tbuckley/cabot-search huggingface dataset:
Gene expression-based outcome prediction in advanced stage classical Hodgkin lymphoma treated with BEACOPP
Authors: Ron D. Jachimowicz, Wolfram Klapper, Gunther Glehr, Horst Müller, Heinz Haverkamp, Christoph Thorns, Martin Leo Hansmann, Peter Möller, Harald Stein, Thorsten Rehberg, Bastian von Tresckow, H. C. Reinhardt, Peter Borchmann, Fong Chun Chan, Rainer Spang, David W. Scott, Andreas Engert, Christian Steidl, Michael Altenbuchinger, Andreas Rosenwald
Journal: Leukemia (2021)

Classical Hodgkin Lymphoma (cHL) is a B cell-derived lymphoid malignancy, affecting 2.5-3/100,000 people per year.To date, in patients diagnosed with advanced cHL no reliable tool is able to-a priori-distinguish the subset of patients at high risk for relapse or refractory disease.Clinical risk indices for cHL, such as the International Prognostic Score (IPS), have not been successfully applied as a treatment decision tool in advanced stage cHL [1].In this study we show, that a previously published gene expression-based predictor in advanced stage cHL patients treated with ABVD [2] does not prove prognostic in 401 BEACOPP-treated advanced stage cHL patients.Using transcriptome profiling, we identified however that three individual genes, PDGFRA, TNFRSF8 (encoding CD30) and CCL17 (encoding TARC), were significantly associated with progression-free survival (PFS) after multiple test correction in the BEACOPP-treated cohort, highlighting the potential of a modified gene expression profiling approach for pre-treatment risk assessment.In search of a predictive tool in advanced stage cHL patients, we have applied the previously published 23-gene gene expression-based predictor [2], that is prognostic for overall survival (OS) in patients with locally extensive and advanced stage disease treated with ABVD chemotherapy in a distinct cohort of patients with advanced-stage cHL patients treated with BEACOPP-based regimens.In particular, we explored the relationship of the predictor score
Can COV Direct: Effectiveness of a tele-medicine self- care interventions for cancer survivors during COVID 19 pandemic.
Authors: Narayanankutty Edavalath Warrier, Uma V Sankar, Sreedharan P. S., Prasanth V. Parameswaran, Sajeevan K. V., Nirmal V
Journal: Journal of Clinical Oncology (2021)

1583 Background: Good mental health improves the overall quality of life. Anxiety and depression in post-treatment cancer survivors is common and can affect adversely on the individual. CanCovDirect is a novel, tele-medicine self-care intervention for cancer survivors. We practiced a randomized controlled superiority trial to compare CanCovDirect with usual standard care (SC) in this population.Methods: Individuals completing cancer treatment within the past 3 years who had symptoms with or without anxiety or depression were recruited from clinical and community settings in Northern Kerala. We allocated the participants using block randomization (CanCovDirect plus SC or to SC alone). Assessments of anxiety and depression severity (Centre for Epidemiological Studies-Depression scale [CES-D]; primary outcome) and secondary outcomes anxiety symptoms (Hospital Anxiety and Depression Scale) health-related quality of life (Short Form Survey-12 mental and physical component summaries), were conducted at baseline, as well as 3 and 6 months (primary time point). Analyses of outcomes were adjusted for covariates using linear regression. Results: Participants recruited between June 2020 and November 2020 were randomly assigned to CanCovDirect (n = 152) or SC (n = 152). Among 350 participants randomly assigned, 304 (86.85%) completed the primary outcome at 6 months. CanCovDirect participants reported less severe anxiety and depressive symptoms on the CES-D than SC participants at 6 months, adjusted effect size (ES) 1.68 (95% CI, 1.28 to 2.05). CanCovDirect participants also had significantly greater quality of life compared with SC. Exploratory analysis suggested that types of cancer was a modifier of the primary outcome (interaction term P value =.04); the intervention was effective in women (ES, 0.62; 95% CI, −0.45 to 0.89). Conclusions: CanCovDirect is an essential method of managing mild-moderate depression and anxiety symptoms in cancer survivors.
Highly selective and potent p16-CDK-RB-E2F targeted oncolytic virus therapies.
Authors: Clodagh O'Shea, Shigeki Joseph Miyake-Stoner, Colin J. Powers, William Partlo
Journal: Journal of Clinical Oncology (2021)

