tbuckley/cabot-search huggingface dataset:
Durability of response to venetoclax (VEN) in patients with CLL relapsed/refractory to ibrutinib and/or idelalisib.
Authors: John C. Byrd, William G. Wierda, Matthew Steven Davids, Michael Y. Choi, Richard R. Furman, Anthony R. Mato, Lang Zhou, Maria E. Verdugo, Jalaja Potluri, Steven Coutre
Journal: Journal of Clinical Oncology (2018)

7512 Background: Therapies are urgently needed for patients (pts) with CLL relapsed/refractory (R/R) to BCRi. We report outcomes for the full trial population from an ongoing phase 2 trial with VEN monotherapy, including the impact on detectable minimal residual disease (MRD). Methods: Pts with CLL R/R to ibrutinib and/or idelalisib received 400 mg daily VEN after initial dose ramp up. Results are from a data cut on 28Nov2017. Results: Pts (N = 127) had received a median of 4 prior therapies (1 – 15). Del(17p) was noted in 40% (50/126) and 28% (34/122) of pts had mutated TP53. After a median of 17 (.1 – 36) months on VEN, the best overall response rate was 66% (84/127; CR/CRi – 10%, nPR/PR – 56%) per investigators (INV) and 70% (89/127) by independent review committee (IRC). Per INV (median follow up, 16 [.03 – 33] months), estimated median progression-free survival (PFS) was 25 months (18-month rate, 66%); neither median duration of response (18-month rate: 75%) nor median overall survival (18-month rate: 88%) was reached. 36/77 pts assessed (47%; 28% [36/127] by intent to treat) had undetectable blood MRD, 9/26 assessed were also undetectable in marrow (2 CR/CRi, 7 PR). Median PFS was longer for pts with undetectable MRD in blood vs positive (not reached vs 21.9 months; HR, .148 [.04 – .49], p= .0019). 64 pts discontinued VEN, most commonly for CLL progression (n = 35; median time, 10 months [.1 – 29]), AEs (n = 8), and Richter’s transformation (n = 6; median time, 13 months [4 – 19]). Common any-grade AEs were GI AEs (diarrhea [50%], nausea [49%]) and cytopenias (anemia [43%], neutropenia [41%], thrombocytopenia [28%], decreased white blood cell count [28%]). Conclusions: Based on longer follow up, VEN monotherapy demonstrates robust activity, with good tolerability in pts with CLL R/R to ibrutinib and/or idelalisib. Though most pts achieved PR, outcomes appear durable with undetectable MRD. Clinical trial information: NCT02141282.n (%) Last prior BCRi Ibrutinib n = 91 Idelalisib n = 36 N = 127 INV IRC INV IRC INV IRC ORR 59 (65) 64 (70) 25 (69) 25 (69) 84 (66) 89 (70) CR 5 (6) 0 2 (6) 0 7 (6) 0 CRi 4 (4) 1 (1) 2 (6) 0 6 (5) 1 (1) nPR 3 (3) 0 0 0 3 (3) 0 PR 47 (52) 63 (69) 21 (58) 25 (69) 68 (54) 88 (69) SD 21 (23) 27 (30) 9 (25) 11 (31) 30 (24) 38 (30) PD 5 (6) 2 (6) 7 (6) Early discontinuation 6 (7) 0 6 (5)
Prognostic rule of programmed cell death protein 1 expression in resectable upper tract urothelial carcinoma.
Authors: Nozomi Hayakawa, Eiji Kikuchi, Ryuichi Mizuno, Mototsugu Oya
Journal: Journal of Clinical Oncology (2017)

