tbuckley/cabot-search huggingface dataset:
Progression and Regression of Chronic Kidney Disease by Age Among Adults in a Population-Based Cohort in Alberta, Canada
Authors: Ping Liu, Rob R. Quinn, Ngan N. Lam, Huda Al-Wahsh, Manish M. Sood, Navdeep Tangri, Marcello Tonelli, Pietro Ravani
Journal: JAMA Network Open (2021)

<h3>Importance</h3> The burden of chronic kidney disease (CKD) is expected to increase worldwide as the global population ages, potentially increasing the demand for nephrology services. Understanding whether CKD inevitably progresses or may regress can inform clinical decision-making and health policy. <h3>Objective</h3> To study CKD progression and regression by age in adults with CKD. <h3>Design, Setting, and Participants</h3> This population-based cohort study used linked administrative and laboratory data to assess adults in the province of Alberta, Canada, with incident mild, moderate, or severe CKD, defined by estimated glomerular filtration rate (eGFR) of 45 to 59, 30 to 44, or 15 to 29 mL/min/1.73 m<sup>2</sup>for longer than 3 months, from April 1, 2009, to March 31, 2015. Data were analyzed from July 20 to November 30, 2020. <h3>Exposures</h3> Age. <h3>Main Outcomes and Measures</h3> Time to the earliest of CKD regression or progression (defined as sustained increase or drop in eGFR category for &gt;3 months, respectively, and a ≥25% increase or decrease in eGFR from baseline, respectively), kidney failure (the earlier of kidney replacement initiation or eGFR &lt;15 mL/min/1.73 m<sup>2</sup>for &gt;3 months), death, or censoring (outmigration, 5 years of follow-up, or end of study on March 31, 2017). <h3>Results</h3> Study participants with CKD (55.2% women and 44.8% men) included 81 320 with mild CKD (mean [SD] age, 72.4 [11.3] years), 35 929 with moderate CKD (mean [SD] age, 77.1 [11.5] years), and 12 237 with severe CKD (mean [SD] age, 76.6 [13.8] years). The annual incidence of CKD increased with advancing age, from 180 per 100 000 population younger than 65 years to 7250 per 100 000 in those 85 years or older. After cohort entry, the 5-year probability of regression was similar to that of progression or kidney failure in mild (14.3% vs 14.6%), moderate (18.9% vs 16.5%), and severe (19.3% vs 20.4%) CKD. As mortality at 5 years increased with advancing age in moderate (from 9.6% for age &lt;65 years to 48.4% for age ≥85 years) and severe (from 10.8% for age &lt;65 years to 60.2% for age ≥85 years) CKD, the risk of progression or kidney failure decreased substantially (for moderate CKD, from 32.3% for &lt;65 years to 9.4% for ≥85 years; for severe CKD, from 55.2% for &lt;65 years to 4.7% for ≥85 years), whereas the probabilities of regression varied to a lesser extent (for moderate CKD, from 22.5% for &lt;65 years to 15.4% for ≥85 years; for severe CKD, from 13.9% for &lt;65 years to 18.7% for ≥85 years). <h3>Conclusions and Relevance</h3> This cohort study found that with advancing age, CKD regression and death were more likely than CKD progression or kidney failure. These findings have important implications for patient care and for assessing the potential effect of population aging on the burden of CKD.
Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non–Muscle-Invasive Bladder Cancer
Authors: Jeffrey S. Damrauer, Kyle R. Roell, Markia A. Smith, Xuezheng Sun, Erin L. Kirk, Katherine A. Hoadley, Halei C. Benefield, Gopakumar Iyer, David B. Solit, Matthew I. Milowsky, William Y. Kim, Matthew E. Nielsen, Sara E. Wobker, Guido Dalbagni, Hikmat A. Al-Ahmadie, Andrew F. Olshan, Bernard H. Bochner, Helena Furberg, Melissa A. Troester, Eugene J. Pietzak
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Improved risk stratification and predictive biomarkers of treatment response are needed for non–muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. Experimental Design: Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts (n = 28, n = 50); targeted panel sequencing was performed in a subgroup (n = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors (n = 438, n = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes. Results: Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures. Conclusions: Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically “cold” tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.
Updated results of ALTER-C002: Anlotinib combined with CAPEOX in first-line treatment of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer.
Authors: Ke-Feng Ding, Yue Liu, Jinlin Du, Yuping Zhu, Zhuo Liu, Jianping Wang, Dong Xu, Jun Li, Xiujun Liao, Lifeng Sun, Jinjie He, Qian Xiao, Jianwei Wang, Hongfeng Cao, Yibo Cai, Cheng Cai, Zhekang Jin, Ying Yuan
Journal: Journal of Clinical Oncology (2021)

