tbuckley/cabot-search huggingface dataset:
Changes in p16INK4a (p16) expression, a biomarker of aging, in peripheral blood T-cells (PBTC) in patients receiving anthracycline (A) vs non-anthracycline (NoA) chemotherapy (CRx) for early-stage breast cancer (EBC).
Authors: Shlomit Strulov Shachar, Allison Mary Deal, Natalia Mitin, Kirsten A Nyrop, Jordan T Lee, Seul Ki Choi, Will Pulley, Emily Fox Bell, Nora Christopher, Grant Richard Williams, Lisa A. Carey, Carey K. Anders, Trevor Augustus Jolly, Elizabeth Claire Dees, Katherine Elizabeth Reeder-Hayes, Hanna Kelly Sanoff, Norman E. Sharpless, Hyman B. Muss
Journal: Journal of Clinical Oncology (2017)

10060 Background: Age-related accumulation of senescent cells plays a causal role in some aspects of mammalian aging. We have shown that the total-body burden of senescent cells can be estimated by measuring the expression of the p16 tumor suppressor, a canonical effector of senescence, in human CD3+ PBTC (Liu et al, Aging Cell, 2009). Expression of p16 increases more than 10-fold over an adult human lifespan, and this rate of accumulation is accelerated by age-promoting exposures such as CRx or stem cell transplant (Sanoff et al, JNCI 2014; Wood et al, EbioMed 2016). Increased molecular age as evidenced by increased expression of p16 prior to CRx predicts a patient’s risk of CRx toxicity independently of chronological age (DeMaria et al, Cancer Discovery, 2017).This study investigates the impact of different types of CRx (A vs NoA) regimens on PBTC p16expression in pts with EBC. Methods: EBC pts who received neoAdj or Adj CRx had blood samples drawn for p16 assay prior to CRx initiation and again between 2 months and 1.5 years after the end of CRx. Expression of p16 mRNA in PBTC was determined using TaqMan real-time quantitative reverse transcription PCR. T-test compared p16change between A and NA groups. Results: 70 pts were evaluable. Pt. characteristics: median age 49 (range 32-76); 52 (74%) White, 14 (20%) black, 4 unknown; 39 (56%) ER or PR+ and HER2 neg, 18 (26%) triple negative, 13 (19%) HER-2 pos (all received trastuzumab). 53 pts (76%) had A (47 AC + taxane, 6 AC no taxane) and 17 (24%) NoA (all TC). Expression of p16 increased 2.0-fold in patients who received A-based CRx compared to 1.2-fold in NoA CRx (p = 0.04). There was no relationship of race, ER, PR or HER-2 status on change in p16expression. Conclusions: This study is ongoing and further results will be presented at the ASCO meeting. In this sample of EBC patients treated with A vs. NoA CRx regimens, A-based CRx is more strongly associated with increased biologic aging of T-cells compared to NoA CRx. These changes are equivalent of increased biologic aging of PBTC of 11 years (A) vs.6 years (NoA) and may have major consequences on the long-term survival of these pts.
Abstract 18348: ATF6 and the Adaptive ER Stress Response Promotes Proliferation and Viability of Mouse Cardiac Progenitor Cells
Authors: Winston T Stauffer, Shirin Doroudgar, Haley N Stephens, Brandi Bailey, Christopher C Glembotski
Journal: Circulation (2015)

