Search

In contrast to nearly all other tissues, the anatomy of cell differentiation in the bone marrow remains unknown. This is owing to a lack of strategies for examining myelopoiesis—the differentiation of myeloid progenitors into a large variety of innate immune cells—in situ in the bone marrow. Such strategies are required to understand differentiation and lineage-commitment decisions, and to define how spatial organizing cues inform tissue function. Here we develop approaches for imaging myelopoiesis in mice, and generate atlases showing the differentiation of granulocytes, monocytes and dendritic cells. The generation of granulocytes and dendritic cells–monocytes localizes to different blood-vessel structures known as sinusoids, and displays lineage-specific spatial and clonal architectures. Acute systemic infection with Listeria monocytogenes induces lineage-specific progenitor clusters to undergo increased self-renewal of progenitors, but the different lineages remain spatially separated. Monocyte–dendritic cell progenitors (MDPs) map with nonclassical monocytes and conventional dendritic cells; these localize to a subset of blood vessels expressing a major regulator of myelopoiesis, colony-stimulating factor 1 (CSF1, also known as M-CSF)1. Specific deletion of Csf1 in endothelium disrupts the architecture around MDPs and their localization to sinusoids. Subsequently, there are fewer MDPs and their ability to differentiate is reduced, leading to a loss of nonclassical monocytes and dendritic cells during both homeostasis and infection. These data indicate that local cues produced by distinct blood vessels are responsible for the spatial organization of definitive blood cell differentiation. A combination of fluorescent antibodies is used to build visual maps of all myeloid cells in the bone marrow, providing new insight into how the bone marrow microenvironment regulates cell-fate decisions.

Courtney Johnson,1 Jennifer Stephens,1 Christopher Walker,2 Joseph C Cappelleri,3 Ahmed Shelbaya4 1Pharmerit International, Real World Evidence and Data Analytics, Bethesda, MD, USA; 2Pfizer Ltd., Global Medical Affairs, Tadworth, Surrey, England; 3Pfizer Inc., Statistics, Groton, CT, USA; 4Pfizer Inc., Health Economics and Outcomes Research, New York, NY, USACorrespondence: Jennifer StephensPharmerit International, 4350 East West Highway, Suite 1100, Bethesda, MD, USATel +1 240-821-1290Email jstephens@pharmerit.comObjective: This study describes treatment patterns, healthcare resource utilization (HCRU), and costs associated with persistence, switching, and dosing of branded celecoxib in osteoarthritis (OA) patients.Methods: This retrospective claims database analysis used MarketScan® Commercial Claims and Encounters (MarketScan) data from 2009 to 2013. Included patients were adult (≥ 18 years), incident celecoxib users with ≥ 1 OA claim. The treatment switch analysis analyzed outcomes in patients persistent on celecoxib versus switched to a generic nonsteroidal anti-inflammatory drug (NSAID). The dosing analysis stratified patients as under-dose (< 200 mg per day) and standard dose (≥ 200 mg per day). HCRU, costs, and treatment duration were compared in persistent versus switched and standard dose versus under-dose patients using descriptive, multivariate logistic regression, and Kaplan–Meier analysis.Results: A total of 65,530 patients met the inclusion criteria. During follow-up, 83% discontinued celecoxib without switching, 10% were persistent, and 5% switched to a generic NSAID. Ninety percent received a standard dose of celecoxib. Switched (versus persistent) patients had significantly higher all-cause hospital admissions, length of stay, emergency room (ER) visits, and office visits per person year (PPY), all P < 0.001; and under-dosed (versus standard dose) patients had significantly higher hospital admissions (P< 0.001), length of stay (P< 0.001), and ER visits (P= 0.021) PPY. Persistent versus switched patients had lower mean total all-cause costs PPY ($20,378 vs $23,949, P< 0.001). Standard dose versus under-dose patients had lower mean total all-cause costs ($23,680 vs $26,955 PPY, P< 0.001), and not statistically significant higher mean total OA-related costs ($5698 vs $5524 PPY, P=0.441).Conclusion: Patients that switched from branded celecoxib to a generic NSAID or received an under-dose of branded celecoxib had higher average overall HCRU and costs. OA-related inpatient and outpatient cost savings may offset the higher drug cost of celecoxib for persistent patients.Keywords: generic, healthcare resource use, Celebrex, NSAIDS, switching, discontinuation

