tbuckley/cabot-search huggingface dataset:
Implementation and impact of a novel multidisciplinary immune-related adverse events tumor board for patients receiving immune checkpoint inhibitor therapy.
Authors: Abhilasha Pankaj Boruah, Kathryn Demski, Pradnya Dinkar Patil, Cassandra Calabrese, Pauline Funchain
Journal: Journal of Clinical Oncology (2021)

e13541 Background: Given the often atypical and diverse presentations of immune-related adverse events, the utilization of an institutional multidisciplinary irAE tumor board is an effective strategy to deliver comprehensive, collaborative, and efficient care to patients experiencing these effects. We report the clinical impact of a multidisciplinary tumor board dedicated towards management of irAEs in patients receiving checkpoint inhibitor therapy. Methods: We completed a retrospective review of patients discussed during our multidisciplinary irAE tumor board at Cleveland Clinic Taussig Cancer Center. Pertinent data collection regarding malignancies, therapies, and reported irAEs was completed through the electronic medical system. Results: Between September 2017-January 2021, 96 patients were discussed in our institutional irAE tumor board. 48 males and 48 females were discussed with the most common primary malignancies being melanoma (53%, 51/96), lung neoplasms (25%, 24/96), and renal cell carcinoma (15%, 14/96). Of the therapies used by these patients, the most frequently associated checkpoint inhibitors were Nivolumab (41%, 39/96), Pembrolizumab (30%, 26/96), and Ipilumumab (17%, 16/96). irAEs affecting the gastrointestinal system such as colitis, hepatitis, and gastritis were most common among discussed patients (40%, 38/96), however several patients also exhibited irAEs targeting the neurological (12.5%, 12/96), rheumatologic (11%, 11/96), dermatologic (8%, 8/96), respiratory (8%, 8/96), and cardiac systems (4%, 4/96). The utilization of tumor board was documented in 41 patients’ notes (43%), with increased documentation over the past year (71%, 24/34), and 70 patients (73%) received a pertinent consult for management of their irAE post tumor board recommendations. Conclusions: Clinical utilization of irAE TB recommendations was high as evidenced by clinical documentation and consequent referrals. Increasing institutional awareness of tumor board over the past year was reflected in a proportionate rise in official documentation. irAE tumor board has the capacity to promote more effective cross-specialty collaboration during treatment of irAEs by both streamlining patient care discussions and encouraging cross-fertilization of therapeutic concepts between multiple subspecialties, and may ultimately increase quality of care for patients experiencing these toxicities.
Healthcare utilization and costs associated with first-line treatment with obinutuzumab- and rituximab-based regimens for follicular lymphoma.
Authors: Jamie T. Ta, Tu My To, Cheryl Sud, Sheila Shapouri, Arpamas Seetasith
Journal: Journal of Clinical Oncology (2021)

e19536 Background: Current real-world data on healthcare utilization (HCU) and costs of common first-line (1L) follicular lymphoma (FL) regimens, including obinutuzumab (G), remain limited. The aim of this study was to examine real-world HCU and costs for the most common National Comprehensive Cancer Network (NCCN)-recommended 1L FL treatments. Methods: This was a retrospective cohort study using administrative claims data from the IQVIA PharMetrics Plus and IBM MarketScan Commercial and Medicare Supplemental databases. We identified patients (pts) ≥18 years, who had ≥1 inpatient claim or ≥2 outpatient claims, with a diagnosis of FL from February 1, 2015 to March 31, 2020, and had received 1L FL treatment (per NCCN guidelines) between February 1, 2016 and September 30, 2019. The first claim for FL treatment was the index date. All pts had ≥12 months of pre- and ≥6 months of post-index continuous enrollment in medical and pharmacy benefits. Pts with other primary cancers, FL treatment, or stem cell transplant during the pre-index period, and clinical trial participation or end-stage renal disease during the study period were excluded. All-cause HCU and costs (2020 USD) per pt during the 6-month post-index period were reported for the five most common 1L FL regimens (only complete NCCN regimens were considered). Results: Overall, 1991 pts met the eligibility criteria, and 53% were male. The mean (standard deviation [SD]) age and Charlson Comorbidity Index at index were 58 (10.4) years, and 1.7 (1.0), respectively. The most common 1L regimens were rituximab-bendamustine (R-benda; n=818 [41.1%]), R-monotherapy (R-mono; n=592 [29.7%]), R-CHOP (n=461 [23.2%]), G-benda (n=86 [4.3%]), and R-CVP (n=34 [1.7%]). The proportion of pts who had ≥1 hospitalization or an emergency room visit was highest with R-CHOP (26.7% and 33.6%, respectively) and lowest with R-mono (11.3% and 18.1%, respectively). Mean (SD) all-cause total healthcare costs were highest with R-benda and G-benda, followed by R-CHOP, R-CVP, and R-mono (Table). Mean (SD) all-cause medical and FL treatment costs (drug and administration) were highest for R-benda ($174,407 [$110,520]; $135,520 [$96,492]) and lowest for R-mono ($87,368 [$83,910]; $54,271 [$40,433]). Conclusions: This real-world study provides an update on HCU and costs among pts initiating current NCCN-recommended 1L treatment for FL. Unadjusted 6-month total healthcare costs were highest with R-benda, followed by G-benda, while the lowest costs were seen with R-CVP and R-mono. Future studies with adjustment for pt characteristics are needed to compare HCU and costs between FL regimens.[Table: see text]
Resource use and costs in patients with relapsed/refractory diffuse large C-cell lymphoma who initiated a third-line therapy in the post CAR-T era: A longitudinal outlook.
Authors: Lei Chen, Jipan Xie, Aozhou Wu, Laura Liao, Ella X. Du, Ahmed Noman, Loretta J. Nastoupil
Journal: Journal of Clinical Oncology (2021)

