tbuckley/cabot-search huggingface dataset:
Immune effector cell therapies in oncology: A systematic analysis and forecast from ClinicalTrials.gov.
Authors: Jose Vicente Forero-Forero, Juan Esteban Garcia-Robledo, Daniela A. Castro-Martinez, Eider Felipe Moreno, Paula Andrea Lengerke Diaz, Natalie Booth, Januario E. Castro
Journal: Journal of Clinical Oncology (2021)

e14516 Background: IEC are arguably the most promising therapy in oncology, and FDA approvals for CAR T cells are a testament to their real potential. This has led to a great growth of clinical trials (CT), making the evaluation of their associated data increasingly challenging. To facilitate this process, we performed a systematic review of ClinicalTrials.gov focused on IEC therapies in oncology. We performed an analysis of the CT data and forecast trends for 2025. Methods: CT registries were retrieved from ClinicalTrials.gov with a systematic search query. We included CT registered between 1993-2020, which used IEC-based therapies in oncology. Statistical analysis using descriptive and inferential methods allowed us to identify trends and establish forecasts. Results: We identified 938 registrations of IEC-CTs in oncology, and 51% of those were active. The most common IEC type was CAR T (51%), followed by NK (15%), TCR T (8%), TIL (8%), and CIK (3%). 69% of IEC-CTs were aimed at a specific target vs. 31% that lack that specificity. The number of annual CAR T-CTs continue to increase, and we forecast 320 registrations during 2025. Since 2018, the number of CTs using unmodified T cells and TIL has increased (largely due to metastatic melanoma studies). NK cells CTs represent 8% of all registrations, and by 2025 we anticipate that &gt;150 NK-based CTs will be registered per year, a number similar to CAR T-CTs registered during 2020. IEC-CTs based on allogeneic sources represent 18% of all registrations and are expected to grow 2.5 fold in the next 5 years. In solid tumors, the most common IEC-CTs are based on Non-CAR studies, while in hem-malignancies 76% of CTs are CAR T. Only one solid tumor, CAR T-CT, has reached phase 2/3, while 7 CIK-CTs were used to target various organ tumors. Conclusions: IEC-CTs continue to grow exponentially and represent an active field of clinical research in oncology. Allogeneic and NK-CTs increase rapidly and are among the most promising IEC-CTs. A rising proportion of CTs in solid tumors are using CIK and TIL rather than CAR T-cells, which are more popular for treating hem-malignancies. This is a direct reflection of the challenges associated with CAR T infiltration and persistence in solid tumors. Our analyses indicate that annual IEC-CTs registrations will double by 2025. We anticipate the increase in cellular therapy options will demand an organized response, including adequate logistical planning and policy implementation in response to the landscape changes in clinical oncology during the upcoming years.[Table: see text]
A phase II open-label study of cpi-613 in combination with modified (m)FOLFIRINOX in patients with locally advanced pancreatic cancer.
Authors: David Lawrence Bajor, AMR MOHAMED, J. Eva Selfridge, Erin E. Anderson, Jeffrey Hardacre, John Brian Ammori, Richard T. Lee, Joel N. Saltzman, Jordan Michael Winter
Journal: Journal of Clinical Oncology (2021)

TPS4176 Background: For patients with locally advanced pancreatic cancer, neoadjuvant trials are the preferred strategy. The goals of neoadjuvant treatment are to diminish the size of the primary tumor to allow for safe surgical resection and to limit the chance of developing metastatic disease. mFOLFIRINOX is the gold-standard for treatment in the adjuvant setting and an acceptable regimen in the neoadjuvant setting with many ongoing neoadjuvant trials using it as a chemotherapeutic backbone. CPI-613 (devimistat) is a small-molecule inhibitor of pyruvate dehydrogenase and alpha-ketogluterate dehydrogenase that has been studied in combination with mFOLFIRINOX in a phase I trial of patients with metastatic pancreas cancer and shown to be safe at the proposed phase II dose. Methods: This is a single-center, single-arm phase II trial for patients with locally advanced pancreatic cancer; defined as either borderline resectable or unresectable according to NCCN guidelines and interpreted by the primary investigator. Patients with metastatic disease are excluded. Patients will receive treatment with CPI-613 and mFOLFIRINOX per the table below. The primary endpoint is overall survival. Secondary endpoints are progression free survival and resection rate. At the time of submission this study has completed initial accrual with 37 patients enrolled. Clinical trial information: NCT03699319. [Table: see text]
Efficacy and pattern failures of early SBRT to primary tumor in advanced EGFR mutation lung cancer (Target-SBRT): A single-arm phase 2 study.
Authors: Dongqing Lv, Hailing Xu, Jiapei Ding, Ling Lin, Chao Zhou, Xiaomai Wu, Yinnan Meng, Wei Wang, Feng-Ming Spring Kong, Haihua Yang
Journal: Journal of Clinical Oncology (2021)

