tbuckley/cabot-search huggingface dataset:
International compliance with WHO infant feeding guidelines – Is the confusion cause for concern?
Authors: Jemima W. Allen, Nicholas Edwards, Jennifer J. Koplin, Merryn J. Netting, Katrina J. Allen
Journal: Allergy (2019)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Localizing radioimmunotherapy via nanochannel device for sustained intratumoral drug delivery for solid tumor treatment.
Authors: Jeremy Ho, Antonia Susnjar, Jessica Rhudy, Antons Sizovs, Graziano Lolli, Ramiro Pino, Corrine Ying Xuan Chua, E. Brian Butler, Sandra Demaria, Alessandro Grattoni
Journal: Journal of Clinical Oncology (2019)

37 Background: Immune related adverse events still occur in up to 91% of patients receiving immunotherapy. Intratumoral administration is a potential solution to limit these events by reducing systemic exposure while increasing local concentration. However, intratumoral injection is hindered by rapid clearance of drug from the tumor. Our group has developed an intratumoral nanochannel implant for sustained delivery of immunotherapy (NDES) as a solution. Recent clinical and preclinical studies have found success in the combination of radiotherapy and immunotherapy in improving both local and distant tumor response. We propose a combination of radiotherapy followed by sustained intratumoral delivery of immunotherapy as a treatment regimen to improve tumor response and reduce side effects. Methods: Mice were implanted with the 4T1 murine mammary carcinoma and separated into treatment and control groups. CD40 agonist antibody was delivered intratumorally via NDES. Radiotherapy was administered at 8 Gy for three consecutive days and implantation of the NDES occurred the day after the final fraction of radiation. The tumor growth curve was plotted and tumor, spleen, lymph nodes, lungs, and blood were collected at the study endpoint for further flow cytometry and histological analysis. Results: The combination of radiotherapy and sustained intratumoral CD40 antibody showed significantly decreased tumor growth rates over radiotherapy or sustained intratumoral immunotherapy alone. Both intratumoral and systemic T-cell activation was observed. Mice treated with sustained intratumoral CD40 antibody showed decreased toxicity when compared to those receiving comparable systemic dosage. Conclusions: Radiotherapy combined with local sustained intratumoral immunotherapy is a potential strategy for improving treatment of solid tumors which currently show suboptimal response to current immunotherapy regimens and for inducing a systemic response to distant metastases while minimizing adverse side effects. The sustained delivery profile of the NDES presents an opportunity for practical intratumoral administration and avoidance of repeated invasive procedures in patients.
C-Reactive Protein Testing to Guide Antibiotic Prescribing for COPD Exacerbations
Authors: Christopher C. Butler, David Gillespie, Patrick White, Janine Bates, Rachel Lowe, Emma Thomas-Jones, Mandy Wootton, Kerenza Hood, Rhiannon Phillips, Hasse Melbye, Carl Llor, Jochen W.L. Cals, Gurudutt Naik, Nigel Kirby, Micaela Gal, Evgenia Riga, Nick A. Francis
Journal: New England Journal of Medicine (2019)

Point-of-care testing of C-reactive protein (CRP) may be a way to reduce unnecessary use of antibiotics without harming patients who have acute exacerbations of chronic obstructive pulmonary disease (COPD).
Sharing of clinical trial data and results reporting practices among large pharmaceutical companies: cross sectional descriptive study and pilot of a tool to improve company practices
Authors: Jennifer Miller, Joseph S Ross, Marc Wilenzick, Michelle M Mello
Journal: BMJ (2019)

