bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Life for Immunotoxin Cancer Therapy
Authors: Hassan Raffit , Alewine Christine , Pastan Ira 
Published: October 2015

Abstract
Immunotoxins are targeted anticancer therapeutics that kill cancer cells using a cytotoxic bacterial toxin payload. Their development for use in solid tumor malignancies was delayed due to issues with their immunogenicity and limited therapeutic window. However, new research has rejuvenated the field. Coadministration with a lymphocyte-depleting regimen of pentostatin and cyclophosphamide can delay antidrug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pretreated patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and nonspecific toxicity has been developed through protein engineering techniques, and one has recently entered the clinic. In preclinical studies in mouse models, these new agents are effective against many tumor types as single agents, and also produce synergistic antitumor responses in combination with chemotherapy. These new immunotoxins have renewed excitement in the field and may prove a promising addition to the targeted therapy repertoire. Clin Cancer Res; 22(5); 1055–8. ©2015 AACR.
First-in-Human Phase I Study of Lumretuzumab, a Glycoengineered Humanized Anti-HER3 Monoclonal Antibody, in Patients with Metastatic or Advanced HER3-Positive Solid Tumors
Authors: Meulendijks Didier , Jacob Wolfgang , Martinez-Garcia Maria , Taus Alvaro , Lolkema Martijn P. , Voest Emile E. , Langenberg Marlies H.G. , Fleitas Kanonnikoff Tania , Cervantes Andres , De Jonge Maja J. , Sleijfer Stefan , Soerensen Morten Mau , Thomas Marlene , Ceppi Maurizio , Meneses-Lorente Georgina , James Ian , Adessi Celine , Michielin Francesca , Abiraj Keelara , Bossenmaier Birgit , Schellens Jan H.M. , Weisser Martin , Lassen Ulrik N. 
Published: October 2015

AbstractPurpose: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer.Experimental Design: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w.Results: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration–time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80–225 days).Conclusions: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards. Clin Cancer Res; 22(4); 877–85. ©2015 AACR.
IMPlicating Mesenchymal Imp1 in Colitis-Associated Cancer
Authors: Koltsova Ekaterina K. , Grivennikov Sergei I. 
Published: October 2015

Abstract
Chronic inflammation and associated pathways are significant facilitators of many disease states, including malignancies. In the context of cancer, fibroblasts can actively regulate both inflammation and carcinogenesis. In this issue, Hamilton and colleagues describe a fibroblast-specific role of the RNA binding protein Imp1 in suppression of intestinal inflammatory responses and development of colitis-associated cancer. Mol Cancer Res; 13(11); 1452–4. ©2015 AACR.
See related article by Hamilton et al., p. 1478
T-cell Exhaustion in Multiple Myeloma Relapse after Autotransplant: Optimal Timing of Immunotherapy
Authors: Chung David J. , Pronschinske Katherine B. , Shyer Justin A. , Sharma Sneh , Leung Samantha , Curran Shane A. , Lesokhin Alexander M. , Devlin Sean M. , Giralt Sergio A. , Young James W. 
Published: October 2015