e21130 Background: It is evitable for advanced NSCLC harboring EGFR mutation with 1st TKI to develop resistance with 9-13 months of PFS and 19-27 months of OS. Initial progression of TKI treatment in NSCLC was 47.2% from the primary sites, 20.4% from the new sites and 32.6% from the primary and new sites. We hypothesized that early stereotactic body radiation therapy (SBRT) to primary tumor in advanced EGFR mutation NSCLC combined with EFGR-TKI treatment could prolong targeted resistance and explored its pattern failures. Methods: Eligible patients pathologically confirmed advanced NSCLC with Exon19 deletion or Exon21 L858R mutation were enrolled (ChiCTR-OIN-17013920). Each patient received EGFR TKI (Icotinib 125mg tid or gefitinib 250mg qd) and early SBRT (40-60 Gy/5-8F/5-10d) for primary tumor about 1 months from the beginning of EGFR TKI until disease progressed. Initial progression in sites of original disease (primary/metastatic) was defined as original site failure (OF) and appearance of new lesions as distant site failure (DF). Simultaneous OF/DF was labeled as ODF. The primary endpoint was PFS and the second endpoints were pattern failures, OS as well as adverse effects (AEs). Study was designed to enroll 50 patients to detect 6 months’ extension of PFS. Results: The study was closed after 41 patients enrolled due to the use of more effective 3rd EGFR-TKI.There were 37 PR and 4 SD after one month of TKI treatment and the average tumor shrinkage rate was 42.5%. The average interval from TKI to SBRT was 1.43 months (0.87-2.77 months). Median PFS and OS were 15.2 months (95% CI 13.1-17.4) and 27.6 months (95% CI 23.1-32.1), respectively. Of 37 patients who progressed, 6 (16.2%) had OF, 21 (56.8%) had DF, and 10 (27.0%) had ODF. The lung was the most common site of initial progression. As for toxicity, there was no ≥Grade 3 AEs and Grade 1-2 radiation Pneumonitis was the most frequent AEs. Conclusions: Early SBRT for primary tumor generated prolonged PFS without serious radiation pneumonitis in advanced EGFR mutation NSCLC patients with TKI treatment. This combined therapy obtained remarkably lower primary tumor progression rate and favorable OS. Clinical trial information: ChiCTR-OIN-17013920.
Intensity of free-radical reactions in metastasizing cervical cancer.
Authors: Natalia V. Chernikova, Irina A. Goroshinskaya, Elena M. Frantsiyants, Ekaterina V. Verenikina, Yuriy A. Poryvaev, Tatiana Yu. Myagkova, Polina S. Kachesova, Ludmila A. Nemashkalova
Journal: Journal of Clinical Oncology (2021)