In the United States, racial/ethnic and sexual youth and young adults (YYA) of color are disproportionately affected by HIV. Subsequently, YYA experience HIV stigma and engage in increased risk behaviors and reduced HIV testing. HIV communication has been identified as a potential buffer to HIV stigma, resulting in health-seeking behaviors, such as HIV testing. In this study, we respond to a meaningful gap in the literature by examining different types of HIV communication and their impact on HIV stigma and HIV testing in a diverse sample of YYA. We analyzed secondary data from the Kaiser Family Foundation National Survey of Teens and Young Adults on HIV/AIDS. A 40-question, web-based survey was conducted with 1437 youth (ages 15–24). Recruitment included a dual sampling method from households with: (1) listed phone numbers, (2) unlisted phone numbers, (3) telephones, (4) no telephone, and (5) only cell phone access. The purpose of the survey was to establish participants’ HIV knowledge, communication, experiences, and testing behaviors. Findings suggested an association between intimate-partner HIV communication, increased HIV testing, and reduced HIV stigma. We also identified differentials in HIV testing and stigma based on gender, income, age, and sexual minority status, explained by HIV communication. Further research is needed that examines ways to use intimate-partner HIV communication to reduce stigma and increase HIV testing among YYA of different sociodemographic characteristics and sexual orientations.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first-or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplanta-tion and be definitive therapy versus those in whom it provides a more effective bridge to hae-matopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully huma-nised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prior-itisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary medi-astinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this pop-ulation. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials.CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell ther-apies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success.The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies.Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regu-latory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially impor-tant as these are very expensive therapies.The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: Early antibiotic switch and early discharge protocols have not been widely studied in Latin America. Our objective was to describe real-world treatment patterns, resource use, and estimate opportunities for early switch from intravenous to oral antibiotics and early discharge for patients hospitalized with methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections. Materials/methods: This retrospective medical chart review recruited 72 physicians from Brazil to collect data from patients hospitalized with documented methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections between May 2013 and May 2015, and discharged alive by June 2015. Data collected included clinical characteristics and outcomes, hospital length of stay, methicillin-resistant Staphylococcus aureus-targeted intravenous and oral antibiotic use, and early switch and early discharge eligibility using literature-based and expert-validated criteria. Results: A total of 199 patient charts were reviewed, of which 196 (98.5%) were prescribed methicillin-resistant Staphylococcus aureus -active therapy. Only four patients were switched from intravenous to oral antibiotics while hospitalized. The mean length of methicillin-resistant Staphylococcus aureus-active treatment was 14.7 (standard deviation, 10.1) days, with 14.6 (standard deviation, 10.1) total days of intravenous therapy. The mean length of hospital stay was 22.2 (standard deviation, 23.0) days. The most frequent initial methicillin-resistant Staphylococcus aureus-active therapies were intravenous vancomycin (58.2%), intravenous clindamycin (19.9%), and intravenous daptomycin (6.6%). Thirty-one patients (15.6%) were discharged with methicillin-resistant Staphylococcus aureus -active antibiotics of which 80.6% received oral antibiotics. Sixty-two patients (31.2%) met early switch criteria and potentially could have discontinued intravenous therapy 6.8 (standard deviation, 7.8) days sooner, and 65 patients (32.7%) met early discharge criteria and potentially could have been discharged 5.3 (standard deviation, 7.0) days sooner. Conclusions: Only 2% of patients were switched from intravenous to oral antibiotics in our study while almost one-third were early switch eligible. Additionally, one-third of hospitalized patients with methicillin-resistant Staphylococcus aureus complicated skin and soft tissue infections were early discharge eligible indicating opportunity for reducing intravenous therapy and days of hospital stay. These results provide insight into possible benefits of implementation of early switch/early discharge protocols in Brazil. Keywords: IV-to-PO switch, Length of stay, Clinical criteria, Antibiotic therapy, Economics

