tbuckley/cabot-search huggingface dataset:
Patients with advanced solid cancers treated with ERK inhibitors exhibit pseudo-progession in lymphatic nodes.
Authors: Reem Abo-Zahrah, Daniel D. Karp, Abha Adat, Timothy A. Yap, Siqing Fu, Jordi Rodon Ahnert, Sarina Anne Anne Piha-Paul, Apostolia Maria Tsimberidou, Aung Naing, Vivek Subbiah, Ecaterina Elena Dumbrava, Michael J. Overman, Sapna Pradyuman Patel, Rodabe Navroze Amaria, Shannon Neville Westin, Funda Meric-Bernstam, Filip Janku
Journal: Journal of Clinical Oncology (2021)

3138 Background: ERK1/2 signaling is often overactivated in cancer, especially in patients with molecular alterations activating the MAPK pathway. MAPK pathway inhibition can result in the increase of CD8+ and CD4+ T-cells and decreased expression of immunosuppressive cytokines. Methods: This is a retrospective study of 52 patients with advanced solid cancers and oncogenic alterations in the MAPK pathway, who were treated in phase I/II clinical trials with five different single agent ERK1/2 inhibitors at MD Anderson Cancer Center. We reviewed serial PET and/or CT imaging obtained before therapy, on therapy, and after therapy completion. We evaluated dynamic changes in the lymphatic nodes (LN) in the context of overall response per RECIST 1.1 and other outcomes. Results: Of the 52 patients, 19 (37%) patients were evaluated with serial PET/CT and 33 (63%) with serial CT imaging only. Of the 19 patients evaluated with PET/CT, 12 (63%) demonstrated increased FDG uptake in LN compared to pre-treatment imaging (LN enlargement, n = 9; no LN enlargement, n = 3) discrepant from the known target and non-target lesions. These 12 patients were on therapy with ERK inhibitors (11 at doses &gt; recommended phase 2 dose [RP2D]) for a median of 3.6 months (range, 1.8-12 months) with a best response per RECIST 1.1. as follows: partial response, n = 1; stable disease (SD), n = 10; progressive disease (PD), n = 1. Of interest, in 6 of those 12 patients, FDG uptake in LN decreased or resolved after treatment discontinuation. Further, one patient had a biopsy of an emerged LN, which showed lymphocytic infiltrate without tumor cells. Of the 33 patients evaluated with CT only, 5 (15%) demonstrated increased size of LN discrepant from the known target and non-target lesions compared to pre-treatment imaging. These 5 patients were on therapy with ERK inhibitors (all at doses &lt; RP2D) for a median of 1.4 months (range, 1.1-3.5 months) with a best response per RECIST 1.1. as follows: SD, n = 2; PD, n = 3. Of interest, in 2 of those 5 patients, size of LN decreased or resolved after treatment discontinuation. In addition, one patient had a biopsy of an emerged LN, which showed lymphoid aggerates without tumor cells. Conclusions: Our data suggest that treatment with ERK inhibitors can result in activation of the lymphatic nodes, which can manifest as pseudo-progression. This can lead to an inconclusive assessment of their therapeutic benefit and further suggests exploration of the potential synergistic effects with immune therapy.
Excess deaths from COVID-19 and other causes by region, neighbourhood deprivation level and place of death during the first 30 weeks of the pandemic in England and Wales: A retrospective registry study
Authors: Evangelos Kontopantelis, Mamas A. Mamas, Roger T. Webb, Ana Castro, Martin K. Rutter, Chris P. Gale, Darren M. Ashcroft, Matthias Pierce, Kathryn M. Abel, Gareth Price, Corinne Faivre-Finn, Harriette G.C. Van Spall, Michelle M. Graham, Marcello Morciano, Glen P. Martin, Tim Doran
Journal: The Lancet Regional Health - Europe (2021)

Excess deaths during the COVID-19 pandemic compared with those expected from historical trends have been unequally distributed, both geographically and socioeconomically. Not all excess deaths have been directly related to COVID-19 infection. We investigated geographical and socioeconomic patterns in excess deaths for major groups of underlying causes during the pandemic.
