tbuckley/cabot-search huggingface dataset:
Associations of mutation profiles with clinical outcomes among metastatic colorectal cancer patients at the United States-Mexico border.
Authors: Reshad Ghafouri, Alexander Philipovskiy, Javier Chavez Corral, Sumit Gaur, Nawar Hakim, Richard McCallum, Ioannis Konstantinidis, Felipe Maegava
Journal: Journal of Clinical Oncology (2021)

e15519 Background: The incidence of CRC among Hispanics living in the USA varies according to their country of origin, supports the idea that differences in ancestry may contribute to the differences in the incidence of CRC. Moreover, Hispanics-Latino(HL) patients usually present with a more advanced stage and have a higher mortality rate compared to other ethnic cohorts. Although it is unknown, the incidence of CRC has been substantially increasing among younger Hispanics. We sought to characterize the tumor mutation profile of mCRC patients and associate with clinical outcomes among Hispanic population. Methods: We retrospectively collected the data from next generation sequencing of 49 patients with metastatic CRC (treated at TTUHSC from 2012 to 2020. We identified the most frequent alterations in our study sample and associated with the clinical outcomes. Association analyses were performed using chi square test, unpaired t-test, log rank test and the Cox proportional hazards regressions. Results: Of 49 patients with mCRC, the average age of patients at the time of diagnosis was 57 years with 98% Hispanic, and 32(65%) male. Most of the patients had stage IV disease (98%) and left side CRC (31, 67%). In our study cohort, the most commonly mutated genes identified as APC (37/11, 77.08%), TP53 (29/19, 60.42%), KRAS (23/25, 47.92%), NOTCH 12/36 (25.00%), BRCA 1&amp;2 11/37 (22.92%) and FLT1 11/37 (22.92%). None of the identified mutations were found to be associated with overall survival. However, the presence of the FLT1 mutation was associated with a reduced risk of progression to additional chemotherapy (P=0.031). Compared to the left side CRC, the BRCA mutation appeared slightly higher on the right side of the CRC (p=0.057). In compare to data from larger national and international colon cancer databases ( COSMIC and METABRICS); HL patients showed a significantly higher proportion of frequent mutations. Compared to other ethnic cohorts, HL patients were relatively younger (57 vs. 63 years) and the male to female ratio was observed to be remarkably higher as well (1.77:1 vs. 1.32:1). In our study, the combination of mutations (TP53, APC, and KRAS) was associated with worse clinical outcomes. Our study demonstrated that worse clinical outcomes were correlated with. Conclusions: Our study is the first to characterize the most common genetic alterations among HL patients with mCRC. The most frequent identified mutations including TP53, APC, KRAS, NOTCH, and BRCA were even higher in HL cohort than the national and international databases ( COSMIC and METABRICS). Our data support the motion that molecular drivers of colon cancer might be different in HL patients.
Single-Cell Methylome and Transcriptome High-Resolution Maps Define the Effects of Epigenetic Modifiers on the Landscape of Hematopoietic Differentiation
Authors: Franco Izzo, Asaf Poran, Stanley Chun-Wei Lee, Ronan Chaligne, Federico Gaiti, Steven Kothen-Hill, Rafael Schulman, Michelle Ki, Kenigsberg Ephraim, Omar Abdel-Wahab, Dan A. Landau
Journal: Blood (2017)
BIOL-10. DISTRIBUTION AND VULNERABILITY OF TRANSCRIPTIONAL OUTPUTS ACROSS THE GENOME IN MYC-AMPLIFIED MEDULLOBLASTOMA CELLS
Authors: Rui Yang, Wenzhe Wang, Meichen Dong, Kristen Roso, Xuhui Bao, Christopher Pirozzi, Darell Bigner, Hai Yan, David Ashley, Vasyl Zhabotynsky, Fei Zou, Yiping He
Journal: Neuro-Oncology (2021)