C-kit+ cardiac stem cells, herein called cardiac progenitor cells (CPCs), are beneficial when administered to infarcted mouse hearts. Though the mechanism of these benefits is unknown, CPC vitality likely plays a major role. Thus, investigating the factors governing CPC survival in the ischemic heart may lead to more effective therapeutic strategies. Our previous studies showed that misfolded proteins accumulate in the sarco/endoplasmic reticulum (SR/ER) of the ischemic heart, and that SR/ER protein quality control, which includes the adaptive ER stress response, is critical for the synthesis of most secreted proteins, receptors, and contractile calcium-handling proteins. The transcription factor, ATF6, is a key component of the adaptive ER stress response because it induces genes that reduce the accumulation of misfolded proteins, improving myocyte survival during ischemic stress. While our lab has shown that, in cardiac myocytes, ATF6 is cardioprotective in the ischemic heart, neither the ER stress response nor ATF6 have been examined in CPCs. Accordingly, the hypothesis of this study is that ATF6 and the adaptive ER stress response are critical for optimal survival of CPCs. To address this hypothesis we compared the viabilities of mouse CPCs to neonatal rat ventricular myocytes (NRVM) subjected to treatments that mimic ischemic ER stress in the heart. We found that, compared to NRVM, CPCs exhibited lower levels of adaptive ER stress response gene expression and increased cell death in response to ER stress. Thus, relative to NRVM, the adaptive ER stress response is not fully developed in CPCs. We also found that either siRNA-mediated knock down of ATF6 or chemical inhibition of ATF6 activation with AEBSF decreased adaptive ER stress response gene expression; therefore, ATF6 is an essential component of the adaptive ER stress response in CPCs. Strikingly, ATF6 knockdown decreased CPC viability and proliferation by as much as 70%. Thus, compared to cardiac myocytes, CPCs exhibit a reduced adaptive ER stress response and are more sensitive to ER stress, suggesting that enhancement of the ATF6-mediated adaptive ER stress response in CPCs may be a viable therapeutic approach for enhancing stem cell-mediated myocardial repair.
A 20-year comparison of definitive chemoradiation with 5-FU versus capecitabine in anal cancer patients treated at a single institution.
Authors: Yoanna S Pumpalova, Margaret M. Kozak, Rie von Eyben, Pamela L. Kunz, George A. Fisher, Daniel Tandel Chang, Sigurdis Haraldsdottir
Journal: Journal of Clinical Oncology (2018)

e15573 Background: Capecitabine is an established treatment alternative to intravenous 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. The objective of this retrospective study was to compare outcomes and toxicities in non-metastatic anal cancer patients undergoing definitive radiotherapy (RT) at Stanford combined with capecitabine/mitomycin (CM) versus 5-FU/mitomycin (FM). Methods: We included all non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997 – 2016. Patients who received cisplatin or induction chemotherapy were excluded. Patient charts were reviewed and cause of death determined from the cancer registry. Fisher’s exact test was used to compare nominal parameters, Mann-Whitney U test for continuous variables. Gray’s test for equality was used to compare recurrence and colostomy incidence, and Log-rank test to compare disease-specific and overall survival. Results: Sixty-eight patients were treated at Stanford. Twenty-nine received FM and RT, 12 received standard 5-FU and 17 received low-dose continuous 5-FU; 39 patients received CM and RT. Median age was 59.5 years, and 56% were female. There was no difference in the 3-year overall and disease-specific survival between the FM and CM groups (81.5% v 90.5% p = 0.262; 88.1% v 96.0% p = 0.229). Incidence of recurrence was equivalent between the two groups (13.8% v 10.6%, p = 0.927) but patients in the combined FM group recurred earlier (6.9 v 20 months, p = 0.004) and distant recurrences were only seen in the CM group. Colostomy rates were higher in the FM group (14.6% v 2.8%, p = 0.082); all colostomies in the FM group were in patients receiving continuous 5-FU. Toxicities were similar between the two groups. The most common grade 2 or higher toxicities were dermatitis (77%), anal pain (77%), diarrhea (54%), stomatitis (19%), and nausea (22%). Conclusions: Overall and disease-specific survival and recurrence rates were equivalent between FM and CM groups. Recurrence patterns differed with loco-regional recurrences and higher colostomy rates in the FM group, while most recurrences in the CM group were distant.
Hedgehog pathway inhibition by topical patidegib to reduce BCC burden in patients with basal cell nevus (Gorlin) syndrome.
Authors: Ervin H Epstein, John Lear, Gillian Saldanha, Jean Y. Tang, Catherine Harwood
Journal: Journal of Clinical Oncology (2018)