e14543 Background: Growth factor and p16-CDK-RB-E2F pathway components are mutated in almost all cancers, resulting in oncogenic E2F transcriptional activity that drives uncontrolled proliferation. Chemotherapies indiscriminately kill all proliferating cells, resulting in limiting toxicities. CDK inhibitors are more targeted but cytostatic as opposed to tumoricidal. E2F was discovered as a factor that transcribes adenovirus (Ad) E2 and cellular genes to drive viral replication. Ad E1A binds to RB, which activates E2F. On this basis, viruses with E1A-RB binding mutations are being evaluated in the clinic as oncolytic viruses (OVs) that selectively replicate in and kill RB mutant tumor cells. However, E1A-RB mutations alone are not sufficient to prevent viral replication in normal cells. The addition of ‘tumor specific promoters’ improves tumor selectivity but drastically impacts replication and lytic activity. Therefore, a critical unmet need is the engineering of E2F addicted OVs that replicate like wildtype viruses in tumor cells, but leave normal cells unharmed. Methods: We have developed a proprietary platform that enables Ad therapeutics to be assembled from libraries of functional genomic parts that confer desirable properties. Here we describe E1 and E4 genomic modules that confer E2F dependent tumor selective replication. We assembled a panel of ̃50 viruses with combinations of mutations that ablate i) E1A interactions with RB/p107/p130 and/or EP300 ii) E4-ORF1 activation of PI3-Kinase and/or MYC iii) E4-ORF6/7 induced E2F1/DP1 dimerization. These viruses were screened in panels of primary, tumor, and CRISPR-engineered cells. Results: These studies reveal that E4-ORF6/7 functions independently of E1A to activate E2F transcriptional targets, S phase entry and viral replication. We show that viruses with both E1A and E4-ORF6/7 mutations (AdSyn-181) have the ideal tumor selectivity/efficacy profiles and outperform existing OVs. We also show that the deletion of p16 in primary cells rescues AdSyn-181 replication by ̃15 fold (̃20% wildtype virus), demonstrating the E2F dependence and tumor selectivity mechanism. Furthermore, we show that in tumor cells, which have multiple p16-CDK-RB pathway mutations, AdSyn-181 replication is rescued to 100% wildtype virus levels. ICVB-1042, which incorporates these selectivity mutations – together with other modules that enhance lytic cell death and spread, tumor tropisms and IV delivery – is in IND-enabling studies. Conclusions: Leveraging extensive research into the overlapping logic of viral and cancer pathways, we have engineered OVs, including ICVB-1042, that distinguish between tumor and normal cell proliferation. Furthermore, unlike therapies that target a single component, ICVB-1042 targets tumors with different p16-CDK-RB mutations, which all converge in activating oncogenic E2F transcription, driving exponential and tumoricidal viral replication.
Nivolumab and stereotactic radiosurgery for patients with breast cancer brain metastases: A non-randomized, open-label phase Ib study.
Authors: Kamran A. Ahmed, Youngchul Kim, John Arrington, Sungjune Kim, Michelle DeJesus, Aixa Soyano, Avan J. Armaghani, Ricardo L Costa, Hung T. Khong, Marilin Rosa, Jimmy J. Caudell, Roberto Diaz, Timothy J. Robinson, Arnold B. Etame, Nam D. Tran, Solmaz Sahebjam, Hatem Hussein Soliman, Peter A. J. Forsyth, Hsiang-Hsuan Michael Yu, Hyo S. Han
Journal: Journal of Clinical Oncology (2021)

e14010 Background: There may be a potential synergy intracranially between stereotactic radiation and immune checkpoint inhibition in brain metastases management. We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated and may improve intracranial tumor control rates compared to SRS alone in the management of breast cancer brain metastases. Methods: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase Ib trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥ 18, ECOG ≤ 2 with ≤ 10 brain metastases. The primary objective was to evaluate the safety and feasibility of study therapy. Secondary objectives included evaluation of local brain metastasis control, distant brain metastasis control, progression free survival (PFS), and overall survival following study therapy. Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) and immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria were used to assess intracranial and extracranial disease, respectively. Treatment was initiated with a dose of nivolumab (480 mg IV) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. Results: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. Median follow-up from start of protocol therapy is currently 9.6 months (range: 2.8-18.7 months). No dose limiting toxicities (DLTs) were noted in our patient population. The most common neurologic adverse events included grade 1-2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% CI 3.0 -14) with 6 and 12 month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic PFS has not been reached with 6 and 12 month rates of 63% and 51%, respectively. Conclusions: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary studies reveal activity in certain breast cancer patients to study therapy. Clinical trial information: NCT03807765.
Cancer care in the time of COVID-19: A conceptual framework to improve cancer outcomes during a pandemic.
Authors: Vivienne Milch, Cleola Anderiesz, Debra Hector, Scott Turnbull, Melissa Austen, Rhona Wang, Carolyn Der Vartanian, Dorothy Mary Kate Keefe
Journal: Journal of Clinical Oncology (2021)

