tbuckley/cabot-search huggingface dataset:
Comparative mutational analysis of biliary tract cancers.
Authors: Zhiquan Qiu, Jun Ji, Yu Xu, Yan Zhu, Chun-Fang Gao, Guoqiang Wang, Chengcheng Li, Shangli Cai, Hao Liu, Bin Li, Xiaoqing Jiang
Journal: Journal of Clinical Oncology (2021)

e16164 Background: Traditional classifications of tumors have utilized tissue of origin and histologic types. These categories have been refined with comprehensive molecular characterizations across large numbers of tumors. We hereby aimed to identify the similarities and differences of mutational profiles among the cancers along biliary tract, and investigate their prognostic effects. Methods: Mutation and clinical data from 99 BTC patients who received surgical resection (gallbladder cancer [GBC], n=42; cholangiocarcinoma [CCA], n=57) were analyzed. Capture-based targeted deep sequencing was performed using a 520-gene panel, spanning 1.64 Mb of the human genome (Burning Rock Biotech). Results: The mutational frequencies of TP53, BRCA1/2, ATM, and PI3K, WNT, HRR, and cell cycle pathway, gradually decreased with the order of the anatomical position (GBC, dCCA, pCCA, iCCA-large duct, and iCCA-small duct), while the changing trend of BRAF mutational frequency was the opposite (Table). In addition, CCND1/E1 and APC mutations were enriched in metastatic BTCs. As for prognostic effect, mutations of BRAF, TGFBR1/2, ARID1A, and MMR pathway were associated with shorter OS, and these association remained significant after adjustment for tissue of origin, TNM stage, histological grade, surgical margin, and serum CEA level. Conclusions: The differentially mutated genes among the cancers along biliary tract may indicate the potential mechanism of tumor development in different anatomic locations. Deeper understanding of the prognosis-related mutational events might change the postoperative management of BTC by enabling risk stratification, ACT monitoring, and early relapse detection. Mutational rate of the differentially mutated genes among the cancers along biliary tract.[Table: see text]
Neuroprotection by WldS depends on retinal ganglion cell type and age in glaucoma
Authors: Michael L. Risner, Silvia Pasini, Nolan R. McGrady, Karis B. D’Alessandro, Vincent Yao, Melissa L. Cooper, David J. Calkins
Journal: Molecular Neurodegeneration (2021)

Early challenges to axonal physiology, active transport, and ultrastructure are endemic to age-related neurodegenerative disorders, including those affecting the optic nerve. Chief among these, glaucoma causes irreversible vision loss through sensitivity to intraocular pressure (IOP) that challenges retinal ganglion cell (RGC) axons, which comprise the optic nerve. Early RGC axonopathy includes distal to proximal progression that implicates a slow form of Wallerian degeneration. In multiple disease models, including inducible glaucoma, expression of the slow Wallerian degeneration (Wld
Real-world clinical effectiveness and safety of camrelizumab in esophageal squamous cell carcinoma.
