tbuckley/cabot-search huggingface dataset:
Overall survival in patients who received checkpoint inhibitors after completing tebentafusp in a phase 3 randomized trial of first-line metastatic uveal melanoma.
Authors: Marlana Orloff, Richard D. Carvajal, Alexander Noor Shoushtari, Joseph J. Sacco, Max Schlaak, Claire Watkins, Shaad Essa Abdullah, Howard Goodall, Marcus O. Butler
Journal: Journal of Clinical Oncology (2021)

9526 Background: Tebentafusp (tebe) is a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells. Tebe significantly improved OS compared to investigator’s choice (IC) in first line (1L) mUM [NCT03070392]. In a phase (ph) 2 study of tebe in 2L+ mUM (NCT02570308), several checkpoint inhibitor (CPI) refractory pts who were retreated with CPI after tebe achieved durable clinical benefit [1]. We therefore evaluated clinical outcomes of post-tebe CPI in patients treated on the ph3 trial of tebe versus investigator’s choice (IC) [NCT03070392]. Methods: In the ph3 trial, 378 HLA-A*02:01+ 1L mUM pts were randomized 2:1 to tebe (n=252) or IC (n=126) [pembrolizumab (82%), ipilimumab (12%) or dacarbazine (6%)]. No crossover to tebe was permitted, investigators were free to choose subsequent therapy, and there was no re-randomization at time of subsequent therapy. This analysis was conducted on the first interim analysis (data extracted Nov-2020). When pts received more than one subsequent therapy, the first was used in these analyses. Medians and 1-yr OS from the start of post-study therapy are obtained from standard Kaplan-Meier analyses; hazard ratios (HR) are from Cox regression models adjusted for age and gender. Results: 106/252 (42%) tebe pts received ≥ 1 subsequent therapy: 35% CPI, 9% chemo, 6% liver directed therapy (LDT), 6% other. 55/126 (44%) of IC pts received ≥ 1 subsequent therapy: 21% CPI, 10% chemo, 12% LDT, 10% other. Median time to first subsequent therapy was longer for tebe pts at 5.2 mo vs. IC pts at 3.8 mo. The median duration from start of first subsequent CPI to end date was longer in the prior tebe pts at 4 mo vs prior IC pts at 2.8 mo. From the start of any first subsequent therapy, prior tebe pts had longer OS compared to prior IC pts, HR 0.67 (95% CI 0.42, 1.07). Most of the subsequent therapy was CPI, and the OS benefit was also seen in this subset, HR 0.62 (95% CI 0.34, 1.14). For prior tebe pts, the median and 1-yr OS rates from start of any first subsequent therapy were 13 mo and 53% and from start of first subsequent CPI were 16 mo and 63%. Both were higher than the sequence of IC followed by any therapy (11 mo and 44%), IC followed by CPI (9 mo and 47%) and a recent meta-analysis of 2L+ mUM (7 mo and ̃35% 1-yr OS rate). Conclusions: Pts who progressed on tebe and then received CPI had better OS compared to pts who progressed on IC and then received CPI. Further analysis will explore whether confounding factors are influencing this effect. These exploratory data suggest that tebe, relative to IC, may improve outcomes to subsequent CPI. (1)Yang J. et al. ASCO 2019, J . Cli n Oncol 37:15_suppl, 9592. Clinical trial information: NCT03070392.
FDG-PET avidity as a prognostic biomarker for overall survival in renal cell carcinoma.
Authors: Justin Ferdinandus, Ines Maríc, Christopher Darr, Claudia Kesch, Thomas Hilser, Wolfgang Peter Fendler, Ken Herrmann, Boris A. Hadaschik, Viktor Grünwald
Journal: Journal of Clinical Oncology (2021)