Survivorship care plans and adherence with surveillance schedule in patients with invasive melanoma.
Authors: Hemali Shah, Paul Feustel, Lindy Davis
Journal: Journal of Clinical Oncology (2021)

e24079 Background: Melanoma accounts for 5.5% of new cancer diagnoses in the United States, and the 5-year overall survival is 93%. Overall, 7% of patients develop a recurrence, and 4-8% develop a second primary melanoma. This study aimed to assess how the standards set by the American College of Surgeons Commission on Cancer (CoC) to provide survivorship care plans (SCP) to patients may improve adherence to surveillance visits. Methods: All patients treated for invasive melanoma at our institution between 8/2018-2/2020 were included. SCP containing stage, treatment summary, and surveillance plan were delivered in-person to patients and sent to primary providers and dermatologists as outlined by CoC Standards for Optimal Care. Psychosocial distress (PSD) screening was performed using the National Comprehensive Cancer Network Distress Thermometer, with scores &gt; 4 requiring further evaluation by oncology social worker. SCP and PSD were provided during the initiation phase of our cancer care program, and half the patients received services. Surveillance adherence was determined from chart review. The two groups were compared by t-test for continuous or chi-square test for categorical variables. Multiple regression analysis with odds ratios were performed. Mann-Whitney analysis was performed to assess the impact of SCP on PSD. Results: Of 146 patients identified for our cohort, 73 received SCP and PSD screening. Stage IA was the most common diagnosis (44%), followed by IB (13%) and IIIC (9%). Ninety-eight patients (67%) were adherent to all surveillance visits, and 55 of these received SCPs. Most patients noted low distress without the need for further support (79%), and 12 (21%) scored ≥4, benefiting from emotional and financial support and appointment and health insurance navigation. High PSD score did not correlate with advanced stage. Reception of SCP (p = 0.036) and close distance to treating facility (p = 0.016) improved adherence to surveillance visits. For patients who did not receive SCP, likelihood to follow up decreased by a factor of 0.469 (95% CI 0.231 - 0.952). Sex, age, PSD score, and stage did not affect surveillance adherence (p = NS). There were 6 recurrences, of which 4 were physician-detected during surveillance, and 8 patients developed second primary melanomas, all physician-detected. Conclusions: Delivery of SCP, a component of which includes counseling regarding signs and symptoms of recurrence or possibility of second primary melanoma, leads to significantly higher rates of surveillance adherence. This was shown for all stages. Melanoma survivors require close clinical follow-up, as demonstrated by our study finding that even with patient education, most recurrences and all new primary melanomas were physician-detected. PSD among melanoma patients is common, and all patients regardless of stage should undergo screening, as even early-stage patients exhibited distress.
Predictors of inpatient admission for pediatric cancer patients visiting the emergency department.
