tbuckley/cabot-search huggingface dataset:
Identifying education, knowledge and communication gaps in biomarker testing between YO-CRC patients, caregivers, and their medical team.
Authors: Kim Lynn Newcomer, Danielle Peterson, Ronit Yarden
Journal: Journal of Clinical Oncology (2020)

e16115 Background: The proportion of new young-onset colorectal cancer (YO-CRC) cases diagnosed in young people (20-49) had doubled over the past 3 decades, and it is becoming an alarming public health issue. YO-CRC patients face unique clinical challenges, as many are diagnosed at advanced stages of the disease and subjected to aggressive treatments. With the increase of targeted therapies and precision medicine available, NCCN and ASCO guidelines recommend that all stage IV, metastatic CRC patients be tested for 4 biomarkers in addition to MSI-H. However, not all eligible patients benefit from biomarker testing and biomarker-driven therapies. Methods: We conducted an online survey to assess patients, survivors and caregivers’ knowledge and understanding of biomarker testing and whether they feel empowered to discuss with their doctor different treatment options based on their unique tumor characteristics and their preferences. Results: The cross-sectional study was completed by patients and survivors (N = 885) and unrelated caregivers of YO-CRC patients (N = 203). The median age of patients and survivors was 42, and the median age of caregivers was also 42. The majority of the participants were college graduates. Although 82% of stage IV, YO-CRC patients felt informed before treatment began, only 70% indicated their tumor was tested for biomarkers, and 54% of them received biomarker testing before treatment initiation. Only 33% of patients reported they became aware of biomarkers by their medical team while others indicated resources such as internet searches, family and friends, or patient navigators. Many of the caregivers who reported that they served as a liaison between patients and medical information retrieval felt that they did not fully understand the critical aspects of the patients' medical treatment plan. Conclusions: Multiple studies have shown that patient-centered care improves patients’ outcomes. Our organization encourages patients and their families to use medical information to navigate their journey. Our patient-reported study suggests that there are gaps in patients’ and caregiver’s understanding of biomarker testing that may hinder patient's empowerment for reaching evidence-based shared-decision treatment plan together with their physicians.
Overall survival (OS) in metastatic melanoma since the introduction of immunotherapy: A National Cancer Database analysis.
Authors: Sunny R K Singh, Sindhu Janarthanam Malapati, Rohit Kumar, Ding Wang
Journal: Journal of Clinical Oncology (2020)

e19333 Background: Metastatic melanoma historically had a very poor prognosis and survival until the utilization of immunotherapy. Ipilimumab, the first immune checkpoint (ICP) inhibitor was approved in March 2011, followed soon after by the approval of PD-1 and PD-L1 inhibitors. We aim to conduct a real-world analysis of survival outcomes before and after 2011 in metastatic melanoma and its subtypes. We will also explore the impact of race on the clinical presentation and outcomes of melanoma. Methods: Adults with metastatic melanoma were identified from the NCDB (2004-2015). Kaplan Meier method was used to estimate survival and Cox proportional hazards model was used to determine hazard ratio (HR) for death after adjusting for age, race, sex, comorbidity index, melanoma type, education, income, insurance, facility type and geographical location. Odds of having metastatic disease at diagnosis were estimated using multivariate log regression analysis. Results: Of the 20,691 metastatic melanoma cases, 19,492 (94.2%) were cutaneous, 326 (1.6%) were ocular and 873 (4.2%) were mucosal. The effect of immunotherapy use on survival in metastatic melanoma was assessed by comparing years 2011-2015 versus 2004-2010. After the introduction of immunotherapy in 2011, the adjusted survival for metastatic melanoma had improved in Caucasians (HR 0.80, p &lt; 0.001, CI 0.77-0.83) but not in African Americans (HR 0.80, p value = 0.08, CI 0.62-1.03). Although, AA constituted a minority in each melanoma group (1.7% cases of cutaneous, 1.5% of ocular and 8.1% of mucosal melanoma), their odds of having metastatic disease at onset was higher in both cutaneous (OR 2.60, p &lt; 0.001 CI 2.28-2.95) and mucosal melanoma (OR 1.85, p &lt; 0.001 CI 1.39-2.47) compared to Caucasians. Conclusions: Real-world data suggested a 20% improvement in survival of metastatic melanoma since the introduction of ICP inhibitors except in the subgroups of ocular melanoma and African Americans. The disproportionately high odds of metastatic disease at presentation in African American patients with melanoma suggests the need for improvement in care delivery, specifically in terms of early detection. [Table: see text]
Anti-CTLA-4 probody BMS-986249 alone or in combination with nivolumab in patients with advanced cancers: Initial phase I results.
Authors: Martin Gutierrez, Georgina V. Long, Claire Frances Friedman, Donald A. Richards, Bradley Corr, Bruno R. Bastos, Marc Isamu Uemura, Paul R. Conkling, Victor Moreno, William Jeffery Edenfield, Carlos Roberto Becerra, Sarina Anne Piha-Paul, Amy C. Peterson, Michelle Brown, Lee P. James, Ming Zheng, Jieying Jiang, Georgia Kollia, Ailsa Swijter, Paolo Antonio Ascierto
Journal: Journal of Clinical Oncology (2020)

