tbuckley/cabot-search huggingface dataset:
Investigation of TLR4 and pSTAT3 expression on tumor and immune cells in the peripheral blood (PB) of patients with breast cancer (BC).
Authors: Maria A Papadaki, Alexia Monastirioti, Christina A Apostolopoulou, Despoina Aggouraki, Chara Papadaki, Kleita Michaelidou, Dimitrios Mavroudis, Sofia Agelaki
Journal: Journal of Clinical Oncology (2021)

e15015 Background: Toll-like receptor 4 (TLR4) and phosphorylated signal transducer and activator of transcription protein 3 (pSTAT3) hold a key role in inflammatory response and tumor immune evasion. Their role in the peripheral immune response and in tumor immune interactions in circulation needs further investigation. In the current report we evaluated the incidence of TLR4 and pSTAT3 expression on tumor and immune compartments within the peripheral blood (PB) of patients with early (eBC) and metastatic breast cancer (mBC). Methods: PB was obtained from patients with eBC (n = 99) and mBC (n = 100), prior to adjuvant and first-line therapy, respectively. Triple immunofluorescence staining for cytokeratins (CK), TLR4 and pSTAT3 was performed on peripheral blood mononuclear cell (PBMC) cytospins. Single cell-level expression of TLR4 and pSTAT3 was assessed on CK+ circulating tumor cells (CTCs) and PBMCs using the Ariol microscopy system. Results: CK+ CTCs were detected in 6.1% and 19% of patients with eBC and mBC, respectively (p = 0.006) (number of CTCs: n = 34 and n = 28, respectively). Higher TLR4 expression rates on CTCs were observed in mBC as compared to eBC (53.6% vs 7.7% of CTCs, 13% vs 3% of patients; p = 0.016). pSTAT3+ CTCs also prevailed in mBC (60.7% vs 10.3% of CTCs; 14% vs 5.1% of patients; p = 0.032). In the metastatic patients, CTC detection was associated with shorter overall survival (median OS: 24.9 vs 36.5 months; p = 0.042; Kaplan Meier), whereas the detection of TLR4+ CTCs predicted for shorter progression free survival (median PFS: 11.4 vs 12.6 months; p = 0.036). At the PBMC level, TLR4 expression was more frequent among patients with mBC as compared to eBC (34% vs 20.2%, respectively; p = 0.029), whereas pSTAT3 expression prevailed in eBC (89.9% vs 77% of patients, respectively; p = 0.014). The detection of TLR4+ PBMCs was associated with reduced disease-free survival (median DFS: not reached; p = 0.007) and shorter OS (median OS: not reached; p = 0.028) in patients with eBC. Conclusions: TLR4 and pSTAT3 expression is demonstrated on CTCs and PBMCs and significantly varies among eBC and mBC, suggesting that the inflammatory signaling through TLR4 and pSTAT3 in PB could be associated with BC progression. Our results further imply that their assessment in PB may hold significant prognostic implications in BC.
Sweet syndrome induced by SARS‐CoV‐2 Pfizer‐BioNTech mRNA vaccine
Authors: Anne‐Sophie Darrigade, Hélène Théophile, Paola Sanchez‐Pena, Brigitte Milpied, Marianne Colbert, Stéphane Pedeboscq, Thierry Pistone, Marie‐Laure Jullié, Julien Seneschal
Journal: Allergy (2021)
EMBR-12. TARGETING THE RNA-BINDING PROTEIN LIN28B IN GROUP 3 MEDULLOBLASTOMA
Authors: Shubin Shahab, Robert Schnepp, Tobey MacDonald, Anna Kenney
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common pediatric malignant brain tumor and is currently divided into WNT, SHH, Group 3 and Group 4 subtypes. Even with multimodal chemotherapy, radiotherapy and surgery, many children with Group 3 MBs do not survive. We have previously demonstrated an oncogenic role for the RNA-binding protein (RBP) LIN28B in neuroblastoma. LIN28B is a key regulator of let-7 family miRNAs, which in turn inhibit LIN28A/B and other oncogenes. LIN28B has also been found to be upregulated in Wilms tumor, hepatoblastoma, germ cell tumors, leukemia among others. We hypothesize that LIN28B plays an important role in Group 3 MB and that a better understanding of LIN28B and LIN28B-driven networks will reveal novel therapeutic vulnerabilities. LIN28B levels are highest in Group 3 MB patients, and its overexpression is associated with significantly worse survival. Here we demonstrate that down-regulation of LIN28B using shRNA results in significant reduction in cell proliferation by CellTiter-Glo and increased apoptosis by Caspase-Glo (as well as induction of cleaved PARP on immunoblots). In contrast overexpression of LIN28B increases Group 3 cell proliferation and tumor sphere formation The LIN28 inhibitor 1632 also leads to significant reduction in G3 MB cell proliferation. In addition, we find that PDZ-binding kinase (PBK) a downstream target of LIN28B is downregulated when LIN28B is depleted. PBK knock down also leads to decreased proliferation of Group 3 MB cells. Finally RNA-seq profiling following LIN28B depletion reveals additional components of the LIN28B pathway which may be amenable to therapeutic targeting. This work will help define the role for LIN28B in Group 3 MB aggressiveness and establish LIN28B and LIN28B-driven networks as novel therapeutic targets in these patients.
Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): Expanded efficacy and safety analyses from CheckMate 577.
Authors: Ronan Joseph Kelly, Jaffer A. Ajani, Jaroslaw Kuzdzal, Thomas Zander, Eric Van Cutsem, Guillaume Piessen, Guillermo Mendez, Josephine Louella Feliciano, Satoru Motoyama, Astrid Lièvre, Hope Elizabeth Uronis, Elena Elimova, Cecile Grootscholten, Karen Paula Geboes, Jenny Zhang, Samira Soleymani, Ming Lei, Prianka Singh, James M. Cleary, Markus H. Moehler
Journal: Journal of Clinical Oncology (2021)

4003 Background: In CheckMate 577 (NCT02743494), NIVO demonstrated a significant and clinically meaningful improvement in disease-free survival (DFS; primary endpoint) vs placebo (PBO) and was well tolerated in patients (pts) with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease. Median DFS doubled with NIVO vs PBO (22.4 vs 11.0 months; HR 0.69; 96.4% CI 0.56–0.86; P = 0.0003). Serious treatment-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported for &lt; 10% of pts with NIVO and 3% with PBO. Methods: Pts were randomized 2:1 to NIVO 240 mg or PBO Q2W for 16 weeks, followed by NIVO 480 mg or PBO Q4W. Here, we present additional efficacy, safety, and quality-of-life (QoL) data from CheckMate 577. Results: 794 pts were randomized (NIVO, 532; PBO, 262). Distant recurrence was reported for 29% vs 39% and locoregional recurrence for 12% vs 17% of pts in the NIVO vs PBO groups, respectively. Median distant metastasis-free survival was 28.3 vs 17.6 months with NIVO vs PBO (HR 0.74; 95% CI 0.60–0.92). Median progression-free survival 2 (PFS2; time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was not reached with NIVO vs 32.1 months with PBO (HR 0.77; 95% CI 0.60–0.99). TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) reported for NIVO are presented in the table. Results for the FACT-ECS and FACT-G7 showed similar trends for QoL improvement from baseline for NIVO and PBO during treatment and maintained benefit post-treatment. Conclusions: Adjuvant NIVO demonstrated clinically meaningful efficacy, an acceptable safety profile, and maintained QoL, providing further support for its use as a new standard of care for pts with resected EC/GEJC who received neoadjuvant CRT with residual pathologic disease. Clinical trial information: NCT02743494. [Table: see text]
Efficacy of Salvage Chemotherapy in Diffuse Large B Cell Lymphoma with Primary Treatment Failure According to Putative Cell of Origin
Authors: Talha Badar, Mehdi Hamadani, Veronika Bachanova, Kami J. Maddocks, Elvira Umyarova, Julio C. Chavez, Narendranath Epperla, Saurabh Chhabra, Ana Xavier, Reem Karamali, Mohammad Salhab, Nishitha Reddy, Francisco J. Hernandez-Ilizaliturri, Christopher Flowers, Andrew M Evens, Zheng Zhou, Frederick Lansigan, Stefan Klaus Barta, Jonathon B Cohen, Timothy Fenseke, Luciano J. Costa
Journal: Blood (2017)
Risk of immunosuppression and hospitalization after checkpoint inhibitor therapy in patients with cancer and radiation therapy.
