tbuckley/cabot-search huggingface dataset:
Serial circulating tumor DNA (ctDNA) analysis as a prognostic marker and a real-time indicator of adjuvant chemotherapy (CT) efficacy in stage III colon cancer (CC).
Authors: Jeanne Tie, Joshua Cohen, Yuxuan Wang, Margaret Lee, Rachel Wong, Suzanne Kosmider, Sumitra Ananda, Jin Hee Cho, Ian Faragher, Joseph James McKendrick, Carmela Corfield, Belinda Lee, Kathryn Maree Field, Ian Jones, Lu Li, Cristian Tomasetti, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Peter Gibbs
Journal: Journal of Clinical Oncology (2018)

3516 Background: Adjuvant CT in stage III CC prevents recurrence by eradicating minimal residual disease (MRD) not visible on imaging. However, many patients (pts) will not have MRD and not all pts with MRD will benefit from standard CT. In this study, we determined (i) if the presence of ctDNA following surgery was predictive of recurrence following CT; (ii) if ctDNA could be used to determine the effectiveness of CT during treatment and (iii) if the presence of ctDNA following CT completion was predictive for later recurrence. Methods: Serial plasma samples from stage III CC pts planned for adjuvant CT were collected post-surgery, during CT and at treatment completion. Somatic mutations in individual tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized Safe-SeqS assays to quantify ctDNA in plasma samples were designed. Clinicians were blinded to ctDNA results. Results: 95 pts were enrolled from Nov-2014 to May-2017, median age was 64 years. All received adjuvant CT and 19 (20%) had recurred at a median follow-up of 21.1 months. We observed an inferior recurrence-free survival (RFS) in the 19 of 95 pts (20%) with positive ctDNA post-surgery (HR, 3.52; p = 0.004). ctDNA status changed from positive to negative in 10 of 17 pts (59%) after 2 months of CT; and 9 of 18 pts (50%) at CT completion. Superior RFS was observed when ctDNA became undetectable after CT (HR 5.11; p = 0.02). Conversely, ctDNA status changed from negative to positive after CT in 6 of 71 pts (8%) and was associated with an inferior RFS (HR 5.30; p = 0.006). Finally, inferior RFS was seen in the 15 of 89 (17%) with positive ctDNA after adjuvant CT completion (HR, 7.14; p < 0.001). Conclusions: ctDNA can reveal the presence of residual metastatic cancer cells not apparent on imaging in stage III CC patients. Serial analysis of ctDNA can define subsets of pts benefiting or not benefiting from CT and is therefore a real-time marker of adjuvant treatment efficacy in solid tumors. Further studies are needed to define how best to use ctDNA analysis to guide a personalized and risk adjusted approach to the initiation and modification of adjuvant CT in stage III CC.
A retrospective analysis to assess the validity of multidisciplinary tumor boards using a new tool: The Subspecialty Academic Multidisciplinary Tumor Board score (SAMTB).
Authors: Hari Anant Deshpande, Michael E. Hurwitz, Michael Cecchini, Maria Ciarleglio, Yanhong Deng, Fangyong Li, Marissa Sherwood, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2016)

e18188 Background: Multidisciplinary tumor board (MTB) meetings have become a standard for evidence based decision making at medical centers worldwide. We believe that the expertise at subspecialty tumor boards is one of many aspects that justify the added expense of care at tertiary care centers. Measuring the quality of tumor boards however is challenging. The MTB-MODe tool for example does not mention the contribution of radiation oncology (Rozh Jalil et al. Validation of Team Performance Assessment of Multidisciplinary Tumor Boards. J Urol 891-898 Vol 192 Sept 2014.). We propose a tool for subspecialty tumor boards to gauge their importance – the Subspecialty Academic Multidisciplinary tumor board score (SAMTB score). Methods: A retrospective review of the Yale Genitourinary Tumor Board (YGUTB) was performed. Scores were assigned for each meeting (Table). Results: Since 2/27/12 the Yale genitourinary tumor (YGUTB) board has presented 1368 cases in 155 tumor board meetings. The maximum score possible for each meeting was 27. The mean score over this time period was 26.09 (CI 25.10 -27.08). Conclusions: The formation of a tool such as the SAMTB score sets a high standard for academic tumor boards, but one that can be achieved at academic centers, as is shown in this retrospective analysis. It emphasizes the presence of key personnel, availability of essential information, as well as communication to the referring and treating providers. SAMTB scoring. Score Attendee see below a Powerpoint presentation of history Prospective Specific question MTB Coordinator present Review of pathology Review of radiology Staging of case Recommendation documented in medical record 0 none No No No No No No No 1 specialist Yes Yes Yes Yes Yes Yes Yes 2 subspecialist a- Attendees include medical oncology, radiation oncology, urology, pathology, radiology, oncology nursing, research staff, social work, interventional radiology and tumor registry and were assigned a score of a 2 if > 33% of their patients had urological cancers (ie: subspecialists in their field).
