bluuebunny/crossref_metadata_2025_split huggingface dataset:
How the NIH Genetic Testing Registry and Medical Genetics Summaries can help oncologists adopt pharmacogenetics guidelines.
Authors: Malheiro Adriana Jose , Dean Laura Charlotte , Hoeppner Marilu A , Lyoshin Vitaliy , Gu Baoshan , Chen Chao , Liu Chunlei , Maddipatla Zenith , Shi Wenyao , Jang Wonhee , Hoffman Douglas , Zhou George , Chitipiralla Shanmuga , Mitchell Joe , Maglott Donna R. , Kattman Brandi L. 
Published: May 2020

e14141 Background: Oncology is one of the few medical specialties where pharmacogenetic dosing is becoming a routine part of patient management. In the US, oncology drugs account for one-third of all drugs with pharmacogenetic data in their labeling. The NIH Genetic Testing Registry (GTR, www.ncbi.nlm.nih.gov/gtr ) is a freely available database of orderable genetic tests voluntarily provided by laboratories, and supports easy identification of both diagnostic and therapy-based tests. Medical Genetics Summaries (MGS, www.ncbi.nlm.nih.gov/books/NBK61999 ) presents actionable pharmacogenetic information by collating guidelines from authoritative professional (e.g. FDA, CPIC) and medical (e.g. ASCO) societies. MGS is regularly updated and can be found by searching PubMed. To increase oncologist adoption of pharmacogenetic recommendations, we analyzed the relationship between genetic tests in GTR and practice guidelines in MGS. Methods: The GTR database was queried to extract content, and we consulted the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling. Results: Of the 90 oncology drugs that have pharmacogenetic information in their labeling, 29 drugs have at least one test for drug response in GTR. The oncology drugs most tested are mercaptopurine and irinotecan with 13 tests each, followed by thioguanine (12) and tamoxifen (9). For the remaining 61 drugs, only one drug (Pertuzumab) has a guideline, which is summarized in MGS. In total, MGS offers 10 summaries focused on oncology drugs. The 90 drug labels mention 49 distinct biomarkers (e.g. genes and variants). All 49 biomarkers can be interrogated using tests via the GTR. In total, GTR has approximately 3,500 tests for cancer diagnostics, 500 tests for cancer management, and 37 pharmacogenetic tests for cancer drugs. Conclusions: Searching for a genetic test in GTR by biomarker (100% coverage) is more efficient than by drug name (32% coverage) because of how laboratories describe their tests. Clinicians need to quickly find the best pharmacogenetic test and how tests are represented in the community affect the ability to search and find them. This presentation will show busy clinicians how to optimally use GTR and MGS. This work was supported by the Intramural Research Program of the National Library of Medicine, National Institutes of Health.
Complementary and alternative medicine use among cancer patients at a private hospital in Brazil.
Authors: Ricardo Eliza Dalsasso , Oishi Denise , Dos Santos Marcelo Oliveira , D'Alpino Renata D'Alpino 
Published: May 2020

e14144 Background: Complementary and alternative medicine (CAM) use is relatively common among cancer patients. Data regarding CAM use in Brazil is scarce. We sought to define CAM use by cancer patients and investigate factors that might influence it. Methods: We conducted a cross-sectional survey of adults diagnosed with any cancer type who came to appointments at our outpatient clinic in January 2020. Chi-square tests were used to investigate the association between CAM use and age and gender Results: We interviewed 156 patients who consented to the face-to-face interview and all of them completed the questionnaires. Most patients were between 51 and 70 years-old; 56% were female and 55% had their cancer diagnosed in the last 12 months. Most cancer types were breast (17.4%), colorectal (16.7%), and lung (16.1%). More than 90% of the participants were on any active treatment. The prevalence of current CAM use was 29.6%. 58.7% of the patients did not believe CAM has anti-cancer properties, including 32.6% of patients who reported CAM use. Two-thirds of the participants have never discussed about CAM with their oncologists. Only 5.1% of the respondents would abandon conventional cancer treatment in order to use just CAM. Among CAM users, 55% referred multiple therapies use. Of those therapies, spiritual surgery was the most prevalent one. There was a significant higher proportion of females reporting CAM use (p = 0,029) as well as a higher proportion of CAM use among younger patients (p = 0,008). Conclusions: CAM use was common among our study population, especially spiritual surgery. Women and younger patients were more prone to use CAM. Although most patients would not abandon conventional treatment, many of them have never discussed about CAM with their oncologists.
Using a tele-oncology service provides a direct benefit to patients and caregivers in rural communities in the Intermountain West.
Authors: Haslem Derrick S. , Reese Zachary , Emfield Kimberlee , Gill David Michael , Wilcox Ryan Eldredge , Rhodes Terence Duane , Tudor Brian P. 
Published: May 2020