Authors: Kate E Lee, David Andrew Bender, Catherine S. Spina, Brigham Hyde, Adam S Faye, Simon Cheng
Journal: Journal of Clinical Oncology (2021)

2588 Background: Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. Radiation therapy (RT) also induces systemic immunologic effects, and data on the interaction and safety of combining ICIs and RT are limited. Methods: In this retrospective cohort study using a large medical claims database from 2010 to 2017, we ascertained the risk of immunosuppressive steroid therapy as well as the risk of hospitalization within 180 days of treatment with an ICI in patients with diagnoses of malignant melanoma or lung cancer. Patients were stratified by use of RT within 30 days before and after ICI therapy. ICIs included pembrolizumab, nivolumab, and ipilimumab, while immunosuppressive agents included oral prednisone and intravenous methylprednisolone. Results: 2020 patients (218 with RT, 1802 without RT) met inclusion criteria for prednisone analysis, while 3519 patients (361 with RT, 3158 without RT) met inclusion criteria for all other analyses. On univariable analysis, RT was not associated with need for prednisone or methylprednisolone (RR 1.2, 95%CI 0.8-1.9 and RR 1.2, 95%CI 0.7-2.1 respectively). When assessing hospitalization, RT was significantly associated with hospitalization following ICI therapy for certain cancer/drug combinations (RR 1.4, 95%CI 1.2-1.6, p&lt;0.001 for lung cancer/PD-1 inhibitors, RR 2.0, 95%CI 1.0-3.5, p=0.03 for melanoma/ipilimumab). Conclusions: In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring immunosuppressive steroid therapy as compared to not receiving RT. However, in those with ICIs, RT was associated with a higher risk of hospitalization as compared to no RT, though this may be a result of underlying differences in patent severity (more severe disease may require ICI and RT).[Table: see text]
Negative SARS-CoV-2 antibodies, T-cell response and virus neutralization following full vaccination in a renal transplant recipient: a call for vigilance
Authors: Rune M. Pedersen, Ditte S. Tornby, Claus Bistrup, Isik S. Johansen, Thomas E. Andersen, Ulrik S. Justesen
Journal: Clinical Microbiology and Infection (2021)
Real-world data of osimertinib in the management of leptomeningeal metastases in EGFR mutant NSCLC: Light at the end of the tunnel?
Authors: Mansi Sharma, Shrinidhi Nathany, Satya Narayan, Pallavi Redhu, Parveen Jain, Ullas Batra
Journal: Journal of Clinical Oncology (2021)

e21197 Background: Presence of leptomeningeal metastases (LM) in NSCLC is indicative of aggressive disease and the incidence is as high as 9%-16% in the EGFR mutant subgroup. Traditionally, these patients had a dismal outcome with WBRT and intrathecal chemotherapy. Osimertinib crosses the blood brain barrier and is efficacious in the second line setting, as seen in BLOOM trial (LM ORR of 62%) and AURA program (LM ORR 55%). Osimertinib has also demonstrated CNS efficacy in the first line (FLAURA trial). This study is a retrospective review of cases with LM treated with osimertinib, and their response outcomes. Methods: 16 patients of EGFR mutant NSCLC developed LM at some point in their disease course and were treated with osimertinib. Clinical features and response outcomes were retrieved from medical record archives. Descriptive statistics were done using SPSS v23 software. LM PFS was defined as the time between 1st dose of osimertinib and date of progression in LM. LM OS was defined as the time between the first dose of osimertinib to the date of last follow up/death. ORR was defined as the percentage of cases showing CR/PR to osimertinib. Results: Median age was 61 years (range: 33-79) with 9 males and 7 females. Del19 mutations were seen in 9 patients and L858R in 7 patients. Only one patient was given WBRT prior to TKI. 6 patients with LM at diagnosis were given 1 st line osimertinib. 3 (50%) progressed in LM and 3 (50%) showed partial response. Median LM PFS and median LM OS was not reached. ORR for osimertinib in the first line was 83.3%. 10 patients developed LM later in the course of the disease and median time to onset of LM was 12.47 months. Median LM PFS for osimertinib was 7.9 months (95% CI:3.2-8.3). Median LM OS was 8.2 months (95% CI: 2.6-19.8 months). ORR for osimertinib in the later line was 60%. Conclusions: This early experience reveals superior efficacy of osimertinib in LM with an excellent LM ORR in the first line setting and concordant results with second line BLOOM Study. Despite the small numbers in this study, this report becomes clinically relevant owing to the rarity of LM occurrence and paucity of available data. Efficacy of osimertinib in EGFR treatment-naive patients with LM requires further investigation and a larger prospective trial with a longer follow up may help confirm our preliminary findings.
