tbuckley/cabot-search huggingface dataset:
Metastatic renal cell carcinoma in the elderly: A single Irish institution experience.
Authors: Jane Sze Yin Sui, Rozana Rahman, Noorsyakira Osman, Emily Harrold, Lynda Corrigan, Laura Healy, Anna Linehan, Lore Kabo Komanyane, Eileen McMahon, Paul Selvadurai, Nabeeha Karadawi, Austin G. Duffy, Michaela Jane Higgins, Desmond N. Carney, David James Gallagher, John McCaffrey
Journal: Journal of Clinical Oncology (2018)

e22048 Background: The incidence of renal cell carcinoma has grown due to increasing aging population. Treatment of renal cell carcinoma has evolved over last decade with the advent of targeted therapies and immunotherapies. We performed this study to evaluate the outcomes of metastatic renal cell carcinoma (mRCC) patients (pts) in our institution. Methods: All patients diagnosed with mRCC from January 2010 until December 2017 were identified from the hospital electronic database. Demographics, clinic-pathological features, lines of therapies and survival data were extracted from electronic health records. The elderly population were identified as ≥65 years. Data was analysed using SPSS software v24. Results: Ninety-four pts were identified of which, 61.0% (n = 57) were < 65 years and 69.1% (n = 65) were males with median age of 60.8 years (range: 29-87 years). 68.0% (n = 64) with clear cell subtypes and 41.5% (n = 39) had de novo stage IV disease at presentation. 37.2% (n = 26) received immunotherapy. 78.7% (n = 74) underwent nephrectomy, of which 45.7% (n = 43) had radical nephrectomy and 33.0% (n = 31) had cytoreductive nephrectomy. The overall survival rates between pts ≥65 vs < 65 years: 43.4 vs 36.8 months with p = 0.756. There is a trend towards survival benefit for pts ≥65 years with nephrectomy (see table). Survival rates were similar in both age groups with first line treatment and with immunotherapy. Conclusions: In our cohort, pts ≥65 years with mRCC was associated with comparable survival with their younger counterpart. Future dedicated studies for elderly patients are warranted in this aging society. Median OS, months p-value (log -rank) < 65 years (n = 57) ≥65 years (n = 37) Nephrectomy 0.06 Radical 36.8 63.9 Cytoreductive 21.4 41.8 None 29.9 15.0 1st line therapy 0.82 Sunitinib 31.4 66.2 Pazopanib 36.8 28.5 Temsirolimus 23.1 17.8 Immunotherapy 0.07 Yes 73.8 66.2 No 36.8 23.5
Cancer patients' interest and preferences for an inpatient smoking cessation program (SCP).
Authors: Lawson Eng, Devon Alton, Yuyao Song, Jie Su, Delaram Farzanfar, Rahul Mohan, Olivia Krys, Tom Yoannidis, Robin Milne, M Catherine Brown, Ashlee Vennettilli, Andrew J. Hope, Doris Howell, Jennifer M. Jones, Peter Selby, Wei Xu, David Paul Goldstein, Meredith Elana Giuliani, Geoffrey Liu
Journal: Journal of Clinical Oncology (2016)

10090 Background: Smoking cessation is becoming an integral part of cancer survivorship care. We assessed cancer patients’ interest and preferences in the design of a SCP. Methods: Cancer patients from all subtypes were cross-sectionally surveyed. Multivariable logistic regression analyses identified factors associated with patient interest and preferences. Thematic qualitative analyses supplemented survey data. Results: Of 985 cancer patients, 23% smoked in the year prior to diagnosis (“current smokers”), of whom 56% quit afterwards; 55% had tobacco related cancers. Among current smokers, 35% of patients were interested in an ambulatory SCP; while 51% were interested in an inpatient SCP (ISCP). Multivariable analysis revealed that higher income (aOR = 3.22 95%CI [1.47-7.14]) and receiving palliative treatment (aOR = 2.90 [1.14-7.38]) were associated with interest in an ISCP. Perceiving that smoking was harmful to quality of life, survival and fatigue were each associated with a greater belief that SCPs are beneficial (aORs = 3.39-4.75, P< 0.001). Believing that a SCP was beneficial to patients (51%) (aOR = 4.65 [2.15-10.03]) or that a SCP should be routine cancer care (64%) (aOR = 4.22 [1.90-9.39]) were each associated with preference for joining an ISCP. Major reasons for lack of interest in joining an ISCP include having just quit prior to diagnosis (26%) and wanting to quit alone (23%). Only 65% of patients interested in ISCPs wished to discuss it at their first oncology visit. Feeling overwhelmed (50%) and wanting to control discussion about smoking cessation (31%) were the major barriers to discussing at first visit. Interestingly, neither level of patient knowledge nor perceptions of smoking on outcomes were associated with interest in ISCP. Significantly fewer patients wanted phone (24%) or WebApp (15%) counselling. Conclusions: ISCPs were favored by cancer patients smoking at diagnosis. Believing in a benefit of a SCP was a more important factor in wanting to join an ISCP than knowledge and perception of the effects of smoking on cancer outcomes. Initial cancer care discussions with patients should highlight the effectiveness of SCPs. ISCPs should be explored as options for cancer patients being admitted for any reason.
Synergy of TLR4 agonist GSK1795091, an innate immune activator, with agonistic antibody against co-stimulatory immune checkpoint molecule OX40 in cancer immunotherapy.
Authors: Hua-Xin Gao, Sabyasachi Bhattacharya, Christopher Jon Matheny, Niranjan Yanamandra, Shu-Yun Zhang, Heidi Emerich, Yufeng Li, Paul Bojczuk, Hong Shi, Wei Wang, Christopher Hopson, Tihui Fu, James Patrick Allison, Padmanee Sharma, James F . Smothers, Roopa Srinivasan, Axel Hoos
Journal: Journal of Clinical Oncology (2018)

12055 Background: GSK1795091 (aka, GSK’091) is a synthetic glycolipid toll-like receptor 4 (TLR4) agonist. TLR4 is a Pattern Recognition Receptor for host defense against bacterial infection, expressed on innate immune cells monocytes, macrophages, dendritic cells. GSK’091 is a potent and selective TLR4 agonist and is being evaluated for use in combination with other immunotherapies to treat cancer Methods: To understand the antitumor activity and pharmacologic effects of intravenously administered GSK’091, in vivo studies were performed in murine syngeneic tumor models. Pharmacodynamic (PD) effects of GSK’091 was examined in peripheral and tumor infiltrating lymphocytes (TILs) using multicolor flow cytometry assays. Additionally, TCRβ sequencing, Nano string and multiplex cytokine assays were employed to understand the molecular and cellular mechanisms induced by this molecule Results: GSK’091 potently activated the immune system and modulated the tumor microenvironment by inducing an array of proinflammatory cytokines, enhancing antigen presentation, activating T cells, and reducing T regulatory cells. At doses sufficient to induce systemic cytokines in mice, GSK’091 inhibited tumor growth and resulted in long term survival in tumor model. When administrated with OX86, a murine surrogate OX40 agonist monoclonal antibody (mAb), the combination induced a robust PD response as demonstrated by a significant increase in Th1 cytokines, expression of interferon regulated genes, higher tumor infiltration by leucocytes, increase in T cell activation , proliferation and increase in the CD8: Treg ratio. Additionally, GSK’091 when combined with anti-OX40 induced clonal expansion of T-cells and drove synergistic interferon and T-cell dependent anti-tumor response Conclusions: The current study demonstrated that GSK’091 activates key initiating immune pathways and can induce robust anti-tumor efficacy when combined with agonistic antibodies directed against the OX40 receptor. This novel combination provides a strong rationale and supports evaluation of GSK’091 in combination with immuno-oncology agents in clinical trials
Proposal of new staging models for gastric cardia cancer after preoperative radiation incorporating tumor grade and LODDS.