e16090 Background: Programmed cell death protein (PD-1) expressed on active T cells are related to immune tolerance. A close association between PD-1 expression and poor prognosis has been reported in several cancers, however, in upper tract urothelial carcinoma (UTUC) the rule of PD-1 expression on clinical outcome have not been investigated. Methods: The protein expression of PD-1 was evaluated by immunohistochemistry and the relationship with clinicopathological features was investigated in surgical specimens obtained from 155 patients who had been surgically treated for UTUC without previous history of bladder cancer. At a magnification of 400x, PD-1 protein expression was estimated and the positive cells was graded as weak and strong. The protein expression of PD-1 was evaluated in the most invasive part of the cancer with tumor periphery and inside separately. Results: The PD-1 expression was weak in 67 (43.2%) and strong in 88 (56.8%) in tumor periphery. On the other hands, the staining was weak in 117 (75.5%) and strong in 38(24.5%) in tumor insides. Regarding to pathological features, high grade (p = 0.026) and pT2≤ (p = 0.008) related to strong PD-1 expression in tumor inside, and high grade (p = 0.002), pT2≤ (p &lt; 0.001) and positive LVI (p = 0.008) were associated with strong PD-1 expression in tumor periphery. The 5-year caner-specific survival (CSS) in patients with strong PD-1 staining in tumor periphery was 79.4%, which was significantly lower than those in their counterparts (86.0%, p = 0.044). The 5-year CSS in patients with strong PD-1 staining in tumor inside was 73.3%, which was significantly lower than those in their counterparts (85.1%, p &lt; 0.021). Multivariate Cox regression analysis demonstrated that positive LVI (HR; 3.92, p &lt; 0.001) and strong PD-1 expression in tumor inside (HR; 2.30, p &lt; 0.036) were independent predictors for CSS. Conclusions: PD-1 expression, especially in tumor inside, may be a novel indicator for identifying a worse prognosis in UTUC patients with radical nephroureterectomy. Targeting therapy against PD-1 might be a promising therapeutic modality for UTUC, especially aggressive UTUC.
Characterization of two potential immunotherapeutics in tumor infiltrating lymphocytes (TILs) using flow cytometry and Meso Scale Discovery.
Authors: Karen K Yam, Stephen Parker, Michael Agrez, Christopher Warburton, Adriana Alcantara, Vicky Sgouroudis, Jean-Francois Poulin
Journal: Journal of Clinical Oncology (2018)

e15052 Background: Inter-K Peptide Therapeutics has developed two synthetic compounds that modulate kinase activity. To investigate the potential of these compounds as cancer immunotherapeutics, a flow cytometric intracellular cytokine staining (ICS) assay was developed to investigate the effect of the compounds on immune cells isolated from tumors from subjects with non-small cell lung cancer (NSCLC). In addition, the concentration of various cytokines was measured in cell culture supernatant after treatment with the compounds. Methods: After optimizing the assays in PBMC from healthy donors, the assay was used for clinical specimens. Tumor infiltrating lymphocytes (TILs) were isolated from two resected tumors by mechanical disaggregation. TILs were stimulated with or without anti-CD3/CD28 antibodies with and without Inter-K Compound A or Compound B for 72 hours. Following stimulation, cell culture supernatants were analyzed for 10 proinflammatory-related cytokines using the Meso Scale Discovery (MSD) assay. TILs were analyzed by flow cytometry with a 10-color immunophenotyping panel to measure the expression of functional markers CD25, IL-2, IFNg and Ki67 in NK, NKT, CD4 T and CD8 T cells. Results: Immunomodulation induced by Compound A treatment included an over two-fold increase in CD25 expression in CD4 T cells, statistically significant increases in IL-6 and IL-8 production while a decrease in Ki67 expression in CD8 T cells and a reduction in IL-2, IFNg, TNFa, IL-4, IL-10 and IL-13 production was observed. Compound B did not appear to have immunomodulatory properties. Conclusions: This work provides an example of the utility of flow cytometry in compound evaluation. In this case, preliminary data suggests that Compound A but not B was able to modulate the response in TIL samples in vitro, and supports the continued investigation of Compound A as an immunotherapeutic. Although TIL specimens are challenging to work with due to tumor availability and low cellular recovery, as the target for the immunotherapy, it is important that compound characterization be conducted in TIL in addition to healthy donor PBMC and cell lines.
P05.35 Intraoperative radiotherapy after resection of brain metastases (INTRAMET) - initial safety/efficacy analysis of a prospective phase II study
Authors: S Brehmer, M Welsch, A Karakoyun, A Förster, M Seiz-Rosenhagen, S Clausen, F Schneider, F Wenz, D Hänggi, F A Giordano
Journal: Neuro-Oncology (2018)