e14153 Background: Cancer treatment is becoming more complex, necessitating subspecialty expertise and multidisciplinary approaches to treatment planning. Simultaneously, there is increasing demand to provide care as close to home as possible. Oncology services are in high demand with a geographical mismatch between where oncologists work and where patients live. Traditionally, patients have been required to travel long distances to seek care outside of their communities resulting in increased financial expense and emotional distress caused by leaving the comforts of their support system. Leveraging existing technologies, most of modern cancer care, including infusions can be delivered through a coordinated effort from consulting/ordering oncologists, onsite administrators, physicians, nurses and ancillary staff. Methods: Using a secure video-conferencing platform, Intermountain Healthcare has implemented 5 tele-oncology clinics (Site A- Sevier, UT; B- Cassia, ID; C- Teton, ID; D- Uintah Basin, UT, E- Star Valley, WY) in rural communities of Utah, Idaho and Wyoming. Patients are referred to the clinic by local providers. With the assistance of a nurse navigator, oncologists meet with patients via video conference for initial consults, follow-up, supportive care, survivorship care and systemic treatment including chemotherapy, immunotherapy, and targeted therapy. Standard NCCN/ASCO guidelines are followed in the treatment strategies for these patients. Care is taken to ensure any treatment that can safely be delivered in the local facility/community is coordinated to take place there. Based on distances from the rural facility to nearest tertiary cancer center, we calculated the mileage avoided and hours traveled avoided by using tele-oncology. Results: Since 2017, the tele-oncology service has managed 269 unique patients (A- 200; B- 21, C- 22, D- 18, E- 8) with 1,237 total tele-oncology visits (A- 1,068; B- 69; C- 39; D- 32; E- 29). In total, there were 397,326 driving miles avoided (A- 326,808; B- 26,358; C- 22,932; D- 9,280; E- 11,948). Travel hours avoided in total were 6,062 hours (A- 4,989; B- 380; C- 341; D- 155; E- 197). Conclusions: Intermountain Healthcare’s tele-oncology program benefits patients and communities by easing travel burden and improving quality of life by making cancer care more convenient and providing the care closer to home. Work is ongoing to prospectively evaluate the effects on the communities in addition to cancer related outcomes.
CNS outcomes in EGFR/ALK wild-type NSCLC patients with brain metastases treated with immune checkpoint inhibitors (ICI).
Authors: Shultz David Benjamin , Lau Sally CM , Poletes Christopher , Le Lisa W , MacKay Kate , Shepherd Frances A. , Bradbury Penelope Ann , Leighl Natasha B. , Liu Geoffrey , Sacher Adrian G. 
Published: May 2020

e14505 Background: Anti-tumor lymphocytes activated in response to ICIs may cross the blood brain barrier with effect on brain metastases (BM). Preliminary evidence suggests that ICIs alone are effective for melanoma BMs. However, the ability of ICI to effectively control NSCLC BMs without radiotherapy is controversial. By comparing serial MRIs and patterns of progression in ICI and chemotherapy treated patients, we sought to investigate the role of ICI in BM control in NSCLC patients. Methods: Serial MRIs were reviewed in ICI treated NSCLC patients with known BMs. Eligible patients must have a minimum of one baseline MRI and a follow-up within 3 months of CNS directed treatment. Patients with EGFR/ ALK mutations were excluded. A control cohort of patients who had never received ICIs was selected using the same criteria. The primary outcome was cumulative CNS progression and intracranial progression free survival (iPFS) analyzed using an accelerated failure time model and competing risk analysis. Results: We identified 137 ICI treated NSCLC patients with known BMs. After excluding for patients without serial MRIs, we analyzed 40 ICI treated patients and 39 controls. All patients received upfront radiotherapy or surgery and the modality used was similar (p = 0.13). CNS failure was less common in the ICI group (p = 0.02). ICI treated patients had a trend to longer iPFS in the PD-L1 ≥50% subgroup (p = 0.058). Cumulative incidence of progressive BM at 12 and 24 months were significantly lower in the ICI treated PD-L1 ≥50% subgroup: 19%/19% vs 50%/56% (p = 0.02). Patients in the PD-L1 ≥50% subgroup who achieved a systemic partial response (n = 10) did not experience any CNS events despite extracranial progression in some. Conclusions: Durable CNS disease control is observed with ICIs in NSCLC with PD-L1 ≥50% and demonstrates a high level of concordance with systemic response. The need for radiotherapy in PD-L1 ≥50% disease should be investigated and may be reasonably delayed in asymptomatic patients with small BMs. Importantly, the same trend was not observed in PDL1 < 50% patients and caution is needed in employing this strategy in this subset of patients.
Prospective investigation of patent foramen ovale as a mechanism for brain metastasis in patients without prior lung involvement.
Authors: Levin-Epstein Rebecca , Rusheen Joshua , Kumar Preetham , Gevorgyan Rubine , McWatters Zoe , Kim Won , Kaprealian Tania Betty , West Brian , Tobis Jonathan 
Published: May 2020