Authors: Terrence C. Lee, Edmund M. Qiao, Alexander S. Qian, Vinit Nalawade, Rohith S. Voora, Nikhil V. Kotha, Christian Dameff, Christopher John Coyne, James Don Murphy
Journal: Journal of Clinical Oncology (2021)

e22019 Background: Pediatric cancer patients represent a vulnerable cohort at risk of adverse outcomes after presenting to the emergency department (ED). Given the severity of cancer-related complications and uniqueness of this population, approaches to better risk stratify this cohort could potentially help define future interventions geared towards improving outcomes. We used a high-dimensional machine learning approach to help define the risk of hospitalization after an ED visit among pediatric patients with cancer. Methods: A cohort of cancer patients under 18 was identified from the Nationwide Emergency Department Sample (NEDS) between 2016-2018. We used a lasso regression model to predict inpatient admission after an ED visit. Model covariates included patient demographics, hospital characteristics, and International Classification of Diseases, version 10 (ICD-10) diagnosis codes. The data were split 75%/25% into training/testing data. The model was constructed with training data, and performance assessed on the test data using the area under the curve (AUC), with an AUC of 1.0 indicating perfect prediction. Results: We identified 129,631 pediatric cancer patients who visited the ED, of which 54.5% were subsequently admitted. The final predictive model included 150 variables, including 9 demographic, 6 hospital, and 135 unique ICD-10 codes. The model demonstrated excellent ability to predict hospitalization with an AUC of 0.96. The top 5 most important variables associated with inpatient admission were diagnoses of paralytic ileus/intestinal obstruction, neutropenia, sepsis, aplastic anemia/bone marrow failure, and bacterial infection. Conclusions: Pediatric cancer patients frequently present to the ED with complications of their cancer or their treatment, and over half of these patients are admitted. This study demonstrates the capacity of high-dimensional prediction models to help identify pediatric patients at risk of hospitalization. Additional research is needed to determine how to implement these predictive models in clinical practice.
Sintilimab plus anlotinib as first-line therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: Xiaofeng Chen, Wei Li, Xiaofeng Wu, Fengjiao Zhao, Deqiang Wang, Hao Wu, Yanhong Gu, Xiao Li, Xiaofeng Qian, Jun Hu, Changxian Li, Yongxiang Xia, Jianhua Rao, Aihua Yao, Poshita kumari Seesaha, Qianwen Shao, XiaoWei Dong, Xiangcheng Li, Yongqian Shu
Journal: Journal of Clinical Oncology (2021)

e16146 Background: The synergic combination of anti-PD-1/PD-L1 and antiangiogenic agents has exhibited as an encourage treatment pattern in aHCC. Multi-targeted antiangiogenic TKIs, such as lenvatinib and sorafenib, are approved for 1st-line treatment of aHCC. Sintilimab, a novel selective anti-PD-1 monoclonal antibody, has demonstrated encouraging clinical activities in aHCC. The trial aims to explore the safety and efficacy of sintilimab plus anlotinib (a TKI against angiogenesis) in aHCC. Methods: This is a single-arm phase 2 study. Eligible Pts with aHCC, BCLC stage C or B (not amenable for surgery and chemoembolization), Child-Pugh scores≤7 and ECOG PS ≤ 1 received 1st-line treatment of sintilimab (200mg, iv, D1) plus anlotinib (12mg, po, QD, D1-14) every 3 wks until disease progression or unacceptable toxicity. Primary endpoints were safety and objective response rate (ORR, per RECIST 1.1), and secondary endpoints included disease control rate (DCR), progression free survival (PFS), duration of response (DOR) and overall survival (OS). Results: As of January 15, 2021, 20 pts were enrolled (males 18 ; median age 56 yrs [range 41-70] ; BCLCB/C: 5/15 ; Child-Pugh A/B7: 19/1 ; HBV infection 20). All pts received at least two cycles of treatments with median cycles 7.5 [range 2-22]. Median follow-up was 12 months [range 3-19]. The most common treatment-related adverse events (TRAEs) were grade 1-2 with thrombocytopenia (45.0%), hand-foot syndrome (40.0%), hypertension (35.0%), increased AST (35.0%), ALT (30.0%), decreased neutrophil count (25.0%), leukopenia (25.0%). 8 pts experienced manageable grade 3 TRAEs, and no grade 4/5. 12 pts required dose reduction of anlotinib (9 pts to 10 mg and 3 to 8 mg). No treatment withdraw caused by TRAEs. ORR was 40.0% (8/20) with 1 CR and 7 PR, 11 pts were SD, and DCR was 95.0% (19/20). Median DoR was not reached. 6m-PFS rate was 66.4% (95%CI: 47.7%-92.5%), immature median PFS was 14.65 months (95%CI: 5.06 -not reached) with 8 events. Conclusions: The combination of sintilimab and anlotinib showed promising clinical activities with manageable toxicity for first line treatment of aHCC. Clinical trial information: NCT04052152. Research Sponsor: Innovent Biologics, Inc., Chia-Tai Tianqing Pharmaceutical Group Co Ltd. Clinical trial information: NCT04052152.