Authors: Rui Zhou, Dongqiang Zeng, Jingwen Zhang, Huiying Sun, Wangjun Liao
Journal: Journal of Clinical Oncology (2017)

e15557 Background: Preoperative radiotherapy (Pre-RT) tends to be more frequently used for advanced gastric cardia cancer (GCC) patients. However, the prognostic values of postoperative pathologic characteristics in these patients remain unclear. This study aimed to examine the outcomes in GCC patients receiving Pre-RT to identify the predictive factors for cancer-specific survival (CSS) and overall survival (OS). Methods: A total of 1818 GCC patients undergoing Pre-RT, recorded in the Surveillance Epidemiology and End Results database from 1998-2013, were reviewed. Results: Univariate analyses showed that grade, histology type, positive lymph node (PLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) classifications significantly correlated with CSS and OS. However, through the four-step multivariate analyses, only grade and LODDS were demonstrated as the final independent risk factors for survival. Next, by combining grade with lymph node status variables, we established three novel staging models namely the grade-PLN (G-P), grade-LNR (G-R), and grade-LODDS (G-L) stages. Similarly, subsequent four-step multivariate analyses also revealed that only G-L predicted CSS and OS independently. Moreover, the new G-L staging system also validated to have better discriminatory ability, monotonicity, and homogeneity for prognostic stratification, as well as a more-accurate 3-year CSS (P = 0.023) and OS (P = 0.015) prediction than AJCC staging system. Conclusions: The G-L staging system was superior in determining the prognosis of GCC patients after Pre-RT. Further large-scale prospective cohort analyses are warranted.
Oral small molecule modulators of p300/CBP to reprogram cancer cells and reactivate the p53 pathway in HPV-associated carcinomas.
Authors: Ulrich Kessler, Valentino Cattori, Marc Labelle, Bernd Hentsch
Journal: Journal of Clinical Oncology (2018)

e14581 Background: Dysregulation of the basal cellular transcription machinery is a fundamental feature of cancer. E1A binding protein (p300) and CREB binding protein (CBP) are two closely related paralog transcription co-activators involved in the expression of many oncogenic drivers that are essential for maintenance of the high proliferative rate of cancer cells. Methods: Small molecule ligands of the TAZ1/CH1 domain of p300/CBP were tested in a broad panel of tumor cell lines (colony formation). The effects of selected compounds were investigated by transcriptome analyses, subsequent qPCR studies and cell cycle analysis. In HPV-positive cervical cancer cells (CaSki), the acetylation, activation and stabilization of p53 were determined by western blotting. The subsequent induction of p21 was measured by qPCR. Senescent cells were stained for ß-galactosidase. In vivo efficacy was assessed in patient derived xenografts (PDX) of head and neck squamous cell carcinoma (HNSCC) and a lung cancer (A549) xenograft model. Results: Several modulators of p300/CBP exhibited broad anti-proliferative effects at low nanomolar concentrations in a colony formation assay. The compounds “normalize” the transcription of cancer cells and induce cell cycle arrest and senescence. Transcriptome analyses revealed the downregulation of (oncogenic) drivers of cell cycle progression. In HPV-positive CaSki cells, the preclinical candidates strongly reactivate the p53 pathway. The blockade of p53-acetylation through the HPV E6 protein is released and cells are enabled to enter apoptosis. In a HNSCC PDX model, the inhibitors cause strong anti-tumor effects upon oral administration and exhibit synergistic effects in combination with cisplatin. A comparison with erlotinib in lung cancer xenografts (A549) indicated superiority of the p300/CBP inhibitors. Conclusions: Reprogramming of cancer cells by modulation of the p300/CBP interactome is a new and broadly applicable approach for the treatment of cancer. The presented data illustrates the clinical potential of this new class of therapeutics in the context of HPV-associated carcinomas and beyond.
