tbuckley/cabot-search huggingface dataset:
Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict efficacy of axitinib for treatment of advanced hepatocellular carcinoma (HCC).
Authors: Po-Hsiang Huang, Bang-Bin Chen, Zhong-Zhe Lin, Ying-Chun Shen, Yee Chao, Yu Yun Shao, Ann-Lii Cheng, Chiun Hsu
Journal: Journal of Clinical Oncology (2017)

e15656 Background: Axitinib, a potent inhibitor of vascular endothelial growth factor receptor, has moderate antitumor efficacy for advanced HCC. Vascular response (VR) measured by DCE-MRI has been demonstrated to correlate with efficacy of systemic therapy for advanced HCC. Methods: Patients enrolled into a phase 2 trial of axitinib as second-line therapy for advanced HCC (NCT01273662) with liver tumors evaluable by DCE-MRI were included. Patients must have documented progression on or intolerance to sorafenib and Child-Pugh class A liver function. The primary endpoint was disease stabilization, defined as complete or partial response per RECIST1.1 or stable disease lasting for 8 weeks without progression of tumor-related symptoms. The quantitative parameter Ktrans and semi-quantitative parameter peak, measured by DCE-MRI at baseline and after 2 weeks of axitinib treatment, were used to evaluate VR, defined by a greater than 40% decrease of Ktrans or peak. Results: From April 2011 to March 2016, 40 patients were enrolled at National Taiwan University Hospital and 5 at Taipei Veterans General Hospital, all had documented progression after sorafenib treatment. Disease stabilization rate was 62.2% (95% CI 48.0-76.4). Median progression-free survival (PFS) and overall survival (OS) were 2.2 months (95% CI 0.3-4.1) and 10.1 months (95% CI 3.6-16.5) respectively. 33 patients were evaluable for VR. VR evaluated by peak was significantly associated with better PFS (5.5 vs. 1.8 months, HR 0.41, 95% CI 0.16-1.02, p = 0.04) and OS (13.0 vs. 5.8 months, HR 0.28, 95% CI 0.09-0.85, p = 0.02). Treatment-related adverse events were compatible with previous reports of axitinib. Conclusions: VR measured by DCE-MRI may help identify HCC patients most likely to benefit from axitinib treatment. Clinical trial information: NCT01273662. [Table: see text]
Cannabis in cancer patients [CP] to improve quality of life [QOL] and cancer related symptoms [CRS]: Illinois Cancer Care cannabis education and clinical analysis.
Authors: Shawn Michael Seibert, Pankaj Kumar, Patrick Leigh Gomez, Christina Nicole Gomez, Laura M. Miller, Matt Logsdon
Journal: Journal of Clinical Oncology (2018)

e18812Background: Improvement [I] in [QOL] and CRS varies greatly with different cannabis products. Evidence supporting specific cannabis products and frequency of use to improve QOL and CRS is lac...
Abstract 13797: Effects of Resveratrol Supplementation on Walking Performance in Peripheral Artery Disease: A Randomized Clinical Trial
Authors: Mary McDermott, Christiaan Leeuwenburgh, Luigi Ferrucci, Jack M Guralnik, Robert Sufit, Lu Tian, Lihui Zhao, James Stein, Ying Gao, Stephen Anton, Rafael De Cabo, Michael Criqui
Journal: Circulation (2016)

Introduction: Resveratrol, a phenol found in red wine and grape skin, has been associated with longevity in animals and with improved endothelial function and mitochondrial activity in humans without cardiovascular disease. Resveratrol supplement sales exceed 30 million dollars per year. Recent evidence suggests that lower resveratrol doses may have greater benefits. Hypothesis: In a randomized trial, we hypothesized that 125 mgs and 500 mgs of resveratrol, respectively, would improve walking performance in people with lower extremity peripheral artery disease (PAD), compared to placebo. Methods: In the RESveratrol To improve outcomes in Older people with PAD (RESTORE) trial, people age 65 and older with PAD were randomized to one of three groups: 500 mgs resveratrol, 125 mgs of resveratrol, and placebo. The trial was double-blinded. The primary outcome was change in six-minute walk distance at 6-month follow-up. Secondary outcomes were changes in maximal and pain-free treadmill walking distance and brachial artery flow-mediated dilation (FMD). Results: 66 PAD participants were randomized (mean age- 74.4 ±6.7 years, mean ankle brachial index- 0.67±0.18). The study population included 21 (31.1%) females and 33 (50%) blacks. The table shows results. P values are relative to the placebo group. Conclusions: These results suggest that resveratrol should not be prescribed to improve walking performance or cardiovascular health in people age 65 and older with PAD.
Utilizing IL-7 to generate melanoma antigen T cell receptor-modified cells for adoptive transfer in the absence of activation.
Authors: Siao-Yi Wang, Gina Scurti, Annika Dalheim, Tamson Moore, Michael Nishimura
Journal: Journal of Clinical Oncology (2017)