Authors: Qiwei Yao, Zhichao Fu, Qisong Chen, Jianli Huang, Jintong Wu, Chunlin Ke, Liangyun Ma, Shouguo Li, Rongqi He, Yuyi Lin, Jiancheng Li
Journal: Journal of Clinical Oncology (2021)

e16023 Background: Camrelizumab, a programmed death 1 (PD-1) inhibitor, has recently demonstrated efficacy for esophageal squamous cell carcinoma (ESCC) patients in a phase III trial. We report real-world clinical outcomes of camrelizumab therapy for ESCC patients in a multicenter prospective cohort. Methods: Eligible patientswereadvanced esophageal squamous cell carcinoma with stage II-IV confirmed by pathology (including histology or cytology). All patients had received at most one systematic treatment and ECOG performance status of 0 or 1. Camrelizumab monotherapy(200mg) or combined with chemo-radiotherapy, chemotherapy, chemotherapy and antiangiogenic therapy as a first or second line of therapy were included. Progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and overall survival (OS) and safety data were evaluated. This abstract summarizes the findings of an exploratory interim analysis (cut-off Dec 2020). Results: From Oct 2019-Dec 2020, 63 patients were enrolled (19 centers in China; mean age 62.26 years; 97% ECOG PS 1; 54% first line therapy). Patients received camrelizumab monotherapy (8; 13%), camrelizumab/chemo-radiotherapy combination therapy (22, 35%), camrelizumab/chemotherapy combination therapy (26, 41%), camrelizumab/chemotherapy/antiangiogenic therapy combination therapy (7, 11%). One patient achieved a complete response and 27 patients achieved a partial response, leading to an ORR of 41.26%. The DCR was 95.24%. The median progression-free survival (PFS) was 6.33 months (95% confidence interval [CI] 4.73-NA). Among patients with adequate samples test for LBH level and (lung immune prognostic index) LIPI score, 15.7% (8/51) patients had a high LBH level;63% (29/46), 32.6% (15/46) and 4.3% (2/46) patients had a good, middle and poor LIPI score, respectively. A significantly longer PFS was observed in patients with a normal LBH level (NA vs. 6.33 months, P = 0.049), and also in patients treated with first-line therapy (6.33 months vs. NA, P = 0.0338). Among adverse events, 4 patients (6.35%) reported grade 3-4 AEs, including pneumonia (n=2 [3.17%]), and bone marrow suppression (n=2 [3.17%]). 10 of 63 patients (15.87%) experienced any grade pneumonia, and 21 of 63 patients (33.33%) experienced grade 1-2 RCCEP. Conclusions: This real-world population showed that camrelizumab as the first- or second-line therapy was an effective and safe treatment for patients with ESCC. Clinical trial information: CHICTR2000039499.
Outcomes of metastatic synovial sarcoma with doxorubicin, pazopanib, and ifosfamide therapy.
Authors: Priscila Barreto Coelho, Philippos Apolinario Costa, Andrea P. Espejo Freire, Deukwoo Kwon, Emily Jonczak, Gina Z. D'Amato, Jonathan C. Trent
Journal: Journal of Clinical Oncology (2021)

e23552 Background: Synovial sarcoma (SS) accounts for 5-10% of all soft tissue sarcoma. SS are aggressive tumors with a median 5-year survival of 60-70% when localized disease but also a propensity for metastatic spread with 40-45% of patients developing metastasis within 5 years. It is considered a chemotherapy-sensitive sarcoma and treatment options are increasing. Herein, we present the outcomes of SS patients by systemic regimen and multimodality approach. Methods: This is a single institution, retrospective cohort of 79 patients with histopathologically confirmed SS treated at from 2004 to 2019. Clinical characteristics, treatment, response and survival were analyzed. We estimated medians of progression-free survival (PFS) and overall survival (OS) using the method of Kaplan-Meier along with the Log-Rank test. All tests were two-sided and statistical significance was considered when p&lt;0.05. Results: Median follow-up was 3.7 years (range 3.13 to 4.33), 59.5% were women and median age at diagnosis was 41 (range 5-77). At presentation, 60 patients (75.9%) had localized disease and 19 (24.1%) presented with metastatic disease. Among the entire cohort the three-year OS rate was 78.9% (95%CI = 66.3-87.3) and five-year OS rate 68.7% (95%CI = 53.5-79.9). OS between localized disease (N = 45) and metastatic (N = 12) was not statistically significant (log-rank p = 0.098). When comparing different regimens, doxorubicin-based regimens (DBR) showed longest median PFS of 10.1 months (95%CI = 3.97-21.16), while pazopanib had a median PFS of 7.45 (95%CI = 2.63-12.3), high dose ifosfamide (HDI) 6.4 months (95%CI = 2.79-15.5) and trabectedin 3.12 months (95%CI = 0.99-6.97). Conversely, patients with metastatic disease treated with pazopanib experienced a median PFS of 11.47 months (95%CI = 2.63-32.9) while those treated with a DBR 8.15 months (95%CI = 1.08-35.8). Conclusions: SS is highly aggressive and, in our cohort, patients with local presentation had non-significant difference in OS to the metastatic disease, this could be due to a small sample size or the high probability for relapse this tumor has. Chemotherapy with DBRs showed superiority to other regimens and pazopanib showed to be slightly superior when evaluating only metastatic disease. Addition of pazopanib maintenance therapy may improve PFS and OS. Continuous evaluation of these patients with further inclusion of SS on immunotherapy is warranted.