e19560 Background: The study described longitudinal costs and healthcare resource utilization (HRU) associated with third-line (3L) treatments in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) post chimeric antigen receptor T-cell (CAR-T) approval. Methods: Adult patients newly diagnosed with DLBCL (ICD-10: C83.3) from 10/01/2015 to 03/31/2020 and receiving 3L after CAR-T approval (10/18/2017) were identified from IQVIA PharMetrics Plus. Monthly HRU and total costs were evaluated during month 1, months 2-6, and months 7-12 following 3L initiation for three treatment groups: CAR-T, stem cell transplantation (SCT), and non-cell therapy including chemoimmunotherapy and the targeted therapies that are recommended by the NCCN guidelines (including brentuximab vedotin, ibrutinib, venetoclax, lenalidomide, polatuzumab, obinutuzumab, nivolumab and pembrolizumab). Results: The study identified 145 R/R DLBCL patients initiating 3L with a mean age of 56.7 years and 66.2% male; 135 patients with ≥1 month of follow-up (median 6.7 months) were included: 24 CAR-T, 15 SCT, 96 non-cell therapy. At each time period, CAR-T had the highest median monthly costs, followed by SCT; both had higher median costs than non-cell therapy. The median monthly costs for CAR-T and SCT were $205,034 and $160,423 in month 1, and reduced to $14,333 and $11,840 in months 2-6, then increased to $27,090 and $17,695 in months 7-12, respectively. The monthly median cost for non-cell therapy was $36,015, $11,878, and $4,806 in month 1, months 2-6 and 7-12, respectively. Inpatient (IP) visits and IP days were higher in month 1 than later months for CAR-T and SCT. In addition, outpatient (OP) and emergency room (ER) visits were more frequent for CAR-T than SCT except for ER visits in month 1 (Table). Conclusions: In R/R DLBCL patients receiving 3L, CAR-T had the highest median monthly costs during month 1, months 2-6 and 7-12. In addition, CAR-T has more frequent OP and ER visits compared with SCT in general.[Table: see text] The maximum observed follow-up time for SCT was 8 months. Other visits were mainly home care visits.
Development of extracellular vesicles-based classifier for detection of early-stage bladder, ovarian, and pancreatic cancer.
Authors: Juan Pablo Hinestrosa, Razelle Kurzrock, Jean Lewis, Nick Schork, Ashish M. Kamat, Andrew M. Lowy, Ramez Nassef Eskander, Orlando Perrera, David Searson, Iryna Clark, Heath Balcer, Mark J. Adler, Scott Michael Lippman, Rajaram Krishnan
Journal: Journal of Clinical Oncology (2021)