e15564 Background: Antiangiogenic therapy plus chemotherapy is one of the standard treatments in mCRC. Anlotinib, an oral small multi-targeted tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, has demonstrated prolonged PFS in refractory mCRC. This trial was conducted to evaluate the efficacy and safety of anlotinib combined with CAPEOX as first-line treatment for unresectable RAS/BRAF wild-type mCRC. Methods: Patients aged 18-75, with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment and ECOG status ≤ 1were enrolled in 3 hospitals in Zhejiang, China. Enrolled patients received capecitabine (850 mg/m 2 p.o., bid, on day 1-14 every 3 weeks), oxaliplatin (130 mg/m 2 i.v., on day 1 every 3 weeks) and anlotinib (12 mg p.o. qd, on day1-14 every 3 weeks) as inducing therapy. After 6 cycles of combined therapy, patients who achieve complete response (CR)/ partial response (PR)/ stable disease (SD) would receive capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint is objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: From November, 2019 to February, 2021, 31 patients had been enrolled. 1 patient was excluded for refused treatment. By now, 27 patients received at least 2 cycles of treatment and were available for efficacy evaluation: 22 patients had partial response (PR), 5 patients had stable disease (SD). The ORR was 81.5% (95% CI: 61.9–93.7%), and DCR was 100% (95% CI: 87.2–100%).1 patient received radical surgery after 6 cycles of treatment. The median PFS has not been reached yet. The most common grade≥3 AEs included hypertension (45.2%), neutropenia (25.8%) and diarrhea (12.9%). No treatment-related deaths occurred. Conclusions: The combination of anlotinib and CAPEOX showed promising antitumor activity and manageable toxicity in unresectable RAS/BRAF wild-type mCRC. Furthermore, we are launching a phase 3, multicenter, double-blind trial to further assess the efficacy of this regimen. Clinical trial information: NCT04080843. [Table: see text]
Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).
Authors: Zhehai Wang, Xiao Han, Jun Guo, Ming Jia, Changbin Zhu, Dongyuan Zhu, Xiqin Zhang, Xiaoyong Tang, Xiangjiao Meng
Journal: Journal of Clinical Oncology (2021)

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]
TSLP disease-associated genetic variants combined with airway TSLP expression influence asthma risk
Authors: Liza Bronner Murrison, Xiaomeng Ren, Kristina Preusse, Hua He, John Kroner, Xiaoting Chen, Seth Jenkins, Elisabet Johansson, Jocelyn M Biagini, Matthew T Weirauch, Raphael Kopan, Lisa J Martin, Gurjit K Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2021)
On-treatment derived neutrophil-to-lymphocyte ratio and response to palbociclib and letrozole: Analysis of a multicenter retrospective cohort and the PALOMA-2 study.
Authors: Chang Gon Kim, Min Hwan Kim, Jee Hung Kim, Seul-Gi Kim, Gun Min Kim, Tae Yeong Kim, Won-Ji Ryu, Jeeye Kim, Hyung Seok Park, Seho Park, Youngup Cho, Byeong-Woo Park, Seung Il Kim, Joon Jeong, Joohyuk Sohn
Journal: Journal of Clinical Oncology (2021)