Emergency endoscopic negative pressure therapy of a long oesophageal perforation in eosinophilic esophagitis with a single-lumen nasogastric tube-like open-pore film drain
Authors: Gunnar Loske, Ernst Scharsack, Olaf Gobrecht
Journal: Endoscopy (2021)

After a bolus event with recurrent hematemesis, a 46-year-old patient complained of severe thoracic pain. Computed tomography revealed extensive paraesophageal mediastinal emphysema over the entire length of the esophagus ([Fig. 1], [Video 1]).
Evaluation of sensitivity to endocrine therapy index (SET2,3) for response to neoadjuvant endocrine therapy (NET) and subsequent prognosis.
Authors: William Fraser Symmans, Lili Du, Tanya L. Hoskin, Meenakshi Anurag, Cynthia X. Ma, Isabelle Bedrosian, Kelly Hunt, Matthew James Ellis, Vera Jean Suman
Journal: Journal of Clinical Oncology (2021)

580 Background: Patients (pts) in Cohort A of the American College of Surgeons Oncology Group Z1031 (Alliance) trial of NET for cStage II-III breast cancer were randomized to anastrozole [ANA], letrozole [LET] or exemestane [EXE] for 16-18 weeks (wks). In Cohort B, pts chose between ANA and LET and switched to chemotherapy or surgery if a tumor biopsy after 2-4 wks of NET had Ki67 &gt;10%. Treatments after surgery were not defined by the trial protocol. SET2,3 measures nonproliferation gene expression related to estrogen and progesterone receptors adjusting for a baseline prognostic index that combines clinical tumor and nodal stage and a 4-gene molecular subtype (RNA4) defined by ESR1, PGR, ERBB2 and AURKA. High SET2,3 in a pre-treatment biopsy using cStage information is defined as SET2,3 &gt;1.77. Methods: 379 pts had gene expression data from a research tumor biopsy prior to NET (Agilent 44K microarrays). A bioinformatician blinded to pt treatment and clinical outcomes determined SET2,3. The trial statistician then examined the association between SET2,3 and pharmacodynamic response at 2-4 wks (N=141, Cohort B): Ki67 ≤10% and complete cell cycle arrest (CCCA Ki67 ≤2.7%); pathologic outcomes in pts who completed NET: ypStage 0/1 (N=329, Cohorts A&amp;B), PEPI-0 rate (N=155, Cohort B); and event-free survival (EFS) post-registration (N=244, Cohorts A&amp;B). We used Fisher’s exact tests to assess whether responses, and Cox modeling to evaluate whether EFS, differed with respect to SET2,3 status. Results: High SET2,3 in 48% of pts (183/379) was associated with older age (median: 66 vs 63 years; p=0.012); cStage II (95% vs 75%; p &lt;0.001); and pre-NET Ki67 ≤10% (37% vs 20%; p&lt; 0.001) in pts with low SET2,3. In Cohort B, pts with high SET2,3 had a higher rate of pharmacodynamic response in their tumor at wk 2-4 than pts with low SET2,3 (Table). In the subset of Cohort B pts with wk 2-4 Ki67 ≤10%, pre-treatment SET2,3 trended numerically higher in pts who achieved PEPI-0 score (p=0.049) but the proportion achieving PEPI-0 did not differ by SET2,3 high/low status (Table). EFS was significantly longer for pts with high SET2,3 than pts with low SET2,3 (HR[H/L]: 0.52; 95% CI: 0.34-0.80; p=0.003). Conclusions: An exploratory analysis of Z1031 data demonstrated that the rate of pharmacodynamic suppression of proliferation by NET at 2-4 wks was greater and EFS was longer for pts with breast cancer expressing high SET2,3 disease than pts with low SET2,3. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Clinical trial information: NCT00265759. [Table: see text]
COVID-eVax, an electroporated DNA vaccine candidate encoding the SARS-CoV-2 RBD, elicits protective responses in animal models