e14510 Background: Brain metastases can lead to significant morbidity and mortality in patients with advanced cancer. Preventing metastatic disease to the brain could thus substantially improve outcomes. The mechanism of brain metastasis is incompletely understood. Circulating tumor cells drain to the right heart and through the pulmonary circulation, where they may manifest as lung metastases, and can circulate further to the left heart and then to the brain. However, in patients who develop brain metastases without prior lung involvement, metastatic cells may take an alternate route. We hypothesized that cancer cells may pass directly from the right to left heart via a patent foramen ovale (PFO), akin to paradoxical embolism. The prevalence of PFO is approximately 20-30% in the general population; if further elevated in this population, PFO may play a role in brain metastasis development, and ultimately, prophylactic PFO closure may provide benefit. We conducted a pilot study to investigate whether PFO is associated with brain metastases in patients without prior lung involvement. Methods: We prospectively identified patients with brain metastases from a non-lung primary cancer with no preceding lung metastases. Participants underwent a transcranial Doppler study to assess for PFO. Agitated saline was injected intravenously at rest and with Valsalva maneuver. High intensity signals were counted in the middle cerebral arteries for 1 minute after each injection. Spencer grade ≥3 indicated a positive study, consistent with the presence of PFO. Results: We accrued 9 participants who met inclusion criteria. Primary cancers were breast (6 participants), upper gastrointestinal (2 participants), and thyroid (1 participant). A positive study was identified in 2/9 (22.2%) participants. One individual was a female with breast cancer who had no preceding extracranial metastases, and the other individual was a male with duodenal adenocarcinoma whose only prior metastatic disease was distant lymphadenopathy, not active at brain metastasis diagnosis. No participants have developed lung metastases as of their most recent imaging. Conclusions: In this prospective pilot study, we found no increased prevalence of PFO in patients who develop brain metastases without preceding lung involvement compared to estimates for the general population. Though a larger study is needed, the development of brain metastases in these patients may reflect tumors’ biological factors directing metastasis organotropism, rather than a structural pathway.
In Vivo-like model of glial tumors: Creation of primary cell lines.
Authors: Timofeeva Sofia V. , Kit Oleg I. , Sitkovskaya Anastasia O. , Mezhevova Irina V. , Filippova Svetlana Yu. , Shamova Tatiana V. , Rostorguev Eduard E. , Ignatov Sergey N. , Kuznetsova Natalya S. , Atmachidi Dmitriy P. , Kavitskiy Sergey E. , Novikova Inna A. 
Published: May 2020