To develop and pilot a tool to measure and improve pharmaceutical companies' clinical trial data sharing policies and practices.Cross sectional descriptive analysis.Large pharmaceutical companies with novel drugs approved by the US Food and Drug Administration in 2015.Data sharing measures were adapted from 10 prominent data sharing guidelines from expert bodies and refined through a multi-stakeholder deliberative process engaging patients, industry, academics, regulators, and others. Data sharing practices and policies were assessed using data from ClinicalTrials.gov, Drugs@FDA, corporate websites, data sharing platforms and registries (eg, the Yale Open Data Access (YODA) Project and Clinical Study Data Request (CSDR)), and personal communication with drug companies.Company level, multicomponent measure of accessibility of participant level clinical trial data (eg, analysis ready dataset and metadata); drug and trial level measures of registration, results reporting, and publication; company level overall transparency rankings; and feasibility of the measures and ranking tool to improve company data sharing policies and practices.Only 25% of large pharmaceutical companies fully met the data sharing measure. The median company data sharing score was 63% (interquartile range 58-85%). Given feedback and a chance to improve their policies to meet this measure, three companies made amendments, raising the percentage of companies in full compliance to 33% and the median company data sharing score to 80% (73-100%). The most common reasons companies did not initially satisfy the data sharing measure were failure to share data by the specified deadline (75%) and failure to report the number and outcome of their data requests. Across new drug applications, a median of 100% (interquartile range 91-100%) of trials in patients were registered, 65% (36-96%) reported results, 45% (30-84%) were published, and 95% (69-100%) were publicly available in some form by six months after FDA drug approval. When examining results on the drug level, less than half (42%) of reviewed drugs had results for all their new drug applications trials in patients publicly available in some form by six months after FDA approval.It was feasible to develop a tool to measure data sharing policies and practices among large companies and have an impact in improving company practices. Among large companies, 25% made participant level trial data accessible to external investigators for new drug approvals in accordance with the current study's measures; this proportion improved to 33% after applying the ranking tool. Other measures of trial transparency were higher. Some companies, however, have substantial room for improvement on transparency and data sharing of clinical trials.
Substitution of single dose intravenous methylprednisolone (MP) for oral prednisone (Pred) in RCHOP in intermediate grade non-Hodgkin’s lymphoma (NHL).
Authors: Walter Quan, Leah I Gutierrez, Francine Marie Quan
Journal: Journal of Clinical Oncology (2019)

e19019 Background: The regimen CHOP (cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Pred) has been the basis of therapy given with curative intent for intermediate grade NHL for over 40 years. Rituximab added to CHOP (RCHOP) has been the standard for more than a decade. For patients (pts) with prior medical problems such as brittle diabetes, gastrointestinal bleeding, or psychiatric disorders, oral Pred given daily for 5 days is problematic. Methods: In this retrospective study between January, 2007 and September 2018, twenty pts, Diffuse Large B-cell (18) or grade III Follicular NHL (2), for whom standard oral Pred (100 mg daily for 5 days) was not felt to be medically well-suited or who refused or were not compliant with such therapy following an initial cycle, were treated with curative intent with the substitution of MP 125 mg IV (one received 60 mg IV) on day 1 (in place of oral Pred for 5 days) in combination with standard doses of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Results: Pt characteristics: 14 males/6 females, median age-56 (range: 24-76), stages: II (8), III (2), IV (10), B symptoms (12), subtypes: activated B-cell (11), germinal center (6), diffuse B-cell NOS (1), follicular grade III (2). Two were treated with 5 cycles. Fifteen received 6 cycles while three were treated with 8 cycles. Sixteen had complete responses (evaluated by PET/CT) following RCHOP. One pt with activated B-cell subtype had a short-lived partial response before experiencing disease progression. The three remaining pts had partial responses, all 3 of which were converted to complete responses following involved site radiation therapy. One with activated B-cell subtype relapsed at 68.2 months. Eighteen remain progression-free with the longest at 120.3+ months. Median progression-free survival has not been reached at 23+ months. Conclusions: RCHOP with the substitution of a single dose of MP in place of oral Pred has activity in intermediate grade NHL. Long-term disease-free survival may be seen.
SWOG S1400C (NCT02154490)—A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration–Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)
Authors: Martin J. Edelman, Mary W. Redman, Kathy S. Albain, Eric C. McGary, Noman M. Rafique, Daniel Petro, Saiama N. Waqar, Katherine Minichiello, Jieling Miao, Vassiliki A. Papadimitrakopoulou, Karen Kelly, David R. Gandara, Roy S. Herbst
Journal: Journal of Thoracic Oncology (2019)
Metastasis Suppressors NME1 and NME2 Promote Dynamin 2 Oligomerization and Regulate Tumor Cell Endocytosis, Motility, and Metastasis
Authors: Imran Khan, Brunilde Gril, Patricia S. Steeg
Journal: Cancer Research (2019)