3058 Background: Blockade of the CTLA-4 pathway with ipilimumab (IPI) ± nivolumab (NIVO; anti–PD-1) is an effective treatment for a variety of cancers. To optimize the risk-benefit profile of CTLA-4–directed therapy, a Probody therapeutic technology platform (Pb-Tx, CytomX Therapeutics) was used to generate BMS-986249, a peptide-masked version of IPI that is unmasked by tumor-associated proteases. Pb-Tx may localize CTLA-4 activity to the tumor, minimize systemic toxicity, and allow for higher doses of anti–CTLA-4 ± anti-PD-1. In preclinical studies, BMS-986249, given at similar doses, showed comparable intratumoral and reduced peripheral pharmacodynamic activity relative to IPI (Engelhardt, AACR 2020). Here, we present the initial results of the first-in-human phase 1/2 study of BMS-986249 ± NIVO in pts with advanced (adv) cancers (NCT03369223). Methods: During dose escalation, pts received BMS-986249 at or above the approved doses of the parent molecule using a Q4W or Q8W dosing schedule as monotherapy (240–2400 mg Q4W or 1600 mg Q8W; ≈ 3–30 mg/kg vs approved 3 mg/kg Q3W IPI) or in combination (240–1200 mg Q4W or 800 mg Q8W) + NIVO 480 mg Q4W. Safety and pharmacokinetics (PK) were evaluated. Efficacy is being assessed in the dose-expansion phase. Results: As of December 7, 2019, 82 anti–CTLA-4 naive pts with various adv cancers received BMS-986249 ± NIVO (mono, n = 39; combo, n = 43). Median age 60 (25–78) y; 95% pts had prior systemic therapy. TRAEs occurred in 59% of pts (Gr 3/4, 23%) with mono and 74% of pts (Gr 3/4, 30%) with combo. Diarrhea was the most common any-Gr TRAE (mono, 23%; combo, 21%) and Gr 3/4 TRAE (mono, 15%; combo, 7%). Rates of Gr 3/4 TRAEs increased with higher doses of BMS-986249 but were substantially reduced with Q8W schedule (eg, 800 mg Q4W, 18%; 1600 mg Q4W, 60%; 1600 mg Q8W, 9%). Most TRAEs resolved, no Gr 5 TRAEs occurred. The peptide-masked intact probody accounted for most (73%) of the systemic BMS-986249-related species; elimination of the probody indicated involvement of both catabolism and cleavage processes. Conclusions: BMS-986249 ± NIVO displayed a clinically manageable safety profile, allowing assessment of comparably higher BMS-986249 dose intensity (240-1200 mg; ≈ 3-15 mg/kg) + NIVO (480 mg Q4W, full dose) than that tested with IPI + NIVO. The types of TRAEs were consistent with CTLA-4 blockade, and the overall data align with the proposed Pb-Tx mechanism of action. The preclinical and clinical data support the ongoing randomized BMS-986249 + NIVO expansion in pts with adv melanoma, in addition to other adv tumors. Clinical trial information: NCT03369223 .
Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).
Authors: Ivor John Percent, Craig H. Reynolds, Kartik Konduri, Matthew Thomas Whitehurst, Emmanuel A. Nidhiry, Ronald H. Yanagihara, Misako Nagasaka, Marshall T Schreeder, James Uyeki, Georges Azzi, Krishna Kishore Pachipala, Jason C. Comer, Rachel E. Lerner, Ticiana Leal, Delia Alvarez, Saskia T.C. Neuteboom, Natasha Reddinger, xiaohong yan, Ronald L. Shazer, David Michael Waterhouse
Journal: Journal of Clinical Oncology (2020)