Authors: Antonella Conforti, Emanuele Marra, Fabio Palombo, Giuseppe Roscilli, Micol Ravà, Valeria Fumagalli, Alessia Muzi, Mariano Maffei, Laura Luberto, Lucia Lione, Erika Salvatori, Mirco Compagnone, Eleonora Pinto, Emiliano Pavoni, Federica Bucci, Grazia Vitagliano, Daniela Stoppoloni, Maria Lucrezia Pacello, Manuela Cappelletti, Fabiana Fosca Ferrara, Emanuela D’Acunto, Valerio Chiarini, Roberto Arriga, Abraham Nyska, Pietro Di Lucia, Davide Marotta, Elisa Bono, Leonardo Giustini, Eleonora Sala, Chiara Perucchini, Jemma Paterson, Kathryn Ann Ryan, Amy-Rose Challis, Giulia Matusali, Francesca Colavita, Gianfranco Caselli, Elena Criscuolo, Nicola Clementi, Nicasio Mancini, Rüdiger Groß, Alina Seidel, Lukas Wettstein, Jan Münch, Lorena Donnici, Matteo Conti, Raffaele De Francesco, Mirela Kuka, Gennaro Ciliberto, Concetta Castilletti, Maria Rosaria Capobianchi, Giuseppe Ippolito, Luca G. Guidotti, Lucio Rovati, Matteo Iannacone, Luigi Aurisicchio
Journal: Molecular Therapy (2021)
Routine Follow-up Visits for Chronic Lymphocytic Leukemia Managed Initially By Watch and Wait Rarely Lead to Interventions: A North Denmark Population-Based Study
Authors: Caroline Holm Nørgaard, Nikoline Buus Søgaard, Jorne Lionel Biccler, Laura Pilgaard, Mathias Holmsgaard Eskesen, Thordis Helga Kjartansdóttir, Hans Erik Johnsen, Martin Bøgsted, Mette Dahl Bendtsen, Tarec Christoffer El-Galaly
Journal: Blood (2017)
High Mobility Group A1 Chromatin Remodeling Proteins: Potential Therapeutic Targets Involved in Polycythemia Vera Transformation to Acute Leukemia in Humans and JAK2 V617F Transgenic Mouse Models
Authors: Linda Resar, Donna Marie Williams, Lingling Xian, Zhizhuang Joe Zhao, Ophelia Rogers, Jerry L. Spivak, Alison R. Moliterno
Journal: Blood (2017)
A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus <i>MLH</i>-1 methylated characteristics (NCT02899793).
Authors: Dana M Roque, Stefania Bellone, Eric R. Siegel, Natalia Buza, Elena Bonazzoli, Adele Guglielmi, Luca Zammataro, Nupur Nagarkatti, Samir Zaidi, Jungsoo Lee, Peter E. Schwartz, Elena Ratner, Ludmil B. Alexandrov, Akiko Iwasaki, Yong Kong, Eric Song, Weilai Dong, Julia Andrea Elvin, Jungmin Choi, Alessandro Santin
Journal: Journal of Clinical Oncology (2021)

5523 Background: Microsatellite instability (MSI-H) is a biomarker for response to immune-checkpoint inhibitors (ICIs); however, these neoplasms are heterogenous including Lynch (germline), Lynch-like (somatic) and sporadic ( MLH1-methylated) tumors. Whether mechanisms underlying MSI alter responses to ICIs is unclear. We report data from a phase II pilot study (NCT02899793) of pembrolizumab in recurrent MSI-H endometrial cancer (EC) patients and potential mechanisms of primary/secondary ICI resistance. Methods: Patients with measurable, MSI-H EC confirmed by immunohistochemistry and polymerase chain reaction were evaluated by next-generation sequencing and received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Twenty-five patients (24 evaluable) were treated. Six (25%) patients harbored Lynch/Lynch-like tumors while 18 (75%) had sporadic EC. Tumor mutational burden (TMB) was higher in Lynch-like (median 2939, IQR:867-5108) versus sporadic tumors (median 604, IQR:411-798) ( P= 0.0076). Median follow-up was 25.8 months with an ORR of 58% (95% CI, 36.6-77.9%). ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients ( P= 0.024). The 3-year progression-free (PFS) and overall survival (OS) proportions were 100% versus 30% ( P= 0.017) and 100% versus 43% ( P= 0.043), respectively. Grade 3/4 treatment-related adverse events (6.8%) occurred in 12 patients. Defective antigen processing/presentation and deranged induction in interferon responses served as mechanisms of resistance in sporadic MSI-H EC. Conclusions: Our study demonstrated prognostic significance of Lynch-like versus sporadic MSI-H EC on ORR, PFS and OS when treated with pembrolizumab. Clinical studies evaluating separate subtypes of MSI-H EC treated with ICIs are warranted. Clinical trial information: NCT02899793.