NM23 (NME) is a metastasis suppressor that significantly reduces metastasis without affecting primary tumor size, however, the precise molecular mechanisms are not completely understood. We examined the role of dynamin (DNM2), a GTPase regulating membrane scission of vesicles in endocytosis, in NME1 and NME2 regulation of tumor cell motility and metastasis. Overexpression of NMEs in MDA-MB-231T and MDA-MB-435 cancer cell lines increased endocytosis of transferrin and EGF receptors (TfR and EGFR) concurrent with motility and migration suppression. The internalized vesicles, costained with Rab5, had AP2 depleted from the cell surface and exhibited increased Rab5-GTP levels, consistent with endocytosis. Dynamin inhibitors Iminodyn-22 and Dynole-34-2, or shRNA-mediated downregulation of DNM2, impaired NME's ability to augment endocytosis or suppress tumor cell motility. In a lung metastasis assay, NME1 overexpression failed to significantly suppress metastasis in the DNM2 knockdown MDA-MB-231T cells. Using the EGF-EGFR signaling axis as a model in MDA-MB-231T cells, NME1 decreased pEGFR and pAkt expression in a DNM2-dependent manner, indicating the relevance of this interaction for downstream signaling. NME-DNM2 interaction was confirmed in two-way coimmunoprecipitations. Transfection of a NME1 site-directed mutant lacking histidine protein kinase activity but retaining nucleoside diphosphate kinase (NDPK) activity showed that the NDPK activity of NME was insufficient to promote endocytosis or inhibit EGFR signaling. We show that addition of NME1 or NME2 to DNM2 facilitates DNM2 oligomerization and increases GTPase activity, both required for vesicle scission. NME-DNM2 interaction may contribute to metastasis suppression by altering tumor endocytic and motility phenotypes. SIGNIFICANCE: NME1 suppresses metastasis via changes in tumor endocytosis and motility, mediated by dynamin (DNM2) GTPase activity.
Admixture between Ancient Lineages, Selection, and the Formation of Sympatric Stickleback Species-Pairs
Authors: Laura L Dean, Isabel S Magalhaes, Andrew Foote, Daniele D’Agostino, Suzanne McGowan, Andrew D C MacColl
Journal: Molecular Biology and Evolution (2019)

Abstract Ecological speciation has become a popular model for the development and maintenance of reproductive isolation in closely related sympatric pairs of species or ecotypes. An implicit assumption has been that such pairs originate (possibly with gene flow) from a recent, genetically homogeneous ancestor. However, recent genomic data have revealed that currently sympatric taxa are often a result of secondary contact between ancestrally allopatric lineages. This has sparked an interest in the importance of initial hybridization upon secondary contact, with genomic reanalysis of classic examples of ecological speciation often implicating admixture in speciation. We describe a novel occurrence of unusually well-developed reproductive isolation in a model system for ecological speciation: the three-spined stickleback (Gasterosteus aculeatus), breeding sympatrically in multiple lagoons on the Scottish island of North Uist. Using morphological data, targeted genotyping, and genome-wide single-nucleotide polymorphism data, we show that lagoon resident and anadromous ecotypes are strongly reproductively isolated with an estimated hybridization rate of only ∼1%. We use palaeoecological and genetic data to test three hypotheses to explain the existence of these species-pairs. Our results suggest that recent, purely ecological speciation from a genetically homogeneous ancestor is probably not solely responsible for the evolution of species-pairs. Instead, we reveal a complex colonization history with multiple ancestral lineages contributing to the genetic composition of species-pairs, alongside strong disruptive selection. Our results imply a role for admixture upon secondary contact and are consistent with the recent suggestion that the genomic underpinning of ecological speciation often has an older, allopatric origin.
Are double-hit lymphoma patients being adequately evaluated for CNS disease?
Authors: Christie Hancock, Jacob D. Bitran, Imad Almanaseer, Angel Green
Journal: Journal of Clinical Oncology (2019)

