophages and myeloid DCs, where they play a key role in antigen recognition, scavenging, and host defense against pathogens. To identify novel immunoregulatory cytokines and networks involved in the control of these functions, we analyzed the coordinate effects of IFN-β and IL-3 on CLR expression, antigen uptake, and phagocytosis in human MDMs and MDDCs. We report that these cytokines exert opposite regulatory effects on the expression of CLRs and endocytic/phagocytic activities of MDMs. Specifically, IFN-β markedly inhibits the expression of MR and Dectin-1 during MDM differentiation and impairs the capacity of MDM to internalize antigens and phagocytose unopsonized Candida albicans. Conversely, IL-3 up-modulates MR, Dectin-1, and DC-SIGN, thus allowing more efficient uptake/phagocytosis. Interestingly, IL-3 counteracts the IFN-β effect on antigen uptake/processing by fully restoring MR expression in IFN-β-primed MDMs. In contrast, the phagocytic activity is only partially restored as a result of the failure of IL-3 in counteracting IFN-β-induced Dectin-1 suppression. Notably, IFN-β-mediated impairment of CLR expression/function occurs in macrophages but not in MDDCs. These results identify IFN-β and IL-3 as unrecognized regulators of CLR expression and function, unraveling a novel interaction between these cytokines instrumental for the regulation of the macrophage response to pathogens.
Integrated geophysical investigation of the St. James Fault Complex: A case study
Authors: Jacob Robert W. , Byler Jeremy B. , Gray Mary Beth 
Published: September 2013

We noninvasively detected the characteristics and location of a regional fault in an area of poor bedrock exposure complicated by karst weathering features in the subsurface. Because this regional fault is associated with sinkhole formation, its location is important for hazard avoidance. The bedrock lithologies on either side of the fault trace are similar; hence, we chose an approach that capitalized on the complementary strengths of very low frequency (VLF) electromagnetic, resistivity, and gravity methods. VLF proved most useful as a first-order reconnaissance tool, allowing us to define a narrow target area for further geophysical exploration. Fault-related epikarst was delineated using resistivity. Ultimately, a high-resolution gravity survey and subsequent inverse modeling using the results of the resistivity survey helped to further constrain the location and approximate orientation of the fault. The combined results indicated that the location of the fault trace needed to be adjusted 53 m south of the current published location and was consistent with a north-dipping thrust fault. Additionally, a gravity low south of the fault trace agreed with the location of conductive material from the resistivity and VLF surveys. We interpreted these anomalies to represent enhanced epikarst in the fault footwall. We clearly found that a staged approach involving a progression of methods beginning with a reconnaissance VLF survey, followed by high-resolution gravity and electrical resistivity surveys, can be used to characterize a fault and fault-related karst in an area of poor bedrock surface exposure.
Laboratory measurements of low- and high-frequency elastic moduli in Fontainebleau sandstone
Authors: David Emmanuel C. , Fortin Jérome , Schubnel Alexandre , Guéguen Yves , Zimmerman Robert W. 
Published: September 2013

The presence of pores and cracks in rocks causes the fluid-saturated wave velocities in rocks to be dependent on frequency. New measurements of the bulk modulus at low frequencies (0.02–0.1 Hz) were obtained in the laboratory using oscillation tests carried out on two hydrostatically stressed Fontainebleau sandstone samples, in conjunction with ultrasonic velocities and static measurements, under a range of differential pressures (10–95 MPa), and with three different pore fluids (argon, glycerin, and water). For the 13% and 4% porosity samples, under glycerin- and water-saturated conditions, the low-frequency bulk modulus at 0.02 Hz matched well the low-frequency and ultrasonic dry bulk modulus. The glycerin- and water-saturated samples were much more compliant at low frequencies than at high frequencies. The measured bulk moduli of the tested rocks at low frequencies (0.02–0.1 Hz) were much lower than the values predicted by the Gassmann equation. The frequency dispersion of the P and S velocities was much higher at low differential pressures than at high pressures, due to the presence of open cracks at low differential pressures.
Phase Ib Study of Panobinostat and Bortezomib in Relapsed or Relapsed and Refractory Multiple Myeloma
Authors: San-Miguel Jesús F. , Richardson Paul G. , Günther Andreas , Sezer Orhan , Siegel David , Bladé Joan , LeBlanc Richard , Sutherland Heather , Sopala Monika , Mishra Kaushal K. , Mu Song , Bourquelot Priscille M. , Victoria Mateos María , Anderson Kenneth C. 
Published: September 2013