e14515 Background: The choice of cell source for 3D bioprinting of in vivo-like models of glial tumors is crucial and must take into account the ability to proliferation and stable metabolism. Oral administration of 5-aminolevulinic acid (5-ALA) in patients prior to surgery increases the fluorescent contrast between tumor and surrounding tissue, but the effect of contrast agents on cells in vitro is unknown. The aim of the study was obtaining viable glial tumor tissues using 5-ALA, as well as the development of a stable primary cell culture for 3D bioprinting. Methods: Tumor tissue was obtained from patients with glioblastoma during surgery under visual control using the Opmi Pentero Blue E400 microscope and 5-ALA. Material was disaggregated on a BD Machine using Medicons 50 μm (BD). Glioblastoma cells were cultured in DMEM/F12 medium with L-glutamine (Gibco) containing 10% fetal bovine serum (Biolot, Russia), 1% non-essential amino acids (NEAA, Sigma-Aldrich) and 0.5% penicillin-streptomycin (Biolot) at 37C. Glial cell lines were characterized immunohistochemically using antibodies to the glial fibrillary acidic protein (GFAP) and proliferation index (Ki-67). Microsatellite analysis was performed using three dinucleotide repeat markers D2S123, D17S250, D5S346 and five mononucleotide loci BAT25, BAT26, NR21, NR24 and NR27. Results: The positive expression of GFAP on the cell processes of the star-like shape was clearly visualized, indicating a morphological feature of glial tumors. The Ki-67 labeling index was 70%. Changes were observed at the D17S250 locus (148-148/148-152) for the glial tumor primary cells after the sixth passage. Microsatellite instability was not observed in the primary cell culture. Conclusions: The accumulation of porphyrins from 5-ALA in glial tumor cells does not prevent the in vitro creation of a cell culture from tumor tissue. Microsatellite analysis showed that the obtained glioblastoma cell lines remain stable for at least 10 passages. Material obtained during resection using 5-ALA is a reliable source of stable glial tumor cell lines.
A retrospective analysis of cost and survival outcomes based on consolidation regimens in primary central nervous system lymphoma.
Authors: Gelhard Savannah , Maxwell Amiee , Colman Howard , Cohen Adam Louis , Mendez Joe Sammy 
Published: May 2020

e14544 Background: Treatment for Primary Central Nervous System Lymphoma (PCNSL) includes induction therapy consisting of polychemotherapy including high-dose methotrexate followed by consolidation therapy. There are various induction and consolidation regimens with wide variability in their treatment duration, inpatient vs outpatient administration, and the number of chemotherapeutic agents utilized. We performed a comparative cost and efficacy analysis of three consolidation techniques in an effort to provide insight into the cost-benefit of these treatment regimens. Methods: Patients treated for newly diagnosed PCNSL at our institution after July 1, 2012 were retrospectively reviewed. Patients who completed one of the following regimens and received consolidation therapy at our institution were included: rituximab/methotrexate/vincristine/procarbazine (R-MVP), rituximab/methotrexate/temozolomide (R-MT), or rituximab/methotrexate (R-M) for induction followed by consolidation with etoposide/cytarabine (EA), high-dose cytarabine (HIDAC), or high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR). Cost to health system was derived from a Value Driven Outcomes tool and filtered to compare major costs of treatment. Survival was calculated from the date of diagnosis and last date of known survival. Results: Twenty-two patients met eligibility criteria and received the following four treatment regimens: R-MT+EA (12), R-MT+ HDC-ASCR (3), R-M+ HDC-ASCR (1), and R-MVP+HIDAC (6). Patients receiving HDC-ASCR (4) had a trend towards a more favorable overall survival (p = 0.0880) compared to the other two consolidation therapies with no recurrence or death in those patients treated with HDC-ASCR. Comparative cost analysis of facility and pharmacy costs of the three consolidation techniques found that HDC-ASCR was 40 times the cost of the cheapest treatment, HIDAC. Conclusions: This small retrospective review provides evidence that HDC-ASCR may be a superior consolidation strategy but with a profound increase in financial cost. To our knowledge this is the first study completed in the U.S. comparing treatment outcomes and cost in PCNSL. Based on our results, it is clear that a larger and prospective review could potentially shed light on selecting a standard of care based on cost-benefit analysis.
Characterization of BDG8: An antibody-human IL-2 complex that selectively activates the effector arm of the immune system.
Authors: Wyant Timothy , Amit Inbar , Levin Itay , Levitan Natali , Grossman Noam , Bluvshtein Olga , Barak Ruet , Nimrod Guy , Fischman Sharon , Strajbl Marek , Sasson Yehezkel , Zehnin Michael , Ofran Yanay 
Published: May 2020