e19036 Background: Double hit lymphoma (DHL) is a high-grade lymphoma with a propensity to involve the central nervous system (CNS) compared to the typically less aggressive diffuse large B cell lymphoma (DLBCL). Guidelines recommend considering cerebrospinal fluid (CSF) evaluation and prophylaxis per institution guidelines in DHL patients (pts). It is not clear when this evaluation should occur and what prophylaxis should be delivered. Methods: We performed an IRB granted retrospective analysis of pts with de novo DHL based on assessing high-grade lymphoma FISH panels treated within the Advocate Health Care System. The pt’s age, IPI score, CNS-IPI score, systemic treatment, CSF evaluation, CNS prophylaxis or treatment, CNS event (yes/no), progression free survival and overall survival were recorded. Results: Thirty-one pts were evaluated. Seventeen were male. Median age was 72 years (range: 40 to 89). Fifteen were stage IV. Median IPI score was 3 and CNS IPI was 3. Fifteen pts had CSF evaluated within their disease course. Fifteen pts received CNS prophylaxis or treatment including intrathecal (IT) methotrexate (n = 10), IT methotrexate plus hydrocortisone (n = 2), IT cytarabine (n = 1), IT methotrexate and systemic methotrexate (n = 1), or only systemic methotrexate (n = 1). The number of patients with a CNS event during their disease course was 3 with all 3 having leptomeningeal involvement. These 3 pts had CNS IPI scores &gt; 4. Two had CSF involvement at diagnosis. One died at 2 months; the other is alive and disease free at 44 months. The third pt developed CSF disease at relapse and ultimately died at 12 months. This pt had previously received IT methotrexate. For all pts, the median disease free survival (DFS) was 8.1 months; median survival was 11 months and 3-year DFS was 45%. Conclusions: Our small, but extensive review of community oncologists treating DHL patients showed there was a lack of CSF evaluation in these high-risk patients with a rate of less than 50%. For the patients evaluated, there was significant heterogeneity in CNS prophylaxis. The rate of 10% of patients having CNS disease is consistent with other reports of high-risk lymphoma and CNS relapse suggesting all DHL patients should have CNS prophylaxis.
Response to: ‘Treatment of systemic lupus erythematosus: don’t forget hydroxychloroquine’ by Michaud<i>et al</i>
Authors: Antonis Fanouriakis, George Bertsias, Dimitrios T Boumpas
Journal: Annals of the Rheumatic Diseases (2019)

Response to: 'Treatment of systemic lupus erythematosus: don't forget hydroxychloroquine' by Michaud et alWe thank Michaud et al for their comment and thorough overview of the multiple benefits of hydroxychloroquine (HCQ) in systemic lupus erythematosus (SLE). 1 We fully agree with the authors' punchline that 'HCQ is still in 2019 the cornerstone of the treatment of SLE'; a detailed description of its beneficial actions can be found in the Supplementary Table 2 of the recommendations' manuscript. 2 In addition to the ones mentioned by the authors, HCQ has also been shown in observational studies to decrease the risk for infections, 3 development of metabolic syndrome/diabetes and dyslipidaemia, 4 5 as well as the risk for evolution to chronic kidney disease in lupus nephritis. 6Importantly, given the recent debate regarding optimal HCQ dose in lupus, it is worth saying that the vast majority of these studies did not examine associations between HCQ dose and effect; rather, HCQ was typically tested as a binary variable, where patients were simply asked if they were taking the drug or not.The present comment by Michaud et al gives us the opportunity to emphasise that the main concern of treating physicians should be to optimise patient compliance, since the latter has been consistently shown to be suboptimal, with complete nonadherence rates (ie, undetectable blood levels of HCQ) ranging from 7% to 29% in different studies. 7 8The actual prescribed dose may 'fluctuate' between 200 and 400 mg/day depending on patient weight, disease status and periodic eye examination, as recommended.
Response to combined ipilimumab and nivolumab after development of a nephrotic syndrome related to PD-1 monotherapy
Authors: Valerie Glutsch, Franziska Grän, Judith Weber, Anja Gesierich, Matthias Goebeler, Bastian Schilling
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy. <h3>Case presentation</h3> We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). <h3>Conclusion</h3> This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE.
Abstract 16882: RBC Stearoyl-CoA Desaturase Activity and the Hepatic Paradox in African Descent Women: The Federal Women's Study
Authors: Stephanie T Chung, Nirupa R Matthan, Mirella Galvan de-La Cruz, Anthony Onuzuruike, Kannan Kasturi, Lilian Mabundo, Ahmed M Gharib, Alice H Lichenstein, Anne E Sumner
Journal: Circulation (2017)