IMMU-03. CHARACTERIZING THE IMMUNE MICROENVIRONMENT OF PEDIATRIC BRAIN TUMORS
Authors: Robert Galvin, Danielle Maeser, Robert Gruener, R Stephanie Huang
Journal: Neuro-Oncology (2021)

Abstract Therapy for pediatric central nervous system (CNS) malignancies can be toxic, and outcomes are suboptimal. Immunotherapy holds promise as a therapeutic avenue, but one of the challenges in its application is the poorly understood microenvironment of pediatric CNS tumors. The Children’s Brain Tumor Network released the Pediatric Brain Tumor Atlas, containing the expression profile of nearly 700 primary CNS tumors. To study the immune microenvironment, a classification from The Cancer Genome Atlas project is applied. High-grade lesions are predominantly lymphocyte deplete (C4, 80%) or immunologically quiet (C5, 7.6%). Low-grade lesions are more mixed with 43% C4, 26% C5, and a higher proportion of inflammatory subtype (C3, 28%). For survival parameters, immune subtype and tumor grade are associated. Using a multivariate cox regression model, the hazard ratio is 2.2 (0.86 – 5.4, p = 0.102) and 3.6 (1.2 – 10.9, p = 0.02) for C4 and C5, respectively. Deconvolution of immune cell gene signatures provides insight into the phenotype of lymphocyte infiltrate, which averages 8.6% (IQR 5.4% – 9.8%) across all samples. For high-grade samples, greater than median expression of T cell-, monocyte-, macrophage-, and B cell-gene signatures are each associated with decreased survival (p &amp;lt; 0.05). Microglia gene signatures have decreased relative expression in high-grade samples compared to low-grade samples (p &amp;lt; 0.001). It is hypothesized that the expression of inhibitory immunomodulators contributes to a pro-tumorigenic microenvironment and represent potential therapeutic targets. In the absence of normal samples in the data set, differential gene expression experiments between disease states can reveal upregulated immunomodulators. Focusing on diffuse midline glioma, immunologic pathways are downregulated. Furthermore, 9 inhibitory immunomodulators, including KDM1A, EZH2, CD276, and VTCN1, are significantly expressed relative to midline low-grade glioma with equivalent immune subtype. Overall, our analysis contributes to the understanding of the immune microenvironment and mechanisms of immune escape for pediatric CNS malignancies.
First results of a randomized phase IB study comparing nivolumab/ipilimumab with or without CBM-588 in patients with metastatic renal cell carcinoma.