e18628 Background: At the start of the COVID-19 pandemic, a plan for cancer management during a pandemic did not exist. It soon became clear that without proper planning, cancer outcomes would worsen. Cancer patients are at increased risk of COVID-19 infection, morbidity, and mortality. Health sectors internationally reduced or paused non-urgent cancer care to protect cancer patients from COVID-19. However, disproportionate delays in screening, diagnosis, and treatment can unduly impact cancer outcomes, and backlogs can further burden a strained health system. Tailored approaches to cancer management are required which balance health resource availability along with the risks of exposure and benefits of treatment. Australia’s relatively low COVID-19 case numbers afforded Cancer Australia an opportunity to proactively plan for optimal cancer management during this, and future, pandemics. Methods: Cancer Australia’s Cancer care in the time of COVID-19: A conceptual framework for the management of cancer during a pandemic (the framework) maps evidence-based cancer care considerations in relation to a health system’s capacity across acute and recovery pandemic phases, in relation to steps of the cancer care pathway. The framework promotes infection control and resource prioritisation in the context of innovative care models, triaging approaches and individualised treatment plans, underpinned by effective communication and shared decision-making. Results: The framework supports health system planning and risk-stratified approaches to guide decision-making and improve cancer outcomes. Many aspects of cancer care are recommended to continue (to varying degrees) in most pandemic phases, with modifications or pauses in some aspects of care as the pandemic curve approaches or exceeds health system capacity. Principles of the framework were employed during the second wave of COVID-19 in the Australian state of Victoria, with continuation of cancer screening programs, diagnostic investigations, and treatments wherever it was safe to do so. This resulted in reductions in cancer services and treatment being relatively smaller than in the first wave. Conclusions: Cancer management in a pandemic is not a one-size-fits-all. Countries and jurisdictions need to tailor cancer care according to the risk of the health system becoming overwhelmed. The framework guides optimal cancer care to improve outcomes for people with cancer, while minimising COVID-19 infection. As further evidence becomes available from this pandemic or in future pandemics, this framework can be refined to inform ongoing and future pandemic health system planning.
Specific and behaviorally consequential astrocyte Gq GPCR signaling attenuation in vivo with iβARK
Authors: Jun Nagai, Arash Bellafard, Zhe Qu, Xinzhu Yu, Matthias Ollivier, Mohitkumar R. Gangwani, Blanca Diaz-Castro, Giovanni Coppola, Sarah M. Schumacher, Peyman Golshani, Viviana Gradinaru, Baljit S. Khakh
Journal: Neuron (2021)
A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression
Authors: Peter Nagele, Ben J. Palanca, Britt Gott, Frank Brown, Linda Barnes, Thomas Nguyen, Willa Xiong, Naji C. Salloum, Gemma D. Espejo, Christina N. Lessov-Schlaggar, Nisha Jain, Wayland W. L. Cheng, Helga Komen, Branden Yee, Jacob D. Bolzenius, Alvin Janski, Robert Gibbons, Charles F. Zorumski, Charles R. Conway
Journal: Science Translational Medicine (2021)