Preclinical development of sunitinib and nivolumab in osteosarcoma and synovial sarcoma: In vitro functional studies.
Authors: Emanuela Palmerini, Darina Ocadlikova, Piero Picci, Mariangela Lecciso, Pier-Luigi Lollini, Javier Martin Broto, Maria Serena Benassi, Stefano Ferrari, Antonio Curti
Journal: Journal of Clinical Oncology (2018)

e14543 Background: The multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and nivolumab (anti-PD-1) have shown remarkable antitumor activity. Preliminar clinical data on TKIs and anti-PD-1 commination in sarcoma are emerging. Here we present preclinical in vitro results. Methods: The human osteosarcoma (Saos-2 and MG-63) and synovial sarcoma cell lines (SYO-1 and SW982) were treated with sunitinib. Cellular proliferation and death were assessed using the CellTiter 96® AQueous One Solution Cell Proliferation and Annexin V assays, respectively. Expression of PD-L1 and PD-1 on sarcoma cells and leukocytes was analyzed by flow cytometry. We hypothesized that PD-L1 sarcoma cell lines were tolerogenic by increasing PD-1 expression on lymphocytes. To test this hypothesis, Saos-2/ SYO-1 (± sunitinb pre-treatment) or dendritic cells (DCs) pulsed with Saos-2/ SYO-1 were cultured with allogenic CD3+ T cells (allogenic mixed lymphocyte reaction - MLR) in presence or absence of nivolumab (20 μg/ml). Results: PD-L1 expression was detected in all tested cell lines, with higher expression (81.3%) in Saos-2. When allogeneic MLR was performed, strong PD-1 upregulation on both CD4 and CD8 cells was induced. Of note, along with its anti-proliferative and direct pro-apoptotic effect on all tested cell lines, sunitinib was able to induce PD-L1 up-regulation in a dose-dependent manner, thus providing the rationale for evaluating the effect of blocking PD-L1/PD-1 axis by nivolumab. Blockade with nivolumab hampered sarcoma-induced-PD1 expression on lymphocytes, which was maintained also when Saos-2 cells had been pre-treated with sunitinib. Conclusions: Sunitinib inhibited the in vitro growth of osteosarcoma and synovial sarcoma cell lines. However, the anti-proliferative effect of sunitinib may be coupled with the up-regulation of PD-L1 on sarcoma, resulting in the induction of PD-1 on T lymphocytes. These data may be clinically relevant, but reveal an additional PD-L1/PD-1-based tolerogenic pathway being in place during sunitinib treatment. In this context, PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD1 approach in sarcoma.
Important chemotherapy terminology patients find difficult to understand.