AbstractMultiple myeloma is the most common indication for high-dose chemotherapy and autologous stem cell transplantation (ASCT), and lenalidomide maintenance after transplant is now standard. Although lenalidomide doubles progression-free survival, almost all patients eventually relapse. Posttransplant immunotherapy to improve outcomes after ASCT therefore has great merit but first requires delineation of the dynamics of immune reconstitution. We evaluated lymphocyte composition and function after ASCT to guide optimal timing of immunotherapy and to identify potential markers of relapse. Regulatory T cells (Treg) decline as CD8+ T cells expand during early lymphocyte recovery after ASCT, markedly reducing the Treg:CD8+ effector T-cell ratio. These CD8+ T cells can respond to autologous dendritic cells presenting tumor antigen in vitro as early as day +12 after transplant, becoming antigen-specific cytolytic T-lymphocyte effectors and thereby demonstrating preservation of cellular reactivity. CD4+ and CD8+ T cells express the negative regulatory molecules, CTLA-4, PD-1, LAG-3, and TIM-3, before and after ASCT. A subpopulation of exhausted/senescent CD8+ T cells, however, downregulates CD28 and upregulates CD57 and PD-1, characterizing immune impairment and relapse after ASCT. Relapsing patients have higher numbers of these cells at +3 months after transplant, but before detection of clinical disease, indicating their applicability in identifying patients at higher risk of relapse. PD-1 blockade also revives the proliferation and cytokine secretion of the hyporesponsive, exhausted/senescent CD8+ T cells in vitro. Collectively, these results identify T-cell exhaustion/senescence as a distinguishing feature of relapse and support early introduction of immunotherapy to stimulate antitumor immunity after ASCT. Cancer Immunol Res; 4(1); 61–71. ©2015 AACR.
Immediate Percutaneous Coronary Intervention Is Associated With Improved Short- and Long-Term Survival After Out-of-Hospital Cardiac Arrest
Authors: Geri Guillaume , Dumas Florence , Bougouin Wulfran , Varenne Olivier , Daviaud Fabrice , Pène Frédéric , Lamhaut Lionel , Chiche Jean-Daniel , Spaulding Christian , Mira Jean-Paul , Empana Jean-Philippe , Cariou, Alain 
Published: October 2015

Background—
Whether to perform or not an immediate percutaneous coronary intervention (PCI) after out-of-hospital cardiac arrest is still debated. We aimed to evaluate the impact of PCI on short- and long-term survival in out-of-hospital cardiac arrest patients admitted after successful resuscitation.

Methods and Results—

Between 2000 and 2013, all nontrauma out-of-hospital cardiac arrest patients admitted in a Parisian cardiac arrest center after return of spontaneous circulation were prospectively included. The association between immediate PCI and short- and long-term mortality was analyzed using logistic regression and Cox multivariate analysis, respectively. Propensity score-matching method was used to assess the influence of PCI on short- and long-term survival. During the study period, 1722 patients (71.5% male, median age 60 [49.6, 72.2] years) were analyzed: 628 (35.6%) without coronary angiography, 615 (35.7%) with coronary angiography without PCI, and 479 (27.8%) with both. Among these groups, day 30 and year-10 survival rates were 21% and 11.9%, 35% and 29%, 43% and 38%, respectively (
P
<0.01 for each). PCI as compared with no coronary angiography was associated with a lower day-30 and long-term mortality (adjOR
coro with PCI versus no coro
0.71, 95% confidence interval [0.54, 0.92];
P
=0.02 and adjHR
coro with PCI versus no coro
0.44, 95% confidence interval [0.27, 0.71];
P
<0.01, respectively). PCI remained associated with a lower risk of long-term mortality (adjHR 0.29; 95% confidence interval [0.14, 0.61];
P
<0.01) in propensity score-matching analysis.

Conclusions—
Immediate PCI after out-of-hospital cardiac arrest was associated with significant reduced risk of short- and long-term mortality. These findings should suggest physicians to consider immediate coronary angiography and PCI if indicated in these patients.
Post-Resuscitation ECG for Selection of Patients for Immediate Coronary Angiography in Out-of-Hospital Cardiac Arrest
Authors: Stær-Jensen Henrik , Nakstad Espen Rostrup , Fossum Eigil , Mangschau Arild , Eritsland Jan , Drægni Tomas , Jacobsen Dag , Sunde Kjetil , Andersen Geir Øystein 
Published: October 2015

Background—
We aimed to investigate coronary angiographic findings in unselected out-of-hospital cardiac arrest patients referred to immediate coronary angiography (ICA) irrespective of their first postresuscitation ECG and to determine whether this ECG is useful to select patients with no need of ICA.