3048 Background: Many cancers are lethal because they present with metastatic disease. Because localized/resectable tumors produce vague symptoms, diagnosis is delayed. In pancreatic cancer, only ̃10% of patients survive five years, and it will soon become the second leading cause of cancer-related deaths in the USA. For patients with metastatic disease, the 2- and 5-year survival is &lt; 10% and ̃3%, respectively. For the few patients with local disease, 5-year survival is ̃40%. Many other cancers have comparable differences between early- and late-stage disease. It is apparent a diagnostic assay for early-stage cancers would transform the field by minimizing the need for aggressive surgeries and other harsh interventions, and by its potential to increase survival. Identifying cancer-specific aberrations in blood-based “liquid” biopsies offers a prospect for a non-invasive cancer detection tool. In the bloodstream, there are extracellular vesicles (EVs) with cargoes including membrane and cytosolic proteins, as well as RNA and lipids derived from their parent cells. Methods: We used an alternating current electrokinetics (ACE) microarray to isolate EVs from the plasma of stage I and II bladder (N = 48), ovarian (N = 42), and pancreatic cancer patients (N = 44), and healthy volunteers (N = 110). EVs were analyzed using multiplex protein immunoassays for 54 cancer-related proteins. EV protein expression patterns were analyzed using stepwise logistic regression followed by a split between training and test sets (67%/33% respectively). This process enabled biomarker selection and generation of a classifier to discriminate between cancer and healthy donors. Results: The EV protein-based classifier had an overall area under curve (AUC) of 0.95 with a sensitivity of 71.2% (69.4% – 73.0%, at 95% confidence interval) at &gt; 99% specificity. The classifier’s performance for the pancreatic cancer cohort was very strong, with overall sensitivity of 95.7% (94.6% – 96.9%, at 95% confidence interval) at &gt; 99% specificity. Conclusions: EV-associated proteins may enable early cancer detection where surgical resection is most likely to improve outcomes. The classifier’s performance for the initial three cancers studied showed encouraging results. Future efforts will include examining additional cancer types and evaluating the classifier performance using samples from donors with related benign conditions with the aim of a pan-cancer early detection assay.
Breast cancer and molecular testing in Brazil.
Authors: Sabina B. Aleixo, Jose Zago Pulido, Narelle Parmanhane
Journal: Journal of Clinical Oncology (2021)

e13602 Background: Breast cancer is a common malignancy among women worldwide. Regardless of the economic status of a country, breast cancer poses a burden in prevention, diagnosis and treatment.Accurate pathologic and molecular diagnosis of high quality in breast cancer is a challenge in low- and middle-income countries (LMIC). The two most important aspects needed are the hormonal and epidermal growth factor receptor 2 (HER2) status as they are used as prognostic factor and as predictive biomarker for treatment. The most commonly used tests for assessing HER2 status are immunohistochemistry (IHC) assays for HER2 protein expression and fluorescence in situ hybridization (FISH) for HER2 gene amplification.In this study, we evaluated the hormonal and HER2 status of women with breast cancer and the need for FISH in HER2+++. Methods: We retrospectively reviewed the database of the Hospital Evangelico de Cachoeiro de Itapemirim, a regional cancer center from the south of Espirito Santo State – Brazil.The period covered in the study was from 01/08/2019 to 01/08/2020. We analyzed all new cases of invasive breast cancer diagnosed by IHC for the estrogen (ER), progesterone (PR) and HER2 receptors. All the HER 2++ and HER2 +++ were tested by FISH. We had during this period 152 newly diagnosed cases, 11 patients were excluded due to missing data. Results: The 141 cases were separated into four categories by hormonal status: 109 ER+PR+ (77,3%), 9 ER+PR− (6,4%), 2 ER−PR+ (1,4%) and 21 ER−PR− (14,9%). When these results were associated to HER 2 status we found 11 (7,8 %) triple negative breast cancer (TNBC) , 26 (18,43%) HER2 ++ and 23 (16,31%) HER 2+++. The HER2++ were tested by FISH and 8 (30,7%,) were found positive, 10 (38,6%) negative and 8(30,7%)indeterminate. Among the HER 2 +++ tested by FISH we found 15 (65,3 %) positive and 8 (34,7 %) indeterminate. Conclusions: Our study demonstrated a lower incidence of TNBC and higher incidence of hormone-receptor positive cases as compared with other institutions. Different from other countries, all HER 2++ and HER2+++ in Brazil need to go to molecular testing. Altough trastuzumab is available in the public Brazilian Health System (SUS) for HER 2 positive women, diagnosis with IHC alone is not permitted and there is a need for molecular testing confirmation. Therefore, the most troublesome data in this study was that 34,7% of HER 2+++ had indeterminate FISH results, in these cases SUS does not offer traztuzumab. Newer guidelines allow the use of IHC only in HER2 +++ . We consider important for SUS to review the recommendation for need of molecular testing for all HER2 +++ so this will avoid subtreating women in Brazil
Modeling shows the NK3R antagonist, ACER-801, reduces treatment-induced vasomotor symptoms.
Authors: Rebecca Baillie, Chris Schelling, Rick Ridgewell, Katherine Kudrycki, Douglas Chung, Christina Friedrich, Mike Reed
Journal: Journal of Clinical Oncology (2021)