In women of African descent, low hepatic fat is paradoxically related to insulin resistance and cardiovascular disease. The reasons for the race/ethnic difference in the relationship between hepati...
Abstract 15455: Increased Aortopulmonary Collateral Flow With Exercise is Associated With Improved Exercise Capacity
Authors: Sofia Weskamp Aguero, Kathryn Rice, Yves d’Udekem, Tim Hornung, Ayer Julian, Michael Cheung
Journal: Circulation (2018)

Introduction: Aortopulmonary collateral (APC) flow is a common finding in the Fontan circulation. It has been suggested that these collaterals should be routinely embolised to reduce volume loading...
Spontaneous bacterial peritonitis: predictive factors of non-response to I.V. cefhalosporin (3RD generation)
Authors: Edna Strauss, Wanda R. Caly, Maria de Fátima G. Ribeiro, Vera Pozzani, Fabiano Martins, Monica Barbosa, Michel Faraco, Nadim Z. Honain
Journal: Hepatology (2001)
Incidence of serious adverse events in bortezomib, lenalidomide and bortezomib plus lenalidomide maintenance for multiple myeloma: Interim analysis of MMRF-CoMMpass study.
Authors: Venkata Vosuri, Mark A Fiala, Wenners Ballard, Tanya Marya Wildes, Mark A. Schroeder, Ravi Vij, Keith Stockerl-Goldstein
Journal: Journal of Clinical Oncology (2019)

e19516 Background: Autologous stem cell transplantation (ASCT) followed by maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. Maintenance typically consists of lenalidomide (LEN), however, bortezomib (BOR) and bortezomib-lenalidomide combination are other options. The respective toxicity of these regimens has not been well studied. We performed secondary data analysis to compare incidence of serious adverse events associated with each maintenance therapy group during post-ASCT maintenance treatment period. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis from the CoMMpass study. We extracted data of first-time autologous stem cell transplant patients who completed maintenance therapy post-ASCT. We categorized patients into three sub groups bortezomib, lenalidomide or combination (bortezomib and lenalidomide) maintenance therapy. Incidence rate for serious adverse events (grade 3 or higher) was calculated by number of events per 100 person-months for each maintenance therapy. Results: 231 patients were eligible for our analysis. 169 patients received lenalidomide, 27 bortezomib and 35 combination. The most common adverse event was neutropenia and second most common is pneumonia. Neutropenia incidence was 1.1,0.7 and 0.9 per 100 person-months in lenalidomide, bortezomib and combination regimens respectively. Incidence of deep vein thrombosis, GI intolerance and peripheral neuropathy 0.1 per 100 person-months respectively was observed in lenalidomide group only. Combination maintenance had the highest total adverse event incidence rate of 5.4 per 100 person-months. Incidence of 1.7 and 3.8 per 100 person-months is observed in bortezomib and lenalidomide cohorts respectively. Conclusions: Lenalidomide and bortezomib maintenance had similar incidence of serious adverse events. A higher incidence of serious adverse events was noted in the combination lenalidomide/bortezomib regimens. Interestingly, we observed lower incidence of adverse events in all groups in CoMMpass study compared to respective clinical trials involving maintenance regimens. This may be due to under reporting of adverse events in CoMMpass study. The incidence of adverse events mentioned above should be interpreted in the context of drugs and other factors involved in the disease.