tbuckley/cabot-search huggingface dataset:
Efficacy and cost-effectiveness of breast cancer (BC) screening in female survivors of childhood Hodgkin lymphoma (HL).
Authors: Florence Lennie Wong, Janie M. Lee, Wendy M. Leisenring, Joseph Philip Neglia, Rebecca M. Howell, Susan A. Smith, Kevin C. Oeffinger, Chaya S. Moskowitz, Tara O. Henderson, Ann Mertens, Paul C. Nathan, Yutaka Yasui, Wendy Landier, Gregory T. Armstrong, Leslie L. Robison, Smita Bhatia
Journal: Journal of Clinical Oncology (2021)

6593 Background: Female childhood HL survivors treated with ≥10 Gy of chest radiation are at high risk of developing BC. The Children’s Oncology Group (COG) guidelines recommend lifetime annual mammography (MAM) and breast Magnetic Resonance Imaging (MRI) starting 8y after chest radiation or age 25, whichever is later, and clinical breast examination (CBE) annually from puberty and semiannually from age 25. Initial model results suggest that CBE adds no survival benefit in this cohort. Digital breast tomosynthesis (DBT) is increasingly replacing digital MAM in clinical practice. Here, we present the efficacy and cost-effectiveness of COG’s imaging-based screening recommendations. Methods: Life-years (LYs), quality-adjusted LYs (QALYs), BC mortality, and costs (2017 U.S.$) were estimated from simulating the lifetimes of 5-million chest-irradiated 25y old HL survivors who underwent BC screening with each of the following strategies: annual digital MAM, MRI, MAM+MRI, annual DBT or DBT+MRI from age 25 onward. Treatment-related BC risk (in-situ and invasive) and non-BC mortality were estimated from female 5y HL survivors in the Childhood Cancer Survivor Study and from U.S. population rates. Test sensitivity was 70-74% for MAM (based on prior HL studies) and 89% for DBT and MRI (based on women at high risk of de novo BC). Costs and quality of life weights were obtained from medical literature. Results: For HL survivors with no screening, lifetime BC risk was 42.7% and BC mortality was 18.1%. BC risk and non-BC mortality were, respectively, 7.4- and 5.2-fold higher at age 50 in HL survivors relative to the general population. Screening at ages 25-74 had similar LY gain and BC mortality reduction compared to lifetime screening; hence, we focused on screening for ages 25-74. For all strategies screening provided LY gain of 0.34-0.47 and reduced BC mortality by 6.7-9.8% compared with no screening; incremental cost-effectiveness ratio (ICER), or cost per QALY gained, for MAM alone was $58,726 and for DBT alone was $62,989. ICER of adding MRI to MAM ($385,285) or to DBT ($513,358) indicated lower cost-effectiveness of supplemental MRI (Table). Conclusions: Annual screening at ages 25-74y in chest-irradiated HL survivors appears beneficial. Using $100K per QALY gained as cost-effectiveness threshold, annual MAM or DBT are more cost-effective, whereas adding MRI to MAM is less cost-effective.[Table: see text]
Palbociclib (P) in patients (pts) with soft tissue sarcoma (STS) with <i>CDK4</i> amplification: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Scott Schuetze, Michael Rothe, Pam K. Mangat, Liz Garrett-Mayer, Funda Meric-Bernstam, Laura Catherine Farrington, Carmen Calfa, Stacy D. D'Andre, Michael B. Livingston, Ramya Thota, Alissa S. Marr, Margaret von Mehren, Kristopher Wentzel, Richard L. Schilsky
Journal: Journal of Clinical Oncology (2021)

11565 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of STS pts with CDK4 amplification treated with P are reported. Methods: Eligible pts had advanced STS, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDK4 amplification and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts (66% male) with STS with CDK4 amplification were enrolled from July 2016 to Nov 2019. 1 pt was not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One pt with partial response (PR) and 12 pts with SD16+ were observed for DC and objective response (OR) rates of 48% (95% CI: 31%, 62%) and 3.7% (95% CI: 0.1%, 19%), respectively, and the null DC rate of 15% was rejected (p&lt;0.001). 9/13 pts with DC continued on treatment for &gt;32 weeks. 14 pts had at least one grade 3-4 AE at least possibly related to P with the most common being low WBC/platelets. Other grade 3 AEs included increased alanine aminotransferase, anemia, and fatigue. Conclusions: Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification. Additional study is warranted to confirm the efficacy of P in pts with STS with CDK4 amplification. Clinical trial information: NCT02693535. [Table: see text]
Analysis of DNA damage repair pathway genes as a predictive biomarker for HAIC in hepatocellular carcinoma.
Authors: Qicong Mai, Zhiqiang Mo, Jian He, Tingting Chen, Mengli Huang, Xiaoming Chen
Journal: Journal of Clinical Oncology (2021)

