tbuckley/cabot-search huggingface dataset:
BIOL-03. PROTEIN TRANSLATION FROM NON-CODING GENOMIC LOCI PRODUCE BIOLOGICALLY-ACTIVE PROTEINS IMPLICATED IN CANCER CELL SURVIVAL IN PEDIATRIC BRAIN TUMORS
Authors: John Prensner, Todd Golub
Journal: Neuro-Oncology (2021)

Abstract Protein translation is both a fundamental cellular process essential for life as well as an oncogenic mechanism employed by tumors to enact cancer cell biology. While protein translation is most readily manifest in the ~20,000 known human protein coding genes, there are, in fact, several thousand additional regions of the cancer genome that are translated and contribute the complexity of the molecular milieu of cancer. Here, we systematically addressed the question of whether such uncharacterized genomic regions encode truly biologically active proteins and applied these findings to pediatric brain tumors. We experimentally interrogated 553 candidates selected from non-canonical open reading frame (ORF) datasets. Of these, 57 induced viability defects when knocked out in a broad array of human cancer cell lines. Upon ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. CRISPR tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We characterized several of these in the context of pediatric brain tumors, where dense CRISPR tiling screens revealed unique functional relevance of dozens of non-canonical ORFs in pediatric brain cancer cell survival. We found that one of these ORFs, ASNSD1 uORF, encodes a well-folded protein whose translation is a selective genetic dependency distinct from the adjacent ASNSD1 annotated protein. In vitro molecular biology assays confirmed the MYC-amplified medulloblastoma cell lines had a heightened dependency on this protein, and that MYC binds to the promoter of this gene, with MYC expression correlating with ASNSD1 in patient tumors. Co-immunoprecipitation assays defined ASNSD1 uORF as a novel member of the prefoldin complex of cytoplasmic protein stability regulators. Overall, our experiments suggest that the abundant protein translation found in the “non-coding” genome may produce biologically active non-canonical ORFs that are potential therapeutic targets.
Role of adjuvant therapy in esophageal cancer patients after neoadjuvant therapy and curative esophagectomy: A systematic review and meta-analysis.
Authors: Yung Lee, Yasith Samarasinghe, Michael H Lee, Luxury Thiru, Yaron Shargall, Christian Finley, Wael Hanna, Oren Hannun Levine, Rosalyn A. Juergens, John Agzarian
Journal: Journal of Clinical Oncology (2021)

e16083 Background: While neoadjuvant therapy followed by esophagectomy is the standard of care for locally advanced esophageal cancer, the role of adjuvant therapy is uncertain. As such, this review aims to analyze esophageal cancer patients who previously underwent neoadjuvant therapy followed by a curative resection (negative margins) to determine whether additional adjuvant therapy is associated with improved survival outcomes. Methods: MEDLINE, EMBASE, and CENTRAL databases were searched up to August 2020 for studies comparing patients with esophageal cancer who underwent neoadjuvant therapy and curative resection with and without adjuvant therapy. Primary outcome was overall survival (OS), and secondary outcomes were disease-free survival (DFS), locoregional recurrence, and distant recurrence at 1 and 5-years. Random effects meta-analysis was conducted where appropriate. Grading of recommendations, assessment, development, and evaluation (GRADE) was used to assess the certainty of evidence. Results: Ten studies involving 6,462 patients were included. 6,162 (95.36%) patients from 7 studies received adjuvant chemotherapy, whereas 296 (4.58%) patients from 3 studies underwent either adjuvant radiotherapy or chemoradiotherapy. When compared to patients who received neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups experienced a significant overall survival benefit by 48% at 1-year (RR 0.52, 95%CI 0.41-0.65, P &lt; 0.001, moderate certainty). This reduction in mortality was consistent at long-term 5-year follow-up (RR 0.91, 95%CI 0.87-0.96, P &lt; 0.001, moderate certainty). Subgroup analysis on pathologic node positive patients demonstrated a consistent survival benefit at 1-year (RR 0.57, 95% CI 0.42-0.77, P &lt; 0.001, moderate certainty) and 5-year (RR 0.89 95%CI 0.84-0.95, P &lt; 0.001, moderate certainty). While adjuvant therapy presented no benefit for the T0-2 stage subgroup, patients with T3-4 disease experienced a significant reduction in mortality with the addition of adjuvant therapy at both 1-year (RR 0.51, 95% CI 0.41-0.63, P &lt; 0.001, moderate certainty), and 5-years (RR 0.91, 95% CI 0.85-0.97, P = 0.005, moderate certainty). Due to incomplete reporting, the added benefit of adjuvant therapy was uncertain regarding DFS, locoregional recurrence, and distant recurrence. Conclusions: Adjuvant therapy after neoadjuvant treatment and curative esophagectomy provides improved OS at 1 and 5 years, but the benefit for DFS and locoregional/distant recurrence was uncertain due to limited reporting of these outcomes.
Association between antibiotic exposure and survival in patients with hepatocellular carcinoma treated with nivolumab.
Authors: Kanan Alshammari, Futoon Alsugheir, Mohammad Aldawoud, Ashwaq Alolayan, Mohammad Ahmad Algarni, Fouad Sabatin, Mohammad F. Mohammad, Abdulaziz Alosaimi, Faisal Sanai, Hassan Odah, Ahmed Alshehry, Omar Aldibasi, Abdullah S Al Saleh, Abdul-Rahman Jazieh
Journal: Journal of Clinical Oncology (2021)