e17508 Background: Cervical cancer (CC) is one of the main causes of death among patients with gynecological tumors. As a rule, patients die from relapses and metastases which rates reach 30-45%. According to research data, treatment of patients with distant metastases is ineffective, and half of them die within 9.7 months, while the average survival is 15.9±0.26 months. The development of many pathological processes is considered to be associated with an increase in free-radical reactions leading to oxidative damage to various biomolecules. The purpose of the study was to analyze some characteristics of the free-radical oxidation and antioxidant defence in metastasizing CC. Methods: The study included 56 patients aged 29-73 years with stage IIB-IV CC after antitumor treatment. The main group – 27 patients who developed metastases within 4 months to 8 years after the CC diagnosis; controls – 29 patients with non-metastatic CC; donors – 19 healthy women aged 27-61 years. The accumulation of carbonyl derivatives in blood plasma proteins was detected in the reaction with 2, 4-dinitrophenylhydrazine. The induced oxidative modification of proteins was stimulated with Fenton's reagent. Free-radical processes was evaluated by the intensity of peroxide-induced luminol-dependent plasma chemiluminescence and the content of nitric oxide metabolites; the intensity of lipid peroxidation - by the content of malondialdehyde (MDA); the activity of catalase and ceruloplasmin was also studied. Results: CC progression was accompanied by increasing lipid peroxidation and spontaneous oxidation of blood plasma proteins. MDA levels in patients with metastases increased by 57.8% compared to donors and by 34.3% compared to patients without metastases (p &lt; 0.05). The concentration of 2, 4-dinitrophenylhydrozones increased on average by 4 times compared to donors and by almost 2 times compared to patients without metastases. Patients with metastasizing CC demonstrated elevated levels of products of the interaction of nitric oxide and its derivatives with proteins and peptides - 3-nitrotyrosine and nitrosoglutathione, compared to both donors (by 31.4% and 55.3%) and patients in remission (by 38.1% and 34.5%). Chemiluminescence activity increased by 54.5% compared to donors (p &lt; 0.05) and by 93% (p &lt; 0.01) compared to controls. Catalase activity in the blood plasma of patients with metastases increased by 54.1% compared to donors, but was lower than the values in the control group (by 22.1%). Ceruloplasmin activity was increased only in patients without metastases (by 33%). Conclusions: The process of CC metastasis is accompanied by a greater intensity of oxidative processes of both proteins and lipids, as well as depletion of the adaptive capabilities of the body's antioxidant system.
Immune-response markers and actual response to immune-oncology therapy in uterine serous carcinoma.
Authors: Nathaniel L. Jones, Sharon Wu, Joanne Xiu, Amaranta Craig, Gina Mantia-Smaldone, Enrique Hernandez, Rodney Paul Rocconi, Jubilee Brown, Thomas J. Herzog, Robert W. Holloway, Wolfgang Michael Korn, Matthew A. Powell, Annelise M. Wilhite
Journal: Journal of Clinical Oncology (2021)

5590 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with poor prognosis and limited treatment options. Immune-oncology (IO) agents have shown promise USC, however data is limited regarding which patients benefit most from IO therapy. In other malignancies, PD-L1, MSI-H status and high TMB have been predictive of IO response. We sought to characterize the immune profiles of USC and investigate treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off &gt;1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high &gt; 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be &lt; 0.05. Results: Molecular analysis was performed on 2,806 USC tumors. The median age was 67 years. 65.3% were from primary tumors, 34.7% from metastatic sites. In total, 92 patients were treated with IO therapy and had a significantly longer median survival than those not treated with IO (months: 59.6 vs 31.2; HR(95% CI): 0.38(0.24-0.61) p &lt; 0.001), resulting in a survival advantage of 867 days. PD-L1 expression was present in 19.1% of cases, but only 2.3% of tumors were MSI-H and 4.2% were TMB-H. Patients with these markers trended toward a better median survival, but this was not significant; PD-L1 (months: 34.4 vs 31.2; HR(95% CI): 0.90 (0.74-1.1), MSI-H (OS not yet reached vs 31.6 months; HR(95% CI): 0.69(0.38-1.25) and TMB-H (months: 36.4 vs 31.6; HR(95% CI): 0.84(0.50-1.39). Regarding the immune microenvironment, the most common infiltrating immune cells were M2 Macrophages (5.35%), B cells (4.71%), myeloid dendritic cells (3.45%), NK cells (2.94%) and regulatory T cells (1.59%). There were few CD8 T cells and non-regulatory CD4 T cells. Conclusions: IO therapy was associated with a median survival benefit of more than 2 years in USC. We did not identify any prognostic markers of IO-therapy response. MSI-H and TMB-H are rare in USC, but PD-L1 is present in nearly 20% of cases. Notably these markers did predict a significant survival benefit, which has important clinical implications. Further study is warranted.
Vo2peak in Adult Survivors of Hodgkin Lymphoma
Authors: Raheel Rizwan, Kimberlee Gauvreau, Cheryl Vinograd, Jessica M. Yamada, Christina Mangano, Andrea K. Ng, Mark E. Alexander, Ming Hui Chen
Journal: JACC CardioOncology (2021)