Methods and Results—
All resuscitated patients admitted after out-of-hospital cardiac arrest without a clear noncardiac cause underwent ICA. Patients were retrospectively grouped according to the postresuscitation ECG blinded for ICA results: (1) ST elevation or presumably new left bundle branch block, (2) other ECG signs indicating myocardial ischemia, and (3) no ECG signs indicating myocardial ischemia. All coronary angiograms were reevaluated blinded for postresuscitation ECGs. Two hundred and ten patients were included with mean age 62±12 years. Six-months survival with good neurological outcome was 54%. Reduced Thrombolysis in Myocardial Infarction flow (0–2) was found in 55%, 34%, and 18% and a ≥90% coronary stenosis was present in 25%, 27%, and 19% of patients in group 1, 2, and 3, respectively. An acute coronary occlusion was found in 11% of patients in group 3. ST elevation/left bundle branch block identified patients with reduced Thrombolysis in Myocardial Infarction (0–2) flow with 70% sensitivity and 62% specificity. Among patients with initial nonshockable rhythms (24%), 32% had significantly reduced Thrombolysis in Myocardial Infarction flow.

Conclusions—
Initial ECG findings are not reliable in detecting patients with an indication for ICA after experiencing a cardiac arrest. Even in the absence of ECG changes indicating myocardial ischemia, an acute culprit lesion may be present and patients may benefit from emergent revascularization.

Clinical Trial Registration—URL:

http://www.clinicaltrials.gov
. Unique identifier: NCT01239420.
Quantifying the Limits of a Linear Temperature Response to Cumulative CO2 Emissions
Authors: Leduc Martin , Matthews H. Damon , de Elía Ramón 
Published: October 2015

Abstract
Recent studies have shown that the transient climate response to cumulative carbon emissions (TCRE) of the global temperature can be well approximated by a constant value for cumulative emissions up to about 2 TtC. However, there has been little attention given in the literature to how the TCRE varies across the range of emissions rates represented by the current RCP emissions scenarios. The authors use an ensemble of simulations generated using the University of Victoria Earth System Climate Model to quantify how the temperature response to cumulative emissions varies as a function of both the total magnitude and the rate of CO2 emissions. This study shows that the 500-yr response to a pulse CO2 emission (1.81°C TtC−1) does not depend on the magnitude of cumulative emissions up to 3 TtC. The TCRE (1.66°C TtC−1), which relates to the short-term response, is relatively insensitive to constant-rate emissions up to 30 GtC yr−1. This experiment shows that the formal way of estimating the TCRE—that is, at the point of CO2 doubling in an idealized scenario with a 1% yr−1 increase of the atmospheric concentration—is a highly robust measure. The authors conclude that the TCRE provides a good estimate of the temperature response to CO2 emissions in RCP scenarios 2.6, 4.5, and 6, whereas a constant TCRE value significantly overestimates the temperature response to CO2 emissions in RCP8.5.
Comparative histopathological study of the venous wall of chronic venous insufficiency and varicose disease
Authors: Dhanarak Nisarat , Kanchanabat Burapa 
Published: October 2015

Objectivew To investigate venous histopathology of chronic venous insufficiency and varicose patients (C2). Methods Retrospective review of venous histopathology of 52 patients (13, 8, 2, and 28 were C2, C4, C5 and C6). Results The intimal thickness, intimal fibrosis, total thickness and intimal/total thickness ratio were highest in venous clinical severity score 0, 1 chronic venous insufficiency (no or minimal varicosity) follow by Venous Clinical Severity Score 2,3 chronic venous insufficiency (trunkal varice) and C2 veins (mean intimal thickness 62, 36, 26 µm, mean intimal fibrosis 74%, 72%, 65%, mean total thickness 184, 159, 133 µm, mean intimal/total thickness ratio 0.32, 0.20, 0.21). The statistical significances were found when comparing intimal thickness, intimal fibrosis, intimal/total thickness ratio and total thickness of Venous Clinical Severity Score 0, 1 chronic venous insufficiency veins and C2 veins. The medial changes are relatively constant among groups. Conclusion Compared with C2 vein, the intimal changes in chronic venous insufficiency venous wall differ, particularly in the VCSS 0, 1 chronic venous insufficiency.
Trigeminal neuralgia (part II): Factors affecting early pharmacotherapeutic outcome
Authors: Benoliel R , Zini A , Khan J , Almoznino G , Sharav Y , Haviv Y 
Published: October 2015