SummaryIn contrast to virtually all other tissues in the body the anatomy of differentiation in the bone marrow remains unknown. This is due to the lack of strategies to examine blood cell production in situ, which are required to better understand differentiation, lineage commitment decisions, and to define how spatial organizing cues inform tissue function. Here we developed imaging approaches to map all myeloid cells in whole bones and generated 3D atlases of granulocyte and monocyte/dendritic cell differentiation during homeostasis. We found that myeloid progenitors leave the hematopoietic stem cell niche during differentiation. Granulocyte and monocyte dendritic cell progenitors (MDP) do not interact, instead they localize to different sinusoids where they give rise to clusters of immature cells. MDP cluster with Ly6Clomonocytes and conventional dendritic cells; these localize to a unique subset of colony stimulating factor 1 (CSF1, the major regulator of monopoiesis1) -expressing sinusoids. Csf1 deletion in the vasculature disrupted the MDP clusters and their interaction with sinusoids, leading to reduced MDP numbers and differentiation ability, with subsequent loss of peripheral Ly6Clomonocytes and dendritic cells. These data indicate that there is a specific spatial organization of definitive hematopoiesis and that local cues produced by distinct blood vessels are responsible for this organization. These maps provide a blueprint for in situ analyses of hematopoiesis in blood disorders.

BACKGROUND: Prolactin-secreting macroadenomas are generally not life-threatening and often present with visual impairment. Medical management with a dopamine agonist is typically the treatment of choice, which significantly reduces the tumor size and improves symptoms without surgical morbidity. In this report, we present a case of an acidophilic stem cell adenoma (ASCA) that was slowly responsive to medical management, but exhibited marked visual recovery after surgical resection. RESULTS: A 15 year-old previously healthy male presented with significantly decreased peripheral vision but no other neurologic or endocrinologic symptoms. Initial magnetic resonance imaging of the brain/spine revealed a mass in the suprasellar and sellar regions with extension into the cavernous sinus and a prolactin level of 644, leading to a presumptive diagnosis of macroprolactinoma. Medical management with cabergoline resulted in some decrease of the prolactin level, but no radiographic improvement or visual recovery after two months. He subsequently underwent endoscopic endonasal transsphenoidal resection with near-total restoration of his peripheral vision post-operatively and significant improvement of his prolactin level. Pathology was consistent with an ASCA (staining positively with prolactin, growth hormone (a-subunit), and pituitary-specific positive transcription factor 1), a rare pituitary adenoma that tends to be invasive and often requires more aggressive therapy; the patient thus underwent focal consolidative proton beam irradiation. CONCLUSION: This case highlights the importance of considering acidophilic stem cell adenomas in the differential of medically-resistant pituitary macroadenomas and early consideration of resection in cases where significant visual or other symptoms exist, as timely intervention may substantially improve functional outcomes.

INTRODUCTION: Sharing research ready data between multiple institutions and across different platforms is a lengthy and cumbersome process which can delay research and potentially negatively impact patient care. Despite the recent surge in generating the genomic and molecular profiles of CNS cancers, correlation of this data with clinical or radiographic data is yet to be streamlined. To address this, CBTTC has partnered with Blackfynn, to develop their HIPAA-compliant, cloud-based platform for integration of histopathology, clinical, molecular, and neuroimaging data. This collaboration provides research ready data that can be easily accessed by clinicians and researchers across different institutions. METHODS: MR imaging, genomic, histological data from a cohort of CBTTC patients diagnosed with midline gliomas were used in a pilot trial. The Blackfynn platform was used to share and annotate MR imaging and histological staining across two academic institutions. Clinicians, basic researchers, and software engineers participated in the project with the goal of integrating a multi-disciplinary, cross-data integration platform. RESULTS: The Blackfynn platform successfully allowed sharing and annotation of neuroimages as well as histopathology slides pertaining to the CBTTC cohort. The neuroimaging on the platform is interactive and can be viewed in axial, coronal and sagittal planes. The pathology slides are also interactive and can be viewed up to 50x magnification. Annotations can be made on all of the multimodal data with the possibility of localizing MR images with the corresponding pathology slides. In conclusion, Blackfynn provides the research community research ready data that is easily uploaded and shared between different institutions.