Upfront stereotactic radiosurgery for brain metastases from triple-negative breast cancer.
Authors: Ran An, Yan Wang, Fuchenchu Wang, Akshara Singareeka Raghavendra, Chao Gao, Diana Amaya, Nuhad K. Ibrahim, Jing Li
Journal: Journal of Clinical Oncology (2021)

e14014 Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with high propensity of brain metastases (BM). Outcomes after upfront stereotactic radiosurgery (SRS) for BM from TNBC patients are not well defined. We evaluated outcomes and identified prognostic factors for such patients. Methods: We reviewed 57 consecutive patients treated with upfront SRS for BM from TNBC in May 2008–April 2018 at a large-volume cancer center. Endpoints were overall survival (OS) from BM diagnosis and freedom from BM progression (FFBMP) after initial SRS. BM progression was defined as local and/or distant brain failure (LBF or DBF) after initial SRS; LBF was radiographic progression of treated lesions, assessed by a neuroradiologist or treating physician excluding post-radiation changes or radiation necrosis. Kaplan-Meier and Cox proportional hazard regression analyses were used to estimate survival outcomes and identify prognostic factors. Results: In this cohort of 57 patients with a median age of 53 y (range 26–82) at BM diagnosis and follow-up time of 12.2 months (mo, range 0.8–97.5), median time to BM development from TNBC diagnosis was 23.7 mo (range 0.7‒271.1). Estimated median OS time from initial BM diagnosis was 13.1 mo (95% CI 8.0‒19.5). In univariate analysis, Karnofsky performance score (KPS) &gt; 70 (p = 0.03), having &lt; 3 BMs (p = 0.016) at BM diagnosis, and BM as first site of metastasis (p = 0.041) were associated with longer OS. On multivariate analysis, KPS ≤70 was associated with higher risk of death (HR 3.0, p = 0.03). Of 46 patients with imaging follow-up for FFBMP assessment, 29 (63%) developed BM progression after initial SRS with an estimated median FFBMP of 7.4 mo (95% CI 5.7–12.7). Median times to LBF and DBF were 10 mo (range 0.3–97) and 5.9 mo (range 0.3–90.8). Estimated cumulative LBF rate was 17.8% (95% CI 2%–31.1%) and DBF 61.1% (95% CI 40.8%–74.4%) at 12 mo. Number of BMs at BM diagnosis (≥3 vs &lt; 3) was not associated with FFBMP (p = 0.7). Of the 29 patients with BM progression, 5 did not receive salvage radiation therapy (RT) and 24 received salvage RT (SRS, whole-brain radiation [WBRT], or both SRS+WBRT). Receipt of salvage RT was associated with longer survival (median 21.7 mo vs. 7.0 mo for no salvage RT, p &lt; 0.0001) and did not differ by type of salvage RT (median OS 18.6 mo for WBRT; 26.2 mo for SRS+WBRT; 35.9 mo for SRS, p = 0.08). Conclusions: We reported a median OS of 13.1 mo and FFBMP of 7.4 mo in TNBC patients with good local control. Good KPS was independent prognostic factor for better OS. FFBMP did not differ by number of SRS-treated brain lesions ( &lt; 3 vs ≥3). Further prospective studies of larger numbers of patients needed for more accurate comparisons of treatment types.