Brain metastases occur in roughly 40% of patients diagnosed with systemic cancer. External beam radiotherapy (to the cavity or whole brain) lowers local recurrence rates but also prolongs the time to (systemic) salvage therapies. We here present initial safety/efficacy data on INTRAMET, a phase II trial that evaluates local efficacy of immediate sterilization of the cavity using intraoperative radiotherapy (IORT). INTRAMET is a monocentric, open-label, one-arm, prospective, phase II study that includes patients aged 18 years and older with newly diagnosed, resectable brain metastases with a KPS of 50 of better. Following resection of the macroscopic tumor, all patients receive IORT with 30 Gy prescribed to the margin of the resection cavity. The primary endpoint is local progression-free survival (L-PFS), secondary endpoints are time to salvage cancer therapy (TTST), overall survival (OS), global (cancer-specific) PFS, cognitive performance, quality of life and dose-limiting toxicities (DLT) defined as wound healing disorders, cerebral hemorrhage, ischemia or radionecrosis requiring surgical intervention. We here report (i) safety and efficacy results of a planned safety/interim analysis after inclusion of 10 patients and (ii) on a pre-planned comparison of TTSTs of IORT-treated patients and of 19 patients treated with surgery and postoperative radiotherapy (consecutively) within the same timeframe. All patients included in this interim analysis had a pulmonary primary (IORT group: n=7 adenocarcinoma, n=3 squamous-cell carcinoma; control group: n=14 adenocarcinoma, n=3 squamous-cell carcinoma, n=2 large cell neuroendocrine carcinoma).The median follow-up was 7.9 months. No DLT occurred. Of the 10 patients receiving IORT, only one had a confirmed local recurrence which occurred synchronous with multiple other new out-of-field metastases 41 days after treatment. The mean TTST after IORT was 46.2 [27–83] days compared to 61.3 [16–229] days in the control group, with a mean time to cerebral radiotherapy after surgery of 26.8 days. IORT for cerebral brain metastases appears to be safe and effective. In addition, the time to systemic therapy trends to be reduced, which is of high impact for palliative care, where patients have very limited survival time.
A novel, robust multiplex urine-based immunoassay for bladder cancer detection.
Authors: Hideki Furuya, Yunfeng Dai, Kanani Hokutan, Yair Lotan, Charles Joel Rosser
Journal: Journal of Clinical Oncology (2018)

4537 Background: Bladder cancer (BCa) is among the most commonly diagnosed malignancies worldwide, and due the high rate of post-operative disease recurrence, it is one of the most prevalent in many countries. The development of non-invasive molecular assays that can accurately detect and monitor BCa would be a major advance, benefiting both patients and healthcare systems. We have previously identified a urinary protein biomarker panel that is being developed for application in at-risk patient cohorts. Here, we investigated the potential utility of the multiplex assay in a prospective study. Methods: The study cohort collected from urology clinics at two institutions was comprised of a total of 145 subjects. The protein biomarker panel (IL8, MMP9, MMP10, ANG, APOE, SDC1, A1AT, PAI1, CA9, VEGFA) was monitored in voided urine samples collected prior to cystoscopy using a custom multiplex ELISA assay. The diagnostic performance of the biomarker panel was assessed using receiver operator curves (ROC), predictive modeling and descriptive statistics. Results: Urinary biomarker concentrations were significantly elevated in cases versus controls, and in cases with high-grade and muscle-invasive tumors. The AUC for the 10-biomarker assay was 0.901 (95% confidence interval, 0.850–0.934), with an overall diagnostic sensitivity specificity of 0.90 and 0.91, respectively. Conclusions: Urinary levels of a 10-biomarker panel enabled discrimination of patients with BCa. The multiplex urinary diagnostic assay will continue in prospective study. Clinical trial information: NCT03193528.
Targeted therapy for non-small cell lung cancer (NSCLC) with HER2, BRAF, or hedgehog alterations: Interim data from MyPathway.
Authors: John D. Hainsworth, Ron Bose, Christopher Sweeney, Funda Meric-Bernstam, Herbert Hurwitz, Charles Swanton, Howard A. Burris, Razelle Kurzrock, Bongin Yoo, Mary Stanley Beattie, Ravindra Gupta, Rajesh D. Patel, Katja Schulze, David R. Spigel
Journal: Journal of Clinical Oncology (2017)