Purpose Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM. Patients and Methods In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria. Results The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m2. Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ≥ minimal response. Conclusion The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.
Tivozanib Versus Sorafenib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma: Results From a Phase III Trial
Authors: Motzer Robert J. , Nosov Dmitry , Eisen Timothy , Bondarenko Igor , Lesovoy Vladimir , Lipatov Oleg , Tomczak Piotr , Lyulko Oleksiy , Alyasova Anna , Harza Mihai , Kogan Mikhail , Alekseev Boris Y. , Sternberg Cora N. , Szczylik Cezary , Cella David , Ivanescu Cristina , Krivoshik Andrew , Strahs Andrew , Esteves Brooke , Berkenblit Anna , Hutson Thomas E. 
Published: September 2013

Purpose Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). Patients and Methods Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. Results A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). Conclusion Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.
Adjuvant Ganglioside GM2-KLH/QS-21 Vaccination Versus Observation After Resection of Primary Tumor > 1.5 mm in Patients With Stage II Melanoma: Results of the EORTC 18961 Randomized Phase III Trial
Authors: Eggermont Alexander M.M. , Suciu Stefan , Rutkowski Piotr , Marsden Jeremy , Santinami Mario , Corrie Philippa , Aamdal Steinar , Ascierto Paolo A. , Patel Poulam M. , Kruit Wim H. , Bastholt Lars , Borgognoni Lorenzo , Bernengo Maria Grazia , Davidson Neville , Polders Larissa , Praet Michel , Spatz Alan 
Published: September 2013

Purpose The GM2 ganglioside is an antigen expressed in the majority of melanomas. The GM2-KLH/QS-21 vaccine induces high immunoglobulin M (IgM) and IgG antibody responses. The EORTC 18961 trial compared the efficacy of GM2-KLH/QS-21 vaccination versus observation. Patients and Methods A total of 1,314 patients with a primary tumor > 1.50 mm in thickness (T3-4N0M0; American Joint Committee on Cancer stage II) were randomly assigned to GM2-KLH/QS-21 vaccination (n = 657) or observation (n = 657). Treatment consisted of subcutaneous injections once per week from week 1 to 4, then every 3 months for the first 2 years and every 6 months during the third year. Primary end point was relapse-free survival (RFS). Secondary end points were distant metastasis-free survival (DMFS) and overall survival (OS). Analyses were by intent to treat. Results After a median follow-up of 1.8 years, the trial was stopped at the second interim analysis for futility regarding RFS (hazard ratio [HR], 1.00; P = .99) and detrimental outcome regarding OS (HR, 1.66; P = .02). After a median follow-up of 4.2 years, we had recorded 400 relapses, nine deaths without relapse, a total of 236 deaths. At 4 years, the vaccination arm showed a decreased RFS rate of 1.2% (HR, 1.03; 95% CI, 0.84 to 1.25) and OS rate of 2.1% (HR, 1.16; 95% CI, 0.90 to 1.51). Toxicity was acceptable, with 4.6% of patients ending study participation because of toxicity. Conclusion GM2-KLH/QS-21 vaccination does not improve outcome for patients with stage II melanoma.
Long-Term Outcomes After Pelvic Radiation for Early-Stage Endometrial Cancer
Authors: Onsrud Mathias , Cvancarova Milada , Hellebust Taran P. , Tropé Claes G. , Kristensen Gunnar B. , Lindemann Kristina 
Published: September 2013

Purpose This follow-up of a randomized study was conducted to assess the long-term effects of external beam radiation therapy (EBRT) in the adjuvant treatment of early-stage endometrial cancer. Patients and Methods Between 1968 and 1974, 568 patients with stage I endometrial cancer were included. After primary surgery, patients were randomly assigned to either vaginal radium brachytherapy followed by EBRT (n = 288) or brachytherapy alone (n = 280). Overall survival was analyzed by using the Kaplan-Meier method. A Cox proportional hazards model was used to estimate hazard ratios (HRs) with 95% CIs. We also conducted analyses stratified by age groups. Results After median 20.5 years (range, 0 to 43.4 years) of follow-up, no statistically significant difference was revealed in overall survival (P = .186) between treatment groups. However, women younger than age 60 years had significantly higher mortality rates after EBRT (HR, 1.36; 95% CI, 1.06 to 1.76) than the control group. The risk of secondary cancer increased after EBRT, especially in women younger than age 60 years (HR, 2.02; 95% CI, 1.30 to 3.15). Conclusion We observed no survival benefit of external pelvic radiation in early-stage endometrial carcinoma. In women younger than age 60 years, pelvic radiation decreased survival and increased the risk of secondary cancer. Adjuvant EBRT should be used with caution, especially in women with a long life expectancy.