e13013 Background: Hot flashes or vasomotor symptoms (VMS) are a common side effect of hormone deprivation (HD) therapy. Up to 80 % of cancer patients treated with tamoxifen (antiestrogen treatment) or leuprolide (androgen deprivation) have VMS. In some cases, patients discontinue HD therapy due to VMS severity and lower quality of life; therefore, reducing VMS is critical for patient compliance. NK3 receptor (NK3R) antagonists have previously been shown to reduce VMS in postmenopausal women. ACER-801 is a candidate NK3R antagonist drug intended to alleviate VMS severity when used with HD therapy. We used Quantitative Systems Pharmacology (QSP) modeling to predict the likely efficacy of ACER-801 in patients on HD therapy and evaluate the potential of hepatic drug-drug interactions between ACER-801 and tamoxifen or leuprolide. Methods: The model is composed of KNDy neurons in the arcuate nucleus with NKB, dynorphin, and estradiol effects on KNDy neurons, HPG axis, sex hormones, and neuroendocrine feedback. ACER-801, tamoxifen, and leuprolide PK, PD, and hepatic metabolism are included in the model. The model was developed, qualified, and tested using literature data. A tamoxifen-treated postmenopausal female virtual patient (VP) and leuprolide-treated male VP were created based on typical patients included in clinical trials. VMS severity and frequency were estimated based on the level of NKB binding to NK3R. Results: In the male VP, simulated leuprolide administration induced hypertrophy of KNDy neurons and VMS over six months. Coadministration of ACER-801 with leuprolide reduced VMS frequency and severity to near 0 in short-term (5-week) simulations. Simulations predict ACER-801 will not alter leuprolide metabolism nor increase plasma testosterone concentrations. Tamoxifen treatment increased VMS by 15% in simulations with the postmenopausal VP. Coadministration of ACER-801 with tamoxifen in this VP reduced VMS by 75% compared to tamoxifen monotherapy. ACER-801 had minimal effects on plasma estradiol concentrations in the postmenopausal VP. Drug-drug interactions between ACER-801 and tamoxifen were dependent on the simulated bioavailability of ACER-801. Using current estimates of ACER-801 bioavailability in the model, the hepatic concentration of ACER-801 had limited effects on tamoxifen metabolism, which are not expected to necessitate dose adjustments. Conclusions: Using a QSP neurobiology model as a research tool enabled us to evaluate the efficacy of the NK3R antagonist, ACER-801, to treat HD therapy-induced VMS. Simulations show ACER-801 may be highly efficacious for the treatment of induced-VMS. The research provided estimates of DDI with ACER-801 and tamoxifen and what clinical experiments would be needed to confirm those estimates.
EPCT-11. RURALITY INDEX SCORE AND PEDIATRIC NEURO-ONCOLOGICAL OUTCOME IN ONTARIO
Authors: Michelle Kameda-Smith, Gregory Pond, Forough Farrokhyar, Hsien Seow
Journal: Neuro-Oncology (2021)