Abstract Myc plays a central role in tumorigenesis by orchestrating the expression of genes essential to numerous cellular processes. While it is well established that Myc functions by binding to its target genes to regulate their transcription, the distribution of the transcriptional output across human genome in Myc-amplified cancer cells, and the susceptibility of such transcriptional outputs to therapeutic interferences remain to be fully elucidated. Here, we analyze the distribution of transcriptional outputs in Myc-amplified medulloblastoma (MB) cells by profiling nascent total RNAs within a temporal context. This profiling reveals a major portion of transcriptional action in these cells was directed at the genes fundamental to cellular infrastructures, including rRNAs and particularly those in the mitochondrial genome (mtDNA). Notably, even when Myc protein was depleted by as much as 80%, the impact on transcriptional outputs across the genome was limited, with notable reduction mostly in genes of involved in ribosomal biosynthesis, genes residing in mtDNA or encoding mitochondria-localized proteins, and those encoding histones. In contrast to the limited direct impact of Myc depletion, we found that the global transcriptional outputs were highly dependent on the activity of Inosine Monophosphate Dehydrogenases (IMPDHs), rate limiting enzymes for de novo guanine nucleotide synthesis and whose expression in tumor cells was positively correlated with Myc’s expression. Blockage of IMPDHs attenuated the global transcriptional outputs with a particularly strong inhibitory effect on the aforementioned infrastructure genes, which was accompanied by the abrogation of MB cell’s proliferation in vitro and in vivo. Together, our findings reveal a real time action of Myc as a transcriptional factor in tumor cells, gain new insight into the pathogenic mechanism underlying Myc-driven tumorigenesis, and support IMPDHs as a therapeutic vulnerability in MB cells empowered by a high level of Myc oncoprotein.
Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19
Authors: Safia Kuriakose, Kanal Singh, Alice K. Pau, Eric Daar, Rajesh Gandhi, Pablo Tebas, Laura Evans, Roy M. Gulick, H. Clifford Lane, Henry Masur
Journal: Annals of Internal Medicine (2021)

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.
Abstract 14401: Culprit-Vessel Only vs Complete Revascularization During Index Hospitalization in ST-Elevation Myocardial Infarction With Multi-Vessel Disease - An Updated Meta-Analysis of Randomized Controlled Trials
Authors: Doosup Shin, Joonseok Kim
Journal: Circulation (2018)

Introduction: It remains controversial whether complete revascularization during index hospitalization can provide superior outcomes after acute ST-segment elevation myocardial infarction (STEMI) i...
A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing
Authors: Muhammad Sohail Arshad, Saman Zafar, Bushra Yousef, Yasmine Alyassin, Radeyah Ali, Ali AlAsiri, Ming-Wei Chang, Zeeshan Ahmad, Amal Ali Elkordy, Ahmed Faheem, Kendal Pitt
Journal: Advanced Drug Delivery Reviews (2021)
Diagnostic discrepancies in second opinion pathology reviews in a community-based cancer center.
Authors: Albert Pedroza, Whitney Wedel, Nicholas Lintel, Adam Horn, Mehmet Sitki Copur
Journal: Journal of Clinical Oncology (2021)

e18650 Background: Tracking diagnostic discrepancies is a common quality indicator in anatomic pathology. Many cases are re-reviewed as care is transferred from one facility to another. Most published data on these discrepancies is from the perspective of the tertiary receiving facility. Disparities in patient access to pathology expertise and technologies in small community hospitals can affect the accuracy of cancer diagnosis and the quality of care. Mary Lanning Healthcare (MLH) is a regional community hospital with a well-established referral pattern to several neighboring health systems. As part of a quality assurance process, we evaluated the diagnostic concordance rate of our cancer related pathology diagnoses with the referred institutions. Methods: Between 2017 and 2020, a cohort of cancer related cases was identified where the initial diagnosis was at MLH, then as part of coordinated care, a second pathologic interpretation was rendered at another instution. Data regarding specimen type, discrepancy in original diagnosis, nature and severity of discrepancy, disagreement in histologic grade, concordance or lack thereof with third party reviewers, and distribution among reviewing pathologists were collected. Results: A total of 521 cancer related cases (890 specimens) were sent to 16 facilities for second opinion. There were 46 (5%) discrepancies. Majority of them 45 (98%) were minor. Third party review of one major discrepancy came back in agreement with our original diagnosis. The most common discrepancy was interobserver variability in findings without strictly defined criteria. A change in histologic grade was the second most frequent deviation with prostate and breast being the most common sites. Upgrades and downgrades to the original diagnoses were nearly evenly split (19 to 21). A total of 33 pathologists were involved. While one reviewing pathologist generated 30% of all discrepancies, 3 other pathologists accounted for 67%. Conclusions: Accurate pathologic diagnoses significantly impact clinical outcomes. Our data which represents a rural community-based cancer program identified an overall discrepancy rate in the range of 0.1 to 1.1% for second opinion review. The vast majority of differences were minor in nature with no change in patient care and could be attributed to expected interobserver variability.[Table: see text]
A phase Ib study of TQB2450 plus anlotinib in patients with advanced triple-negative breast cancer.
Authors: Jiayu Wang, Binghe Xu, Tao Sun, Quchang Ouyang, Yiqun Han, Qing Li, Pin Zhang, Fei Ma, Yang Luo, Ying Fan, Ruigang Cai, Qiao Li, Bo Lan, Hongnan Mo, Jiani Wang, Yiqun Li
Journal: Journal of Clinical Oncology (2021)