1066 Background: Relevant predictive biomarkers for cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors have not been identified in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). We investigated whether dynamic changes in the peripheral immune cells can predict therapeutic response to CDK4/6 inhibitors in ABC with translational relevance. Methods: Postmenopausal women who received palbociclib and letrozole for HR-positive, HER2-negative ABC from tertiary referral centers were analyzed (n = 221; exploratory cohort). Pre- and on-treatment leucocyte, neutrophil, lymphocytes counts, neutrophil-to-lymphocyte ratio (NLR), and derived NLR (dNLR; neutrophil/[leucocyte-neutrophil]) were correlated with survival outcomes. Patients from the PALOMA-2 study (NCT01740427) treated with letrozole with or without palbociclib (n = 410 and 209, respectively) were analyzed for validation (validation cohort). Prospectively enrolled patients were subjected to immunophenotyping with flow cytometry to explore the immune cell dynamics after CDK4/6 inhibitor treatment. Results: In the exploratory cohort, palbociclib administration significantly reduced leucocyte, neutrophil, and lymphocyte counts on cycle 2 day 1. Not baseline, but on-treatment neutrophil and lymphocyte counts were associated with superior and inferior outcomes, providing predictive significance to on-treatment NLR and dNLR for progression-free survival (PFS; HR = 1.64 and 2.52; all P&lt; 0.001). In the validation cohort, higher on-treatment dNLR was associated with inferior PFS in patients treated with palbociclib and letrozole (HR = 1.50 and P= 0.009 with 1.04 cut-off), whereas not correlated with outcome in placebo and letrozole-administered patients. Exploratory analysis revealed that CDK4/6 inhibitor prevented T cell exhaustion and diminished relative frequencies of myeloid-derived suppressor cells, both of which trigger antitumor immunity. Conclusions: On-treatment dNLR significantly predicted treatment outcome in HR-positive, HER2-negative ABC treated with palbociclib and letrozole, allowing early prediction of treatment response with mechanistic insights. Clinical trial information: NCT01740427 .
Patient-reported quality of life data from patients with pre-treated metastatic colorectal cancer receiving trifluridine/tipiracil: Interim results of the TALLISUR study.
Authors: Meinolf Karthaus, Albrecht Kretzschmar, Stefan Fuxius, Jorge Riera Knorrenschild, Florian Kaiser, Rolf Mahlberg, Manfred Welslau, Henning Pelz, Volker Heinemann
Journal: Journal of Clinical Oncology (2021)