e14552 Background: Metastatic melanoma remains a fatal disease as many patients fail to respond to novel therapies. Presently, we have an ongoing trial utilizing T cell receptor (TCR)-modified cells reactive to the melanoma antigen, tyrosinase, for treatment of metastatic melanoma (NCT01586403). Current protocols using viral vectors to generate cells for adoptive transfer require activation in the presence of IL-2. While IL-2 stimulates proliferation and production of mature effector cells, it also induces T cell exhaustion. We hypothesize that tyrosinase-reactive TCR-modified cells generated in the absence of activation have an increased potential for expansion, persistence, and anti-melanoma activity. In these studies, we investigate whether IL-7, a homeostatic regulator, facilitates the transfer of a tyrosinase-reactive TCR to lymphocytes without activation. Methods: Gene-modified cells were generated using a lentiviral vector including alpha and beta chains of a TCR reactive to tyrosinase and a truncated CD34 molecule as a transduction marker. Peripheral lymphocytes from normal human donors were transduced with lentivirus following no treatment, treatment with IL-7, or activation in the presence of IL-2. Transduced CD34 positive cells were isolated using magnetic activated cell sorting (MACS) and injected intravenously into NOD scid gamma (NSG) mice. Results: We found that IL-7 treatment improved transduction in non-activated cells and resulted in expression levels of CD34 and TCR variable beta chain 12 (vbeta12) comparable to cells activated in the presence of IL-2. When non-activated tyrosinase-reactive TCR-modified human T cells were adoptively transferred into NOD NSG mice, the cells were detectable in the peripheral blood of mice up to 7 days after transfer. Conclusions: These findings suggest that generating melanoma antigen TCR-modified cells in the absence of activation for adoptive transfer is feasible with IL-7 treatment. Ongoing studies in NSG mice transplanted with melanoma will help determine whether non-activated gene-modified cells will improve the efficacy and longevity of cell therapy for melanoma and other malignancies.
Graduates are being blocked from entering medical school, students warn
Authors: Abi Rimmer
Journal: BMJ (2018)

The closure and shrinkage of graduate entry medical degree courses is stopping candidates from diverse backgrounds from entering the profession, students have warned.

In a letter to the Journal of the Royal Society of Medicine , six graduate entry medical students from King’s College London said that in recent years several four year, graduate entry courses had closed or narrowed requirements to exclude candidates …
Combination of triapine, olaparib, and cediranib for epithelial ovarian cancer therapy.
Authors: Z Ping Lin, Yong-Lian Zhu, Peter E. Schwartz, Elena Ratner
Journal: Journal of Clinical Oncology (2018)

e17551 Background: PARP inhibitors target BRCA-mutated or homologous recombination (HR) repair-defective epithelial ovarian cancer (EOC). However, primary and recurrent EOC with proficient HR repair is resistant to PARP inhibitor therapy. We have previously demonstrated that triapine, a small molecule inhibitor of ribonucleotide reductase, impairs HR repair and sensitizes BRCA-wild type EOC cells to PARP inhibitors and platinum-based therapies. The objective of this study was to evaluate whether addition of triapine augmented the efficacy of the olaparib-cediranib combination to treat BRCA wild-type EOC cells in xenograft mouse models. Methods: SKOV3, OVCAR3, and PEO4 are BRCA-wild type and PARP inhibitor-resistant EOC cell lines. PEO4 cells were derived from a BRCA2-mutated EOC patient who developed platinum-resistant disease at second relapse following platinum-based chemotherapy. Athymic nude mice were injected subcutaneously (s.c.) with SKOV3 and OVCAR3 cells. SCID-Beige mice were injected intraperitoneally (i.p.) with PEO4 cells. Mice were then administered i.p. daily with olaparib, cediranib, triapine, various double or triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID-Beige mice were measured to evaluate the ability of drug treatment to delay tumor growth and prolong the survival time of mice. The body weight was also measured to monitor the toxicity of treatment and adjust the dosing schedules accordingly. Results: In both xenograft mouse models, addition of triapine to the olaparib-cediranib combination resulted in marked suppression of BRCA-wild type EOC tumor growth and significant prolongation of the survival time of mice. The drug combination with varied triapine to olaparib-cediranib ratios and dosing schedules were tolerable to mice. Conclusions: The combination of triapine, olaparib, and cediranib is efficacious to target BRCA-wild type EOC. The use of triapine allows lower doses of the olaparib-cediranib combination and minimizes the side effects. This combination regimen holds promise in treating patients who have BRCA-wild type or PARP inhibitor-resistant EOC.
Sensor-controlled scalp cooling to prevent chemotherapy-induced alopecia in women treated for either breast or female genital tract cancer: A German experience using the Paxman system.
Authors: Christian M. Kurbacher, Susanne Herz, Gabriele Kolberg, Nele Kettelhoit, Claudia Schweitzer, Katja Monreal, Jutta Anna Kurbacher
Journal: Journal of Clinical Oncology (2016)