Adult survivors of Hodgkin lymphoma (HL) are at increased risk of cardiovascular (CV) events secondary to mediastinal radiation therapy (RT).In this group of patients, we assessed the association between cardiopulmonary exercise testing (CPET), as determined by percent-predicted peak Vo2 (ppVo2peak), and clinical outcomes, as well as the rate of ppVo2peak decline and sex differences.All survivors of HL who were >10 years post chest RT and who underwent ≥1 CPET were enrolled from a single center. Traditional CV and treatment risk factors, along with CV events, were ascertained.A total of 64 patients (67% female; median age 51 years [range 26 to 70 years]) with a median follow-up time after RT of 23 years (range 11 to 41 years), and 141 CPET studies, were included. Median initial ppVo2peak was 91% (range 58% to 138%). ppVo2peak in survivors declined by 7.5 percentage points every 10-year period after RT, as compared with age- and sex-based norms (P = 0.001), even after adjusting for hypertension and history of anthracycline. Both male and female patients had a similar rate of ppVo2peak decline. However, women had a lower ppVo2peak at all times, and they developed abnormal ppVo2peak (≤85%) on average earlier than men (24.1 years vs 47.0 years after RT). Patients with abnormal ppVo2peak vs normal ppVo2peak (>85%), had an increased risk of CV events (59% vs 16%). Abnormal ppVo2peak was independently associated with the risk of CV events (adjusted HR: 6.37; 95% CI: 2.06-19.80; P = 0.001).Percent-predicted Vo2peak in long-term survivors of HL who were treated with chest RT progressively declined as compared with population- and sex-based norms. Importantly, women developed abnormal ppVo2peak more than 2 decades earlier than male survivors. Abnormal ppVo2peak was associated with an increased risk of CV events in this group of patients.
Single-cell analysis of the cellular heterogeneity and interactions in the injured mouse spinal cord
Authors: Lindsay M. Milich, James S. Choi, Christine Ryan, Susana R. Cerqueira, Sofia Benavides, Stephanie L. Yahn, Pantelis Tsoulfas, Jae K. Lee
Journal: The Journal of Experimental Medicine (2021)

The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor–ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.
Concordance between 21-gene score (Oncotype DX) and clinical-pathologic prognostic models in early-breast cancer in Medellín, Colombia.
Authors: Mauricio Lujan, Mauricio Lema, Diego Moran, Beatriz Preciado, Jorge Egurrola, Camila Lema
Journal: Journal of Clinical Oncology (2021)

e12521 Background: The genomic-based 21-gene recurrence-score assay (Oncotype DX, Genomic Health)(ODx) is used to decide on the use of adjuvant chemotherapy (ACT) in luminal-type Early-Breast Cancer (LT-EBC). Patients with low RS can safely avoid ACT. Other predictive models based on standard clinical and histopathological (C&amp;H) variables also have been developed. These include, Magee equations (ME), Predict model (PM), and Tennessee nomogram score (TNS). This study aims to establish the concordance between ODx and ME, PM and TNS models in a set of patients with EBC in Medellín, Colombia. Methods: Patients with unifocal, stage I and IIA, LT-EBC (HR+/Her2-) with results for ODx were included. For inclusion, key standard C&amp;H variables needed to be available as to allow accurate assessment of ME, PM and TNS predictive models. ODx was used as the reference test and the predictive models as index tests. Low-risk (LR) was defined &lt; 18 in all three ME; &lt; 3% in the PM; and a probability calculated for LR &gt; 90% in the TNS. A second analysis was performed in the &gt; 50 years-old cohort (+50C), using standard and a modified criteria. In the last one, intermediate-risk (IR) patients were either excluded or grouped with high-risk scores for analysis. Concordance between the models and the ODx was evaluated using Cohen's kappa index (K). The degree of concordance was classified according to the categories established by Landis and Koch. AUROC (area under receiver operating characteristics) was estimated. Statistical analyses were performed with Stata v16. Results: 122 patients were included. Median age: 58 (IQR 49-66). Main histology was ductal carcinoma (85.2%), and median size was 15 mm (IQR 10-20). LR was adjudicated in 80.3%, 57.4%, 89.3% and 69.7% with ODx, ME, PM and TNS, respectively. Concordance between the ODx and ME and PM in the all patient population was fair, with K of 0.35 (95% CI: 0.18-0.50; p &lt; 0.001), and 0.24 (95% CI: 0, 04 - 0.45; p &lt; 0.001), respectively. Concordance of ODx and TNS was inferior with a K of 0.16 (95% CI: 0.03-0.34, p = 0.04). AUC for ME, PM, and TNS was 0.61 (95% CI: 0.49-0.73), 0.61 (95% CI: 0.52-0.70) and 0.59 (95% CI: 0.48-0.70), respectively. 85 patients were included in the +50C (69.7%). For one analysis, 41 patients with IR with either ME or PM were excluded. Concordance between the ME and the ODx was fair. LR in both ME and ODx was found 41/43 patients (95.5%, 95% CI 87.9-100). As for PM and TNS, the degree of concordance with ODx were low, and non-significant, respectively. Concordance between ODx LR was found in 36/37 patients with LR in all three ME, PM and TNS (97.3%, 95% CI: 90.7-100). Discrimination capacity: 79%. Conclusions: The high cost of ODx can be safely avoided in stage I/IIA luminal-type EBC and &gt; 50 year-old with low-risk scores in all three ME, PM, and TNS.
Do you hear us? Elevating the voice of patients from Asia Pacific (AP) and Middle East (ME) in pharmaceutical research.
Authors: Julie Rihani, Noha Mohamed Mahmoud Abdelbaky, Chandra Rekha Gulabani, Dexter Patel, Rami El Sayegh, JungHo Park, Michaela Dinboeck, Dawn Aubel, Cassandra Alice Slader
Journal: Journal of Clinical Oncology (2021)