Twenty-five percent inhaled nitrous oxide improves symptoms of treatment-resistant major depression with fewer adverse effects than the 50% concentration.
Incorporating oral PrEP into standard prevention services for South African women: a nested interrupted time-series study
Authors: Deborah Donnell, Ivana Beesham, Julia D Welch, Renee Heffron, Melanie Pleaner, Lara Kidoguchi, Thesla Palanee-Phillips, Khatija Ahmed, Deborah Baron, Elizabeth A Bukusi, Cheryl Louw, Timothy D Mastro, Jennifer Smit, Joanne R Batting, Mookho Malahleha, Veronique C Bailey, Mags Beksinska, Helen Rees, Jared M Baeten, Peter B Gichangi, Kate B Heller, Nomthandazo Mbandazayo, Charles S Morrison, Kavita Nanda, Caitlin W Scoville, Kathleen Shears, Petrus S Steyn, Douglas Taylor, Katherine K Thomas, James Kiarie, Jessica Justman, Zelda Nhlabatsi, Linda-Gail Bekker, Gonasagrie Nair, G Justus Hofmeyr, Mandisa Singata-Madliki, Raesibe Agnes Pearl Selepe, Sydney Sibiya, Margaret Phiri Kasaro, Jeffrey Stringer, Nelly R Mugo
Journal: The Lancet HIV (2021)
Development and validation of an improved pathologic nodal classification system for cutaneous melanoma.
Authors: Anthony Tuan Nguyen, Michael Luu, Vina Nguyen, Omid Hamid, Mark B. Faries, Nima M. Gharavi, Diana J. Lu, Jon Mallen-St. Clair, Allen S. Ho, Zachary Stephan Zumsteg
Journal: Journal of Clinical Oncology (2021)

e21563 Background: Given recent therapeutic advances and evolving patterns of lymph node (LN) evaluation for cutaneous melanoma, accurate and precise LN staging is needed to guide adjuvant treatment and future investigations. Current staging was developed primarily for patients undergoing completion LN dissection (CLND) for node-positive disease and do not produce LN classification groups with continuously increasing mortality. Thus, we developed and validated an improved LN classification system for cutaneous melanoma. Methods: Retrospective cohort analysis of 105,785 patients with cutaneous melanoma who underwent surgery from 2004 to 2015 in the National Cancer Database. Extent of LN dissection (sentinel LN biopsy [SLNB] and/or CLND) was available for patients diagnosed 2012 onward. Multivariable models were generated with number of positive LNs modeled using a non-linear restricted cubic spline function. Recursive partitioning analysis (RPA) was used to derive a modified LN classification system based on LN variables independently associated with overall survival (OS). The proposed LN classification system was validated in 85,499 patients from SEER-18. Results: Number of positive LNs (1-2 LN+: hazard ratio [HR] 2.48 per LN, 95% CI, 2.37-2.61, P&lt; 0.001; ≥3 LN+: HR 1.10 per LN, 95% CI, 1.07-1.13, P&lt; 0.001), clinically detected metastases (HR 1.35, 95% CI 1.27-1.42; P&lt; 0.001), and in-transit metastases (HR 1.48; 95% CI 1.34-1.65; P&lt; 0.001) were associated with OS. An RPA-derived LN classification system using these variables demonstrated continuously increasing mortality risk for each proposed LN classification group (HR: 1.83, 2.72, 3.79, 4.56, 6.15, and 8.25 for the proposed N1a-N3b groups, Table, P&lt; 0.001). By contrast, AJCC 8E produced a more haphazard mortality profile (HR: 1.83, 3.81, 2.59, 2.71, 4.51, 3.44, 6.06, 8.15, and 6.90 for N1a-N3c). As a sensitivity analysis, the proposed system continued to accurately predict outcomes when we excluded patients undergoing CLND for microscopic LN metastases. Lastly, we validated this system for OS and cause-specific mortality in SEER-18 ( P&lt; 0.001). Conclusions: A modified and simplified LN classification system can accurately predict mortality in cutaneous melanoma in an era of increasing use of SLNB without CLND and should be considered for future staging systems.[Table: see text]
The impact of a genomic sequencing classifier (GSC) on clinical decision making in patients with a high-risk lung nodule.
Authors: Sonali Sethi, Scott Oh, Alexander Chen, Christina Bellinger, Lori Lofaro, Jennifer Tom, Marla Johnson, Jing Huang, Sangeeta Maruti Bhorade, Giulia Kennedy
Journal: Journal of Clinical Oncology (2021)