e16186 Background: Nivolumab, an immune checkpoint inhibitor, has improved the outcomes of patients with hepatocellular carcinoma (HCC). It is approved for HCC patients previously treated with sorafenib. Outcomes have been reported in previous studies, in malignancies other than HCC, to be worse when patients have been exposed to antibiotics while receiving immune checkpoint inhibitors. We aimed to evaluate the effects of antibiotics on survival in HCC patients treated with nivolumab. Methods: We performed a retrospective review of 59 patients with advanced HCC that have been treated with nivolumab in two academic centers in Saudi Arabia. Patient characteristics, tumor data, antibiotic use (2 weeks prior, during, and 4 weeks after nivolumab therapy), survival data, and other factors were collected. Log-rank test analysis was performed to test the difference in overall survival (OS) time with and without antibiotics use. Results: The majority of patients were males (n=51, 85%), and 38 were Child-Pugh A (64%). A large number of patients had Barcelona Clinic Liver Cancer (BCLC) stage C tumors (n=42, 71%), and 20 patients (34%) used antibiotics. Most patients received nivolumab as second-line therapy after exposure to sorafenib (n=49, 83%). In patients who received nivolumab as first- or second-line therapy (n=57) and did not receive antibiotics, the median OS was double that of patients who received antibiotics (10 vs. 4.5 months, P=0.04). In child A patients who received nivolumab as second-line therapy (n=32), those who were exposed to antibiotics had a statistically significant shorter median OS compared to those who did not (5.5 vs. 20 months, P=0.04). More patients achieved partial response, or complete response (as per modified RECIST criteria) in the cohort that did not receive antibiotics compared to patients who received antibiotics (21% vs. 15%) but that was not statistically significant (P=0.6). Conclusions: This study shows that HCC patients receiving nivolumab have worse survival if they received antibiotics. Antibiotic mediated alteration of the gut microbiome may impact nivolumab response and shorten patient survival. Although this finding may warrant a prospective larger study but it is consistent with other previous studies. Antibiotics should be used very cautiously when treatment with checkpoint inhibitors is considered.
Progression-free survival at 24 months as a landmark after autologous stem cell transplant in relapsed or refractory diffuse large B-cell lymphoma.
Authors: Aung M. Tun, Seth Maliske, Yucai Wang, Matthew J. Maurer, Ivana N. M. Micallef, David James Inwards, Luis F. Porrata, Allison Claire Rosenthal, Mohamed Kharfan-Dabaja, Jacob Orme, Brian K. Link, James Robert Cerhan, Carrie A. Thompson, Thomas Matthew Habermann, Thomas E. Witzig, Stephen M. Ansell, Grzegorz S. Nowakowski, Umar Farooq, Patrick B. Johnston
Journal: Journal of Clinical Oncology (2021)