Real world experience with standalone immunotherapy regimens: Immune-related adverse events, healthcare utilization and cost among patients with commercial or Medicare Advantage insurance.
Authors: Krishna Soujanya Gunturu, Timothy Pham, Sonali Shambhu, Michael Jordan Fisch, John Barron, David Joseph Debono
Journal: Journal of Clinical Oncology (2021)

2625 Background: Immunotherapy is a fast growing class of cancer therapy. We evaluated the rates of immune-related adverse events (irAEs), healthcare utilization, and costs up to 1 year post-index among patients using monotherapy (PD-1/PD-L1 inhibitor) and combination therapy (PD-1/PD-L1 with CTLA-4 inhibitors). Methods: We reviewed claims from the HealthCore Integrated Research Database (HIRD), which contains commercially insured/Medicare Advantage members and captures clinical, utilization, and cost measures. We analyzed both the monotherapy (M) and combination therapy (C) cohorts focusing on members with ≥ 6 months of baseline continuous medical and pharmacy coverage. Descriptive and multi-variate analyses were performed. Results: The C cohort had 904 and M had 9,084 patients, with mean ages of 58 and 64 years, respectively. Prominent cancer types were melanoma for C and lung for M. The most common incident irAEs (%) for C vs. M were: endocrinopathies (27.7, 14.7), hepatitis (17.1, 7.7), nephritis (21.0, 14.0), neuropathy (6.6, 7.0), followed by colitis, dermatitis, and myocarditis. After adjustment, C therapy showed greater risk of all-cause inpatient admissions (OR 2.27, 95% CI 1.93, 2.66), all-cause emergency department (ED) visits (OR 1.55, 95% CI 1.33, 1.81) and irAE-related visits (See table). Mean adjusted all-cause cost difference for C vs M was +$43,747 (95% CI $38,440, $49,427). In age ≥65 subset, 222 received C and 4,208 received M. C therapy patients had more irAE-related hospitalizations (45.3% vs. 57.7%, p=0.0004). Costs were similar to the main cohort. Conclusions: C therapy showed greater incident irAE rates, increased utilization and medical costs compared to M therapy. Limitations include less precise ascertainment of irAEs in claims data and generalizability only to those with commercial or Medicare Advantage insurance. Our study highlights the increased toxicity and cost tradeoffs involved in choosing combination immunotherapy over monotherapy.[Table: see text]
Cancer and COVID-19: A proposed mechanism with therapeutic interventions.
Authors: Yan Leyfman, Nancy Emmanuel, Aleksey Tentler, Jared Cappelli, Timothy K Erick, Pushpa Sharma, Chandler H. Park
Journal: Journal of Clinical Oncology (2021)

3135 Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel betacoronavirus that causes the respiratory illness coronavirus disease 2019 (COVID-19). COVID-19 ranges in severity from an asymptomatic viral infection to life-threatening cases of pneumonia, acute respiratory distress syndrome (ARDS), multi-organ damage and sepsis. Cancer patients are at an increased risk of severe SARS-CoV-2 infection due to their immunocompromised status. We propose a mechanism by which SARS-CoV-2 infection causes multiple organ damage through IL-6-mediated inflammation and hypoxia-induced cellular metabolic alterations leading to cell death. Hypoxia is also induced by malignancy due to alterations in metabolism, resulting in greater IL-6 secretion. Methods: To highlight the possible effect of active cancer on the likelihood of hypoxia in COVID-19, we analyzed the correlation between cancer status and the severity of COVID-19 from the COVID-19 and Cancer Consortium data registry. For cancer status, we looked at progressive cancer and remission of cancer only -- those being the two extremes of presence and absence of uncontrolled cancer. Similar to prior studies, the severity of COVID-19 was used as an indication of hypoxia. Results: We observed a 24% positive deviation between expected and actual number of patients with actively progressing cancer who had hypoxic COVID-19 (moderate to severe), and a 26.9% negative deviation between expected and actual number of patients with active cancer who had no hypoxia with COVID-19 (p&lt;0.0001). Conversely, for patients with cancer in remission, there was only a +5.8% and -5.1% deviation between expected and actual number of patients who did not have hypoxia and who had hypoxia, respectively. Conclusions: These results suggest that in the presence of poorly controlled malignancy, there is an increased likelihood of hypoxia in patients with COVID-19, thereby exacerbating downstream cytokine release syndrome and contributing to prolonged systemic inflammatory injury. Appreciating this pathway, future therapies can be developed to target the pathogenesis of both diseases and prevent progression, as seen with mesenchymal stem cells, which demonstrated a 91% overall survival and 100% survival in patients younger than 85 years old at one month after a single treatment.[Table: see text]
Reducing hospitalizations: Implementation of CADD pumps in infusion clinic at a Los Angeles safety net hospital.