e16159 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide.Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, fluorouracil, and leucovorin (FOLFOX) is one of the effective treatment for advanced HCC patients. DNA damage repaired (DDR) pathway has been widely researched in many cancers recent years, which was a promising predictive biomarker for the response to platinum-based chemotherapy and Immunotherapy. But the DDR characteristics of different subset pathways in HCC, and its correlation with HAIC efficacy were unknown. Methods: Whole exome sequencing (WES) data of 366 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS, panel on 381/733-gene) was performed on FFPE tumor samples from 2092 Chinese HCC patients (Chinese cohort). Germ-line or somatic mutations of 32 DDR pathway genes (including Mismatch Repair and Homologous Recombination) were classified as DDR gene mutations. TMB was defined as total number of somatic non-synonymous mutations in coding region. Whole exome sequencing (WES) data and clinical data of 21 HCC advanced patients treated with HAIC were obtained to survival analysis. Results: In total, 59.84% (219/366) of HCC patients in TCGA harboring DDR mutation and 67.38% (1316/2092) in Chinese cohort. In Chinese HCC cohort, the mean TMB level of DDR mutant group was significant higher than wild-type group (mean TMB, mutation vs wild-type = 8.12 vs 6.42 Muts/Mb, P &lt; 0.0001). The top three mutation frequency DDR genes were BRCA2 (17%), ATM (13%) and BARD1 (12%), respectively. The highest mutation frequency DDR subset pathways were Fanconi anemia (FA, 44.14%, 862/2092), homologous recombination repair (HRR, 38.71%, 756/2092) and check point factors (CHP, 17.31%, 338/2092) come in second and third, respectively. Next we compared the TMB level between different DDR subset pathways, the mutant of nucleotide excision repair (NER) pathway harbored the highest medium TMB level (7.26 Muts/Mb). The survival analysis was performed on HCC patients treated with HAIC with FOLFOX. There was no difference in clinical baseline information between DDR mutation group (n = 6) and wild-type group (n = 15). The progression-free survival (PFS) of DDR mutation group were significantly longer than wild-type group (median PFS, mutation vs. wild-type = 8.9 vs. 4.5 months; HR 0.34[95% CI 0.13-0.85]; P = 0.0349), and an extending trend on overall survival (OS) without significant difference (median OS, 15.7 vs 8.9 months; HR 0.37[95% CI 0.13-1.00]; P = 0.0921). Conclusions: The DDR pathways was associated with higher TMB level. Preliminary data from clinical cohorts suggested better treatment outcomes of HAIC with FOLFOX in DDR mutation HCC patients.
RARE-05. ANAPLASTIC ASTROCYTOMA AND OLIGODENDROGLIOMA PRESENTING AS SIMULTANEOUS PRIMARY BRAIN TUMORS IN A PEDIATRIC PATIENT: THE FIRST KNOWN REPORT OF A RARE CONDITION
Authors: Amber Brown, Stanley Chaleff
Journal: Neuro-Oncology (2021)

