tbuckley/cabot-search huggingface dataset:
Serum neurofilament light protein correlates with unfavorable clinical outcomes in hospitalized patients with COVID-19
Authors: Mercedes Prudencio, Young Erben, Christopher P. Marquez, Karen R. Jansen-West, Camila Franco-Mesa, Michael G. Heckman, Launia J. White, Judith A. Dunmore, Casey N. Cook, Meredith T. Lilley, Yuping Song, Caroline F. Harlow, Björn Oskarsson, Katharine A. Nicholson, Zbigniew K. Wszolek, LaTonya J. Hickson, John C. O’Horo, Jonathan B. Hoyne, Tania F. Gendron, James F. Meschia, Leonard Petrucelli
Journal: Science Translational Medicine (2021)

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.
Hereditary cancer testing in an ethnically diverse U.S. population.
Authors: Michele Basiliere, Stephanie Woods, Heidi Owen, Lindsay Dohany, Lisa McDaniel, Nicholas Wisniewski
Journal: Journal of Clinical Oncology (2021)

10579 Background: The clinical utility of hereditary cancer multigene testing is well-established. Most testing has been performed in the White European population, with a relative shortage of data in other ethnic groups. Evaluation of hereditary cancer variants within diverse ethnic populations is important to drive accurate variant interpretation. This study aims to review the outcomes of hereditary cancer testing in an ethnically diverse U.S. population. Methods: We conducted a retrospective analysis of 8,888 test results from a 31-gene hereditary cancer test using next-generation sequencing with copy number variant analysis. Results were separated into seven categories based on the ethnicity selected on the test requisition: African American (AA), Asian (A), Ashkenazi Jewish (AJ), Hispanic (H), White (W), Other (O), and Unknown (U). O was used for any handwritten ethnicity or if multiple ethnicities were selected and U if no ethnicity was chosen. We quantified the number of negative, positive (pathogenic or likely pathogenic (P/LP) variant) and variant of uncertain significant (VUS) results for each ethnic group. We tallied the gene and variant for each result with a positive, negative or VUS. We used a Fisher's Exact test and Bonferroni-adjusted p-values to account for multiple hypothesis testing. Results: Of the 8,888 orders reviewed, 45% were non-White ethnic groups. The P/LP variant rate was lower for AA (4%, p=2e-04) compared to W (9%). The VUS rate was higher for O, AA and A (48%, 56%, and 57%; p=0.0045, 3.1e-17 and 4.8e-06, respectively), compared to 38% in W. Lower negative rates were found in A and AA (37% and 40%; p=0.00024 and 9.4e-10, respectively), and trending lower in O (46%, p=0.0097), compared to 58% for W. The VUS rate for H is 41% (p value = 0.095). Conclusions: Our results suggest that non-Whites may be at a disadvantage when it comes to hereditary cancer multigene testing due to the higher rate of VUS results. The inverse correlation between the overall rates of VUS and negative results when comparing these populations suggests there may be limited variant information for the non-White population in medical literature and available databases. This underrepresentation may make it more difficult to accurately characterize a variant. Despite the small sample size, these findings are consistent with previous publications; however, gene specific outcomes could not be evaluated. This finding suggests that providers could give these patients uninformative results more often, which has potential to impact screening protocols for these families. More research is needed to understand the impact of variant classification across ethnicities to decrease health disparities.
The present scenario of colorectal cancer in Southeastern Brazil.
Authors: Jose Zago Pulido, Sabina B. Aleixo, Narelle Parmanhane, Luciana Sogame
Journal: Journal of Clinical Oncology (2021)