TPS9635 Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m 2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT &lt; 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .
Analytical validation of iSort digital cytometry for leukocyte enumeration in clinical tumor specimens.
Authors: Aaron M. Newman, Aki Nakao, Kathy Li, Douglas Collins Wilson, Chih-Long Liu, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2020)

e15243 Background: Tumor infiltrating leukocytes (TILs) are major determinants of anti-tumor immune responses and mediate effector functions for diverse immunotherapies. Techniques relying on intact cells such as flow cytometry (FACS), immunohistochemistry (IHC), and scRNA-Seq can be powerful for measuring TIL heterogeneity. However, such methods are often impractical on large patient cohorts, can be poorly quantitative, and some cannot be applied to formalin-fixed paraffin embedded (FFPE) specimens. We developed iSort, a transcriptome deconvolution method based on CIBERSORTx for TIL enumeration. We evaluated iSort by comparing its performance in FFPE and fresh frozen (FF) human tumor tissues to established methods. Methods: We profiled human tumors for diverse TIL subsets, as quantified by iSort, FACS, and IHC. iSort was performed on RNA-Seq libraries derived from bulk human tumors, including FF tumor tissue samples, tumor cell suspensions obtained after dissociation, and FFPE specimens. We assessed the influence of tissue fixation on common TIL subsets enumerated by iSort, by comparing matched pairs of FF and FFPE lung tumor specimens (NSCLC). Finally, we compared iSort with automated microscopic enumeration of CD8 TILs by IHC on primary human lung tumors (FFPE/NSCLC). Results: iSort TIL enumeration was highly correlated with FACS across primary human tumors (CRC = 3, HNSCC = 1) for common TIL subsets (B cells, CD8 T, CD4 T, monocytes/macrophages, dendritic cells, PMNs/MDSCs) and total immune content (median r = 0.91 [0.71 - 0.99]). Tissue dissociation caused significant depletion of monocytes/macrophages (p &lt; 0.01), when comparing bulk tumor specimens with cell suspensions after sample digestion. iSort showed high correlation across 12 TIL subsets when comparing 9 pairs of FF and FFPE specimens (r = 0.90). Finally, we observed high linearity between iSort and microscopic enumeration of CD8 TILs from IHC (r = 0.87, n = 5). Conclusions: iSort digital cytometry achieves accurate and robust TIL enumeration as compared with FACS and IHC, showing comparable performance in fixed and frozen primary human tumors. Importantly, iSort is directly applicable to bulk tumors and is unaffected by tissue dissociation artifacts, unlike methods requiring cell suspensions for TIL enumeration (FACS, scRNA-seq). Therefore, iSort is a promising approach for development and measurement of immunotherapy biomarkers.
治疗规范化用药贵在达标
Authors: 许玉韵
Journal: BMJ (2005)