e21626 Background: Oral hedgehog (HH) inhibitors can produce complete clinical and histologic remission of non-advanced basal cell carcinomas (BCCs) in patients with Gorlin syndrome. However, class-specific hair loss, taste loss, and muscle cramps cause most patients to discontinue treatment, following which BCCs recur. PellePharm's goal is to develop a topical HH inhibitor with sufficient percutaneous absorption to have anti-HH/BCC-preventive activity, but without enough absorption to produce the characteristic systemic AEs. This would be a first in class topical drug to manage the chronic burden of continuously developing BCC tumors in Gorlin patients. We report here the first Phase 2 double-blind, vehicle controlled randomized trial of topical patidegib, a small molecule HH inhibitor derived from plant-produced cyclopamine. Methods: In this Phase 2 clinical trial, patients with Gorlin syndrome applied vehicle (n = 5), 2% patidegib (n = 6), or 4% patidegib (n = 6) gel twice daily for six months to their entire face, including 4 evaluable target surgically-eligible BCCs (SEBs). The primary endpoint was change in BCC diameter; secondary endpoints were prevention of new tumors, percent of existing target tumors with complete clinical response (CR), and safety/dermal irritation. Results: In a modified ITT analysis, 2% gel shrank SEBs compared with vehicle (P = 0.04); 2% and 4% gels caused tumor CR in 25% of existing SEBs (P = 0.02). No vehicle-treated SEB disappeared. 3 of 5 (60%) patients applying vehicle gel developed a new facial SEB; 2 of 12 (16%) patients applying 2% or 4% gel developed a new facial SEB (p = 0.02 for prevention). Shrinkage of SEBs only occurred in those in whom HH pathway activity was reduced after 6 weeks of topical application. Importantly, unlike oral HH inhibitors, topical patidegib caused no hair loss, taste loss, or muscle cramps and produced circulating blood levels three orders of magnitude lower than those with oral patidegib. Conclusions: Topical patidegib gel has the potential to prevent and mitigate facial BCCs in Gorlin patients. These results will be confirmed in a Phase 3 trial enrolling approximately 150 patients in the United States and Europe. Clinical trial information: NCT02762084.
Comparison of annotation services for the VA Precision Oncology Program.
Authors: Evangelia (Eva) Katsoulakis, Jill Duffy, Bradley J Hintze, Neil L Spector, Michael J. Kelley
Journal: Journal of Clinical Oncology (2018)

12109 Background: Multigene NGS testing has become widespread, including through the VA healthcare system through the VA Precision Oncology Program (POP). Algorithms to interpret the pathogenicity of NGS-detected sequence variants and clinical actionability have been implemented as clinical services, but little is known about their relative performance in clinical practice. Methods: NGS testing results from patients who had NGS results from VA POP were included. NGS results were generated at Personal Genome Diagnostics and Personalis and annotated by a commercial annotation service (N-of-One) as well as through Watson for Genomics (WfG) and OncoKB. Comparison of annotation results consisted of two parts: determination of pathogenicity and treatment actionability recommendations. Cohen’s kappa statistic was calculated for agreement between annotation services. Results: Among 1228 NGS results, 1388 unique variants were observed in 117 genes (TP53 270, STK11 92, CDKN2A 81, ATM 67, PTEN 52). Cancer type was lung adenocarcinoma in 440 samples, colon adeno 113, lung squamous 111, unknown primary 88, prostate 62, melanoma 57, H&N 41, NSCLC 40. For pathogenic and likely pathogenic variants, there was 87% agreement between WfG and N-of-One (kappa 0.729), 76% agreement between WfG and OncoKB (kappa 0.227) and 42% agreement between N-of-One and OncoKB (kappa -0.078). For level 1 drug actionability recommendations (not available from N-of-One) there was 91% agreement between WfG and OncoKB (kappa 0.19) with 54 variants identified only by WfG as level 1 and 74 variants identified only by OncoKB as level 1. Conclusions: There is substantial variability in assessment of pathogenicity of NGS variants in solid tumors by clinically available annotation services. In addition, there was only slight agreement in level 1 therapeutic actionability recommendations. Improvement of the precision of oncology NGS annotation is needed.
The prevalence of Merkel cell polyomavirus in Russian patients with Merkel cell carcinoma.
Authors: Kristina V. Orlova, Valery V. Nazarova, Vera V. Delektorskaya, Y. Vishnevskaya, Ekaterina A. Lesovaya, Irina V. Tsyganova, Kirill I. Kirsanov, Marianna G. Yakubovskaya, Lev V. Demidov
Journal: Journal of Clinical Oncology (2018)