e16564 Background: Positron emission tomography with (18F)-fluorodeoxyglucose (FDG-PET) is not considered a standard of care (SOC) in renal cell carcinoma (RCC) because of its variability in metabolic activity. We investigated the rate of PET-positivity in our institutional cohort and tested whether PET-positivity had prognostic value in metastatic (m)RCC. Methods: Patients with FDG-PET imaging at any time during the course of disease were identified from medical records. PET-positivity was defined according to PERCIST criteria and a five-point rating scale analogue to Deauville Scoring was used to stratify PET-avidity. Tracer uptake of the hottest lesion was measured as SUVmax. Clinical parameters and PET-positivity were correlated with overall survival (OS). Kaplan-Meier plots, log-rank analyses, kendall rank correlation, univariate and multivariable cox regression models were employed, where appropriate. Results: A totalof 90 patients was analyzed. The median age was 64.0 (34.0-83.0) and 56 (62.2%) patients had clear cell RCC. Metastatic disease was present in 64 (71.1%) and 22 (24.4%) patients received ongoing medical treatment. 72 (80.0%) patients had prior nephrectomy. PET-positivity occurred in 57 (63.3%) patients, with similar rates among metastatic (41/64; 64%) and non-metastatic patients (16/26; 62%). PET-positive patients had shorter median OS compared to PET-negative patients (38.5 months (CI95:24.5-NR) vs. not reached (CI95: 69.6-NR), P= 0.0013). A weak correlation was found between PET-Uptake and histologic grade (Kendall’s tau 0.22; P= 0.03). Prior nephrectomy, presence of primary lesions, presence of distant metastases, histologic grade and PET-positivity were significant predictors of OS in univariate regression. In multivariable analysis, only PET-positivity remained significant (HR 4.1 (CI95: 1.1-15.4), P= 0.04). Conclusions: RCC is a metabolically active cancer, which in the majority of patients is suitable for FDG-PET diagnostic procedures. PET-positivity was an independent prognostic factor for OS in RCC, indicating its putative clinical use. Further studies to define the role of FDG-PET imaging in RCC are ongoing.
Clinicopathological characteristics of CML in children and young adults.
Authors: Sobia Yaqub, Amjad Zafar, M Ahmed Latif, Zain Ahmad, Kausar Bano, Muhammad Abbas Khokhar
Journal: Journal of Clinical Oncology (2021)

e19029 Background: CML, although a disease of middle age, is not uncommon in younger age groups in developing countries like Pakistan. Methods: In this single center, cross sectional study, all patients diagnosed with CML below 30 years of age were enrolled. After collection, data was analyzed using Spss version 23.Quantitative variable were presented as mean and percentages. Chi-square was used for correlation between variables with p&lt;0.05 considered significant. Results: Total 101 patients, with age range 7-30 years (mean 21.99±6.3), including 18(17.8%) below 15 years, were enrolled. Fever was most common presenting symptoms seen in 61(60.4%) followed by fatigue, abdominal distension in 40(39.6%) and 33(32.7%).Mean presenting TLC was 158.9±136.95. Of these, 97(96.03%) patients were in chronic phase, 3(2.97%) had accelerated and 1(1%) in blast phase. As per SOKAL score, 27 (26.73%), 51(50.49%) and 23(22.77%) had low, intermediate and high risk disease respectively. Imatinib was started in 80.19% while Nilotinib in 19.80% as 1 st line TKI. Among these, 88.1% achieved CHR by end of 3 rd month. After 1 st year, 60.8% achieved a molecular response (MR≥3). 1(1%) transformed from chronic to blast phase.2 nd line TKI was started in 13.8% due to lack of response. Grade ¾ thrombocytopenia and grade ½ per-orbital edema were main toxicities seen in 10.7% and 9.6% respectively. Co-relation of increasing age with high TLC (p=0.039) and better response to TKI (p=0.014) was statistically significant. Conclusions: Distinct clinical behavior of CML in children and young adults necessitates further studies to ensure better disease management.[Table: see text]
EMBR-09. EXAMINING THE ROLE OF THE DEVELOPMENTALLY ENCODED TRANSCRIPTION FACTOR, LHX9, IN GROUP 3 MEDULLOBLASTOMA
Authors: Sarah Injac, Bryan Rivas, Amir Arabzade, Yanhau Zhao, D William Parsons, Stephen Mack
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Despite major advances in our understanding of the biology of MB, novel treatments remain urgently needed. Using a chemical-genomics driven drug repositioning strategy, we identified the cardiac glycoside family of compounds as potential treatments for Group 3 MB. We subsequently demonstrated that single-agent treatment with digoxin prolongs survival in a patient-derived xenograft model (PDOX) of Group 3 MB to a degree comparable to radiation therapy, a mainstay in the treatment of MB. Finally, we examined the mechanism of digoxin-mediated cell killing using RNA-seq. This work identified LHX9, a member of the LIM homeobox family of transcription factors, as the gene most significantly down-regulated following treatment (Huang and Injac et al, Sci Trans Medicine, 2018). Homologs of LHX9 play key roles in cerebellar development via spatially and temporally restricted expression and LHX9 has been proposed as a core transcription factor (TF) in the regulatory circuitry of Group 3 tumors. Loss of function of other core TFs has been shown to impact MB growth. The role of LHX9 in MB, however, has not been previously experimentally evaluated. We now report that knockdown of LHX9 in MB-derived cell lines results in marked growth inhibition. RNA-seq analysis of LHX9-depleted cells showed changes which included alterations in extracellular matrix-receptor interactions and TGFb signaling. These findings raise the possibility that loss of LHX9 plays a major role in digoxin-mediated cell killing and that LHX9 represents a key dependency required for the growth of Group 3 MB. Clinical targeting of core TFs would represent a novel approach to targeting this devastating disease.
A diverse collection of B cells responded to HIV infection in infant BG505
Authors: Cassandra Simonich, Mackenzie M. Shipley, Laura Doepker, Theodore Gobillot, Meghan Garrett, Evan M. Cale, Brianna Hennessy, Hannah Itell, Vrasha Chohan, Nicole Doria-Rose, Ruth Nduati, Julie Overbaugh
Journal: Cell Reports Medicine (2021)