9073 Background: Treatments targeting critical molecular alterations (EGFR, ALK, and ROS1) in NSCLC are highly effective. MyPathway (NCT02091141) is an ongoing, phase 2, multi-basket study evaluating the efficacy of targeted treatment in non-indicated tumor types harboring alterations in the HER2, BRAF, Hedgehog (Hh), or EGFR pathways. Interim results in NSCLC are presented. Methods: Patients with previously treated advanced NSCLC and alterations in the HER2 (amplification and/or mutation), BRAF (V600E or other mutations), Hh (SMO or PTCH-1 mutations), or EGFR (mutations other than known activating mutations) pathways received standard doses of pertuzumab + trastuzumab, vemurafenib, vismodegib, or erlotinib, respectively, until disease progression or unacceptable toxicity. The HER2, BRAF, and Hh cohorts are included in this analysis. The primary endpoint is investigator-assessed objective response rate (ORR, defined as complete response [CR] + partial response [PR]) by RECIST v1.1. Results: As of November 30, 2016, 61 patients with NSCLC and HER2 (n = 36), BRAF (n = 22), or Hh (n = 3) alterations have been treated (median age of 64 years, 49% male, 85% adenocarcinoma, and a median of 2 previous regimens). Median treatment duration was 1.8 (range, 0–21.4) months. Efficacy in the 55 patients with the minimum required follow-up for efficacy analysis is summarized in the table. Conclusions: Targeted therapy is active in patients with previously treated NSCLC harboring BRAF V600E mutations or HER2 alterations (amplifications and/or mutations). These cohorts have been expanded as MyPathway accrual continues. Additional efficacy data and details regarding molecular alterations will be presented. Clinical trial information: NCT02091141. [Table: see text]
Targeting p63 upregulation may prevent the development of MAPK inhibitor resistance in melanoma
Authors: T.-M. Borg, A. Patel, D. Bergamaschi, C. Harwood
Journal: Annals of Oncology (2018)

Background: Melanoma progression is often characterized by mutations in the mitogen-activated protein kinase (MAPK) and phosphoinositol-3-kinase (PI3K) pathways. Understanding regulation of these pathways has led to the development of novel targeted therapies which show high response rates. However, many patients relapse with ensuing resistant disease. P63, a p53 homologue, carries a poorer prognosis when overexpressed. In keratinocytes, degradation could be regulated by two ubiquitin ligases, MDM2 and FBXW7.
Construction and analysis of a novel pseudogene-associated ceRNA network to identify potential pseudogene signature for diagnosis and prognosis of human triple-negative breast cancer.
Authors: Yuan Li, Huihui Song, Yu Ma, Sunkai Ling, Xiaoxue Li, Peilin Huang
Journal: Journal of Clinical Oncology (2018)