e18782 Background: Cancer is the second leading cause of death in the world and in Brazil. Most of colorectal cancers (CRC) are sporadic and occur in individuals over the age of 50. Since almost all CRC originate from a polyp , the early detection and excision of an adenomatous polyp is essential to avoid the adenoma-carcinoma sequence that occurs over the years. Most colorectal polyps are asymptomatic and identified during screening colonoscopies or in patients with positive fecal occult blood test . There is evidence that detecting and removing these cancer precursor lesions can prevent many cases of cancer and reduce mortality. The CRC are public health problem in Brazil and fulfills criteria to merit the implementation of a structured screening program. and in this sense, several medical societies recommend screening through organized programs and not just opportunistic as done in Brazil. It is believed that this strategy is related to late diagnosis and has impact on high mortality. Most evidence on CRC screening interventions comes from high-income countries. The large disparities in CRC incidence and mortality rates between high-income and low-income countries are attribute to screening. The study will evaluate the stage of colorectal cancer at diagnosis at Southeastern Brazil. Methods: We collected retrospective data of patients with CRC registered in the Hospital Evangélico de Cachoeiro de Itapemirim (HECI) Health Information System - SISRHC from 2010 to 2017 to know the clinical characteristics (TNM) of the patients diagnosed during this period, age and sex. From January 1, 2010 to December 31, 2017, 6,962 newly diagnosed cases of cancer were identified. Of this total, 676 (9.7%) were new cases of colorectal cancer. When submitting to the inclusion and exclusion criteria of the present study 91 cases were excluded (1 case under the age of 18 years; 64 cases that started their first cancer treatment before the pathological result; 26 cases without information from the anatomopathological diagnosis). Data from the remaining 585 cases were analyzed. Results: Among 585 analyzed, the distribution of stage at diagnosis was : 0 (0,68%), I 45 (7,69%), II 109 (18,63%), III 225 (38,45%), IV 129 (22,05%) and 73 (12,48%) had this information missing. Mean age at diagnosis was 62 years, with 411(70,50%) between ages 51-80 years. Regarding sex we found 306 (52,49%) male and 277 (47,51%) female. Conclusions: The results found in the studied population are in agreement with the literature regarding age at diagnosis and sex. Unfortunately demonstrates that most of colorectal,cancer in southeastern region of Brazil are diagnosed in late stages. The lack of screening is an explanation to this fact. Only the implemention of national organized screening program can improve cancer detection and provide better chances of cancer survival.
Lurbinectedin (LUR) in combination with Irinotecan (IRI) in patients (pts) with advanced endometrial carcinoma.
Authors: Alejandro Falcon Gonzalez, Luis G. Paz-Ares, Gregory Michael Cote, Santiago Ponce Aix, Julia Martinez, Elizabeth Jimenez Aguilar, Elena Brehcist, Rafael Nuñez, Jesus R Fernandez, Sonia Extremera, Carmen Maria Kahatt, Ali Hassan Zeaiter, Inmaculada Sanchez-Simon
Journal: Journal of Clinical Oncology (2021)

5586 Background: LUR is a new agent that exerts antitumor activity through inhibition of trans-activated transcription and modulation of tumor microenvironment. Preclinical synergism/additivity in combination with IRI has been reported, thus prompting the conduct of this trial. This synergism had been evaluated and recently reported in patients with Small Cell Lung Cancer, with encouraging results (Ponce et al. WCLC, 2020). Methods: Phase I trial to evaluate escalating doses of LUR on Day (D) 1 plus a fixed dose of IRI 75 mg/m 2 on D1 and D8 every 3 weeks (q3w) in pts with advanced solid tumors, enrolled following a standard 3+3 dose escalation design. Phase II to expand in selected indications at the Recommended Dose (RD). In this abstract, the cohort of patients with endometrial carcinoma treated at the RD is presented. Results: 21 pts (all female) with endometrial carcinoma were treated at the RD (LUR 2 mg/m2 + IRI 75 mg/m2 + G-CSF); 57% had ECOG PS=1; median age was 64 years (range 34-74); subtype of tumour was split: 67% (14 pts) endometroid, 33% non-endometroid (3 pts serous-papilar, 3 pts clear-cell and 1 pt undifferentiated); median of 2 prior lines (range, 1−7) per pt. Common G1/2 toxicities were nausea, vomiting, fatigue, diarrhea and anorexia; G3/4 hematological toxicities comprised neutropenia (33%), thrombocytopenia (5%) and anemia (38%). Two episodes of febrile neutropenia occurred (9.5%). G3/4 non hematological toxicities consisted of diarrhea (24%), asthenia (19%), nausea (14%) and vomiting (5%), all were transient and manageable. 1 patient (5%) discontinued treatment due to toxicity drug-related (generalized muscular weakness), but no treatment-related deaths were reported. Objective RECIST responses were documented in 4/21 evaluable pts (19%). With 6 pts censored for progression, median PFS was 4.4 months (95% CI 2.1-9.6 months), and PFS at 6 months was 40.4%. The clinical benefit rate (% of pts with Complete Response (CR), Partial Response (PR) or Stable Disease &gt; 4 months) was 43%, and the Disease Control Rate (% of pts with CR, PR or SD) 81%. 3/21 pts (14%) have been more than 12 months on treatment so far. Conclusions: The combination of Lurbinectedin and Irinotecan is active in heavily pretreated patients with endometrial carcinoma. The combination was well-tolerated and consistent with the known safety profile for this combination. Myelosuppression, diarrhea, nausea and asthenia were predictable and manageable. Updated results of this cohort will be presented at the meeting. Clinical trial information: NCT02611024.
Concurrent chemoradiation in the management of newly diagnosed glioblastoma multiforme: Retrospective review of single center experience over a period of 10 years.
Authors: Louise Price, Charlotte Ziff, Abdelfattah Elmasry, Selvaraj Giridharan
Journal: Journal of Clinical Oncology (2021)