e18519 Background: Incorporating patient (pt) perspectives in the development of new therapies (from trial design to regulatory &amp; reimbursement decisions) and providing pts with plain language summaries (PLS) of clinical trial results is increasingly important to minimise knowledge and experience disparities. One model to facilitate this in pharmaceutical research is via Patient Expert Panels (PEPs). Aim: To assess the feasibility &amp; impact of PEPs consisting of members from AP&amp;ME on the development of 1. PLS of data presented at ESMO and ASH 2020 for selected Novartis-sponsored clinical trials 2. Disease education material for sickle cell disease (SCD). Methods: Thematic analysis of meeting minutes from PEPs conducted between Sep – Dec 2020 was performed. Data relating to meeting duration were extracted. The responses from an 8-item survey of PEP members were analysed descriptively for 6 items, thematically for 2. Results: Five virtual PEPs were conducted, with a median duration of 60 mins [range 60-120]. In total, 9 PLS were reviewed (8 breast cancer, 1 CML) &amp; 1 SCD education booklet. Five common themes emerged regarding the input &amp; impact of the PEP [Table]. 88% panelists responded they “Definitely will” participate in future PEPs, thereby confirming their feasibility, with the following quote being representative of the panelists’ experience &amp; impact “I appreciated how our input as patients was valued and highly taken into consideration. It felt like our time and feedback was important to everyone.” Conclusions: PEP constituted of pts from countries in AP&amp;ME are feasible and lead to impactful improvements in the development of PLS and disease education information. Given pt advocates in these countries are volunteers from organisations with limited resources, have diverse backgrounds in terms of culture, language &amp; disease awareness, their input is more representative of a broader pt population. As a result, the final versions of the reviewed documents were more inclusive &amp; accessible. [Table: see text]
“We Do Not Want Him Because He Is a Jew”: The Montreal Interns' Strike of 1934
Authors: Edward C. Halperin
Journal: Annals of Internal Medicine (2021)

Speeches by modern-day White supremacists often include such statements as "Jews will not replace us." In 1934, the French-speaking medical interns of Montreal's Roman Catholic hospitals went on strike because, they alleged, a Jew "replaced" a Roman Catholic French Canadian. Anti-Semitic social and economic boycotts and educational quotas were in existence in Canada from the 19th through the mid-20th century. There were particularly strong anti-immigrant and anti-Semitic feelings in the first half of the 20th century in Quebec, along with anti-Semitic pro-fascist political parties. In 1934, Montreal's Hôpital Notre-Dame (HND), a teaching hospital of the Université de Montréal (UM) medical school, was unable to hire a full complement of medical interns from among the newly graduated French-speaking Roman Catholic medical students. The hospital hired a French-speaking Jewish graduate of UM, Samuel Rabinovitch. The prospective interns at HND submitted a petition demanding that Rabinovitch be fired, stating, "We do not want him because he is a Jew." On 14 and 15 June 1934, HND's interns went on strike to prevent Rabinovitch from taking up his duties. The strike spread to multiple hospitals in Montreal. A Jewish urology trainee at the Hôtel Dieu hospital, Abram Stilman, was also targeted. Rabinovitch resigned in order to bring the strike to an end. The strike buttressed the case in the first half of the 20th century for American and Canadian Jewish hospitals and medical schools to ensure the education of Jewish physicians, reminds us of the origins of the slogans of modern White supremacists, and reinforces the historical basis of efforts to promote diversity and inclusion in medical education.