例1 患者男,72岁,半年来反复心前区闷痛,多与劳累和情绪有关.近3天以来于休息或夜间时有发作.体格检查:心界不大,心率82次/min,律齐,发作时肺底可闻及少许湿啰音,血压136/80 mm Hg(1mm Hg=0.133 kPa)。
IMpower150: Exploratory efficacy analysis in patients (pts) with bulky disease.
Authors: Robert M. Jotte, Marta Batus, Eric Bernicker, Mehmet Sitki Copur, Eli Kirshner, Han A. Koh, Mark Kozloff, Kert D. Sabbath, Janakiraman Subramanian, Wei Yu, Michael Nowicki, Ilze Bara, Gene Grant Finley
Journal: Journal of Clinical Oncology (2020)

e21637 Background: In the Ph 3 IMpower150 study (NCT02366143), 1L treatment (tx) with atezolizumab (A) + bevacizumab (B) + carboplatin + paclitaxel (CP; ABCP) significantly improved PFS and OS vs B + CP (BCP) in pts with chemotherapy-naive metastatic (met) nsq NSCLC. As pts with high tumor burden or large size (bulky disease) have poor survival outcomes, an exploratory analysis was conducted to determine whether pts with bulky disease in IMpower150 could derive benefit from ABCP. Methods: 1202 pts (ITT population) were randomized 1:1:1 to ABCP, atezo + CP (ACP) or BCP arms. Doses were given q3w: A, 1200 mg; B, 15 mg/kg; C, AUC 6 mg/mL/min; P, 200 mg/m 2 . Disease burden subgroups (high or low) were defined using the 3rd quartile of the sum of the longest diameter (SLD) of the target lesions or median number (no.) of met sites at baseline (BL). Exploratory efficacy analyses included PFS, OS, ORR, time to response (TTR) in these subgroups; safety was also assessed. Outcomes are reported for pts enrolled in the ABCP vs BCP arms. Results: Per 3rd quartile SLD (108 mm), 91 ABCP and 85 BCP pts had high disease burden. Per median no. of met sites (median = 2), 210 ABCP and 190 BCP pts had high disease burden. BL characteristics were generally balanced between ABCP and BCP in high disease burden subgroups. With a minimum follow-up of 32.4 mo (data cutoff: Sep 13, 2019), ABCP showed improved OS, PFS and ORR vs BCP in pts with high and low disease burden (Table). High disease burden did not impact TTR. The safety profile of ABCP was comparable between ITT-WT (no EGFR or ALK alterations) pts and high disease burden subgroups. Conclusions: A tx effect for OS, PFS and ORR was seen in pts with and without bulky disease when ABCP vs BCP was compared, regardless of the method used to define “bulky”; TTR was not affected in high disease burden pts. ABCP had a comparable safety profile in bulky disease and ITT-WT pts. ABCP may be a 1L tx option for pts with nsq NSCLC who have high disease burden. Clinical trial information: NCT02366143. [Table: see text]
The impact of frailty on the occurrence of immune-related adverse events in older patients with advanced melanoma.
Authors: Cheryl P. Bruijnen, Josephine J Koldenhof, Erwin H.J. Tonk, Rik Jasper Verheijden, Frederiek van den Bos, Mariëlle H. Emmelot- Vonk, Petronella Witteveen, Karijn Suijkerbuijk
Journal: Journal of Clinical Oncology (2020)

e24028 Background: Immune checkpoint inhibitors (ICIs) have changed the melanoma treatment landscape by inducing durable responses and significantly improving survival. ICI can cause immune-related adverse events (irAES) ranging from mild to life threatening. Clinical trials have not shown major increase of irAES in older patients when compared to younger patients. However, older patients have been underrepresented and were relatively fit in these trials. In this study, we assessed the occurrence of irAEs treated with systemic corticosteroids and/or leading to treatment discontinuation (relevant irAEs) in older patients with melanoma and, if relevant irAEs occurred more often in frail patients, as assessed with the Geriatric 8 (G8). Methods: Patients ≥70 years diagnosed with advanced melanoma, about to start with ICI, and screened with a G8, were enrolled in this prospective observational study. Patients were classified according to the G8 score as “fit” (G8 score &gt;14) or “frail” (G8 score ≤14). Toxicity was scored according to CTCAE v4.03. Primary outcome was occurrence of relevant irAEs in “fit” and “frail” patients. Secondary outcomes were the occurrence of irAEs any grade and severe irAE (grade ≥3). Results: In total, 49 patients were included for statistical analyses. Thirty-three patients were classified fit according to the G8 and, 16 patients were frail. Relevant irAEs occurred statically significantly more often in in frail patients: 12 (75%) versus 15 patients (46%) ( p=0.05). In addition, more irAEs grade ≥3 were reported in frail patients, although not significant: 7 (44%) versus 8 patients (25%) ( p= 0.11). Conclusions: Frailty, classified by the G8, is associated with the occurrence of relevant irAEs in the older patient with advanced melanoma. These data need to be confirmed in larger series.
An exploratory study on clinical application of radiofrequency endometrium ablation in treatment for dysfunctional uterine bleeding
Authors: 曹树军, 陈双郧
Journal: BMJ (2006)