P01.070 Increasing TTFields acceptance with a patient-oriented communication
Authors: I Lütge
Journal: Neuro-Oncology (2018)

Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor in adults. Treatment includes surgery, radiation, chemotherapy and more recently tumor treating fields (TTFields), which in combination with temozolomide results in significantly increased progression-free survival and overall survival compared to temozolomide chemotherapy alone. As TTFields-compliance (average monthly time on treatment) acts as an independent predictor for overall survival the quality of information given to patients and their education about the treatment is important. Materials and Methods: We analyzed our consultation strategy with respect to the way we communicate TTFields therapy and its mode of action, efficacy results, importance of compliance, side effects, treatment duration and handling of the device. We found that not only the wording but also the time point is key for efficient communication. The following aspects are particularly relevant for successful patient communication and education: Be precise and honest about the disease and the available therapies; Use and maintain a clear and structured communication scheme; Use clear, patient adapted words and understandable explanations; Ask the patients about their interests, preferences and personal living conditions. Conclusions: With this patient-centered TTFields communication scheme, we feel comfortable and we believe to generate higher treatment commitment and compliance in our patients and their relatives.
Population health and cancer testing pilot protocol (PHACT).
Authors: Mallika Sachdev Dhawan, Jason Budge, Kerry Inokuchi, Niki Lovick, Julie Mak, Alicia Zhou, Will Stedden, Pagan Morris, Kelly Williams, Pamela N. Munster
Journal: Journal of Clinical Oncology (2018)

1546 Background: There is considerable uncertainty on cancer risk and recommendations for genetic testing in various populations. The purpose of this study is to test types and frequencies of cancer risk mutations in large, unaffected multiethnic populations, as well as feasibility and acceptance of general population germline testing. Methods: After consent, germline genetic testing via Color Genomics Multigene Cancer Risk panel with personal and family cancer history assessment, was offered to at least 500 participants residing in the San Francisco Bay Area. Participants were older than 21 and without a known personal history of a cancer risk mutation. Recruitment occurred at random and by various community events. Genetic counseling through a genetic counselor at UCSF was offered to all participants. Results: 457 total samples have been submitted by 535 consented participants. 28 participants in 440 finalized tests were found to have a cancer risk mutation (6.4%). The majority of these have been in moderate risk cancer mutations including CHEK2 (1.4%), APC (0.9%), MUTYH (1.6%) and NBN (0.4%); higher risk mutations were found in BRCA1 (0.4%), BRCA2 (0.4%), BRIP1 (0.2%), PMS2 (0.2%) and PALB2 (0.2%). 4 additional participants were found to have mutations (3 BRCA1, 1 ATM) but had a known family history of a cancer risk mutation. Ancestry data via self-reporting and SNP testing via the Color Genomics platform was collected to contextualize these results. Rates of VUS (variants of uncertain significance) differed among the various ethnic groups (p = 0.029) with the lowest rates in Europeans (18% vs. 31% p = 0.002). Conclusions: The PHACT study demonstrates that large population screening of cancer risk mutations is feasible. The number of participants found to have mutations was greater than expected although the majority of these were in moderate risk genes. We found high rates of VUS in non-Europeans, which supports the need to broaden genetic testing in minority populations to better understand the significance of these variants. This is to our knowledge the largest study of cancer risk mutations in an unaffected multiethnic population and serves as a pilot to a much larger 10,000-person study of the prevalence of cancer risk mutations across California.
Effect of infusion duration on high-dose methotrexate (HDMTX) acute kidney injury (AKI).