e14028 Background: Glioblastoma Multiforme (GBM) is the most common primary intracranial tumour of the brain. The standard of care first line management is maximum safe debulking followed by concurrent chemo radiation (Stupp et al, 2005). In spite of further recent advances, median survival still remains poor and ranges between 14 to 21 months, especially in the MGMT unmethylated group. There are no randomised trials investigating less than 6 cycles of adjuvant temozolomide (TMZ). In our study we retrospectively analyse the impact on overall survival (OS) and progression free survival (PFS) in cases where adjuvant treatment has been discontinued due to toxicity or patient’s fitness Methods: We collected data from 2007 to 2016 for a cohort of patients who underwent adjuvant treatment for GBM following histological diagnosis. The final analyses included patient’s who completed concurrent chemoradiotherapy to a dose of 60 Gray in 30 fractions and had at least one cycle of adjuvant TMZ chemotherapy Results: Of 110 patient cohorts, 57% of patients completed adjuvant chemo radiotherapy followed by 4-6 cycles of adjuvant TMZ, 43% received 3 or less cycles of TMZ. Overall PFS was 11.9 months. Those that completed 4 or more cycles of adjuvant TMZ had an improved PFS (Log rank test P-value 0.001) versus those that completed 3 or less cycles. On cox analysis the number of adjuvant cycles of TMZ significantly affects OS, P-value 0.0003. Median overall survival was 16 months for the whole group, but was 10 vs. 20 months for the two groups. On cox analysis we also identified second line chemotherapy had a significant impact on OS (cox model P-value 0.002) Conclusions: We identified patients receiving three or fewer cycles of adjuvant TMZ had poorer outcomes. Second-line chemotherapy improved outcomes at relapse regardless of redo surgery.
lncRNA lnc-POP1-1 upregulated by VN1R5 promotes cisplatin resistance in head and neck squamous cell carcinoma through interaction with MCM5
Authors: Yingying Jiang, Haiyan Guo, Tong Tong, Fei Xie, Xing Qin, Xiaoning Wang, Wantao Chen, Jianjun Zhang
Journal: Molecular Therapy (2021)

Cisplatin resistance is a major therapeutic challenge in advanced head and neck squamous cell carcinoma (HNSCC). Here, we aimed to investigate the key signaling pathway for cisplatin resistance in HNSCC cells. Vomeronasal type-1 receptor 5 (VN1R5) was identified as a cisplatin resistance-related protein and was highly expressed in cisplatin-resistant HNSCC cells and tissues. The long noncoding RNA (lncRNA) lnc-POP1-1 was confirmed to be a downstream target induced by VN1R5. VN1R5 transcriptionally regulated lnc-POP1-1 expression by activating the specificity protein 1 (Sp1) transcription factor via the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. VN1R5 promoted cisplatin resistance in HNSCC cells in a lnc-POP1-1-dependent manner. Mechanistically, lnc-POP1-1 bound to the minichromosome maintenance deficient 5 (MCM5) protein directly and decelerated MCM5 degradation by inhibiting ubiquitination of the MCM5 protein, which facilitated the repair of DNA damage caused by cisplatin. In summary, we identified the cisplatin resistance-related protein VN1R5 and its downstream target lnc-POP1-1. Upon upregulation by VN1R5, lnc-POP1-1 promotes DNA repair in HNSCC cells through interaction with MCM5 and deceleration of its degradation.
EPCT-02. COMPARISON OF TARGETED AGENTS RECOMMENDED BY THE CNS-TAP TOOL TO THOSE SELECTED BY A TUMOR BOARD IN A MOLECULARLY-DRIVEN DIPG CLINICAL TRIAL
Authors: Holly Roberts, Karthik Ravi, Bernard Marini, Cassie Kline, Sabine Mueller, Carl Koschmann, Andrea Franson
Journal: Neuro-Oncology (2021)