7522 Background: Patients with newly diagnoseddiffuse large B-cell lymphoma (DLBCL) who achieve event-free survival at 24 months (EFS24) following immunochemotherapy (IC) have excellent overall survival (OS) similar to that of age- and sex-matched general population. The standard of care for patients with relapsed or refractory (RR) DLBCL following frontline IC is salvage therapy followed by autologous stem cell transplant (ASCT). The goal of this study is to evaluate the role of progression-free survival (PFS) at 24 months (PFS24) as a landmark after ASCT in patients with RR DLBCL. Methods: Patients with RR DLBCL after frontline R-CHOP or R-CHOP-like IC who underwent salvage therapy and ASCT at Mayo Clinic or University of Iowa between 07/2000 and 4/2020 were identified from institutional lymphoma transplant databases. Clinical characteristics, treatment information, and outcome data were abstracted. Post-ASCT PFS, OS, and post-relapse survival (PRS) were plotted by Kaplan-Meier method, and cumulative incidences of relapse vs non-relapse mortality (NRM) and different causes of death were compared accounting for competing events. Statistical analyses were performed in EZR v1.54. Results: A total of 437 patients were identified. Median age at ASCT was 61 years (range 19-78), and 280 (64%) were male. After a median post-ASCT follow up of 8.0 years (95% CI 7.2-8.7), 215 patients had a relapse (or disease progression), 180 within 2 years and 35 after 2 years. For the entire cohort, post-ASCT relapse rate was much higher than NRM rate (48.1 vs 9.1% at 5-year). Median PFS and OS after ASCT was 2.7 and 5.4 years, respectively. Lymphoma was the primary cause of death after ASCT. In contrast, for patients who had achieved PFS24 (n = 220), rates of post-PFS24 relapse and NRM were similar (14.8% and 12.3% at 5-year). Median PFS and OS after achieving PFS24 was 10.0 and 11.5 years, respectively. Lymphoma related and unrelated death rates were similar after achieving PFS24 (Table). For all patients who had a post-ASCT relapse, median PRS was 0.7 years (95% CI 0.5-0.9), and late relapse ( &gt; 2 vs ≤2 years after ASCT) was associated with better PRS (median 2.3 [1.7-4.8] vs 0.5 [0.3-0.7] years, p &lt; 0.001). Conclusions: Post-ASCT PFS24 is an important prognostic predictor of post-ASCT outcomes in patients with RR DLBCL following frontline IC.[Table: see text]
Analysis of esophagogastric cancer patients enrolled in National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP)-sponsored phase I trials.
Authors: Hideaki Bando, Larry Rubinstein, Pamela Jo Harris, Takayuki Yoshino, Toshihiko Doi, Atsushi Ohtsu, Jack Welch, Naoko Takebe
Journal: Journal of Clinical Oncology (2015)

12 Background: In phase I trials, an important entry criterion is life expectancy predicted to be more than 90 days, and this is notoriously difficult to predict. The Royal Marsden Hospital (RMH) prognosis score was developed to help project patient outcomes. At present, there have been no systemic analyses of clinical benefits and prognoses for esophagogastric cancer patients who were registered in phase 1 trials. Methods: All non-pediatric phase I oncology trials sponsored by NCI-CTEP, that began between 2001 and 2013 were considered in this review. The RMH score was determined by 3 variables: LDH level, albumin level, and number of metastatic sites of disease. A log-rank test was used to assess the differences of treatment duration and overall survival (OS) between the groups with different RMH scores. Multivariate Cox proportional hazards model was also used to select the covariates related to the prognosis. Results: Of 4,722 patients with solid tumors, 115 (2.4%) patients were eligible for our analysis. Median age was 59 (range: 30-85), and 73% of patients were men. 54 (47%) patients with esophagus cancer and 61 (53%) with stomach cancer were analyzed. 86 (75%) patients had good (0-1) RMH score and 29 (25%) had poor (2-3) RMH score. Although response rates for good and poor RMH patients were not significantly different (8% vs. 3%; 1-side Fisher's exact test p=0.35), clinical benefit rate (complete response +partial response +stable disease) were significantly different (49% vs. 17%; 1-side Fisher's exact test p=0.002). The median treatment duration and OS for good and poor RMH patients were significantly different, respectively (treatment duration: 86 days and 29 days, Log-rank test P=0.016; OS: 332 days and 63 days, Log-rank test P&lt;0.001). In the multivariate analysis that included the RMH score, age (≥60), ECOG PS (≥2) and the RMH score (2-3) were significant predictors of poor survival. Conclusions: The RMH score is a strong tool to predict the prognosis of esophago-gastric cancer patients who will participate in a phase I trial. The median OS of 63 days for patients with poor RMH score suggests that these patients should not be included in phase 1 clinical trials.
A novel organ-chip system emulates three-dimensional architecture of the human epithelia and the mechanical forces acting on it
Authors: Antonio Varone, Justin Ke Nguyen, Lian Leng, Riccardo Barrile, Josiah Sliz, Carolina Lucchesi, Norman Wen, Achille Gravanis, Geraldine A. Hamilton, Katia Karalis, Christopher D. Hinojosa
Journal: Biomaterials (2021)
Giant cell tumor of bone: Effect of longer dosing intervals of denosumab on tumor control and bone related complications.
Authors: Cindy Jiang, Lili Zhao, Scott Schuetze, Rashmi Chugh
Journal: Journal of Clinical Oncology (2021)