e21605 Background: Merkel cell carcinoma (MCC) is a rare, but highly aggressive skin cancer with the clonal integration of Merkel cell polyomavirus (MCPyV). The aim of this study was to assess the prevalence of MCPyV in MCC by polymerase chain reaction (PCR) and immunohistochemistry (IHC) in Russia and to analyze the correlation between both methods. Methods: We analyzed formalin-fixed, paraffin-embedded (FFPE) tissue samples (n = 47) from 47 patients with MCC. All initial diagnoses were defined according to morphologic criteria established by the World Health Organization and were approved by 2 other pathologists.We used MCPyV Large T-antigen antibody (CM2B4) for IHC (47 cases), 3 primer sets for which the sequences were previously published (LT1, LT3, and VP1) (25 cases) and DNA extracted from the MKL-2 cell line as a positive control. The CM2B4 positivity was based on the nuclear staining and scored on the amount of positive tumor cells as negative ( < 10%), 1+ (10%-50%), 2+ (50%-75%), and 3+ ( > 75%). Results: In total, 19 of 25 (76%) MCC cases were positive for MCPyV by PCR and 32 of 47 (68%) MCC cases were strongly positive for MCPyV by IHC, which was consistent with published data. When comparing the results of 25 cases of IHC and PCR, IHC staining for MCPyV produced a negative result in two samples (15 and 23), while PCR analysis showed the presence of viral DNA in the tissue (Table 1). Conclusions: MCPyV was highly positive in Russian patients with MCC, but it is of note that the positive rate differs depending upon the detection method. For pathologists, CM2B4 IHC offers a convenient method for identifying MCPyV. One of the limitations of our study is the orphan disease status of MCC: it comprises of a limited number of patients. This is the largest cohort of MCC patients studied in Russia and we need to accumulate evidence in orphan disease. Table 1. Comparison of MCPyV detection by PCR with ICH from FFPE tissue samples. Case № IHC results PCR results VP1 LT1 LT3 1 3+ - - - 2 0 - - - 3 3+ + - + 4 3+ - - + 5 0 - - - 6 2+ - - + 7 3+ - - - 8 2+ + - + 9 3+ - + - 10 2+ + - + 11 2+ + - + 12 3+ + - + 13 3+ - - + 14 3+ - - + 15 0 + + + 16 3+ + + + 17 0 - - - 18 3+ - - + 19 2+ + - + 20 2+ + - + 21 0-1+ - - + 22 0 - - - 23 0-1+ + - + 24 2+ + - + 25 3+ + - + 26 0 NA 27 0 28 3+ 29 2+ 30 3+ 31 3+ 32 2+ 33 0 34 0 35 3+ 36 2+ 37 0 38 2+ 39 3+ 40 3+ 41 0 42 2+ 43 0-1+ 44 0 45 2+ 46 3+ 47 2+
Universal health insurance does not protect from financial burden: A survey of Israeli cancer patients.
Authors: Barliz Waissengrin, Ofer Merimsky, Waller Emmanuel, Michal Bar-Yosef, Dan Mirelman, Sharon Pelles, Ido Wolf
Journal: Journal of Clinical Oncology (2018)

e18898 Background: In Israel, the vast majority of cancer therapies are covered by a universal health insurance. We hypothesized that cancer poses a significant financial burden even in the presence of a comprehensive insurance. Methods: A survey was conducted among 233 actively treated cancer patients regarding their income, direct (i.e. medications, medical tests) and indirect expenses (i.e. transportation) and perception of financial burden. Income was stratified into three groups, low, average and high, as defined by the Israeli Statistical Bureau. Results: Median age of the patients was 63, 56% were women and 65% had metastatic disease. Low income was reported by 96 patients (41%) average by 62 patients (26%) and high by 75 patients (33%). As expected, less patients in the low income group had higher educations and more were religious and of non-Ashkenazi origin (p < 0.05 for all comparisons). Supplementary private health insurance was owned by 17%, 45% and 72% of the low, average and high income groups (p = 0.001). Surprisingly, all groups reported on similar out of pockets expenses on second opinion (~60% spent over 850 us$) and out of pocket drugs (~45% spent over 5500 us$), as well as on indirect expenses. The majority of the patients reported on significant financial burden, but this was more pronounced in the low income group (low 84%, average 65% and high 69%, p- 0.004). Despite similar expenses and similar utilization of private services, most patients in the low and average groups perceived their treatment as compromised compared to the high income group. Conclusions: Despite having comprehensive health insurance, most patients reported on out of pocket expenses on a wide array of non-evidence based services, and similar utilization was reported regardless of income. This has led to financial burden among most patients. These findings pose financial and ethical issues that should be considered by the oncologist as well as the ministry of health.
A phase I-II clinical trial to evaluate the safety, pharmacokinetics, and efficacy of high-dose intravenous ascorbic acid synergy with mEHT in Chinese patients with stage III-IV non-small cell lung cancer.
Authors: Junwen Ou, Xinyu Zhu, Yimin Lu, Changlin Zhao, Hongyu Zhang, Xinting Zhang, Tao Zhang, Clifford L.K. Pang
Journal: Journal of Clinical Oncology (2017)