e24167 Background: The human genome comprises more numbers of pseudogenes than corresponding functional genes. Recent studies have evidenced that some dysregulated pseudogenes are contribute to tumor biology as tumor suppressor or oncogene. In particular, pseudogene transcripts can function as miRNA-decoy in competing endogenous RNAs network. Triple-negative breast cancer (TNBC) shows a higher malignant and poorer clinical outcome compared with other subtypes, but the implications of pseudogenes for diagnosis and prognosis in TNBC remain unclear. Methods: We developed a novel method for predicting the potential pseudogenes associated with TNBC by a series of analysis tools. We comprehensively integrated expression profiles, including data on parental genes, pseudogenes, and miRNAs obtained from 1097 breast cancer tissues and 114 normal tissues from TCGA project. As a result, we detected more expressed pseudogenes ( [RPKM]20 cutoff≥0.3, |log2FC| > 2.0, p-value > 0.05 ) to obtain the differentially expressed mRNAs, miRNAs and pseudogenes. Co-expression analysis was performed to identify the dysregulated genes. We computered Pearson correlation coefficients to different column and related clinical overall survival. By means of correlating target genes and pseudogenes with interaction network analysis that had identified the key microRNAs. Results: Our analysis identified 45 pseudogenes and 18 of them possess binding sites for co-expressed miRNAs and reveal relatively high expression correlations to parental genes with high confidence, suggesting that they are highly associated with TNBC. We also explored the clinical utility of pseudogene-expression in terms of predicting patient survival. Moreover, we found that 18 differentially expressed parental genes could interact with 12 key miRNAs. Conclusions: The network was constructed by utilizing pseudogenes, parental gene mRNAs and key miRNAs. Taken together, these results increased the putative pseudogene ceRNAs than previously appreciated. This research may illuminate the pseudogenes detection of TNBC and the clinical value in forecasting prognosis.
P01.022 Non-measurable speckled contrast-enhancing lesions appearing during course of disease are associated with IDH mutation in high-grade astrocytoma patients
Authors: A Berberich
Journal: Neuro-Oncology (2018)

As treatment options at progression are limited for glioma patients, the accuracy in definition of progression is pivotal. Clinically asymptomatic, newly detected, non-measurable, speckled contrast-enhancing lesions (SCE) without immediate relation to prior immune- or radiotherapy appear relatively frequently during course of disease in glioma patients and challenge the definition of progression based on Response Assessment in Neurooncology (RANO) criteria. Therefore, data characterizing these SCEs are needed for recommendations of subsequent clinical management. MRIs of seven hundred forty-six glioma patients included in this study were retrospectively revised for appearance of newly detected SCEs during course of disease. Associations with molecular and clinical baseline parameters as well as their prognostic impact were statistically analyzed and frequency, natural course and location of SCEs described. SCEs occurred more frequently in World Health Organization (WHO) grade II and III astrocytoma and oligodendroglial tumors and were significantly associated with isocitrate dehydrogenase (IDH) mutation in WHO grade III astrocytoma and glioblastoma. SCEs mostly remained stable or dissolved in follow-up MRIs, even if no new treatment was initiated. SCEs were frequently located within the tumor or tumor-associated FLAIR abnormalities, but distant appearance also occurred. In glioblastoma patients, SCEs were associated with a favorable prognosis, which was also observed in the subgroup of glioblastoma patients with IDH wildtype status. The data demonstrate a predominantly benign course of SCEs after its appearance and emphasize for cautious definitions of progression as well as for regular clinical and radiographic follow-ups rather than premature initiation of new anti-tumor therapies until progression is confirmed.
Impact of skeletal muscle loss after adjuvant chemoradiotherapy in patients with gastric cancer.
Authors: Yan Gao, Zongmin Yu, Zhengye Liu, Fuxiang Zhou
Journal: Journal of Clinical Oncology (2016)