Abstract Recently, sequencing of diffuse intrinsic pontine glioma (DIPG) biopsy specimens has revealed genomic heterogeneity of these tumors, fueling an interest in individualized, targeted treatment options. The Pacific Pediatric Neuro-Oncology Consortium recently completed enrollment onto a feasibility study PNOC003: Molecular Profiling for Individualized Treatment Plan for DIPG (NCT02274987), in which a multidisciplinary tumor board recommended molecularly-targeted agents based on genomic and molecular profiling of each patient’s tumor. Separately, our group developed the Central Nervous System Targeted Agent Prediction (CNS-TAP) tool, which combines pre-clinical, clinical, and CNS penetration data with patient-specific genomic information to allow for numeric scoring of targeted anticancer agents to objectively evaluate these therapies for use in patients with CNS tumors. We hypothesized that highly-scored agents within CNS-TAP would overlap with the agents recommended by the tumor board in this study. For each PNOC003 participant, we utilized the genomic report to identify actionable alterations and input patient-specific data into CNS-TAP to identify the highest scoring agents. We compared high-scoring agents within CNS-TAP with recommendations from the PNOC003 tumor board for each of the enrolled 28 subjects. Overall, 93% (26/28) of patients had at least one agent recommended by both the tumor board and CNS-TAP. Additionally, 38% (37/95) of all agents recommended by the tumor board were also selected by CNS-TAP. Furthermore, we identified factors that likely contributed to the discordance between these two methods. Without clinician input, CNS-TAP is unable to account for drug-drug interactions, includes only designated anticancer agents, and cannot easily be updated in real time. However, CNS-TAP provides an objective evaluation of targeted therapies, whereas tumor boards are inherently subjective. Given the discordance identified between these methods and the strengths of each, a prospective study incorporating both CNS-TAP and a molecular tumor board for targeted therapy selection in DIPG patients is warranted.
AdvanTIG-202: A phase 2 study investigating anti-TIGIT monoclonal antibody ociperlimab plus anti-PD-1 monoclonal antibody tislelizumab in patients with previously treated recurrent or metastatic cervical cancer.
Authors: Lingying Wu, Peng-Hui Wang, Sheng-Yen Hsiao, Chih-Long Chang, Hee Seung Kim, JUNG-YUN LEE, Sang-Young Ryu, Yunxia Zuo, Xiyan Mu, Yujuan Gao, Silu Yang, Jae-Kwan Lee
Journal: Journal of Clinical Oncology (2021)

TPS5595 Background: Women with recurrent/metastatic cervical cancer represent a poor prognostic group with high unmet clinical needs. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor expressed on immune cells and upregulated on T-cells and natural killer cells in multiple solid tumors, inhibiting anticancer immune responses. Ociperlimab (BGB-A1217) is a novel, humanized, monoclonal antibody that binds TIGIT with high specificity and affinity, blocking the interaction with its ligands on tumor cells. Tislelizumab is an anti-PD-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Preclinical and clinical studies suggest that dual targeting with anti-TIGIT and anti-PD-1 antibodies produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-202 is a Phase 2, randomized, multicenter, open-label study (NCT04693234). Approximately 167 pts with cervical squamous cell or adenosquamous carcinoma or adenocarcinoma, recruited from 100 centers, whose disease progressed on or after ≥ 1 prior line of chemotherapy for recurrent/metastatic disease will be included in this 2-Part study. In Part 1, approximately 80 pts will be randomized (1:1) to either ociperlimab 900 mg intravenously (IV) in combination with tislelizumab 200 mg IV every 3 weeks (Q3W) (Arm 1), or tislelizumab monotherapy 200 mg IV Q3W (Arm 2), until disease progression, unacceptable toxicity, or withdrawal of consent. In Part 2, Arm 1 will be expanded by approximately 87 additional pts whose tumors are evaluable for PD-L1 expression. The primary endpoint is overall response rate (ORR) (RECIST v1.1) assessed by Independent Review Committee (IRC) in Arm 1. Secondary endpoints are investigator-assessed ORR in Arm 2, IRC-assessed and investigator-assessed ORR in Arm 1, IRC-assessed and investigator-assessed duration of response, progression-free survival, time to response, disease control rate, clinical benefit rate and overall survival, cancer-specific health-related quality of life (HRQoL), safety, pharmacokinetics and immunogenicity in Arms 1 and 2. Exploratory endpoints are generic HRQoL and the association of biomarkers with patient prognosis, response or resistance. Clinical trial information: NCT04693234.
Ligand conjugate SAR and enhanced delivery in NHP
Authors: Richard James Holland, Kieu Lam, Xin Ye, Alan D. Martin, Mark C. Wood, Lorne Palmer, David Fraser, Kevin McClintock, Sara Majeski, Agnes Jarosz, Amy C.H. Lee, Emily P. Thi, Adam Judge, James Heyes
Journal: Molecular Therapy (2021)