Abstract Multiple metastatic brain tumors and multiple histologically identical primary brain tumors have been reported in adults and children. The concurrent presence of multiple histologically distinct primary brain tumors is rare without prior chemotherapy, radiotherapy, or phacomatosis. Exceedingly rare are simultaneous histologically distinct primary brain tumors in children without therapeutic or genetic predisposition, with only five previously reported cases. Gliomas are the most common primary brain tumor in adults and children. Gliomas encompass a heterogenous group characterized by astrocytic, oliogodendroglial, and ependymomal histology, further subdivided into pathologic World Health Organization (WHO) grades I to IV. In children, grade I astrocytomas are the most common, with grade III astrocytomas (anaplastic astrocytomas) and oligodendrogliomas being rare. We report a case of simultaneous anaplastic astrocytoma and grade II oligodendroglioma in a pediatric patient. A previously healthy 6-year-old female presented with persistent headaches. Initial magnetic resonance imaging (MRI) demonstrated non-enhancing right frontal lobe and left peri-thalamic lesions without mass affect. Serial MRIs showed progression of both lesions, prompting frontal lobe biopsy, which revealed a grade II oligodendroglioma. The patient was started on standard low-grade glioma chemotherapy, which was stopped due to an allergic reaction. Following chemotherapy cessation, both lesions increased in size, and the peri-thalamic lesion demonstrated new heterogenous enhancement. The patient underwent gross-total resection of the peri-thalamic lesion and repeat biopsy of the frontal lobe lesion. Pathology confirmed the frontal lobe lesion to be a grade II oligodendroglioma and revealed the peri-thalamic lesion to be an anaplastic astrocytoma. The tumors were additionally proven molecularly distinct. The patient responded well to cranial radiotherapy and standard high-grade glioma chemotherapy. To the best of the authors’ knowledge, this is the first case of simultaneous anaplastic astrocytoma and oligodendroglioma in a child, increasingly unique given the histological and molecular rarity of the tumors in pediatric patients.
Combined endoscopic ultrasound-guided gastrojejunostomy and anterograde biliary stenting
Authors: Michael Ma, Daniel Hogan, Arvind J. Trindade, Evin McCabe, Petros Benias
Journal: Endoscopy (2021)

Malignant involvement of the second portion of the duodenum and surrounding structures can create therapeutic challenges. We report a case of combined endoscopic ultrasound (EUS)-guided gastrojejunostomy (GJ) and anterograde biliary stenting in a patient with an infiltrative porta hepatis mass causing gastric outlet obstruction (GOO) and biliary obstruction.
Prediction of the Progression of Undifferentiated Arthritis to Rheumatoid Arthritis Using DNA Methylation Profiling
Authors: Carlos de la Calle‐Fabregat, Ellis Niemantsverdriet, Juan D. Cañete, Tianlu Li, Annette H. M. van der Helm‐van Mil, Javier Rodríguez‐Ubreva, Esteban Ballestar
Journal: Arthritis & Rheumatology (2021)

Objective The term “undifferentiated arthritis (UA)” is used to refer to all cases of arthritis that do not fit a specific diagnosis. A significant percentage of UA patients progress to rheumatoid arthritis (RA), others to a different definite rheumatic disease, and the rest undergo spontaneous remission. Therapeutic intervention in patients with UA can delay or halt disease progression and its long‐term consequences. It is therefore of inherent interest to identify those UA patients with a high probability of progressing to RA who would benefit from early appropriate therapy. This study was undertaken to investigate whether alterations in the DNA methylation profiles of immune cells may provide information on the genetically or environmentally determined status of patients and potentially discriminate between disease subtypes. Methods We performed DNA methylation profiling of a UA patient cohort, in which progression to RA occurred for a significant proportion of the patients. Results We found differential DNA methylation in UA patients compared to healthy controls. Most importantly, our analysis identified a DNA methylation signature characteristic of those UA cases that differentiated to RA. We demonstrated that the methylome of peripheral mononuclear cells can be used to anticipate the evolution of UA to RA, and that this methylome is associated with a number of inflammatory pathways and transcription factors. Finally, we designed a machine learning strategy for DNA methylation‐based classification that predicts the differentiation of UA toward RA. Conclusion Our findings indicate that DNA methylation profiling provides a good predictor of UA‐to‐RA progression to anticipate targeted treatments and improve clinical management.
<i>RNF43</i> mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.
Authors: Liping Li, Mengmei Yang, Mengli Huang
Journal: Journal of Clinical Oncology (2021)

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.
Encephalapp Stroop Test, Number Connection Test B,および連続Doting Testによるスコアの組み合わせスコアは,隠れた肝性脳症を有する患者を正確に同定する【JST・京大機械翻訳】
Authors: Zeng Xin, Zhang Li-Yuan, Liu Qing, Lu Cui-Hua, Wei Jue, Shi Zhi-Wen, Huang Wei-Rong, Qu Li-Hong, Xu Fei, Wang Xiao-Hang, Shi Pei-Mei, Tan Yu, Tan Wei, Yuan Zong-Li, Xia Chun-Yan, Liu Yu-Lan, Xie Wei-Fen
Journal: Clinical Gastroenterology and Hepatology (2020)
From translation to integration: how to approach the complexity of atrial fibrillation mechanisms
Authors: Ulrich Schotten
Journal: Cardiovascular Research (2021)