10118 Background: Chemotherapy (Ctx)-induced alopecia (CIA), produces a deep emotional impact in many female cancer patients (pts). Sensor-controlled scalp cooling (SCSC) has been found to be effective in preventing CIA, However, this technique is infrequently used in many countries due to concerns regarding both safety and feasibility. This prospective non-interventional study was initiated to gain detailed information about the effectiveness and reasons of discontinuation of SCSC using the Paxman system (Paxman, Huddersfield, UK) in German women exposed to CIA-inducing Ctx due to breast cancer (BC) or genital tract malignancies. Methods: 72 pts were included: BC, 54; epithelial ovarian carcinoma, 14; others, 4; premenopausal, 38; postmenopausal, 34. 51 pts were treated in a curative intent, 21 were treated in a palliative setting; 49 pts were Ctx-naïve, 23 pts had a history of prior Ctx. The following Ctx regimens were used: anthracycline-based (A), n = 4; taxane-based (T), n = 18; AT-based, n = 39; non-AT-based, n = 11. Pts were subjected to SCSC during each Ctx cycle. CIA was quantified according to the Dean score (DS) determined 3 wks after the end of Ctx. The primary endpoint was feasibility indicated by the treatment completion rate. Secondary endpoints were the degree of hair preservation (success: DS 0-2, failure: DS 3-4, or discontinuation of SCSC), and safety. Results: 46 pts (63.9%) completed SCSC, with 38 (52.8%) experiencing complete hair preservation (DS 0), and 8 (11.1%) showing partial success (DS 1-2). 26 pts (36.1%) discontinued CTCS, with CIA being the main reason in 18 pts (25%). Headache was reported in 4 (5.6%), and discomfort in 2 pts (2.8%). In the remaining 2 pts (2.8%), the reason for discontinuation was unclear. Side effects were not severe and resolved completely after cessation of SCSC. Conclusions: CTCS using the Paxman system is feasible, safe and effective in order to prevent CIA in pts with BC and female genital tract carcinomas in the clinical routine. Our study is in good agreement with previous reports on CTCS although including a higher proportion of pts in the palliative setting or with a history of prior Ctx.
Spectrum of tumor mutational load (TML) in genitourinary cancers (GU CA).
Authors: Muhammad Azam Hussain, Elisabeth I. Heath, Bradley G. Somer, David Arguello, Curtis Johnston, Joseph J. Drabick, Monika Joshi
Journal: Journal of Clinical Oncology (2017)

4535 Background: Immunotherapy (IO) is now standard of care for bladder and kidney cancer (CA) and is investigational in other GU CA such as prostate and germ cell CA. Tumor mutational load (TML) has correlated with response to IO in several tumor types. Herein, we explore TML across different histological subtypes in GU CA. In addition, we also assess the correlation between TML and PD-L1 status. Methods: 544 GU specimens were identified: bladder, 145; kidney, 164; prostate, 221; penile, 2; testicular, 12. TML was calculated using somatic non-synonymous missense mutations from a 592-gene panel (Illumina NextSeq). A high TML was &gt; 17 mutations/MB. PD-L1 (SP142) was done depending tumor availability. Results: High TML was more prevalent in bladder CA (14.5%, 21/145) compared to other GU CA. Urothelial carcinomas had a noticeably high TML while squamous histology had a pronounced PD-L1 expression (Figure 1). A comparison of TML-high (n=15) versus TML-low (n=76) urothelial bladder CA showed the following differences (Figure 2). TML was rare in kidney CA (1.8%, 1/57); PD-L1 was high in sarcomatoid (33.3%, 5/15), CDC/RMC (28.6%, 2/7). Prostate adenocarcinoma had few TML-high (2.3%, 5/219) or PD-L1 expressing tumors (1.4%, 3/208). Tumors of penile or testicular origin lacked high TML and PD-L1 expression. No correlation was found between a high TML and PD-L1 expression. Conclusions: TML varied considerably amongst GU CA. As in other CA, TML-high scores did not predict PD-L1 expression and vice versa. Comprehension of the underlying biology may assist in determining which CA may respond better to IO. [Table: see text] [Table: see text]
A phase II study of oral azacitidine (CC-486) in combination with pembrolizumab (PEMBRO) in patients with metastatic melanoma (MM).
Authors: Emily Keung, Elizabeth M. Burton, Rodabe Navroze Amaria, Isabella Claudia Glitza, Sapna Pradyuman Patel, Adi Diab, Cassian Yee, Michael K Wong, Wen-Jen Hwu, Patrick Hwu, Scott Eric Woodman, Michael T. Tetzlaff, Denai Milton, Kristen Perez, Michael A. Davies, Kunal Rai, Jennifer Ann Wargo, Hussein Abdul-Hassan Tawbi
Journal: Journal of Clinical Oncology (2017)