8549 Background: Current guidelines recommend that patients who have lung nodules with high risk of malignancy (ROM) ( &gt; 65%) should undergo surgical and other ablative therapies. However, prior studies have shown that clinicians may opt for more conservative management in these high-risk patients. Percepta Genomic Sequencing Classifier (GSC), a RNA-seq based classifier derived from bronchial epithelial cells to assess risk of lung cancer, was designed to risk stratify lung nodules by both down classifying ROM as a “rule -out“ test with high sensitivity as well as up-classifying ROM as a “rule- in” test with high specificity for malignancy. This study assesses the impact of up-classification of high ROM to very high- risk (ROM &gt; 90%) by Percepta GSC in increasing the number of ablative therapies recommended for high-risk lung nodules. Methods: This prospective randomized decision impact survey included 37 patients from the AEGIS I/ II cohorts and the Percepta Registry who were undergoing work up of a lung nodule and had a high ROM that was up-classified to very high ROM by Percepta GSC. 97 physicians assessed 10 randomly assigned patient cases. They then responded to a survey designed to test the hypothesis that including a Percepta GSC result will increase the recommendation for surgical or other ablative therapy in very high- risk patients as well as their level of confidence of this recommendation. Physicians were first presented with the patient’s clinical information without Percepta GSC and then with Percepta GSC. Results: 97 physicians provided a total of 682 evaluations of 37 patients. In this study, the recommendation for surgical or other ablative therapy increased from 19/341 (5.6%) prior to the Percepta GSC result to 157/341 (46%) after the Percepta GSC result (odds ratio of 4.76, p-value &lt; 0.001). The number of extremely confident recommendations increased from 72/341 (21%) without Percepta GSC to 106/341 (31%) with Percepta GSC. Significantly more physicians had increased confidence in their recommended next step post-Percepta GSC when collapsing the confidence level responses into increased confidence (n = 93) and decreased confidence (n = 44) (p-value = 0.002). Conclusions: Percepta GSC had a quantifiable impact on clinical decision making. It increased the number of surgical and other ablative therapies recommended when patients were re-classified from high to very high- risk of lung cancer with a higher confidence in the recommended next step. By up-classifying nodules from high to very high ROM, Percepta GSC will improve the likelihood and timeliness of appropriate therapies and assist clinicians more effectively manage patients to improve patient outcomes.
Efficacy of naxitamab in patients with refractory/relapse (R/R) high-risk neuroblastoma (HR-NB) by bone/bone marrow (BM) evaluation, potential sites of residual disease.
Authors: Brian H. Kushner, Daniel A. Morgenstern, Karsten Nysom, Melissa K. Bear, Karen Tornøe, Nedjad Losic, Jaume Mora
Journal: Journal of Clinical Oncology (2021)

10022 Background: NB is the most common extracranial solid tumor in children and half of patients present with high-risk disease. Bone and BM are frequent sites of metastatic disease and can serve as a reservoir for residual disease driving relapse. Naxitamab, a GD2-binding monoclonal antibody, was recently approved in the United States in combination with GM-CSF for the treatment of pediatric patients ≥1 year of age and adult patients with R/R HR-NB in the bone/BM who have demonstrated a partial response (PR), minor response (MR), or stable disease (SD) to prior therapy. Here we describe outcomes from the registrational Trial 201 (NCT03363373) detailed by bone/BM involvement. Methods: HR-NB patients with primary refractory disease or incomplete response to salvage treatment following relapse or progressive disease (PD) (in both cases including SD, MR and PR) with disease limited to bone and/or BM were eligible. Naxitamab was administered over ≥30 min in the outpatient setting on Days 1, 3 and 5 at 3 mg/kg/infusion (9 mg/kg/cycle) in combination with GM-CSF at 250 µg/m2/day on Days -4 to 0 and at 500 µg/m2/day on days 1 to 5. Treatment cycles were repeated every 4 weeks. Response was assessed after Cycle 2 and then every 2-3 months by revised International Neuroblastoma Response Criteria (INRC) using BM biopsies/aspirates and 123I-MIBG scintigraphy or FDG-PET. Effectiveness was concluded if the lower limit of the Clopper-Pearson exact 95% confidence interval (CI) of overall response rate (ORR) was &gt;20%. We report efficacy data on 22 patients and safety data on the first 25 patients enrolled. Results: 13 (59%) patients had NB in bone, 2 (9%) had NB in BM, and 7 (32%) had NB in both bone and BM. Summary of overall response and response by compartment. Conclusions: Naxitamab provided clinically meaningful activity in both bone and BM with ORR of 68% and had a manageable AE profile. Clinical trial information: NCT03363373. [Table: see text]