1074 Background: TQB2450 is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). Anlotinib is an antiangiogenic small molecule, multi-target tyrosine kinase inhibitor that has improved clinical outcomes in various solid tumors. This phase 1b study aims to evaluate the safety and efficacy of TQB2450 plus anlotinib for patients with advanced triple-negative breast cancer (TNBC) after the failure of standard therapy. Methods: This ongoing study included a dose-escalation phase and an expansion phase. Advanced TNBC patients with prior anthracyclines and/or taxanes treatment and failed at least first-line therapy were enrolled. In the dose-escalation phase, eligible patients received anlotinib (8mg, 10mg, and 12mg, qd, days 1-14; 21 days per cycle) plus TQB2450 (1200mg, day 1; 21 days per cycle) following the conventional 3+3 design. If the starting dose of 10mg anlotinib led to ≥2 dose-limiting toxicities (DLTs), 8mg anlotinib would be administered. After the dose-escalating phase, eligible patients were enrolled into the expansion cohort. The primary endpoint was objective response rate (ORR), and the secondary endpoints were overall survival (OS), disease control rate (DCR), progression-free survival (PFS), and safety. Results: Between May 29, 2019, and December 31, 2020, in the dose-escalation phase, three patients receiving 10mg anlotinib plus 1200mg TQB2450 had no DLTs in the first cycle, neither did three patients with 12mg anlotinib plus TQB2450. Next, 28 patients with advanced TNBC received 12 mg anlotinib plus TQB2450 in the expansion phase. Finally, a total of 34 patients were included with median age of 49.5 (32-70) and median prior lines of 2 (1-6). Numbers of patients with prior platinum therapy: 16, prior anthracycline therapy: 32. The ORR was 26.47% (9/34) and DCR was 82.35% (28/34). The median PFS was 8.57 months. Seventeen patients experienced grade 3 treatment-related AEs (TRAEs). Most frequently occurring (&gt;5%) grade 3 TRAEs were QT interval prolongation (17.65%), hypertension (14.71%), diarrhea (8.82%), hand-foot syndrome (HFS) (8.82%), and hypertriglyceridemia (5.88%). Conclusions: TQB2450 plus anlotinib showed an acceptable safety profile with promising activity for previously anthracyclines and/or taxanes-treated advanced TNBC patients. Clinical trial information: NCT03855358 .[Table: see text]
Breastfeeding Beyond 12 Months: Is There Evidence for Health Impacts?
Authors: Kimberly A. Lackey, Bethaney D. Fehrenkamp, Ryan M. Pace, Janet E. Williams, Courtney L. Meehan, Mark A. McGuire, Michelle K. McGuire
Journal: Annual Review of Nutrition (2021)

Because breastfeeding provides optimal nutrition and other benefits for infants (e.g., lower risk of infectious disease) and benefits for mothers (e.g., less postpartum bleeding), many organizations recommend that healthy infants be exclusively breastfed for 4 to 6 months in the United States and 6 months internationally. Recommendations related to how long breastfeeding should continue, however, are inconsistent. The objective of this article is to review the literature related to evidence for benefits of breastfeeding beyond 1 year for mothers and infants. In summary, human milk represents a good source of nutrients and immune components beyond 1 year. Some studies point toward lower infant mortality in undernourished children breastfed for >1 year, and prolonged breastfeeding increases interbirth intervals. Data on other outcomes (e.g., growth, diarrhea, obesity, and maternal weight loss) are inconsistent, often lacking sufficient control for confounding variables. There is a substantial need for rigorous, prospective, mixed-methods, cross-cultural research on this topic.
Anlotinib combined with s-1 in the third-line or later-line treatment of stage IV non-small cell lung cancer: Study for phase II clinical trial.
Authors: Xiyue Yang, Xiaobo Du
Journal: Journal of Clinical Oncology (2021)

