tbuckley/cabot-search huggingface dataset:
Radiation-induced increases in PARP1 activity to predict for long-term radiosensitization by PARP1 inhibition in preclinical breast cancer models.
Authors: Felix Yi-Chung Feng, Meilan Liu, Kari Wilder-Romans, Corey Speers, Reshma Jagsi, Lori J. Pierce
Journal: Journal of Clinical Oncology (2013)

1025 Background: Sustained locoregional (LR) control of breast cancer (BCa) is a significant issue for patients with inflammatory disease or chest wall recurrences. Inhibition of poly(adenosine diphosphate-ribose) (PAR) polymerase 1 (PARP1), a DNA damage response protein, is a promising strategy for radiosensitization (RS). We investigated RS by PARP1 inhibition and aimed to identify early biomarkers (BMs) predictive of long-term treatment efficacy in preclinical BCa models. Methods: Clonogenic survival assays in 12 BCa and normal epithelial cell lines were used to determine the degree of RS conferred by the PARP1 inhibitor ABT-888 and to optimize the sequencing of therapy. Immunoblots, immunofluorescent staining, flow cytometery, and xenograft studies were used to evaluate for pre-/intra-treatment BMs predicting for subsequent response to therapy. Results: ABT-888 preferentially radiosensitized BCa (vs. normal) cells (enhancement ratios (EnhR) up to 2.3 across different subtypes). The highest EnhRs resulted from concurrent and adjuvant ABT-888. The degree of RS did not correlate with pretreatment markers of PARP1 activity (e.g., PAR levels), DNA damage/repair (e.g. gamma-H2AX &amp; RAD51 foci), or cell cycle distribution. However, increases in PARP1 activity from pretreatment to 24 hours after RT, was associated with long-term clonogenic death after treatment with ABT-888 + radiation (RT) (Spearman's coefficient=0.8, p=0.002). The four cell lines significantly radiosensitized by PARP1 inhibition (EnhR&gt;1.5) averaged a 2-fold increase in PAR levels following RT. Findings were also confirmed in SKBR3 and MDA-231 BCa xenograft models. Conclusions: Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT in BCa cell lines. Treatment-induced increase in PARP1 activity 24 hours after RT predicts for long-term radiosensitization by PARP1 inhibition and is a potential biomarker of response. These studies have led to a clinical trial, incorporating intratreatment BM analyses, of PARP inhibitors and RT in BCa patients currently open for accrual through the Translational Breast Cancer Research Consortium.
Final results of a phase II study of neoadjuvant metformin in prostatic carcinoma.
Authors: Anthony Michael Joshua, Vanessa E. Zannella, Michelle R Downes, Barbara Bowes, Marianne Koritzinsky, Joan Sweet, John Trachtenberg, Michael A. S. Jewett, Antonio Finelli, Neil Eric Fleshner, Michael N. Pollak
Journal: Journal of Clinical Oncology (2013)

5070 Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who were found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that began treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 21 patients evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported during treatment or radical prostatectomy that were related to metformin. Significant pre-and post changes were noted in serum IGF1 (p=0.02), fasting glucose (p=0.03), BMI (p&lt;0.01) and waist/hip ratio (p&lt;0.01). There was a trend for a PSA reduction (p=0.08). There were no correlations between any metabolic, morphometric or cancer-related serum indices. On a per patient analyses, metformin reduced a computerised relative ki67 proliferation index by an average of 29% (absolute difference of 1.4%) compared to the baseline biopsy (p=0.006). P-4eBP1 staining was also reduced as assessed by H-score (p&lt;0.01) consistent with the ability of metformin to inhibit mTOR. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy and shows promising effects on proliferation and signaling indices. Further research is needed to define the clinical utility of metformin in prostate cancer. Clinical trial information: NCT00881725.
XPG D1104 single-nucleotide polymorphisms and the prognosis of melanoma
Authors: J. C. Becker, M. Schneider, D. Scherer, S. Ugurel, M. Zapatka, D. Schadendorf, R. Kumar, D. Schrama
Journal: Journal of Clinical Oncology (2009)

11096 Background: Sunlight is a major risk factor for melanoma. Since UV radiation causes DNA damage, it is not surprisingly, that genetic variants in DNA repair enzymes contribute to the susceptibility to cutaneous melanoma. Methods: Presence of common non-synonymous single-nucleotide polymorphism in different DNA repair enzymes were established and correlated with overall survival of melanoma patients. To this end, the SNPs of 6 different DNA repair enzymes were evaluated in a cohort of 742 melanoma patients. The impact of these polymorphisms on overall survival was subsequently calculated by the cox hazard model. Results: This analysis demonstrated that after adjustment to gender and primary tumor T classification XPG 1104 His/His as well as XPD 751 Lys/Lys genotypes were significantly associated with improved survival. Cox hazard coefficients were 0.744 for XPG 1104 His/His (p = 0.0059) and 0.651 for XPD 751 Lys/Lys (p = 0.017). Importantly, bootstrapping confirmed theses results for subpopulations. Furthermore, multivariate analysis demonstrated that XPG 1104 His/His is an independent factor affecting overall survival (cox coefficient 0.95788; p = 0.0011). Conclusions: XPG codon 1104 polymorphism may be predictive of survival outcome in patients with cutaneous melanoma. No significant financial relationships to disclose.
The MEK Inhibitor in Low-Grade Serous Ovarian Cancer (MILO)/ENGOT-ov11 study: A multinational, randomized, open-label phase 3 study of binimetinib (MEK162) versus physician’s choice chemotherapy in patients with recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum.
Authors: Bradley J. Monk, Rachel N. Grisham, Christian Marth, Susana N. Banerjee, Felix Hilpert, Robert L. Coleman, Eric Pujade-Lauraine, Sandro Pignata, Mansoor Raza Mirza, Amit M. Oza, Josep M. del Campo, Martin Klaus Oehler, Adam James, Janna Christy-Bittel, Emma Barrett, Adam P. Boyd, Ignace Vergote
Journal: Journal of Clinical Oncology (2014)