Aims We conducted a cohort study to examine demographic and clinical features associated with the pharmacotherapeutic outcome in classical trigeminal neuralgia (CTN) patients. Methods Patients with a clinical profile indicating a diagnosis of CTN, as per the International Headache Society’s published classification, were enrolled prospectively. Demographic and pain-related characteristics were carefully collected. For the purposes of the study, patients with features such as autonomic signs and longer attack duration were included. All patients were then initiated on a standardised and accepted stepped pharmacotherapeutic protocol for the management of CTN. Initial pain scores and prospectively collected pain scores from pain diaries were used to assess the treatment outcome, with a ≥50% reduction considered significant. Results A total of 86 patients were seen, of whom five had an underlying disorder that could account for the pain. The study cohort therefore consisted of 81 patients, and based on attack duration these were divided into short (≤2 minutes, n = 61) and long (>2 minutes, n = 20) groups, for further analysis. The features of these patients and a discussion on the differential diagnosis have been presented in part 1 of this report. Employing an accepted stepped pharmacotherapeutic protocol for the management of CTN, significant improvement was more frequent in the short (74%) than in the long attack group (50%, p = 0.05). In the short attack group there were statistically significant associations between a poor treatment response and longer disease duration, the presence of autonomic signs and atypical pain descriptors for pain quality ( p < 0.05). Conclusion This report supports previous findings that prolonged disease duration and autonomic signs are negative prognostic indicators. The present study now adds long attack duration as a further negative prognostic sign.
British Association for Sexual Health and HIV: framework for guideline development and assessment
Authors: Kingston Margaret , Radcliffe Keith , Cousins Darren , Fifer Helen , FitzGerald Mark , Grover Deepa , Hardman Sarah , Higgins Stephen , Rayment Michael , Sullivan Ann 
Published: October 2015

Summary The Clinical Effectiveness Group of the British Association for Sexual Health has updated their methodology for the production of national guidelines for the management of sexually transmitted infections and related conditions. The main changes are the adoption of the GRADE system for assessing evidence and making recommendations and the introduction of a specific Conflict of Interests policy for Clinical Effectiveness Group members and guideline authors. This new methodology has been piloted during the production of the 2015 British Association for Sexual Health & HIV guideline on the management of syphilis.
Baseline findings from the Anal Cancer Examination (ACE) study: screening using digital ano-rectal examination in HIV-positive men who have sex with men
Authors: Ong Jason J , Grulich Andrew , Walker Sandra , Hoy Jennifer , Read Tim , Bradshaw Catriona , Garland Suzanne M , Hillman Richard , Templeton David , Hocking Jane , Eu Beng , Tee BK , Fairley Christopher K 
Published: October 2015

Objective Cytological screening for anal cancer precursors is not always possible. We investigated digital ano-rectal examination (DARE) as a means of early anal cancer detection in HIV-positive men who have sex with men (MSM). Methods We recruited 327 HIV-positive MSM aged 35 and over from clinics with HIV physicians in Melbourne, Australia, to receive an annual DARE. We analyzed baseline data from patient questionnaires regarding general, anal and sexual health, adverse effects from the anal examination, cancer worry, and quality of life. Results The majority of men (82%, 95% CI:78–87) felt relaxed during the DARE, 1% (95% CI:0–3) complained of pain, and 1% (95% CI:0–4) reported bleeding after the examination. Nearly all men (99%, 95% CI:96–100) were willing to continue with an annual DARE. Quality of life was unaffected with utility scores of 0.76 before examination vs. 0.77 two weeks after examination, (p = 0.41). An anal abnormality was detected in 86 men (27%, 95% CI:22–31), with one anal cancer identified. The specialist referral rate following DARE was 5% (95% CI:3–8). Recruitment rates were significantly associated with the clinic setting (sexual health centre 78%, general practice 13%, hospital 14%, p = 0.002) and specialty (sexual health physician 67%, general practitioner 20%, infectious disease physician 14%, p = 0.031). Conclusion Annual DARE to detect anal cancer in HIV-positive MSM was acceptable for patients, with minimal side effects. Strategies to increase HIV physician’s patient recruitment would be needed if DARE were to be implemented in anal cancer screening.
APHON/ASPHO Policy Statement for the Transition of Patients With Sickle Cell Disease From Pediatric to Adult Health Care
Authors: Bryant Rosalind , Porter Jerlym S. , Sobota Amy 
Published: October 2015