Increasing evidence suggests infants develop unique neutralizing antibody (nAb) responses to HIV compared to adults. Here, we dissected the nAb response of an infant whose virus is in clinical trials as a vaccine immunogen, with a goal of characterizing the broad responses in the infant to this antigen. We isolated 73 nAbs from infant BG505 and identified a large number of clonal families. Twenty-six antibodies neutralized tier 2 viruses—in some cases, viruses from the same clade as BG505, and in others, a different clade, although none showed notable breadth. Several nAbs demonstrated antibody-dependent cellular cytotoxicity activity and targeted the V3 loop. These findings suggest an impressive polyclonal response to HIV infection in infant BG505, adding to the growing evidence that the nAb response to HIV in infants is polyclonal—a desirable vaccine response to a rapidly evolving virus like HIV.
Burkitt Lymphoma/Leukemia Presented on 68Ga-Pentixafor and 18F-FDG PET/CT
Authors: Zhenying Chen, Qianqian Xue, Chao Huang, Shaobo Yao, Weibing Miao
Journal: Clinical Nuclear Medicine (2021)

An 18-year-old man with newly diagnosed Burkitt lymphoma/leukemia was referred for 18F-FDG and 68Ga-Pentixafor PET/CT. 68Ga-Pentixafor PET/CT revealed similar radioactivity uptake pattern to the 18F-FDG PET/CT in superior phrenic lymph node, ascending colon, ileocecum, peritoneal, marrow, and spleen. This case highlighted that it might be interesting to further investigate the role of 68Ga-Pentixafor PET/CT imaging in staging, treatment evaluation, and especially the feasibility of CXCR4-directed radioligand therapy in Burkitt lymphoma with positive expression of CXCR4.
Prevalence of Nonheterosexual Identity and Same-Sex Sexual Contact Among High School Students in the US From 2015 to 2019
Authors: Eli Rapoport, Christian E. Athanasian, Andrew Adesman
Journal: JAMA Pediatrics (2021)

This national cohort study uses Youth Risk Behavior Survey data to identify changes in the prevalence of high school students reporting nonheterosexual identities and same-sex sexual contact between 2015 and 2019.
Relationship between circulating tumor cells and ZEB1 expression in tumor cells in colorectal cancer.
Authors: Inna A. Novikova, Oleg I. Kit, Elena Yu. Zlatnik, Elena P. Ulianova, Aleksandr B. Sagakyants, Anastasia O. Sitkovskaya, Oksana G. Shulgina, Yuriy A. Gevorkyan, Natalya V. Soldatkina, Vladimir E. Kolesnikov, Maksim K. Aleksandrovich, Andrey V. Dashkov, Sergey I. Poluektov, Dmitry O. Kaymakchi, Ellada A. Mirzoyan, Vladislav K. Pavlov, Elena A. Dzhenkova, Aleksandr V. Shaposhnikov, Maksim A. Vereshchak, Oksana V. Katelnitskaya
Journal: Journal of Clinical Oncology (2021)