Ahmed Shelbaya,1,2 Caitlyn T Solem,3 Chris Walker,4 Yin Wan,3 Courtney Johnson,3 Joseph C Cappelleri1 1Pfizer Inc., New York, NY, 2Columbia School of Public Health, New York, NY, 3Pharmerit International, Bethesda, MD, USA; 4Pfizer Ltd., Tadworth, Surrey, UK Objective: This study aimed to evaluate the characteristics associated with early versus late initiation of celecoxib treatment after osteoarthritis (OA) diagnosis and whether economic and safety outcomes differ between patients with early versus late initiation of celecoxib.Methods: Adults (≥18 years) with a confirmed OA diagnosis (International Classification of Diseases, 9th Edition, Clinical Modifications code: 715.XX), ≥12 months of continuous pre- and post-index enrollment, and ≥1 post-index claim for celecoxib were included from the MarketScan® Commercial Claims and Encounter Database (2009–2013). Index date was defined as initial OA diagnosis. Patients were categorized as initiating celecoxib early (within 6 months of index date) or late (≥6 months after index date). Logistic regressions were used to assess characteristics associated with early versus late celecoxib initiation. Key outcomes included health care resource utilization (HCRU) and costs post-index, and adverse event incidence post-celecoxib initiation. Unadjusted and adjusted comparisons (using generalized linear models with a gamma distribution for costs and Poisson distribution for event and resource utilization) were made between early and late celecoxib initiators.Results: Of the 62,434 OA patients identified, 27,402 were early and 35,032 were late initiators. Post-index hospital admissions and length of stay did not differ statistically between early versus late initiators after controlling for pre-index event rates and covariates, but early patients had significantly fewer outpatient (incidence rate ratio [IRR]: 0.96; 95% confidence interval [CI]: 0.95, 0.97) and emergency room visits (IRR: 0.89; 95% CI: 0.84, 0.95). After adjustment for key covariates, early initiators (versus late initiators) had lower all-cause (US$12,909 versus US$13,781, P

This retrospective study compared effectiveness of (brentuximab vedotin) BV to other chemotherapies in patients with rrHL following an autologous stem cell transplant (ASCT). Data originated from a medical chart review of patients treated in real-world clinical settings at 50 sites in the United Kingdom and Germany. Inverse probability of treatment weights based on propensity scores were used to adjust for differences in baseline characteristics between treatment groups. Among 312 rrHL patients included, 196 received BV and 116 received physicians' choice chemotherapy. Median PFS was significantly longer (27.0 months vs. 13.4 months; p = .0144) and 12-month OS survival greater (78.1% vs. 65.9%; p = .0129) with BV compared to chemotherapy. Documented adverse events included leukopenia (12.8%) and peripheral neuropathy (8.7%) for BV and leukopenia (12.1%), anemia (5.2%) and diarrhea (5.2%) for chemotherapy. In this real-world study, rrHL patients treated for relapse after ASCT with BV had longer median PFS and 12-month OS than patients receiving chemotherapy.

Objective Brentuximab vedotin (BV) is an anti-CD30 antibody-drug conjugate licensed for the treatment of relapsed/refractory Hodgkin lymphoma (rrHL) following autologous stem cell transplant (ASCT) or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option. The objective of this study was to describe real-world outcomes with BV in rrHL patients considered ASCT-ineligible or who refuse ASCT. Methods This was a retrospective medical chart review study that enrolled patients ≥18 years old who were initially diagnosed with HL between 1 January 2008 and 30 June 2014, considered ASCT-ineligible, and treated in routine care with BV for progressive disease after multi-drug chemotherapy regimens. Clinical outcomes included best response to treatment, progression-free survival (PFS), overall survival (OS), and adverse events. Results A total of 136 patients were included, with a median age of 70 years at initial HL diagnosis. The most common reasons for ASCT-ineligibility were comorbidities (74%) and age (57%). Overall response rate was 74% and PFS and OS were 15.1 and 17.8 months, respectively. Peripheral neuropathy was observed in 9.6% of patients. Conclusion The results of this study provide real-world evidence on the feasibility and effectiveness of BV in elderly or frail ASCT-ineligible patients with rrHL in a real-world setting. This article is protected by copyright. All rights reserved.