Summary: With advances in medical care, the majority of children with sickle cell disease are surviving to adulthood. Patients, families, and providers now face the need for this growing population to move from pediatric- to adult-focused care. In order to facilitate a successful transfer to adult health care, and prepare young adults for greater independence, it is recommended that all pediatric patients with sickle cell disease receive transition preparation. Association Position: As the professional voice of pediatric hematology/oncology healthcare practice, the Association of Pediatric Hematology/Oncology Nurses (APHON) and the American Society of Pediatric Hematology Oncology (ASPHO) recommends that the discussion of transition begin early and is presented as part of the natural process of becoming an adult; that patients, providers, and families are all involved in creating a transition plan and assessing transition preparedness annually; and that transfer of care involve direct communication between the pediatric team and the accepting adult provider.
Vitamin D and axonal injury in multiple sclerosis
Authors: Sandberg L , Biström M , Salzer J , Vågberg M , Svenningsson A , Sundström P 
Published: October 2015

Background: Previous studies in patients with multiple sclerosis (MS) have shown an association between high serum 25-hydroxyvitamin D (25[OH]D) levels and decreased inflammatory activity. Objective: The purpose of this study was to examine the association between 25(OH)D levels and axonal injury in MS. Cerebrospinal fluid neurofilament light (CSF-NFL) was used as a marker for axonal injury. Methods: Patients were identified through clinical practice at the Department of Neurology in Umeå University Hospital, Sweden. Blood draw, magnetic resonance imaging, scoring of disability and lumbar puncture were performed at inclusion in 153 patients, and also at median 12 months follow-up in 87 patients. For analyses of serum 25(OH)D levels and CSF-NFL, enzyme-linked immunosorbent assays were used. Results: There was an inverse association between serum 25(OH)D and CSF-NFL levels in categorical (dichotomized at 75 or 100 nmol/l) analyses. A dose-response effect for 25(OH)D levels on CSF-NFL levels ( p for trend=0.034) was also present. Serum 25(OH)D levels above 100 nmol/l were associated with lower CSF-NFL levels independently of ongoing MS treatment. Conclusion: High 25(OH)D levels are associated with decreased axonal injury in MS.
Should consent forms used in clinical trials be translated into the local dialects? A survey among past participants in rural Ghana
Authors: Baiden Frank , Akazili James , Chatio Samuel , Achana Fabian Sebastian , Oduro Abraham Rexford , Ravinetto Raffaella , Hodgson Abraham 
Published: October 2015

Background: Obtaining informed consent is part of the expression of the principle of participant autonomy during clinical trials. It is critical that participants understand the content of informed consent forms and remain in a position to seek independent advice on its content. We conducted a survey among past participants of a clinical trial in the Kassena-Nankana Districts of rural northern Ghana about the usefulness of informed consent forms that are written in the local dialects. The written forms of local dialects are largely undeveloped. Method: We contacted a randomly selected sample of caregivers whose children were enrolled in a completed clinical trial and interviewed them using a structured questionnaire. Analysis sought to determine participants’ preference and whether or not they were likely to find confidants who will be able to read, understand and give advice on the content of the informed consent form to them when they take the informed consent forms home. Results: We interviewed 394 caregivers, 88.6% of whom were women. About half (54%) of the respondents wanted the informed consent forms to be in the English language. Caregivers with higher than primary level education were more likely to prefer the informed consent form to be in English than those with no formal education (74% versus 26%, p = 0.04). The majority (85%) indicated that they would be able to find close confidants who would be able to read and explain it to them if it is in English. In contrast, only 8% thought they would be able to do the same if the informed consent form was written in the local language. Respondents were more likely to find close confidants to read and explain the informed consent form if it were written in English than if it were written in the local language (94% versus 19%, p value < 0.01). Conclusion: The practice of translating informed consent forms into undeveloped local dialects and giving such copies to trial participants to send home needs to be re-evaluated. In populations where the written forms of local dialects are undeveloped and literacy is low, the use of local dialect versions of informed consent forms could ironically enhance the vulnerability of trial participants.