e15509 Background: Intravasation and circulation of tumor cells involves active invasion of cells with an enhanced migration potential as a result of the epithelial-mesenchymal transition (EMT). The ZEB1 protein is one of the key regulators of this process. Our purpose was to evaluate the association between the amount of circulating tumor cells (CTCs) in the peripheral blood of patients with different stages of colorectal cancer and the expression of ZEB1 by tumor cells. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. The numbers of CTCs were measured in the peripheral blood before surgery using the Veridex CellSearch system (Janssen). CTCs were registered taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45, cytokeratins 8,18,19. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Tissues of surgically removed tumors were studied with IHC analysis using rabbit polyclonal anti-ZEB1 antibodies (Biorbyt Ltd.) diluted 1:200 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: From 1 to 402 CTCs were determined in 62.9% cases (in 188 of 299 patients); CTCs were not registered in 37.1% cases (111 of 299). Positive ZEB1 expression was observed in 80.6% (241 of 299 patients), while the negative one was much more rare – 19.4% (58 of 299 patients). The rates of CTC detection significantly increased with the positive ZEB1+ expression, compared to the negative expression (75.1% vs. 12.1%). CTCs &gt;3 were detected in the blood in 39.0% in ZEB1+ tumors, but not in ZEB1- tumors. 1-3 CTCs were observed 3 times more often in ZEB1+ tumors (36.1% vs. 12.1; p≤0.05). Conclusions: Statistically significant association was revealed between the epithelial-mesenchymal transition marker ZEB1 expression by tumor cells and the amount of CTCs in the peripheral blood (p &lt; 0.001).
Mathematical predication models to optimize post-treatment surveillance in HPV-associated oropharyngeal cancer.
Authors: Vivek Nair, Samuel Auger, Sara Kochanny, Frederick Howard, Daniel Ginat, Olga Pasternak-Wise, Aditya Juloori, Evgeny Izumchenko, Nishant Agrawal, Ari Rosenberg, Everett E. Vokes, Reza Skandari, Alexander T. Pearson
Journal: Journal of Clinical Oncology (2021)

6027 Background: In this study we develop post-treatment imaging surveillance schedules for locally advanced oropharyngeal carcinoma (OPC) specific to the unique recurrence patterns of tumor stage and HPV status, using mathematical models. Current post-treatment imaging surveillance recommendations for OPC are not evidence based. The exception is the use of a positron emission tomography (PET) scan at 3 months post-treatment, after which practice across institutions diverge. An optimized and personalized surveillance schedule for OPC patients can minimize costs and diagnostic delays. Methods: A Markov multi-state model defining local and distant recurrences was trained using 2159 patients from the National Cancer Database. Patients from 2010-2015 treated at an academic or major cancer center with curative radiotherapy were included. Tumors must have been stage III to IVB (AJCC 7 th edition) with known p16/HPV status. Model performance was then successfully externally validated using the 2016 International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) study. Optimized radiographic surveillance schedules were created using this model, assuming a PET at month 3 and including 0 to 6 additional computed tomography (CT) scans of the neck and chest. Optimization was done for minimization of latency, defined as time between disease recurrence and radiographic discovery. Results: Model-selected schedules varied significantly from commonly utilized-surveillance schedules (such as imaging every 3 months within the first year from treatment) and showed lower mean diagnostic latency for every stage and HPV status (shown in Table). In the lowest risk cohort (Stage III HPV+), the optimized schedule had a sensitivity of 65% and latency of 3.1 months. In the highest risk group (Stage IVB HPV-), the optimized schedule had a sensitivity of 76% and latency of 1.9 months. Conclusions: Mathematical model optimization for HPV status and stage is feasible and produces non-intuitive results. These results could be used to inform surveillance if payors reimburse for fewer total scans. Across all cohorts, each added CT scan increases surveillance sensitivity and decreases latency. Incorporation of physical exam and direct visualization results into the model are still needed. Future steps include cost effectiveness research and prospective clinical trials.[Table: see text]
The efficacy and safety of anlotinib in neoadjuvant treatment in locally advanced thyroid cancer: A single-arm phase II clinical trial.
Authors: Naisi Huang, Guohua Sun, Yulong Wang, Jiaying Chen, Qing Guan, Zhongwu Lu, Jun Xiang, Wenjun Wei, Ben Ma, Qinghai Ji, Yu Wang
Journal: Journal of Clinical Oncology (2021)