Abstract Introduction Rapid access to neurosurgical decisions and definitive management are vital for the outcome of neurocritical patients. There are increased challenges of providing services and to maintain critical infrastructure for rural citizens. The relationship between rurality, marginalization and health outcomes has been identified as associated with higher mortality rates and higher rates of many diseases[G1]. Methods Employing linked administrative databases, we retrospectively analyzed a population based cohort of patients diagnosed with a pediatric brain tumour between 1996 to 2017 in Ontario, Canada. The Ontario Marginalization Index was employed as a surrogate for rurality providing an overall Rurality Index for Ontario (RIO) in addition to the 2016 Ontario Marginalization Index (ON-MARG). Results Of 1457 patients included, 54.0% were male, 277 of whom were diagnosed in infancy (i.e., &amp;lt; 3 years of age). Income quintile was evenly distributed with 11.5% classified as living in a rural area of Ontario. The median[G2] distance to the nearest pediatric neurosurgical hospital was 59.6km. The rurality index score (RIO) was 0 in 38.8% of children with the majority of patients with a RIO score of &amp;lt;39. The ON-MARG identified 51.9% of patients living in communities with low concentration of individuals without income from employment. A higher RIO score was not a significant factor (Continuous p=0.092/Ordinal p=0.20) associated with length[G3] of follow up, indicating rurality was not a significant factor for determining compliance to[G4] clinical follow-up. However, a trend towards reduced follow-up compliance in the higher RIO score cohort was identified. Conclusion Rurality and social determinants of health of the region pediatric neuro-oncological patients reside were not associated with patient outcome but a trend towards lower follow-up compliance was identified when children were from regions with RIO&amp;gt;39. Implementation of telehealth follow-up for these patients may overcome barrier to clinical follow-up.[G5]
Abstract 241: MDM2 E3 Ligase-mediated Ubiquitination and Degradation of HDAC1 in Vascular Calcification
Authors: Hyun Kook, Duk-Hwa Kwon, Gwang Hyeon Eom, Hyun-Ki Min, Somy Yoon, Yong Sook Kim, Youngkeun Ahn
Journal: Circulation Research (2016)

Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.
SIENDO/ENGOT-EN5/GOG-3055: A randomized phase 3 trial of maintenance selinexor versus placebo after combination platinum-based chemotherapy in advanced or recurrent endometrial cancer.
Authors: Ignace Vergote, Jose Alejandro Perez-Fidalgo, Erika P. Hamilton, Toon Van Gorp, Giorgio Valabrega, Annouschka Laenen, Amit M. Oza, Tally Levy, David Cibula, Jalid Sehouli, Eva Guerra, Hye Sook Chon, Alice Bergamini, Ignacio Romero, Dayana Michel, Jatin J. Shah, Bradley J. Monk, Brian M. Slomovitz, Mansoor Raza Mirza, Vicky Makker
Journal: Journal of Clinical Oncology (2021)

TPS5610 Background: Endometrial cancer (EC) is the most common gynecologic malignancy. Options for advanced or recurrent EC following platinum-based therapy and/or radiotherapy are limited and prognosis remains poor. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone is approved for relapsed/refractory multiple myeloma. In addition, selinexor monotherapy has demonstrated broad activity in other hematologic malignancies and solid tumors. In a phase 2 study, 50 mg/m 2 (̃80 mg) selinexor administered twice weekly demonstrated a disease control rate ( SD ≥ 12 weeks or a PR) of 35% with 2 confirmed partial responses among 23 heavily pretreated EC patients); similar results were observed in 60 pts with platinum resistant or refractory ovarian cancer (median 5 prior regimens, ORR 8%, DCR 30%) (Vergote I et al. Gynecol Oncol 2020). In the absence of approved maintenance therapies, we conducted this study to evaluate the efficacy of selinexor compared with placebo as maintenance therapy in patients with advanced or recurrent EC following platinum-based chemotherapy. Methods: This is a multicenter, double-blind, placebo-controlled, randomized phase 3 study in patients in partial (PR) or complete remission (CR) after completing at least 12 weeks of taxane-platinum combination therapy for primary Stage IV disease and recurrent disease (i.e., relapse after primary therapy for early stage disease including surgery and/or adjuvant therapy). A total of 248 patients will be enrolled at 80 sites in Europe, North America, and Israel. Patients will be randomized in a 2:1 ratio to either maintenance therapy with 80 mg oral selinexor once weekly or placebo. Stratification factors include primary Stage IV versus first recurrence at the time of taxane-platinum therapy and disease status after chemotherapy (PR vs CR). Treatment will continue until disease progression. The primary endpoint is progression free survival (PFS) per RECIST v1.1. Secondary endpoints include disease-specific survival, overall survival, time to first subsequent therapy, time to second subsequent therapy, PFS on subsequent therapy and safety and tolerability. The study is currently open and enrolling patients. Clinical trial information: NCT03555422.