e20078 Background: Ascorbic acid (AA) infusion and modulated electrohyperthermia (mEHT) are widely used by integrative cancer practitioners for many years. However, there are no safety and pharmacokinetics data in Chinese cancer patients. Methods: Blood ascorbic acid in the fasting state was obtained from 35 NSCLC patients; selecting from them 15 patients with stage III-IV entered the phase I-II study. They were randomized allocated into 3 groups. Pharmacokinetic profiles were obtained when they received solely IVAA at concentrations of 1g/kg, 1.2g/kg, and 1.5g/kg, and when IVAA in combination with mEHT. The process was applied 3 times a week for 4 weeks. Participants in the first group received IVAA when mEHT was finished, in the second group IVAA was administered simultaneously with mEHT and in the third group IVAA was applied first, and followed with mEHT. All patients started the trial doses of 1 g/kg for 8 treatments. When there was no DLT observed, the test dose for patients increased to 1.2 g/kg and 1.5 g/kg. DLT was defined as any reversible grade ≥3 adverse events, whether haematological or non-haematological. Results: Fasting plasma AA levels were significantly correlated with stage of the disease. Peak concentration of AA were significantly higher in the simultaneous treatments than in other combinations with mEHT or in solely IVAAmanaged groups. The average scores for the functioning scales continuously increased and the symptoms gradually decrease over the full cycle of the study.3/7 patients with squamous cell lung cancer were CR, 4/7 were PR. 1/8 patient with adenocarcinoma cell lung cancer was PR, 5/8 were SD, and 2/8 were died. Conclusions: IVAA synergies with simultaneous mEHT is safe and the concomitant application significantly increases the plasma AA level for NSCLC patients. QOL is improved when they receive the above treatments. Patients diagnosed with squamous cell lung cancer were sensitive to the above two treatments. Clinical trial information: NCT02655913.
Differential expression of tumorspheres in CSC-markers and signaling pathways from non-small cell lung cancer.
Authors: Alejandro Herreros-Pomares, Ester Munera-Maravilla, Eloisa Jantus-Lewintre, Silvia Calabuig-Fariñas, Ana Blasco, Aminta Isabel Martinez, Atilio Navarro, Ricardo Guijarro, Miguel Martorell, Carlos Camps
Journal: Journal of Clinical Oncology (2016)

e23276 Background: Chemoresistance, tumor progression and metastasis have made of lung cancer the first cause of death cancer-related worldwide. Cancer stem cells (CSCs) are small subpopulations of stem-like cells with self-renewal, differentiation and tumorigenic properties that, in spite of remaining largely unknown, constitute a promising target. The aim of this study was to isolate and analyze gene expression of CSCs from lung cancer cell-lines and tumor-tissue from resectable NSCLC patients. Methods: This study was performed on cells from NSCLC tumor samples and cell lines (H1650, H1993, A549 and PC9) grown in monolayer and as spheroids. The expression of: CSC-markers (CD133, EPCAM1, ALDH1A1, CD166, ABCG2, CD44, MUC1, BMI1); pluripotency (KLF4, OCT4, NANOG, SOX2, MYC, CCND1); cell cycle (CDKN1A, CDKN2A, MDM2, WEE1); invasiveness (CDH1, VIM, SNAI1, MMP2, MMP9, CEACAM5); Notch pathway (NOTCH1, NOTCH2, NOTCH3, DLL1, DLL4, HEY1, HES1); Wnt pathway (WNT1, WNT2, WNT3, WNT5A, CTNBB1, DKK1, FZD7) and Hedgehog pathway (SMO, PTCH1, SHH, GLI1) were analyzed by RTqPCR. ACTB, CDKN1B and GUSB were used as endogenous controls for relative expression calculation. Results: Lung tumorspheres had increased expression of EPCAM1, CD44, ALDH1A1 andCDKN1A (p = 0.028, p = 0.021, p = 0.043 and p = 0.021, respectively) when compared to their paired-adherent cells. In addition, epithelial to mesenquimal transition (EMT) inducer SNAI1 was overexpressed (p = 0.011) in tumorspheres. Regarding Notch pathway, DLL4, NOTCH1 and NOTCH2 showed higher expression in spheroids (p = 0.028, p = 0.038 and p = 0.036, respectively). In Wnt pathway, we found higher expression levels of WNT3, CTNBB1 and GSK3B (p = 0.021, p = 0.008 and p = 0.021, respectively) in lungspheres whereas WNT5A, activator of the non-canonical Wnt pathway, tended to be less expressed in spheroids compared to adherent-cultured cells. Conclusions: Lung spheroids from cancer cell lines and primary tumors showed increased levels of CSC-markers. Genes related to Notch and Wnt were found to be more expressed in tumorspheres, suggesting that these pathways as interesting lung-CSC targets. Supported by grants RD12/0036/0025 from RTICC, and PI12-02838/PI15-0753 from ISCIII.