Authors: Rebecca D. Pentz, Minisha Lohani, Rathi Narayana Pillai, Richard Defeo, Margie Dixon
Journal: Journal of Clinical Oncology (2016)

e14024 Background: Since oncology relies heavily on chemotherapy clinically and in research, it is imperative that chemotherapy terminology be comprehensible in order for patients to participate in shared decision making. Methods: Providers at an underserved public hospital were asked for words deemed most crucial for their patients to understand prior to starting chemotherapy. The consent conversation for chemotherapy was observed and technical terms used by the provider recorded. The patients were interviewed and queried about their understanding. Patients receiving chemotherapy were queried during their infusions about words they found confusing and their understanding of a list of common chemotherapy terms. Fifteen of these patients were asked what words they thought other patients need to know. All provided consent. Results: 65 participants (15 healthcare providers, 20 patients consenting to chemotherapy, 30 patients receiving chemotherapy) were interviewed. Providers identified 36 words as important for patients to understand with curative (80%) and palliative (80%) cited most frequently. Low blood count (67%), chemotherapy (60%), risk of Infection (53%), stage (47%), cycles (47%), metastatic (47%), and risk of fever (47%) also were considered important. Patients consenting to chemotherapy identified 48 words as difficult to understand. Chemotherapy (40%), stage (20%), cycles (20%), and port (20%) were most commonly cited. Patients receiving chemotherapy identified 44 words. Most common were chemotherapy (53%), lymph node (27%), stage (23%), adjuvant (20%), radiation (20%), neuropathy (205), and edema (20%). The words others need to understand included chemotherapy (80%), lymph node (73%) stage (73%), and port (60%). Combining the patient cohorts, the most frequently mentioned words were chemotherapy (48%), stage (24%), radiation (18%) and neuropathy (18%), with both chemotherapy and stage being deemed by many providers to be important. Conclusions: The majority of patients receiving chemotherapy reported difficulty understanding medical terminology, with chemotherapy itself being the most commonly cited word. Oncologists may need to simplify their language when discussing treatment options with patients.
Abstract 12489: Association of Longitudinal Blood Pressure Changes and Kidney Function Decline: Findings From the Multi-Ethnic Study of Atherosclerosis
Authors: Gregory L Judson, Anna D Rubinsky, Rebecca Scherzer, Michael Shlipak, Ronit Katz, Holly Kramer, Joacim Ix, David Jacobs, Michelle Odden, Carmen A Peralta
Journal: Circulation (2016)

Background: Few studies have examined the association of blood pressure (BP) change over time with kidney function decline. We hypothesized that increasing systolic blood pressure (SBP), decreasing diastolic blood pressure (DBP), and widening pulse pressure (PP) trajectory would be associated with worsening renal function, independent of baseline BP, among persons with relatively preserved estimated glomerular filtration rate (eGFR) and free from cardiovascular disease at baseline. Methods: We used data from 4,156 participants in the MESA Study who had at least two BP measurements from study year 0 to year 5 and eGFR measurements at year 5 and 10. Participants were then grouped into one of three groups based on the distribution of change (top 20% = increasers, middle 21-79% = stable, bottom 20% = decreasers). We calculated eGFR from cystatin C and defined rapid decline as a &gt;30% decrease in eGFR. We used multivariable logistic regression adjusting for demographics, baseline eGFR and BP to determine associations of BP change category with later renal function decline. We also estimated the association of change in BP with annual change in eGFR using adjusted linear regression. Results: The stable SBP group had a mean age of 59, was 50% male, 41% white, and had 29% of participants on an anti-hypertensive medication. The increasing SBP group was similar except for having fewer men (43%). Median year 0 and year 5 SBP for increasing SBP was 110 and 131, for stable 119 and 118, for decreasing 145 and 119 mmHg respectively. Increasing SBP and widening PP trajectory were associated with higher odds of rapid renal function decline compared to stable groups after adjusting for all covariates including baseline BP. Decreasing SBP was not associated with rapid renal function decline after adjusting for baseline BP. Similar findings were seen with annual renal function decline. Implication: Increasing SBP and widening PP appears to increase the risk for accelerated kidney function decline.
Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): Phase 3 OPTIMISMM trial.