目的 探讨射频子宫内膜消融术(RFEA)治疗功能失调性子宫出血的临床疗效及疗效影响因素.方法 选择自愿接受RFEA治疗的功能失调性子宫出血患者108例为研究对象,在B超监视和引导下将射频自凝刀经阴道宫颈置入子宫腔行宫内膜自凝固治疗.结果 治疗后随访6～12个月,随访104例,治疗总有效率为94.4%(102/108),治愈率即闭经率45.3%(49/108),贫血纠正率94.9%(75/79).结论 RFEA是治疗功能失调性子宫出血安全有效的微创方法;规范操作是提高疗效的关键。
Monitoring immunotherapy response in non-small cell lung cancer patients using 5-hydroxymethylcytosine signatures in circulating cell free DNA.
Authors: Gulfem Guler, David Haan, Yuhong Ning, Jeremy Ku, Erin McCarthy, Tierney Phillips, Michael Antoine, Anna Bergamaschi, Paul Lloyd, Aaron Scott, Chris Ellison, Samuel Levy
Journal: Journal of Clinical Oncology (2020)

e21505 Background: Liquid biopsies are gaining prominence for not only cancer diagnosis but also patient monitoring. Mutational signals derived from cell-free DNA (cfDNA) show promise to assess response to cancer treatment, including immunotherapy. However, reliance of these methods on mutational data from tissue biopsies limit their applicability when a tumor biopsy is unavailable, or when mutational landscape of tumor changes under the selective pressures of cancer drug treatment. Epigenomic approaches have the potential to address these shortcomings. Methods: Blood draws were obtained from a cohort of non-small cell lung cancer (NSCLC) patients (n = 19) who went on to anti-PD1 treatment prior to therapy start and while on therapy. cfDNA was isolated from plasma and was subsequently processed to generate 5hmC genome-wide profiles. Results: We analyzed cfDNA from NSCLC patients undergoing anti-PD1 therapy to investigate whether immunotherapy response can be detected from plasma. Using a predictive model trained on lung cancer and non-cancer samples, we were able to detect changes in prediction scores in patient treated with immunotherapy that were consistent with RECIST. Patients with progressive disease (n = 3), determined by RECIST, had prediction scores that increased while they received treatment. On the other hand, majority of the patients that exhibited partial response to treatment (n = 12) had predictive scores that decreased with treatment, again consistent with RECIST. Furthermore, score changes consistent with RECIST was observed one cycle prior to the RECIST timepoint in all except one patient, where an extra blood draw after baseline was available (n = 7). Annotation of the regions that account for differential scoring identified enhancer, 5’UTR and promoter regions. Comparison of partial responders to patients with progressive disease revealed genes involved in metastasis, oncogenes and tumor suppressors that change in opposing directions between these patient groups, consistent with the underlying biology. Conclusions: Our results suggest that 5hmC profiles from cfDNA can be used to determine immunotherapy response in non-small cell lung cancer patients. Compared with mutation based liquid biopsy methods to assess response, epigenomics-based methods have the advantage of being agnostic to starting tumor mutations, and not relying on a mutational analysis from tumor biopsy. Future work will help determine applicability of this method to other kinds of therapies and cancer types.