Recent observations that early and aggressive rhythm control for atrial fibrillation (AF) reduces adverse cardiovascular outcomes 1 and that catheter ablation may outperform anti-arrhythmic drug therapy as first-line treatment 2,3 refuel research efforts for new target mechanisms driving AF.The current spotlight issue of Cardiovascular Research contains a number of very elegant studies adding new mechanistic concepts to our current knowledge of mechanisms involved in AF.Over many years, basic, translational, and clinical research has generated a wealth of insights into the basic pathomechanisms of AF.However, more recently most of the significant progress was based on empirical clinical research and the current pipelines for new pharmacological compounds for AF are drying out.The reasons for the modest progress in identifying new anti-arrhythmics drugs for AF have expertly been summarized by Nattel et al. in this spotlight issue 4 and include limited efficacy, safety concerns, and regulatory hurdles.Also, the progress in catheter ablation for AF was modest and largely driven by the improvement of ablation technology rather than advances in mechanistic understanding of AF.A factor significantly contributing to the limited progress in therapeutic interventions is the complexity and diversity of disease mechanisms leading to AF.This problem deserves more attention than it received in the past as it may profoundly affect future research strategies of basic and translational scientists in the field.The multi-factorial nature of AF is the result of a large diversity of comorbidities causing AF ranging from hypertension and heart failure to diabetes and sleep apnoea.Also, non-modifiable factors such as age, gender, and the individual genetic background significantly contribute to the inter-individual mechanistic variability.The transient nature of the presence of risk-or life-style factors add another layer to the mechanistic complexity of AF. 5 Despite the fact that the need for a better understanding of mechanistic AF subtypes has been recognized in consensus conferences years ago, 6 progress in defining a realistic and effective strategy in order to systematically investigate the mechanistic heterogeneity of AF has been limited so far.This is only partially due to the lack of tools to address the complexity of AF mechanisms but is primarily caused by the logistic challenge to bring these technologies together in an integrative research approach.
Duration of pemetrexed maintenance therapy with or without pembrolizumab is associated with risk of renal toxicity in patients with metastatic nonsquamous NSCLC.
Authors: Tejas Patil, Yunan Nie, Junxiao Hu, Erin Lynn Schenk, Jose Maria Pacheco, William T. Purcell, Paul A. Bunn, D. Ross Camidge
Journal: Journal of Clinical Oncology (2021)

e21205 Background: Use of maintenance pemetrexed with pembrolizumab is the standard of care among patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations treated with the KEYNOTE-189 regimen. Whether the addition of pembrolizumab to pemetrexed maintenance alters the risk of renal toxicity is not well characterized. Methods: A single center retrospective study was performed. The frequency of acute kidney injury as well as the rates of discontinuation due to renal injury was assessed. Acute renal injury was defined as ≥ 0.3 increase in serum creatinine (sCr) above the upper limit of normal or a rise in sCr ≥ 1.5 times baseline per KDIGO criteria. A Fisher exact test was conducted to compare the rate of renal injury between the two groups. Logistic regression adjusting for performance status, prior lines of treatment, and number of maintenance cycles was performed. Results: We identified 114 patients who received either maintenance pemetrexed or pemetrexed + pembrolizumab. The median number of cycles for the maintenance pemetrexed and pemetrexed + pembrolizumab groups was 5 and 7 cycles respectively. Of these, 41% (47/114) patients developed acute renal injury during their treatment course. Renal injury was seen in 14.3% (5/35) patients who received single agent pemetrexed maintenance and 25% (3/12) who received maintenance pemetrexed + pembrolizumab with no significant difference in the rates of renal injury between both arms (p = 0.403). Among patients who developed acute renal injury, 9% (4/47) permanently discontinued maintenance due to nephrotoxicity. All patients who permanently discontinued therapy received maintenance pemetrexed alone. When adjusting for covariates, ECOG performance status and number of prior lines of therapy did not increase the risk of renal toxicity. Logistic regression analysis identified that the rate of renal injury was significantly associated with the number of maintenance cycles received (p-value = 0.017, OR = 1.14, 95% CI 1.03 - 1.29). The odds of developing renal injury were 1.14 times higher with each additional cycle of maintenance therapy received. Conclusions: Renal injury is common among patients treated with patients receiving maintenance therapy. The addition of pembrolizumab to maintenance pemetrexed did not significantly increase the rate of renal injury. The risk of renal injury appears to correlate with the total number of maintenance cycles received suggesting a cumulative risk of nephrotoxicity over time.