11525 Background: Giant cell tumor of bone (GCTB) is a benign but locally aggressive bone neoplasm characterized by osteoclast activation causing destructive osteolysis. Denosumab, a human monoclonal antibody against RANK ligand, has emerged as an effective treatment option when surgery is not recommended, but can cause significant bone toxicity. Current standard dosing is every 4 weeks after 3 weekly loading doses. As patients (pts) with GCTB are often young adults, frequent denosumab administration long-term may be burdensome and associated with increased risk of complications. We assessed whether alternative, longer dosing intervals are associated with differences in efficacy or bone toxicity. Methods: Retrospective chart review was conducted on GCTB pts over 18 years old at University of Michigan who received at least 1 year of standard denosumab treatment. Pts were identified using a free-text medical record search engine with keywords “giant cell tumor” and “denosumab” until August 2020. We compared bone-related adverse effects and tumor control in pts who continued denosumab every 4 weeks versus longer treatment intervals. Decision to increase interval between doses was based on provider and pt discussion and preference as part of routine medical care. Results: 37 GCTB pts were identified; 51% female and 49% male. Average age was 41 years (range 22-73). Most common primary location was lower extremity (38%), followed by pelvis (35%), upper extremity (14%), spine (8%), and head/neck (5%). Metastasis were present at start of treatment in 14% of pts, involving lung (n = 4) and spine (n = 1). Pts received median of 71 (range 15-139) total doses of denosumab. Dosing interval was increased in 38% (n = 14). With the first interval change, 43% changed to every 6 weeks, 29% every 8 weeks, and 29% every 12 weeks dosing. Most common final dosing interval was 12 weeks (n = 8). 6 pts (16%) had bone complications after mean of 56 doses. This included osteonecrosis of the jaw (n = 4), atypical fracture (n = 1), and non-healing dental wounds (n = 2). All pts with bone complications were treated on the monthly dosing schedule, but there was no statistically significant difference compared to longer intervals (p = 0.22). Pts with GCT progression (n = 10) were either no longer receiving therapy or had missed denosumab doses. There was no statistically significant difference in PFS with standard vs. interval increased dosing (p = 0.97). However, 5-year PFS was superior with interval increased vs standard dosing (p = 0.036). Conclusions: Increasing the interval of denosumab dosing for GCTB provided similar tumor control as compared to standard dosing and is potentially associated with less bone toxicity and more convenience for afflicted pts. Further larger scale studies are needed to better define the optimal interval of denosumab administration in GCTB and the effect on efficacy, toxicity, and associated health care expense.
MYC as a candidate upstream controller involved in <i>TYMS</i> gene expression and 5-FU/folate treatment efficacy in colorectal cancer.
Authors: David A. Drubin, Anne-Katrin Hess, Natalie L. Catlett, Alessandro Di Cara, Yvonne Wettergren, Roger Tell
Journal: Journal of Clinical Oncology (2021)

e15512 Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene. To enhance the effect of 5-FU, a folate analogue is often provided as part of the treatment. In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin. Methods: To better understand the role of TYMS expression as a predictor of response to 5-FU + folate-based therapies and identify potential mechanisms and biomarkers of sensitivity/resistance, we leveraged data from the publicly available cancer genome atlas database (TCGA). We combined this information with a knowledgebase of causal biological relationships extracted from peer reviewed publications, to identify other relevant genes and candidate upstream controllers directly or indirectly related to TYMS expression and 5-FU + folate efficacy. Results: In TCGA subjects suffering from colorectal cancer (CRC) (stage IV tumors, treated with FOLFOX/FOLFIRI (n = 38)), lower TYMS expression was associated with a better overall survival (OS). This is consistent with what has been observed in the ISO-CC-005 study. Applying our causal biology knowledgebase to both genes identified as correlated to TYMS expression in TCGA CRC tumors and other published sets of genes associated with FOLFOX or FOLFIRI efficacy, we identified overlap with a MYCN signature. Notably MYC has been shown to directly activate TYMS expression. Thus, the MYC family is a compelling candidate upstream controller of these genes. We scored TCGA CRC tumors for inferred MYC activity, using this MYCN gene signature, and evaluated the inferred activity with respect to OS. In stage IV tumors, higher inferred MYC activity appears to be associated with worse OS. To further characterize this inferred MYC activity, we employed a transcriptomics-based cell deconvolution estimation of immune cell population proportions in the TCGA CRC cohort. We found inferred MYC activity inversely correlated with immune cell proportions overall, specifically strongest with those of pDCs and classical monocytes. Conclusions: MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy. Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC. MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.
Dispersal strategies shape persistence and evolution of human gut bacteria
Authors: Falk Hildebrand, Toni I. Gossmann, Clémence Frioux, Ezgi Özkurt, Pernille Neve Myers, Pamela Ferretti, Michael Kuhn, Mohammad Bahram, Henrik Bjørn Nielsen, Peer Bork
Journal: Cell Host & Microbe (2021)