N-Acetylgalactosamine (GalNAc) conjugated short interfering RNAs (siRNAs) are a leading RNA interference (RNAi) platform allowing targeted inhibition of disease-causing genes in hepatocytes. More than a decade of development has recently resulted in the first approvals for this class of drugs. While substantial effort has been made to improve nucleic acid modification patterns for better payload stability and efficacy, relatively little attention has been given to the GalNAc targeting ligand. In addition, the lack of an intrinsic endosomal release mechanism has limited potency. Here, we report a stepwise analysis of the structure activity relationships (SAR) of the components comprising these targeting ligands. We show that there is relatively little difference in biological performance between bi-, tri-, and tetravalent ligand structures while identifying other features that affect their biological activity more significantly. Further, we demonstrate that subcutaneous co-administration of a GalNAc-functionalized, pH responsive endosomal release agent markedly improved the activity and duration of effect for siRNA conjugates, without compromising tolerability, in non-human primates. These findings could address a significant bottleneck for future siRNA ligand conjugate development.
Are antimicrobial stewardship interventions effective and safe in long-term care facilities? A systematic review and meta-analysis
Authors: Juan Carlos Crespo-Rivas, Ana Belén Guisado-Gil, Germán Peñalva, Ángel Rodríguez-Villodres, Cecilia Martín-Gandul, María Eugenia Pachón-Ibáñez, José Antonio Lepe, José Miguel Cisneros
Journal: Clinical Microbiology and Infection (2021)
Impact of immune checkpoint inhibitor (CPI) and EGFR tyrosine kinase inhibitor (TKI) sequence on time to treatment failure (TTF) among EGFR plus NSCLC treated in a community-based cancer research network.
Authors: Carissa Jones, Rebecca Lachs, Emma Sturgill, Amanda Misch, Caressa Lietman, Suzanne Fields Jones, Melissa Lynne Johnson, David R. Spigel, Andrew Jacob McKenzie
Journal: Journal of Clinical Oncology (2021)

9099 Background: The development of CPIs and driver-targeted TKIs has transformed the treatment of NSCLC and increased survival rates. However, the role of CPIs in patients with oncogenic-driven NSCLC remains an area of investigation. We sought to examine the impact of CPI sequence on treatment response among patients with oncogenic-driver mutation-positive NSCLC. Methods: Patients with NSCLC being treated within the Sarah Cannon Research Institute network were identified through Genospace, Sarah Cannon’s clinico-genomic analytics platform. Advanced stage oncogenic-driven tumors (driver+) were defined as those with a record of receiving an FDA-approved TKI targeting EGFR, ALK, RET, ROS1, NTRK, MET, or BRAF. Kaplan-Meier estimates were used to examine TTF (defined as time from therapy start to start of next therapy, death, or loss to follow-up) and overall survival (OS). Results: We identified 12,352 patients with lung cancer and available therapy data (2005-2020), including 2,270 (18%) driver+ patients. Eleven percent (N=245) of driver+ patients received a CPI, including 120 (49%) with CPI prior to TKI, 122 (50%) with CPI post TKI, and 3 (1%) who received CPI both pre and post TKI. The CPI TTF was significantly longer for those who received CPI post TKI compared to those who received it prior (Table). EGFR+ tumors accounted for 82% (N=1,867) of driver+ patients, 10% of whom (N=188) received a CPI. Of the EGFR+/CPI+ patients, 78 patients (41%) received CPI prior to TKI, 107 (57%) received CPI post TKI, and 3 (2%) received CPI both pre and post TKI. EGFR+ tumors exposed to a CPI post TKI had a longer CPI TTF compared to patients who received it prior (Table). In contrast, there was no difference in length of benefit from TKI if it was received pre vs. post CPI (Table). There was also no difference in OS based on sequence of TKI and CPI (p=0.88). Larger sample sizes are needed for analysis of additional driver-stratified cohorts. Conclusions: Patients with oncogenic-driven NSCLC benefited from CPI longer when it was administered after TKI compared to before. Importantly, therapy sequence only affected length of benefit from CPIs and did not affect length of benefit from TKIs. This effect was present in EGFR+ NSCLC, but sample sizes were too small to determine if the same is true for other oncogenic-drivers. Therapy sequence had no impact on OS, indicating the presence of additional clinical, therapeutic, and/or genomic factors contributing to disease progression. Continued research is needed to better understand markers of CPI response in driver+ NSCLC.[Table: see text]