Authors: Paul G. Richardson, Albert Oriol Rocafiguera, Meral Beksac, Anna Marina Liberati, Monica Galli, Fredrik Schjesvold, Jindriska Lindsay, Katja Weisel, Darell White, Thierry Facon, Jesus San-Miguel, Kazutaka Sunami, Peter O'Gorman, Pieter Sonneveld, Xin Yu, Thomas Doerr, Amine Bensmaine, Mohamed H. Zaki, Kenneth Carl Anderson, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2018)

8001Background: POM, a standard-of-care treatment (Tx) in RRMM, has demonstrated synergistic anti-myeloma activity with dexamethasone (DEX) and proteasome inhibitors (PIs). POM + DEX is indicated f...
Abstract 11874: Sympathetic Control of Reflex Cutaneous Vasoconstriction in Human Hypertension
Authors: Jody L Greaney, W. L Kenney, Lacy M Alexander
Journal: Circulation (2016)

Introduction: Cardiovascular-related morbidity and mortality during environmental cold exposures increase disproportionally in hypertensive (HTN) adults. Although alterations in central control of sympathetic outflow and peripheral regulation of vascular function are evident in hypertension and contribute to increased cardiovascular risk, no studies have examined sympathetic control of reflex cutaneous vasoconstriction during cold stress in humans with hypertension. We hypothesized that 1) whole-body cold stress would elicit exaggerated increases in skin sympathetic nervous system activity (SSNA) and greater reductions in skin blood flow in HTN [n=10; 56±3 yrs; resting blood pressure (BP) 145±7/84±3 mmHg] compared to normotensive adults (NTN; n=12, 55±3 yrs; resting BP 126±4/79±3 mmHg) and 2) cutaneous adrenergic sensitivity would be increased in HTN adults. Methods: In Protocol 1, reflex vasoconstriction was induced by gradual whole-body cooling (to a mean skin temperature of 30.5°C) using a water-perfused suit. SSNA (peroneal microneurography) and red cell flux (laser Doppler flowmetry; dorsum of foot) were measured continuously. SSNA was expressed as a percent change from baseline. In Protocol 2, an intradermal microdialysis fiber was placed in the skin of the lateral calf to measure red cell flux in response to graded intradermal infusions of norepinephrine (NE; 10 -12 to 10 -2 M). In each study, cutaneous vascular conductance (CVC=flux/mean arterial pressure) was expressed as a change from baseline. Results: During cooling, HTN exhibited greater increases in SSNA compared to NTN adults (Δ = 194±26% HTN vs. 51±12% NTN; P&lt;0.01) but cutaneous vasoconstriction was not different between groups (ΔCVC base = -0.03±0.003 ητν vs. -0.02±0.01 flux units mmHg -1 NTN; P=0.97). The slope of the relation between ΔSSNA and ΔCVC base during cold stress was blunted in HTN adults (P&lt;0.01). There was no group difference in cutaneous adrenergic responsiveness to exogenous NE (dose-response logEC 50 ; -7.2±0.2 HTN vs. -7.5±0.4 NTN; P=0.75). Conclusion: Although cutaneous microvascular adrenergic responsiveness to NE is preserved, the sensitivity of the sympathetic reflex response to whole-body cold stress is diminished in human hypertension.
Identifying t cell profiles that associate with clinical response to anti-PD-1 treatment in non-small cell lung carcinoma (NSCLC) patients.