Human gut bacterial strains can co-exist with their hosts for decades, but little is known about how these microbes persist and disperse, and evolve thereby. Here, we examined these processes in 5,278 adult and infant fecal metagenomes, longitudinally sampled in individuals and families. Our analyses revealed that a subset of gut species is extremely persistent in individuals, families, and geographic regions, represented often by locally successful strains of the phylum Bacteroidota. These "tenacious" bacteria show high levels of genetic adaptation to the human host but a high probability of loss upon antibiotic interventions. By contrast, heredipersistent bacteria, notably Firmicutes, often rely on dispersal strategies with weak phylogeographic patterns but strong family transmissions, likely related to sporulation. These analyses describe how different dispersal strategies can lead to the long-term persistence of human gut microbes with implications for gut flora modulations.
NRG-RTOG 1106/ACRIN 6697: A phase IIR trial of standard versus adaptive (mid-treatment PET-based) chemoradiotherapy for stage III NSCLC—Results and comparison to NRG-RTOG 0617 (non-personalized RT dose escalation).
Authors: Feng-Ming Spring Kong, Chen Hu, Randall Ten Haken, Ying Xiao, Martha Matuszak, Vera Hirsh, Daniel A. Pryma, Barry A. Siegel, Daphna Y. Gelblum, James Hayman, Clifford Grant Robinson, Billy W. Loo, Gregory M.M. Videtic, Sergio Faria, Catherine Ferguson, Neal E. Dunlap, Vijayananda Kundapur, Rebecca Paulus, Jeffrey D. Bradley, Mitchell Machtay
Journal: Journal of Clinical Oncology (2021)

8548 Background: NRG-RTOG 0617 (R0617) found that non-personalized dose escalation of radiotherapy (RT) with concurrent chemotherapy was deleterious. NRG-RTOG 1106/ACRIN 6697 (R1106) studied adaptive chemoradiotherapy, using tumor and patient individualized RT dose intensification simultaneously with field reduction, based upon mid-treatment FDG-PET. Methods: The control arms of both studies used 60 Gy (+ weekly carboplatin/paclitaxel). The investigational arm of R0617 used 74 Gy in 37 fractions, with no field/dose adaptation, while R1106 used mid-treatment FDG-PET (after ̃40 Gy) to design an individualized dose adaptive RT plan with daily-fraction size 2.2 to 3.8 Gy (up to 80.4 Gy/30 fractions), based upon a model of isotoxic lung risk. Nearly all (93%) patients had IMRT. No patients had consolidation immunotherapy. The primary endpoint for R1106 was local-regional-progression freedom (LRPF) assessed by central review. Other endpoints reported here were survival, toxicity, and institution-defined local/regional control. Results: From 2012-2017, 127 patients were enrolled to R1106 (43 in the standard and 84 in the adaptive arms), with a median follow-up of 3.6 years. The median actual RT dose in the adaptive arm was 71 Gy (Q1-Q3 68-76 Gy). The 2-year LRPF was 59.5% versus 54.6% (p=0.66) for standard versus adaptive RT; the 3-year survival rates were 49.1% versus 47.5% (p=0.80). An exploratory analysis of 2-year in-field local primary tumor control and local-regional tumor control (institution-assessed) were 58.5% and 55.6% for standard RT, and 75.6% and 66.3% for adaptive RT, respectively. As shown in the table, there were no significant differences in cardiac or esophageal adverse events between the two arms; the adaptive RT arm had more Grade 3+ respiratory events (23.8% versus 14.3%). Conclusions: NRG-RTOG1106 did not meet its primary endpoint of demonstrating improved LRPF. Unlike R0617, there was no suggestion of a detrimental effect of adaptive dose-intensified RT on survival and cardiac events. Studies to refine personalized RT, especially in the immunotherapy era, should be considered. Outcome comparison between R0617 and R1106. Clinical trial information: NCT01507428. [Table: see text]