Authors: Elizabeth Fox, Christine Busch, Alexander DeBernardo, Kristin Levin, Yan Zhu, Rochelle Bagatell, Naomi Jill Balamuth, Richard B. Womer, Frank M. Balis
Journal: Journal of Clinical Oncology (2017)

e22013 Background: HDMTX AKI delays MTX excretion and increases the risk for severe systemic toxicity. MTX is thought to crystalize in renal tubules at urine [MTX] above the solubility limit, leading to AKI. Methods: Pharmacokinetic simulations of plasma and urine [MTX] at varying infusion durations (IDs) for 12 g/m 2 MTX dose identified 12 h as the shortest duration with urine [MTX] below the solubility limit at pH 7.5. Using a randomized crossover design, we compared 4h and 12h IDs in patients with osteosarcoma treated with 12 g/m 2 MTX. Urine AKI biomarkers (NAG, NGAL, KIM-1), urinalysis, and estimated glomerular filtration rate (GFR) were endpoints. [MTX] was measured in plasma using a commercial fluorescence polarization assay and in urine by HPLC. Results: Twelve patients, age 12.8 (5.6-19) y, received 12 g/m 2 HDMTX over 4 h (40 infusions) and 12 h (35 infusions). At baseline (BL), GFR was 120 (100-175) mL/min/1.73m 2 ; Median (range) NAG [21(5-64) U/gCr] and NGAL [11(0.7-325) µg/gCr] were normal and KIM-1 [0.9(0.4-6.3) µg/gCr] was elevated. Urine pH was maintained &gt; 7 for all infusions. Proteinuria occurred during 93% of infusions. Table 1 compares 4h and 12h IDs. One patient had HDMTX AKI during a 12 h ID (data excluded from Table); end of infusion (EOI) [MTX] was 930 µM in plasma and 38 mM in urine. By 24h after the start of the HDMTX infusion, serum creatinine (sCr) was 1.4 mg/dL (3.5x BL), cystatin C was 1.0 (1.4x BL); NAG, NGAL and Kim-1 increased by &gt; 350%. At 40h, plasma [MTX] was 40 µM; glucarpidase was administered. Plasma [MTX] &lt; 0.1 µM was achieved at 310 h. Recovery to BL occurred at 20 d for sCr and 40 d for cystatin C. Conclusions: Transient proteinuria, increase in KIM-1 and NAG indicate acute proximal renal tubular damage in all HDMTX infusions regardless of ID. EOI urine [MTX] after 4 h or 12 h IDs did not exceed the solubility limit, including the patient with clinical HDMTX AKI. These results suggest that MTX crystallization in urine may not be the primary mechanism of HDMTX AKI. Clinical trial information: NCT01848457. [Table: see text]
Phase I study of pexidartinib (PLX3397) in children with refractory leukemias and solid tumors including neurofibromatosis type I (NF1) related plexiform neurofibromas (PN).
Authors: Lauren Hittson, John Glod, Melissa Amaya, Joanne Derdak, Brigitte C. Widemann, Rosandra N. Kaplan
Journal: Journal of Clinical Oncology (2017)

10546 Background: Refractory tumors remain a significant treatment challenge, and novel approaches targeting the tumor microenvironment may hold promise. Pexidartinib, an oral inhibitor of tyrosine kinases including CSF1R, KIT and FLT3, has activity in adults with tenosynovial giant cell tumor. Methods: We are conducting a phase 1 trial (NCT02390752) to determine the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK) of pexidartinib in patients (pts) 3-21 years old with refractory leukemias and solid tumors including NF1 PN. The MTD is based on cycle (C) 1 toxicities. Pexidartinib is given once daily continuously (1C = 28 days) at DL 1: 400 mg/m2/dose, 2: 600mg/m2/dose, or 3: 800 mg/ m 2 /dose. Response is assessed after C1 and then every other C, and for NF1 PN with volumetric MRI analysis after every 4 C. Results: Fourteen pts (8 M:6 F, median age 16 years, (range 4-21) with CNS tumors (n = 2), sarcomas (n = 7), peritoneal mesothelioma (n = 1), leukemia (n = 1), NF1 PN (n = 3) have enrolled at DL1 (n = 4), DL2 (n = 4) and DL3 (n = 6). No dose-limiting toxicities have been observed and 11 pts are evaluable for MTD determination (received ≥ 85% of pexidartinib doses in C1). Common non-DLT toxicities are fatigue, decrease in WBC, increase in creatinine kinase and serum amylase, headache, anorexia, vomiting, diarrhea, and hair hypopigmentation. Mean (SD) pexidartinib C1 day 1 PK parameters at [DL1 (n = 4), DL2 (n = 4), and DL3 (n = 4)] were: C max DL1 2,813 ng/mL (1,483), DL2 6,065 ng/mL (1,308), DL3 10,323 ng/mL (2,129); AUC 0-24h DL1 44,492 ng·h/mL (12,904), DL2 76,569 ng·h/mL (25,790), DL3 132,903ng·h/mL (40,482). The mean (SD) accumulation ratio (C1 D15 AUC 0-24h : C1 D1 AUC 0-24h ) was 3.9 (0.7) for DL1, 2.4 (0.3) for DL2, and 1.4 (0.6) for DL3. Pts received a median of 1 C (range (1-21+). Pts with NF1 PN received 1, 4, and 6 C of pexidartinib and had stable disease. One pt with peritoneal mesothelioma is receiving C 21. Conclusions: In children, pexidartinib was tolerated at all dose levels, and the recommended phase II dose (RP2D) is 800 mg/m 2 /dose once daily. This dose exceeds the adult RP2D of 1000 mg/day. Enrollment on the expansion cohort is ongoing. Clinical trial information: NCT02390752.
Alteration of immune markers in the tumor microenvironment after chemoradiation for rectal cancer.
Authors: Prashant Mukesh Jani, Paul Renz, Candice Brem, Shaakir Hasan, Ariel Sandhu, Paul Joseph, Ali Hussainy Zaidi, James McCormick, Alexander V. Kirichenko, Stacey Miller, Moses S. Raj, Jan F Silverman, Gene Grant Finley
Journal: Journal of Clinical Oncology (2018)

e24146 Background: Immunotherapy (IO) is a new treatment option for advanced microsatellite unstable colorectal cancer. Radiotherapy is an integral part of neoadjuvant treatment for locally advanced rectal adenocarcinoma and has been shown to increase tumor PD-L1 expression and tumor infiltrating lymphocytes (TIL). These changes in the tumor microenvironment enhance the response to IO. We report herein on expression of PD-L1 and CD-8 + TIL pre and post neoadjuvant chemoradiotherapy (CRT) in rectal adenocarcinoma. Expression of TIM-3, LAG-3, IDO1, OX40, IFN-ɤ, IL-17 and CXCL9 will also be reported. Methods: We retrospectively evaluated 39 patients with rectal adenocarcinoma from 2007-2016 treated with neoadjuvant CRT using 5FU based therapy. Pre and post CRT tissue samples were stained with VENTANA PD-L1 (SP263) rabbit monoclonal antibody to quantify PD-L1 expression. CD8 + TIL were recorded over one high power field (40x objective) in the area of densest infiltrate. Additional biomarkers are being assayed with RT-PCR. Relevant clinical endpoints of local relapse, distant metastasis, and survival were also collected. Results: Median age was 60 years (range 32-87). Median follow up was 16.7 months (range 2.6 -120.1). Median duration from completion of CRT to resection was 73 days (range 44 - 315). Among the pre-CRT cases 7.7% expressed PD-L1 versus 20.5% post-CRT (OR 3.1, p = 0.11). Median number of CD8+ TIL in the pre-CRT biopsies was 49. In post-CRT specimens, 82.1% cases had TIL > 50 (p = 0.002). PD-L1 expression did not correlate with pathological complete response, local or distant failure. Radiation dose/fractionation, time from CRT completion to resection, and CD8+ TIL did not correlate with increase in PD-L1 expression. Conclusions: Neoadjuvant CRT for rectal adenocarcinoma increased PD-L1 expression and CD8+ TIL which are known biomarkers for IO response. These data suggest a novel role for IO in neoadjuvant treatment of rectal cancer.