Authors: Andre Kunert, Edwin A. Basak, Daan Hurkmans, Yarne Klaver, Mandy van Brakel, Astrid Oostvogels, Cor Lamers, Sander Bins, Stijn L.W. Koolen, Astrid Van Der Veldt, Stefan Sleijfer, Ron H.J. Mathijssen, Joachim G.J.V. Aerts, Reno Debets
Journal: Journal of Clinical Oncology (2018)

e21239 Background: Checkpoint inhibitors, such as the PD-1 antibody nivolumab, have been approved for the treatment of several cancer types, including NSCLC. As only a limited subset of NSCLC patients experiences durable benefit, there is a need for early prediction of clinical response. Here, we aim to identify immune markers in peripheral blood samples of NSCLC patients treated with nivolumab. Methods: In 71 NSCLC patients treated with 2nd line nivolumab (2-weekly), whole blood samples were collected at 3 time points (pre-treatment; prior to 2nd and 3rd administration of nivolumab). Multiplex flow cytometry was applied to enumerate 19 immune cell subsets and determine frequencies of T cell subsets positive for 28 markers (single + combinations), enabling classification of T cells according to activation, maturation, co-signaling, and chemotaxis. Best overall response (BOR) within 90 days was assessed using RECIST (v1.1). Standard statistical tests were applied. Results: Patients showing partial response (PR) displayed increased numbers of CD8 T cells prior to and throughout therapy with a median (range) of 560 cells/μl (170-1900), while patients with progressive disease (PD) showed a median of 220 cells/μl (90-1070) (p = 0.022). PR patients also possessed significantly higher frequencies of CD8T cells positive for the maturation marker CD95 (60% (9-87)) at baseline and throughout therapy when compared to PD patients (45% (5-82)) (p = 0.041). With regard to co-signaling, PD patients displayed a significantly lower median frequency of CD8 T cells positive for CD279 (PD-1) and CD366 (TIM3) at baseline (4.8% (1.2-17.6)) and, unlike PR patients, a drop in CD4 T cells positive for multiple co-inhibitory receptors from 24% (8-36) to 17% (8-36) following therapy. In addition, PD patients showed a higher frequency of CD4 T cells positive for co-stimulatory CD28 and CD278 (ICOS) (35% (12-48)). Conclusions: We demonstrate that total numbers of CD8 T cells as well as T cells subsets in peripheral blood, in particular those expressing co-signaling receptors, associate with response to nivolumab in NSCLC patients. When confirmed, these findings will facilitate clinical decision making.
Phase I/Ib study of pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC).
Authors: Andreas Nicholas Saltos, Tawee Tanvetyanon, Charles C. Williams, Eric B. Haura, Ben C. Creelan, Scott Joseph Antonia, Nishan Tchekmedyian, Kristen Goas, Trevor Mamplata, Ram Thapa, Dung-Tsa Chen, Amer A. Beg, Jhanelle Elaine Gray
Journal: Journal of Clinical Oncology (2018)

9046 Background: The oral histone deacetylase inhibitor (HDACi) vorinostat (V) enhances tumor immunogenicity through several mechanisms and may augment response to PD-(L)1 blockade (IO). We report mature results from a phase I/Ib trial testing the combination of V with pembrolizumab (P) in mNSCLC. Methods: In phase I, pts with either IO-naïve or IO-pretreated mNSCLC were treated with P (200mg IV q3 wk) + V (200 or 400 mg PO daily). In phase Ib expansion, pts were required to have progressed on prior IO treatment. Primary endpoints were safety/tolerability; secondary endpoints included RR, PFS, DOR, and OS. Tissue and blood specimens from pre- and post-treatment were collected for correlative analyses to determine tumor gene expression changes, levels of myeloid-derived suppressor cells and changes in peripheral T-cell phenotype. Results: Between 3/2016 - 9/2017, Phase I: 14 pts were treated (4 at 200mg, and 10 at 400mg V dose); and Phase Ib: 20 pts were treated. Median age: 67 (range 38-82); Females: 11 (32%); ECOG 1: 32 (94%); and never/former/current smokers: 3/23/8 (9%/68%/23%). No DLTs were observed. The RP2D is P 200mg and V 400mg. Most common AE of any grade were fatigue (11%), anorexia (9%) and nausea/vomiting (8%). Most common G3 AE were myalgia, anemia and diarrhea. There were no G4/5 AEs. 3 (9%) pts had treatment discontinued due to toxicity. 30 pts are evaluable for response. PD-L1 expression was ≥ 1% in 18/30 (60%), and ≥ 50% in 11/30 (37%). 6 pts were IO-naïve and 24 IO-pretreated. 4 (13%) had PR (2 confirmed), 16 (53%) had SD, and 10 (33%) had PD for a disease control rate of 67%. In the IO-pretreated Ib cohort, 2 pts (1 confirmed; 1 pending repeat CT) had a PR and 10 had SD (8 confirmed). For IO-pretreated pts, mPFS was 3.2 months. For IO-naïve, mPFS was 7.6 months. Preliminary tumor RNA-seq studies showed increase in IFN gamma and HDACi target gene expression, including CXCL9. Conclusions: V + P was well tolerated. The combination demonstrates preliminary anti-tumor activity despite progression on prior IO treatment and gene expression changes consistent with mechanism of HDACi action. A randomized phase II portion of this study, examining P combined with V vs. placebo in immunotherapy naïve pts, is ongoing. Clinical trial information: NCT02638090.