e15004 Background: Interleukin 2 is a 15.4 kDa type I cytokine of the four helix bundle structure. IL-2 signaling has two opposite effects, it can enhance immune response by activation of effector cells and regulate immune response by activation proliferation of regulatory T cells (Tregs). IL-2 mediates its effect by binding to two forms of IL-2 receptor: i) trimeric receptors made of IL-2Rα (CD25), IL-2Rβ (CD122), and a common IL-2Rγ (γc, CD132) chains or ii) a dimeric receptor of only the IL-2Rβ and IL-2Rγ subunits. In Tregs, activation of the trimeric receptor is associated with FoxP3 mediated transcription leading to the production of suppression factors. Tregs express higher levels of the αβγ trimeric IL-2 receptor than effector cells. However binding of IL-2 to the βγ dimer is associated with activation of effector cells expressing relatively high levels of the βγ dimer and express low levels of trimer. High dose IL-2 therapy is used in melanoma and metastatic renal cell carcinoma with response rates 10%-15%. While efficacious, this approach has several disadvantages: 1) IL-2 dependent adverse effects such as Vascular Leak Syndrome (VLS) excluding many patients from being considered 2) The short half-life of IL-2 requires frequent administration, resulting in repeated spikes in the level of circulating IL-2. 3) Administered IL-2 is not selective and enhances a non-desired activation of Tregs. Methods: Antibodies were computational designed to bind to a specific epitope on Il-2 allowing for the binding to the CD122/CD132 complex and exclude the CD122/CD132/CD25 complex. Results: Here we show that we specifically designed and tested a humanized antibody (BD8) that: i) binds tightly the human IL-2 (hIL-2) and ii) the antibody- hIL-2 complex preferentially to bind the IL-2Rβ sub-unit and blocks the IL-2Rα subunit. We show administering the BD8 Ab-IL-2 complex to C57BL/6 mice has a profound effect on activation of MP CD8+, NK and NKT effector cells with minimal effect on Tregs. In mice the antibody-hIL-2 complex serum half -life is much longer then the half-life of hIL-2. In the B16-F10 Melanoma model, BD8-hIL2 resulted in robust effect compared to hIL-2 alone. Conclusions: BD8 is a computationally designed antibody specifically binds to IL-2 inducing the activation of effector cells without stimulating Tregs and demonstrates efficacy in animal cancer models.
Lymphoma cell-killing activity and cytokine release by CD20-directed bispecific IgM antibody-based T-cell engager (IGM-2323).
Authors: Keyt Bruce , Baliga Ramesh , Li Keyu , Manlusoc Marigold , Hinton Paul , Ng Dean , Tran Madeline , Shan Bing , Lu Hai , Rahman Sachi , Saini Avneesh , Cao Yuan , Saraiya Chitra , Peterson Marvin , Godfrey Wayne R , Carroll Steve 
Published: May 2020

e15007 Background: Bispecific antibodies which tether T-cells to cancer cells, and additionally activate T-cell mediated killing, have shown promise in treating B-cell malignancies. Dose intensity, however, is limited by cytokine release from the activated T-cells. Side effects include fever, hypotension, and hypoxia. Methods: A novel type of bispecific antibody (IGM-2323) was constructed using the pentameric IgM framework. Recombinant IgM heavy chains and kappa light chains with high affinity variable domains derived from an anti-CD20 IgG, were co-expressed with a J-chain fused to anti-CD3 single chain Fv domain. IGM-2323 has 10 binding domains for CD20, and one binding domain for CD3. Results: IGM-2323 binds to the CD20 antigen with > 1000-fold increased avidity relative to an IgG antibody format. IGM-2323 in human cell cultures shows highly potent T cell dependent cytotoxicity (EC50 20 pM), even on cells with very low cell surface expression of CD20, rituximab-resistant lymphoma cell lines, and patient derived CLL cells. Significantly, IGM-2323 exhibits vastly reduced cytokine release, with equivalent T cell dependent killing of CD20-expressing cancer cells, as compared to corresponding IgG-based T cell bispecifics made with the same binding domains. IGM-2323 mediated killing can occur at low T-cell/cancer cell ratios, as low as (1:5). In addition, IGM-2323 mediates complement dependent cytotoxicity (CDC) of CD20-expressing cells with > 100-fold higher potency than IgG. IgM-based bispecific (anti-CD20 x anti-CD3) completely depletes circulating B cells in cynomolgus monkeys at doses of > 300 µg per kg. Furthermore, durable depletion of B cells in spleen and lymphoid tissues was noted with multiple doses of > 1 mg/kg. Importantly, in these studies no observable adverse effects were seen, despite repeated doses at up to 25 mg/kg (the highest dose tested). Low levels of transiently increased circulating IL-6 and no increased levels of circulating TNF-α and IFN-γ were observed in these primate studies. Conclusions: These data indicate that IgM-based bispecifics can induce T cell engagement and very potent cytotoxicity that can be dissociated from cytokine release syndrome in the primate model. These preclinical data demonstrate the potential for broad application of this novel modular IgM-based bispecific antibody format. A Phase I dose-escalation study of IGM-2323 in patients with relapsed/refractory Non-Hodgkin’s lymphoma has been initiated (NCT04082936) and is currently enrolling patients.