e21115 Background: At present, for stage IV non-small-cell lung cancer (NSCLC), after the failure of second-line treatment, the effective rate of third-line treatment is not very well. We designed this study to evaluate the efficacy and safety of anlotinib combined with S-1 as a third-line treatment for patients with stage IV NSCLC. Methods: According to the inclusion and exclusion criteria, 29 patients will be treated with anlotinib plus S-1 based on Simon’s optimal two-stage design.They will undergo computed tomography (CT) every two cycles to assess the therapeutic effect according to RECIST.If the efficacy is assessed as SD, PR, CR after six cycles, anlotinib will be maintained until disease progression or death. Statistical analysis of the data will be conducted using SPSS (version 22.0).The primary endpoint is the objective response rate (ORR). The secondary endpoints are disease control rate(DCR),progression-free survival(PFS), overall survival(OS), and safety. Results: Between Jan 10, 2019, and Oct 31, 2020, a total of 29 patients were enrolled for treatment.At data cutoff (Jan 11, 2021),27(93.1%) patients had discontinued the study, and 2 (6.9%) patients were still receiving treatment. The median follow-up time was 11.2 months (IQR 8.2-20.1). Objective responses were achieved in 11 (37.9%; 95%CI 20.7-57.7) of 29 patients in the intention-to-treat population,which reached this trial’s primary endpoint. Disease control was achieved in 18 patients (62.1%; 95%CI 42.3-79.3);The median overall survival was 16.7months (95%CI 14.9-18.6);the median progression-free survival was 5.8 months (95% CI 2.9-8.7). The most common grade 3 adverse events were Gastrointestinal reactions (3[10.3%]),Fatigue (2[6.9%]), and Hypertension (2 [6.9%]).No grade 4 treatment-related adverse events, or treatment-related deaths occurred. Conclusions: The combination of anlotinib with S-1 in the third-line or later-line treatment of stage IV NSCLC shows promising anti-tumour activity and manageable toxicities in patients with NSCLC, and further study in phase 3 trials will be planned in the future. Clinical trial information: ChiCTR1900020948.
Abstract 12256: Association Between the Built Environment and Heart Failure Progression in an Urban Retrospective Cohort Study
Authors: Yiye Zhang, Subhi Alaref, Mohammad Tayarani, Evan Sholle, Arindam RoyChoudhury, H. Oliver Gao, James K Min, Jyotishman Pathak, Jessica Ancker
Journal: Circulation (2019)

Introduction: The built environment constitutes human-made aspects of the environment including buildings, urban infrastructure, and parks for both physical and social human activities. Studying th...
Effect of high-dose corticosteroid use on efficacy of immune checkpoint inhibitors in patients with renal cell carcinoma (RCC).
Authors: Chris Labaki, Sarah Abou Alaiwi, Andrew Lachlan Schmidt, Talal El Zarif, Ziad Bakouny, Pier Vitale Nuzzo, Wenxin Xu, David A. Braun, Bradley Alexander McGregor, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2021)