Authors: Luis A Meza, Nazli Dizman, Paulo Gustavo Bergerot, Tanya B. Dorff, Yung Lyou, Paul Henry Frankel, Valerie Mira, Marian Llamas, Joann Hsu, Zeynep Busra Zengin, Nicholas Salgia, Sabrina Salgia, Jasnoor Malhotra, Neal Shiv Chawla, Alex Chehrazi-Raffle, John D Gillece, Lauren J Reining, Jeffrey M. Trent, Sarah K Highlander, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2021)

4513 Background: Recent evidence suggests that the gut microbiome is a potent mediator of immune checkpoint inhibitor (ICI) activity in metastatic renal cell carcinoma (mRCC), with both specific bacterial species and cumulative microbial diversity driving response (Routy et al Science 2018; Salgia et al Eur Urol 2020). We examined whether the butyrate-producing bacterium Clostridium butyricum, the key constituent of CBM-588, could modulate the gut microbiome in patients (pts) with mRCC receiving nivolumab/ipilimumab (N/I) and secondarily improve clinical outcome. Methods: An open-label, randomized study was conducted, with key eligibility criteria including confirmed clear cell and/or sarcomatoid mRCC, intermediate/poor risk by IMDC criteria and no systemic therapy for metastatic disease. Patients were randomized 2:1 to receive either N/I+CBM-588 or N/I alone. N/I was dosed at 3 mg/kg and 1 mg/kg IV every 3 weeks for 12 weeks, followed by N at 480 mg IV every 4 weeks. CBM-588 was dosed orally at 80 mg bid. Stool was collected for bacteriomic profiling at baseline and 12 weeks. Metagenomic sequencing was employed using previously published methods (Dizman et al Cancer Med 2020). The primary endpoint of the study was change in Bifidobacterium spp. from baseline to week 12. Secondary endpoints included change in microbial diversity and clinical outcomes including response rate (RR) and progression-free survival (PFS). Results: 30 pts were randomized between April 2019 and Nov 2020; 1 pt was excluded after genomic sequencing clarified a diagnosis of sarcoma. Among 29 evaluable patients (21:8 M:F), median age was 66, 10 pts (34%) had sarcomatoid features and 24 pts (83%) were intermediate risk. Metagenomic sequencing of paired stool specimens showed an 8-fold increase in B. bifidum and a 6-fold increase in B. adolescentis in pts receiving N/I+CBM-588 from baseline to week 12. C. butyricum was detected only in pts receiving CBM-588. Pathogenic species (e.g., Escherichia. coli and Klebsiella spp.) were more prevalent in pts not receiving CBM-588. RR was significantly higher among pts receiving N/I+CBM-588 vs N/I alone (59% vs 11%; P = 0.024). Median PFS was also prolonged with the addition of CBM-588 to N/I (NR vs 11 weeks; P &lt; 0.001). No significant difference in grade 3/4 toxicities were observed between study arms. Conclusions: This is the first randomized, prospective study to suggest enhancement of ICI response with a live bacterial product. The observed clinical impact is corroborated by biologic findings supporting gut modulation by CBM-588. Clinical trial information: NCT03829111.
A phase II trial combining nivolumab and stereotactic brain radiosurgery for treatment of brain metastases in patients with NSCLC.
Authors: Philip Wong, Marie Florescu, Marc-Emile Plourde, Valerie Panet-Raymond, Michel Pavic, Scott Peter Owen, Laurence Masson-Cote, Cynthia Menard, Bertrand Routy, Mustapha Tehfe, Normand Blais, David Roberge, Laura Masucci
Journal: Journal of Clinical Oncology (2021)

2023 Background: Previous studies suggested activity of anti-PD-1 in brain metastases from non-small cell lung cancer (NSCLC) and renal cell cancer (RCC). This investigator initiated phase 2 trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with brain metastases from NSCLC and RCC. Methods: This is a multicentre open-label trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated brain metastases, no whole brain radiotherapy and no prior immunotherapy were eligible. Study treatment commenced with a dose of nivolumab (240mg or 480mg IV), which was continued for up to 2 years at bi-weekly or monthly intervals until progression. SRS (15-21Gy) to all visible un-irradiated brain lesions was administered within 14 days after the first dose of nivolumab (cycle 1). Patients were followed by brain MRI, CT scan of the chest, abdomen and pelvis, neurocognitive and quality of life questionnaires (FACT-Br) every 3 months. The primary endpoint was intracranial progression free survival (icPFS), with death and disease progression within the brain as events. Results from NSCLC patients are presented here. Results: Of the 26 study patients, 22 NSCLC patients were enrolled between Aug 2017 and January 2020. Patients had a median of 2 (1-9) brain metastases. The median diagnosis-specific graded prognostic score was 2 (1-3). Median treatment and follow-up durations were 4.3 months (0-24.8 months) and 11 months (0-24.8 months), respectively. Forty-two percent of the patients had received prior cytotoxic chemotherapy, and 1 patient had received prior brain SRS. PD-L1 status was known for 21 of the 22 NSCLC (12 with ≥50% PD-L1 expression (DAKO 22C3). Median icPFS was 5.0 months (3 intracranial progression and 8 deaths without progression in the brain). Accounting for death as a competing risk, the 1-year cumulative incidence of intracranial relapse was 17.4%. Median extracranial PFS and overall survival were 2.9 months and 14 months, respectively. Four grade 3 adverse events in 2 patients were related to nivolumab or SRS. The rate of survival free of neurocognitive decline (Hopkins Verbal Learning Test total recall) was estimated to be 89% by 4 months. Mean FACT-Br total scores were 89.4 at baseline and improved (p = 0.01) to 139.3 within 2-4 months. Conclusions: Neurocognitive and quality of life assessments suggest that upfront SRS during nivolumab is well tolerated. High intracranial control was observed, but deaths from extracranial disease progression resulted in short icPFS. Studies evaluating the strategic addition of SRS combined with more efficacious systemic treatments are needed. Clinical trial information: 02978404.
Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for metastatic breast cancer with hormone receptor-positive and HER2-positive: The sysucc-002 randomized clinical trial.
Authors: Zhongyu Yuan, Jia-Jia Huang, Xin Hua, Jian-Li Zhao, Ying Lin, Yuan-Qi Zhang, Zhiyong Wu, Lehong Zhang, XiWen Bi, Wen Xia, Yong-yi Zhong, Shu-Sen Wang, Fei Xu, Ruoxi Hong, Kuikui Jiang, Yanxia Shi, Cong Xue, Xin An
Journal: Journal of Clinical Oncology (2021)

1003 Background: For metastatic breast cancer with hormone receptor-positive and HER2-positive, no evidence showed that which first-line regimens were preferred, either anti-HER2 therapy plus endocrine therapy or anti-HER2 therapy plus chemotherapy. This study aimed to determine whether trastuzumab plus endocrine therapy is as efficacious as trastuzumab plus chemotherapy and with decreased toxic effects. Methods: We conducted an open-label, non-inferiority, phase 3, randomized, controlled trial at nine hospitals in China. Patients with hormone receptor-positive and HER2-positive histologically confirmed advanced breast cancer were randomly assigned (1:1) to receive trastuzumab plus chemotherapy (CT group) or endocrine therapy (ET group). The primary endpoint was progression-free survival with a non-inferiority upper margin of 1.35 for the hazard ratio (HR). This trial is registered with ClinicalTrials.gov, number NCT01950182. Results: Between Sep 16, 2013, and Dec 28, 2019, 392 patients were enrolled and randomly assigned to receive trastuzumab plus endocrine therapy (n = 196) or trastuzumab plus chemotherapy (n = 196). In the intention-to-treat population, the median PFS was 14.8 months (95% CI 12.8-16.8) in the CT group and 19.2 months (95% CI 16.7-21.7) in the ET group (HR 0.88, 95% CI 0.71-1.09; P non-inferiority &lt; 0.0001). Significantly higher frequency of toxicities were observed in CT group compared with ET group, including: leucopenia (98 [50%] vs 13 [6.6%]), nausea (93 [47%] vs 24 [12%]), fatigue (47 [24%] vs 31 [16%]), vomiting (45 [23%] vs 12 [6%]), headache (65 [33%] vs 24 [12%]) and alopecia (125 [64%] vs 8 [4%]). No patients died from treatment-related causes. Conclusions: Trastuzumab plus endocrine therapy was non-inferior to and had decreased toxicities to trastuzumab plus chemotherapy in patients with metastatic breast cancer with hormone receptor-positive and HER2-positive. Trastuzumab plus endocrine therapy could provide more convenient treatment and allow better treatment tolerance. Clinical trial information: NCT01950182 .