Authors: Tiffanie Thy Do, James Jen-Chi Yeh
Journal: Journal of Clinical Oncology (2021)

e18648 Background: Computerized ambulatory drug delivery (CADD) pumps introduced in the 1980s made it possible to move infusion delivery from the hospital to the home. At Harbor-UCLA Medical Center, hundreds of scheduled chemotherapy admissions occur annually. The procurement and implementation of CADD pumps was a collaborative effort with members of pharmacy, nursing, physicians and administration. The implementation of CADD pumps for home chemotherapy demonstrated a cost-savings by decreasing the number of inpatient hospital days required for scheduled chemotherapy admissions. Methods: The first outpatient chemotherapy infusion by CADD pump began on 12/5/2017. Records from 12/5/2017 through 12/4/2018 (365 days) were reviewed to assess the benefit of CADD pumps, defined by inpatient hospital days avoided. Eight chemotherapy regimens were administered through outpatient CADD pumps; the equivalent number of inpatient hospital days were estimated based on inpatient hospital records between 2015 and 2017. The average number of hospital days that would have occurred inpatient per chemotherapy regimen was multiplied by the number of outpatient CADD pump chemotherapy infusions to estimate the number of inpatient hospital days avoided. Based on information provided by our hospital’s finance department, including reimbursement for inpatient and similar outpatient care, each hospital day avoided was estimated to provide $1,695 in cost-savings. On average, a typical hospitalization for infusional 5-FU chemotherapy was three days in length. Results: Over one year, 35 patients received a total of 178 outpatient CADD infusions. The average number of CADD infusions per patient was five. We estimated that 642 hospital bed days were saved over a 1-year period following the implementation of outpatient CADD pumps. With the estimate that each hospital bed day saved was valued at $1,695, we concluded a savings of $1.1 million dollars at our hospital through the implementation of CADD pumps within the first year. Conclusions: The implementation of CADD pumps for home chemotherapy demonstrated cost-savings by decreasing the number of inpatient hospital days required for scheduled chemotherapy admissions. This shift provides a superior value for the patient with equivalent treatment outpatient, spending less time in the healthcare setting, and reduced health care costs. [Table: see text]
Differentiating the causes of adynamic bone in advanced chronic kidney disease informs osteoporosis treatment
Authors: Mathias Haarhaus, Pieter Evenepoel
Journal: Kidney International (2021)

Patients with chronic kidney disease (CKD) have an increased fracture risk because of impaired bone quality and quantity. Low bone mineral density predicts fracture risk in all CKD stages, including advanced CKD (CKD G4-5D). Pharmacological therapy improves bone mineral density and reduces fracture risk in moderate CKD. Its efficacy in advanced CKD remains to be determined, although pilot studies suggest a positive effect on bone mineral density. Currently, antiresorptive agents are the most commonly prescribed drugs for the prevention and therapy of osteoporosis. Their use in advanced CKD has been limited by the lack of large clinical trials and fear of causing kidney dysfunction and adynamic bone disease. In recent decades, adynamic bone disease has evolved as the most predominant form of renal osteodystrophy, commonly associated with poor outcomes, including premature mortality and progression of vascular calcification. Evolving evidence indicates that reduction of bone turnover by parathyroidectomy or pharmacological therapies, such as calcimimetics and antiresorptive agents, are not associated with premature mortality or accelerated vascular calcification in CKD. In contrast, chronic inflammation, oxidative stress, malnutrition, and diabetes can induce low bone turnover and associate with poor prognosis. Thus, the conditions causing suppression of bone turnover rather than the low bone turnover per se may account for the perceived association with outcomes. Anabolic treatment, in contrast, has been suggested to improve turnover and bone mass in patients with advanced CKD and low bone turnover; however, uncertainty about safety even exceeds that of antiresorptive agents. Here, we critically review the pathophysiological concept of adynamic bone disease and discuss the effect of low bone turnover on the safety and efficacy of anti-osteoporosis pharmacotherapy in advanced CKD.