TPS9594 Background: Immune checkpoint inhibitors have impressive response rates and improved survival for many pts with MM, offering durable responses in up to 35% of pts while others have short-lived or no response ( &gt; 40%). A potentially targetable mechanism for immune escape is for cancers to subvert the cellular epigenetic machinery, affecting multiple aspects of the immune response from suppression of tumor antigen expression [such as Cancer Testis Antigens (CTA)] to antigen processing and presentation, thus allowing tumor proliferation to continue undetected. In preclinical models, decitabine (DAC), a DNA hypomethylating agent (HMA), has been able to revert heterogeneous CTA expression profiles, increasing cancer cell immunogenicity. HMAs also increased TH1-chemokine expression, T cell tumor infiltration, T cell-mediated tumor killing, and have been shown to be synergistic with checkpoint inhibitors in preclinical models. This suggests that epigenetic therapy with checkpoint inhibition is a rational combination to target MM. Clinical advantages of the HMA CC-486 over DAC include oral bioavailability and potential versatility in dosing and schedule. We hypothesize that CC-486 + PEMBRO will be tolerated at biologically relevant doses; enhance response to PEMBRO in pts with mm who are PD-1 naïve; and reverse resistance to immunotherapy in pts refractory/resistant to PD-1 directed therapy. Methods: This study will evaluate the safety and efficacy of CC-486 + PEMBRO defined by Objective Response Rate (ORR) by RECIST 1.1 in pts with MM. Pts who are PD-1 naïve (Arm A, n = 36) and pts who have progressed on prior PD-1 directed therapy (Arm B, n = 35) will be enrolled. Unlimited prior systemic therapies will be allowed. Pts will receive 300mg PO of CC-486 on days 1-14 and 200mg IV of PEMBRO every 3 weeks. Continuous monitoring for toxicity and futility will be performed and assumes an ORR of &gt; 35% and &gt; 15% for Arms A and B, respectively (95% power). Tumor biopsies at baseline and post treatment are required. Effects of CC-486 + PEMBRO on CTAs, MDSCs and Tregs, and correlation between mutation burden and response will be studied. This study is open for enrollment. Clinical trial information: NCT02816021.
TCT-363 Impact of the heart team in decision making in patients with severe aortic stenosis – data from the IMPULSE registry
Authors: Stefano Salizzoni, Samuel Mancuso, Richard Steeds, Matthias Lutz, Tanja Rudolph, Martin Thoenes, Peter Bramlage, Norbert Frey, Alberto Clerici, David Messika-Zeitoun
Journal: Journal of the American College of Cardiology (2018)
Treatment-free survival (TFS), a novel outcome applied to immuno-oncology (IO) agents in advanced melanoma (AM).
Authors: Meredith M. Regan, Lillian Werner, Ahmad A. Tarhini, Sumati Rao, Komal Gupte-Singh, Corey Ritchings, Michael B. Atkins, David F. McDermott
Journal: Journal of Clinical Oncology (2018)