e15515 Abstract Background: Emerging evidence on body composition suggests that Skeletal muscle depletion (sarcopenia) is closely associated with mortality and toxicity of chemotherapy combined with radiation in cancer patients. This study evaluated the value of skeletal muscle status on predicting the toxicity of adjuvant treatment and overall survival (OS)in patients with gastric cancer. Methods: We conducted a retrospective analysis of 80 patients with gastric cancer before and after adjuvant therapy which included chemotherapy and radiotherapy or chemoradiotherapy after radical subtotal gastrectomy. Skeletal muscle cross-sectional area was measured by single-slice computed tomography (CT) at the level of third lumbar(L3) vertebrae via ImageJ medical imaging software. The predict value on toxicity and OS was evaluated by skeletal muscle index(SMI) ,a parameter standardized by height squared, and the change rate of skeletal muscle during treatment ,respectively. Results: Of 80 patients who met our inclusion criteria, median postoperative follow-up was 36.5 months. approximately 25% of patients were classified as sarcopenic. Prevalence of grade3/4 toxicity was higher in sarcopenic (31.6%)compared with non-sarcopenic patients(21.3%),but there was no significant difference(p = 0.54) . However, 14 patients with skeletal muscle loss ( ≥ 5%) after adjuvant chemoradiotherapy showed significantly shorter OS compared with those without skeletal muscle loss ( log-rank p = 0.011). Multivariate Cox- regression analysis revealed that skeletal muscle loss( ≥ 5%) after chemoradiotherapy (hazard ratio, 3.085; 95%confidence interval, 1.152 - 8.257; p = 0.025) was independently associated with OS. Conclusions: Skeletal muscle loss after chemoradiotherapy was an independent, negative prognostic factor in gastric cancer. Sarcopenia evaluated by SMI is a potential predictor of toxicity in gastric cancer patients receiving adjuvant therapy.
A multicenter phase 2 study of nivolumab combined with ipilimumab in patients with pediatric solid tumors in adulthood (GETHI021).
Authors: Xabier Mielgo, Robert Diaz Beveridge, Estela Pineda, Juan Manuel Sepúlveda, Rafael López Castro, Maria José Lecumberri-Biurrun, María Ángeles Vaz Salgado, Ramon De Las Penas, Carlos López-López, Nuria Rodriguez Salas, Juan Antonio virizuela, Rafael Lopez, Javier Medina, Claudia Valverde, Carmen Beato, Nuria Lainez, Cristina Rodríguez-Antona, Pedro Berraondo, Alejandro Herrador, JesÃºs GarcÃa-Donas
Journal: Journal of Clinical Oncology (2018)

TPS3123 Background: Solid pediatric tumors that appear in adulthood are a heterogeneous group that share some characteristics such as low incidence, lack of standard therapeutic options and reduced survival. Pediatric cancers usually originate from embryonic cells that likely present genetic alterations and epitopes different from mature cells. These may be targeted by the immune system, if properly stimulated by immune checkpoint inhibitors (ICI). Thus, ICIs could achieve a significant activity in these tumors. Here, we present the first phase II clinical trial of nivolumab and ipilimumab in this setting. Methods: A multicenter, open-label, single arm Phase II study was designed to evaluate the efficacy, safety and tolerability of the combination of nivolumab and ipilimumab in adult patients (≥18 years) with locally advanced or metastatic childhood malignancies that have progressed or are not candidates to standard therapy. The Spanish Group for Infrequent and Orphan Tumors (GETHI) is the sponsor of the study and 15 associated Spanish centers are participating. Main inclusion criteria are: adult subjects, ECOG PS ≤2, no prior anti-PD1 or anti-CTLA4 therapy. Treatment schedule is nivolumab 3 mg/kg IV q2w + ipilimumab 1 mg/kg IV q6w for 6 months or until RECIST v1.1 progression/unacceptable toxicity. Study treatment may continue beyond disease progression and may be extended for a maximum of 24 months if clinical benefit exists. Primary endpoint is objective overall response rate (ORR) according to RECIST v1.1 criteria. Secondary endpoints are toxicity profile, quality of life, PFS and OS. In addition, a comprehensive molecular study to identify potential biomarkers will be performed. Following Simon optimal two-stage design, the first stage includes 30 evaluable patients If ORR is > 10%, the study will continue to a second stage until 89 evaluable patients are recruited. The null hypothesis will be rejected if ORR ≥20%. This design yields a type I error rate of 0.05 and power of 80% when true response rate is 0.20. Accrual started in July 2017 and 26 patients have been enrolled up to January 2018. Scheduled recruitment period is 18 months. EudraCT number: 2016-003946-99. Clinical trial information: 2016-003946-99.