Retraction Note to: Effects of HDM2 antagonism on sunitinib resistance, p53 activation, SDF-1 induction, and tumor infiltration by CD11b+/Gr-1+ myeloid derived suppressor cells
Authors: David J Panka, Qingjun Liu, Andrew K Geissler, James W Mier
Journal: Molecular Cancer (2021)

The studies reported herein were undertaken to determine if the angiostatic function of p53 could be exploited as an adjunct to VEGF-targeted therapy in the treatment of renal cell carcinoma (RCC). Nude/beige mice bearing human RCC xenografts were treated with various combinations of sunitinib and the HDM2 antagonist MI-319. Tumors were excised at various time points before and during treatment and analyzed by western blot and IHC for evidence of p53 activation and function. Sunitinib treatment increased p53 levels in RCC xenografts and transiently induced the expression of p21waf1, Noxa, and HDM2, the levels of which subsequently declined to baseline (or undetectable) with the emergence of sunitinib resistance. The development of resistance and the suppression of p53-dependent gene expression temporally correlated with the induction of the p53 antagonist HDMX. The concurrent administration of MI-319 markedly increased the antitumor and anti-angiogenic activities of sunitinib and led to sustained p53-dependent gene expression. It also suppressed the expression of the chemokine SDF-1 (CXCL12) and the influx of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSC) otherwise induced by sunitinib. Although p53 knockdown markedly reduced the production of the angiostatic peptide endostatin, the production of endostatin was not augmented by MI-319 treatment. The evasion of p53 function (possibly through the expression of HDMX) is an essential element in the development of resistance to VEGF-targeted therapy in RCC. The maintenance of p53 function through the concurrent administration of an HDM2 antagonist is an effective means of delaying or preventing the development of resistance.
The impact of demographics and Medicare payments on quality of external beam radiotherapy for bone metastases in U.S. hospitals.
Authors: Nikol Mladkova, Kavita Vyas Dharmarajan
Journal: Journal of Clinical Oncology (2021)

e18504 Background: External Beam Radiotherapy (EBRT) has a well-established role in palliation of metastatic bone disease, yet the adherence to evidence based palliative EBRT doses and fractionation schemes is not universal across United States outpatient treatment facilities. We aimed to explore potential disparities in palliative EBRT quality in relation to Medicare visit payments and population demographics. Methods: Centers for Medicare &amp; Medicaid Services (CMS) EBRT for Bone Metastases process measure score for 2018 included in the Hospital Outpatient Quality Reporting Program (Hospital OQR) was available for a total of 824 facilities across the US. The score represents the percentage of evaluated patients that received an acceptable palliative dose/fractionation regimen. Radiation Oncology Office Visit Costs per zip code for new and established patients were obtained from CMS. Demographics (percentage of total population representing males, females, 5 years or younger, under 18 years, 65 or older, white, black or African American, Latino) were obtained from US census. Linear regression analysis was carried out with score representing the dependent variable. Results: The median score was 95% (range 5-100%), average 88.86%. In the final multivariate model, the score was significantly positively associated with the percentage of white population (p = 0.04) and negatively associated with the percentage of population under 18 (p = 0.03), and there was a trend toward association with the mode of Medicare pricing for a new patient visit (p = 0.06). Of note, the percentage of population under 18 was positively correlated with percentage of Latino population (p = 3.155e-09) but not black population (p = 0.9.) There was no association with gender, or with the percentage of those patients who were very young (under 5) or over the age of 65 years. Conclusions: The quality of palliative EBRT in US outpatient facilities is associated with demographic diversity of a given area, with predominantly nondiverse neighborhoods generally receiving higher quality EBRT-based palliative care. Additionally, it appears to be negatively affected by Medicare payments. This data suggests that disparities in healthcare quality are directly mediated by race and partially by geography.