6069 Background: Surgery is the primary treatment for locally advanced thyroid cancer (TC). For some locally advanced TC, R0/R1 resection could not be achieved at initial diagnosis and neoadjuvant treatment would be an option. However, there is still little evidence regarding neoadjuvant treatment in locally advanced TC. Methods: This single-arm, phase 2 study investigated the efficacy and safety of Anlotinib (12mg orally daily, for two weeks on/on week off) for 2-6 cycles in patients with locally advanced TC in the neoadjuvant setting. Operable patients received surgery after neoadjuvant treatment. The primary endpoint was objective response rate (ORR). Results: A total of 13 patients were included and received an average of 3.5 cycles (range: 3-6 cycles) of Anlotinib treatment. 12 cases were papillary thyroid cancer, and 1 was follicular thyroid cancer. The ORR of Anlotinib was 76.9% with 10 partial response (PR), 2 stable disease (SD), and 1 progressive disease (PD). 8 PR and 1 SD patients received surgery after neoadjuvant treatment, of whom 8 had R0/1 resections and 1 had R2 resection. 2 PR patients refused to have surgery and the rest 2 patients were not operable. The R0/1 resection rate for intent to treat population was 61.5% and for per-protocol population was 72.7%. The maximum reduction in sum of tumor diameter was an average of 34.8% (range: 30.9%-45.5%) for PR patients. Most adverse events were grade 1 or 2. Common adverse events of all grade were hypertension (76.9%), hypertriglyceridemia (69.2%), proteinuria (53.8%), TSH increase (53.8%), cholesterol elevation (53.8%) and hand-foot syndrome (38.5%). The majority of adverse events discontinued after the neoadjuvant treatment stopped. Conclusions: Anlotinib demonstrated antitumor activity in the neoadjuvant treatment in locally advanced TC and the majority of patients achieved R0/1 resection. Adverse events were consistent with the known Anlotinib adverse event profile. These results suggest that Anlotinib neoadjuvant treatment represents a new option for locally advanced TC. Clinical trial information: NCT04309136.
Predictive and prognostic biomarker identification in a large cohort of androgen receptor-positive salivary duct carcinoma patients scheduled for combined androgen blockade.
Authors: Gerben Lassche, Yuichiro Tada, Carla M.L.- Van Herpen, Marianne A. Jonker, Diederick Keizer, Wim Verhaegh, Toshitaka Nagao, Takashi Saotome, Hideaki Hirai, Natsuki Saigusa, Adriana C.H. van Engen - van Grunsven, Jack A. Schalken, Chihiro Fushimi, Gerald W. Verhaegh
Journal: Journal of Clinical Oncology (2021)

6071 Background: Patients suffering from recurrent or metastatic (R/M) salivary duct carcinoma (SDC) are often treated with combined androgen blockade (CAB). This treatment however frequently fails (response rates: 18-53%), resulting in a worse prognosis. Therefore, biomarkers that have prognostic value and can predict treatment response are urgently needed. Methods: mRNA from 77 R/M androgen receptor (AR) positive SDC patients treated with leuprorelin acetate combined with bicalutamide was extracted from pre-treatment tumor specimens. AR, Notch, Mitogen-Activated Protein Kinase (MAPK), Transforming Growth Factor beta (TGFβ), Estrogen Receptor (ER), Hedgehog (HH) and the Phosphoinositide 3-Kinase (PI3K) signaling pathway activities were calculated based on expression levels of relevant target genes. Besides this, 5-alpha reductase type 1 ( SRD5A1) expression and Human Epidermal growth factor Receptor 2 (HER2) status were determined. Clinical benefit was defined as complete or partial response or stable disease ≥6 months. Results: Of the 7 signaling pathways, AR pathway activity was the best predictor of clinical benefit (AUC 0.67, 95%-CI 0.54-0.80). At a threshold of 47.8, 21% of the patients tested negative, with a negative predictive value of 93%. SRD5A1 expression outperformed the signaling pathways regarding predictive value (AUC 0.78, 95%-CI 0.67-0.88). Fitting of a multivariable model led to the identification of SRD5A1, Notch and TGFβ as most predictive combination (AUC 0.82, 95%-CI 0.72-0.91). AR, Notch, HH and SRD5A1 were also of prognostic importance regarding progression free survival and SRD5A1 expression levels also for overall survival (median of 175.0 weeks for high versus 96.7 weeks for low expression). Conclusions: Our study revealed predictive and/or prognostic value of AR, HH, Notch and TGFβ signaling activities and SRD5A1 expression in SDC patients treated with CAB. AR pathway activity can be used for identifying non-responders. Further clinical validation is required before implementation of these biomarkers in clinical practice. The observed role of SRD5A1 expression in CAB response forms a rational basis for including SRD5A1-inhibitors in the treatment of SDC patients.[Table: see text]