3526 Background: Compared to placebo, trifluridine/tipiracil (FTD/TPI) significantly improved overall and progression-free survival in patients (pts) with pre-treated metastatic colorectal cancer (mCRC) in the phase III RECOURSE trial. Although time to deterioration of ECOG performance status (PS) from 0/1 to ≥ 2 was significantly longer in pts treated with FTD/TPI, health-related quality of life (HRQoL) was not formally assessed by direct means. Therefore, a two-arm trial with best supportive care (BSC) as appropriate comparative treatment was designed to specifically address the effect of FTD/TPI on HRQoL. Methods: In this prospective, multi-center, German, open-label, phase IV study, pts with pre-treated mCRC could choose between BSC or oral FTD/TPI (35 mg/m 2 bid on days 1-5 and 8-12 of each 28-day cycle). EORTC QLQ-C30 and EQ-5D-5L questionnaires were employed to assess HRQoL. Primary endpoint was the rate of responders with stabilized ( &gt; -10 and &lt; 10 scores) or improved (≥ 10 scores) response (RR). Response was calculated as the mean score of the EORTC QLQ-C30 global health status/ QoL scale from the 2 nd cycle until the end of treatment/ observation compared to the baseline score. Results: Of 194 eligible pts, 185 pts chose treatment with FTD/TPI (median 3 cycles), while 9 pts decided to receive BSC only. Questionnaires from 109 pts receiving FTD/TPI and from 6 pts with BSC were evaluable for RR. The primary endpoint (RR) was 59.6% (95% CI 49.8 – 68.9) in FTD/TPI-treated pts and 50.0% (95% CI 11.8 – 88.2) in pts receiving BSC. Analysis of the extended follow-up period, demonstrated that RR was 67.0% (95% CI 57.3 – 75.7) in FTD/TPI-treated pts. In the FTD/TPI-group, median time to deterioration of HRQoL was 121 days ( n = 61; 95% CI 87 – 151) according to EORTC QLQ-C30 and 119 days ( n = 63; 95% CI 85 – 138) according to EQ-5D-5L. Conclusions: If pts can choose between treatment and BSC in late-stage CRC, the vast majority opts for treatment. According to the present results, FTD/TPI-treatment induced prolonged stabilization of HRQoL, a highly desired attribute of therapies for pts with late-stage cancer. Clinical trial information: No 2017-000292-83.
Young-onset colorectal cancer treatment side effects: Infertility, sexual dysfunction, and quality-of-life outcomes.
Authors: Laura Diane Porter, Ronit Yarden, Kim Lynn Newcomer, Negeen Fathi
Journal: Journal of Clinical Oncology (2021)

3587 Background: Colorectal cancer is the third-most commonly diagnosed cancer and the second-leading cause of cancer death in men and women combined in the United States. Young-onset colorectal cancer refers to individuals diagnosed under the age of 50. In recent years, the incidence has increased by 2.2% annually in individuals younger than 50 years and 1% in individuals 50-64, in contrast to a 3.3% decrease in adults 65 years and older. Young-onset (YO) CRC patients and survivors face unique clinical challenges with fertility and sexual dysfunctions, but this risk is not well quantified. There is limited data and public discussion on the long-term effects of colorectal cancer treatments on fertility and sexual dysfunction and the long-term impact on the quality of life. Methods: To explore the unique challenges and unmet needs of the young-adult patient population, a cross-sectional study was conducted. Colorectal cancer patients and survivors (N = 884) diagnosed between the ages of 20 to 50 years old (median age 42 ± 7.0) completed an online questionnaire based on established instruments EORTC-QOL-30, EORTC-CR-29, and EORTC-SHC-22. Results: Thirty-one percent of respondents stated that a medical professional spoke to them about fertility preservation at the time of diagnosis and during treatment. Only 31% were referred to a reproductive endocrinologist, even though 37% of women and 16% of men reported that treatment left them infertile or sterile. Among survey respondents, 12% of women had an egg retrieval procedure, and 36% of men had their sperm preserved prior to the start of treatment. Fifty-three percent of women reported treatment led to premature menopause. Sixty-five percent of respondents suffer from some level of sexual dysfunction due to treatment. In patients who received radiation therapy, women were 12% less likely than men to have discussed sexual side effects with the provider before treatment. Patients who have an ostomy reported more severe sexual dysfunction (17.8%). Rectal cancer patients were 2.5 times more likely than those with colon cancer to report severe dysfunction after their treatment. More than 25% of the respondents said they would have considered alternative treatment if they would have known the risks of sexual dysfunction. Conclusions: Our survey demonstrates inadequate communications between patients and providers about the irreversible fertility and sexual effects of colorectal cancer treatments. Younger patients and survivors face unique long-term challenges and require further information about fertility preservation options and emotional support regarding their sexuality post-treatment. Other studies are needed to assess the physical and psychological side effects endured by young-onset CRC patients and survivors.
Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment
Authors: Shota Aoyama, Ryosuke Nakagawa, Satoshi Nemoto, Patricio Perez-Villarroel, James J Mulé, Adam William Mailloux
Journal: Journal for ImmunoTherapy of Cancer (2021)

The temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth. C57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays. The distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth. Despite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.