Randomized phase 2 trial of patritumab (P) or placebo (PBO) + cetuximab (C) + cisplatin (CIS) or carboplatin (CAR) for recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN).
Authors: Kevin J. Harrington, Martin David Forster, Christophe Le Tourneau, Jose Ariza, Shuquan Chen, Jonathan Greenberg, Kenji Hirotani, Eva Remenar
Journal: Journal of Clinical Oncology (2018)

6045 Background: P, a fully human monoclonal antibody can block HER3 activation. HER3 activation is a resistance mechanism to C, induced by the ligand heregulin (HRG). This randomized phase 2 study in Europe evaluated first-line C + CIS or CAR + P or PBO for R/M SCCHN. Methods: Patients (pts) age ≥18 y with confirmed R/M SCCHN, stratified by HRG high vs low expression (via RT-PCR from tumor RNA) and human papilloma virus (HPV)+ vs HPV-, received IV P (18 mg/kg loading dose [LD]; 9 mg/kg maintenance dose [MD] every 3 weeks [q3w]) or PBO, and C (400 mg/m2 LD; 250 mg/m2 MD weekly) + ≤6 cycles of CIS (100 mg/m2 q3w) or CAR (AUC of 5). Co-primary endpoints were progression-free survival (PFS) in the intent-to-treat (ITT) and HRG high arms. Results: In all, 87 pts (44 P, 43 PBO; median age 59 y; 83% male) were treated; a median 6 (1-20) P cycles were completed. Pts received CAR (70%) or CIS (34%) (median 5 [2-6] CAR and 5 [1-6] CIS cycles) in the P arm and CAR (7%) or CIS (20%) (median 5 [1–6] cycles each) in the PBO arm. Discontinuations due to adverse events (AEs) were higher with P (16%) vs PBO (5%). Treatment-emergent AEs grade ≥3 were more frequent with P (84%) vs PBO (58%) (most frequent: acneiform dermatitis [14% vs 7%] and rash [14% vs 0%]). Serious AEs occurred in 43% (41% grade ≥3) (P) and 37% (33% grade ≥3) (PBO) of pts. In P and PBO arms, PFS and objective response rates (ORR; complete + partial response) in ITT, HRG-high (Table), HRG low (difference in PFS: HR 1.2, 95% CI 0.6–2.6, and ORR: 11.1%, 95% CI -15.8–36.0) and HPV- (difference in PFS: HR 1.5, 95% CI 0.9–2.7, and ORR: 4.7%, 95% CI -16.6–25.3) arms were similar (HPV+ arm was too small [n = 16] to draw meaningful results). Conclusions: P + C + CIS or CAR was not more effective than C + CIS or CAR. Clinical trial information: NCT02633800. PFS, mo, median (95% CI) P PFS, mo, median (95% CI) PBO PFS difference, HR (95% CI) P vs PBO ORR, % (95% CI) P ORR, % (95% CI) PBO ORR difference, % (95% CI) P vs PBO ITT (N = 87) n = 44 5.6 (4.1–6.5) n = 43 5.5 (4.2–6.5) 1.11 (0.7–1.9) P= 0.70 n = 16/44 36.4 (22.8–52.3) n = 12/43 27.9 (15.8–43.9) 8.5 (-10.9–26.8) HRG high (n = 51) n = 26 5.6 (4.1–7.1) n = 25 5.6 (3.1–8.3) 1.12 (0.6–2.3) P= 0.75 n = 11/26 42.3 (24.0–62.8) n = 9/25 36.0 (18.7–57.4) 6.3 (-19.1–30.4)