9531 Background: Conventional measures, such as median progression-free survival, may suboptimally characterize the full impact of IO agents. Patients (pts) discontinuing IO agents may experience periods of disease control without needing subsequent systemic anticancer therapy (Rx). We propose TFS to simultaneously characterize the antitumor activity and adverse events of this period. Here we present the antitumor activity seen in the TF periods following IO therapy in AM. Methods: Data were pooled from 1077 pts initiating Rx in CheckMate 067 and 069 trials of ipilimumab (I) and nivolumab (N) as monotherapy and combination for AM (407 N+I, 313 N, 357 I). I was given for 4 doses; N was given until progression/intolerability. We defined TFS as the area between Kaplan-Meier (KM) curves for 2 conventional time to event endpoints: (A) duration of protocol Rx (randomization until Rx cessation) and (B) subsequent Rx-free survival (randomization until initiation of subsequent Rx or death). We estimated overall survival (OS). Area under each KM curve was estimated by the 36 mo restricted mean time to event. Area under the OS curve until 36 mo was partitioned as time on protocol Rx (mean A), TFS (mean B-A), and post-subsequent Rx time (mean OS-B), and summarized as percentage of the 36 mo period. Results: At 36 mo, 58% N+I, 52% N, 36% I pts were alive. Few pts remained on protocol Rx (11% N+I, 17% N, 0% I) and many pts were surviving free of subsequent Rx (47% N+I, 37% N, 15% I). 36 mo restricted mean OS was longer for N+I and N than I (Table). Mean TFS was 31% of time for N+I vs 13% for N, as N+I had shorter mean protocol Rx duration and longer time until subsequent Rx, and 24% for I. Clinical trial information: NCT01844505 and NCT01927419. Conclusions: Defining TFS by the area between KM curves for time to protocol Rx cessation and time to subsequent Rx or death, showed AM pts receiving N+I spent more time free of any Rx compared to N or I, and will allow integration of toxicity data to also characterize patient well-being while treatment free. Restricted mean time, mo (% of 36 mo period) N+I N I OS 25.7 (72%) 24.9 (69%) 21.4 (59%) Duration of protocol Rx, A 10.3 (29) 13.9 (39) 2.6 (7) TFS, B-A 11.1 (31) 4.6 (13) 8.7 (24) Time after subsequent Rx initiation, OS-B 4.3 (12) 6.4 (18) 10.1 (28)
BAX-BAK heterodimer as a pharmacodynamic biomarker of on-target drug action of Mcl-1 inhibitors to evaluate in-vivo effectiveness.
Authors: Apurva K. Srivastava, Jeevan P Govindharajulu, Melinda G. Hollingshead, William J Moore, Francesca Tomaino, Kelly Banfield, Taekyu Lee, Edward T Olejniczak, John Sensintaffar, Myrtle Davis Millin, Ralph E. Parchment, James H. Doroshow, Stephen Fesik
Journal: Journal of Clinical Oncology (2018)

2582 Background: Clinical development of promising small molecule Mcl-1 inhibitors is underway. The Mcl-1 inhibitors act by disrupting complexes of Mcl-1 with pro-apoptotic proteins such as BAK/BIM/Noxa, leading to formation of oligomers of BAK and BAX at the mitochondrial membrane and activation of an apoptosis cascade. Therefore, measurement of BAX-BAK heterodimers on the mitochondrial membrane is considered an on-target pharmacodynamic (PD) biomarker for this class of drugs. We describe use of the BAX-BAK assay to screen and prioritize small molecule Mcl-1 inhibitors (Taekyu et al, FEBS Let 2017) for on-target activity and in vivo potency in relevant cancer models. Methods: The BAX-BAK heterodimer immunoassay was developed on the Luminex platform using monoclonal antibodies specific to active BAX and BAK proteins. Single-dose PD and PK of each Mcl-1 inhibitor was evaluated at 100-mg/kg (IP) in nude mice bearing AMO-1 (myeloma) or NCI-H929 xenografts. Tumors quadrants were collected at 4, 8, 12, 18 and 24 hours after dosing, mitochondrial (mito.) fractions prepared, and biomarkers measured as described previously (Srivastava et al, Clin Can Res 2016). Results: The sandwich oassay provided a reliable, quantitative measurement of BAX-BAK levels in mito. fractions from both in-vitro (AMO-1, MOLP-8, MOLT-4, NCI-H929) and in-vivo xenograft (AMO-1, NCI-H929) models. The PD study showed a wide range of BAX-BAK activation, with the most potent compounds causing a 10-20 fold increase in peak BAX-BAK levels between 4-18 hours after dosing. Compounds that produced the highest levels of BAX-BAK also produced the highest cleaved caspase-3 levels and were associated with the highest tumor drug concentrations. The PD biomarker strategy, in conjunction with PK, prioritized select compounds for further development. Conclusions: We describe the application of a BAX-BAK heterodimer assay to effectively identify potent Mcl-1 inhibitors with early proof of on-target activity in tumor tissue. The PD biomarker could provide a benchmark assay to compare and contrast potency and mechanism-of-action of Mcl-1 inhibitors in clinical studies. Funded by NCI Contract No HHSN261200800001E.