4583 Background: The use of High-Dose Corticosteroids (HDC) has been linked to poor outcomes in patients with lung cancer treated with immune checkpoint inhibitors (ICIs) (Ricciuti B, JCO, 2019). There is no data on the effect of HDC on renal cell carcinoma patients (RCC) treated with immunotherapy. We hypothesized that HDC use would be associated with worse outcomes in RCC patients receiving ICIs. Methods: This study evaluated a retrospective cohort of patients with RCC at Dana-Farber Cancer Institute in Boston, MA. Clinical information including demographics, IMDC risk score, RCC histology, steroid administration, ICI regimen, line of therapy, time to treatment failure (TTF) and overall survival (OS) were collected. Patients were divided into those receiving HDC (prednisone ≥10 mg or equivalent for ≥ 1 week, HDC group) or not receiving HDC (No-HDC group). HDC administration was evaluated in relation to TTF and OS in a univariate analysis (Log-rank test) and a multivariate analysis (Cox regression). Results: 190 patients with RCC receiving ICIs were included, with a median age of 59 years. HDC were administered to 56 patients and 134 patients received no (N= 116) or only low-dose (N=18) steroids. In the HDC group, 40 patients received steroids for immune-related adverse events, 8 for other cancer-related indications, and 8 for non-oncological indications. There was no difference in TTF between the HDC and No-HDC groups (12-mo TTF rate: 34.8 vs. 32.3%, respectively; log-rank p=0.65). Similarly, there was no difference in OS between the HDC and No-HDC groups (36-mo OS rate: 56.7 vs. 62.4%, respectively; log-rank p=0.97). After adjusting for IMDC risk group, RCC histology, ICI regimen type, and line of therapy, TTF and OS did not differ in the HDC group as compared to No-HDC group (HR=1.14 [95%CI: 0.80-1.62], p=0.44 and HR=1.17 [95%CI: 0.65-2.11], p=0.59, respectively). Conclusions: In this retrospective study of patients with RCC treated with ICIs, administration of high-dose corticosteroids was not associated with worse outcomes.[Table: see text]
A phase 1 study evaluating preliminary safety, pharmacokinetic and pharmacodynamic of pemigatinib in Chinese patients with advanced malignancy.
Authors: Yi Ba, Ting Deng, Yehui Shi, Le Zhang, Guiying Bai, Yueyin Pan, Aizong Shen, Xinghua Han, Zhaoyi Yang, Lian Cao, Yang Luo, Yan Wang, Hui Zhou
Journal: Journal of Clinical Oncology (2021)

e15051 Background: Dysregulation of fibroblast growth factor receptor (FGFR) is strongly associated with establishment and progression of cancer. Pemigatinib is a selective FGFR1–3 inhibitor that are active in a targeted manner against cancers with activated FGFR pathway. The study was aimed at evaluating the tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) of pemigatinib in Chinese patients (pts) with advanced malignancy. Moreover, potential efficacy of pemigatinib was explored in a broad spectrum of FGFR alteration in variety of cancer types. Methods: In this phase 1 study, Chinese patients with advanced, recurrent or metastatic malignancy that were histologically or cytologically confirmed and harboring FGF/ FGFR 1-3 variation were enrolled. Pemigatinib was self-administered orally at 13.5 mg QD on a 3-week cycle (2-weeks-on/1-week-off schedule). Adverse events and other safety factors were monitored throughout the study. Blood samples were obtained at prespecified time points for PK and PD analysis and efficacy was assessed every 9 weeks per RECIST v1.1 guideline. Results: As of Jan 31, 2021, 12 patients with 5 different cancer types (colorectal cancer (4 pts), gastric and gastroesophageal junction carcinoma (3 pts), cholangiocarcinoma (2 pts), esophageal carcinoma (2 pts) and breast cancer (1pts)) were enrolled. Documented FGF/ FGFR1-3 alterations were FGFR amplification (6), FGFR point mutation (5), FGFR2 fusion (2) and FGF alteration (4) with 2 subjects had more than one alteration types. All the subjects were failed to at least 1 line of prior standard therapy. All patients had at least 1 treatment related adverse events (TRAE) and the most common ones were hyperphosphatemia (100%), decreased appetite (50%) and diarrhea (33.3%). Two patients (16.7%) reported ≥ grade 3 TRAEs, which were hyponatremia (8.3%) and proteinuria (8.3%). There were no TEAEs leading to death or treatment discontinuation. Among 11 efficacy evaluable patients, 2 of them had partial responses (PR) as evaluated by investigators with 1 cholagiocarcinoma harboring FGFR2 point mutation (p.F276C) and the other esophageal carcinoma carrying FGFR1 mutation (p.A354V). 3 patients had a best overall response of stable disease (SD). The objective response rate (ORR) was 16.7% (95%CI: 2–48%) and disease control rate was 41.7% (95%CI: 15–72%). Conclusions: Pemigatinib had an acceptable and manageable toxicity and demonstrated a possible anti-cancer benefit in Chinese patients with advanced malignancy that accompanied with FGF/FGFR1-3 aberrance. A significant implication of the data is that it extended the population that potentially benefit from pemigatinib other than FGFR2 fusion/rearrangement. Clinical trial information: NCT04258527.