TPS5618 Background: Low-grade serous (LGS) carcinomas of the ovary, fallopian tube and primary peritoneum are rare and unique tumors for which current therapies (chemotherapy, hormonal) have demonstrated limited efficacy. As LGS carcinoma is characterized by mutations in genes of the RAS/RAF/MEK/ERK signaling pathway, such as BRAF and KRAS, evaluating therapies that target this pathway is warranted. This study will evaluate the efficacy of the MEK1/2 inhibitor binimetinib (MEK162) vs physician's choice chemotherapy in patients with LGS carcinoma. This study will enroll patients regardless of RAS/RAF mutational status; however, tumor tissue will be retrospectively analyzed for mutations in RAS/RAF and other genes (NCT01849874). Methods: This is a 2-arm, open-label, 2:1 randomized Phase 3 study of binimetinib vs physician's choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel or topotecan). Eligible patients must have LGS carcinoma that is recurrent or persistent following at least 1 prior platinum-based chemotherapy and no more than 3 prior lines of chemotherapy, and must have RECIST v1.1-defined measurable disease confirmed by independent central review. Prior to randomization, independent central review of a patient's tumor specimen is required to confirm LGS diagnosis. Prior treatment with a MEK or BRAF inhibitor is prohibited. Randomization is stratified by last platinum-free interval and number of prior systemic therapy regimens. The primary endpoint is progression-free survival as determined by blinded independent central review; secondary endpoints include overall survival, overall response, duration of response, disease control rate, safety, quality of life and pharmacokinetics of binimetinib. Binimetinib is administered 45 mg BID orally. Patients receive therapy until disease progression or unacceptable toxicity. This study will enroll 300 patients worldwide. Clinical trial information: NCT01849874.
A pilot study of interferon-alpha-2b dose reduction in melanoma: High dose interferon is not necessary for optimal activation of immune signal transduction.
Authors: Kala M. Levine, Sara E. Martin Del Campo, Taylor Brooks, Elizabeth Streaker, Leslee Sprague, Volodymr Karpa, Joseph Markowitz, Anissa Bingman, Susan Michelle Geyer, Thomas Olencki, Kari Lynn Kendra, William Edgar Carson
Journal: Journal of Clinical Oncology (2015)

e20035 Background: High dose interferon-alpha-2b (IFNa) is the only approved adjuvant therapy after surgery for high-risk melanoma lesions. The side-effects of standard year-long, high dose IFNa therapy results in treatment delays or dose reductions in nearly 50% of patients. Our group has shown that IFNa-induced activation of the Jak-STAT pathway within host immune cells mediates the anti-tumor effects of IFNa. We also showed that Jak-STAT activation can be measured via flow cytometry for the phosphorylated form of STAT1 (pSTAT1) and that this signaling event correlates with the activation of interferon-stimulated genes (ISGs). We hypothesized that intermediate doses of IFNa would be just as effective as higher doses in activating Jak-STAT signaling and inducing the transcription of ISGs in patient (pt) immune cells. Methods: Pts eligible for adjuvant IFN-α received one month of standard iv IFNa followed by subcutaneous (sc) IFNa starting at a dose of 10 MU/m2 thrice weekly, followed by dose reductions to 8, 6 and then 4 MU/m2at two week intervals. Flow cytometry for pSTAT1 and PCR for a panel of ISGs in immune cells served as a measure of IFNa-induced activation of the immune system. Results: 34 pts participated in the study and 15 of 34 (44%) completed one year of therapy. Toxicities were consistent with those normally seen and occurred at the higher IFNa doses. Five pts (15%) had their treatment stopped as a result of IFN-related toxicity. 50% of patients had recurred at the last censored date. The estimated 5- and 10-year overall survival rates from time of surgery were 81% and 60%. The median time to recurrence after surgery was 5.1 years (n = 17 of 34). The mean fluorescence intensity of pSTAT1 at the 10 MU/m2 dose level was 5.96 (0.31-19.1), and the MFI of pSTAT1 at the 4 MU/m2dose level was 4.80 (0.11–21.17). This difference was not statistically different (p = 0.22). The induction of pSTAT1 at either dose was similar regardless of: age, gender, mitotic rate, or lymph node involvement. PCR analysis revealed similar induction of ISGs at each dose. Conclusions: Dose reduction of sc IFNa does not lead to diminished Jak-STAT signal transduction or gene regulation within pt immune cells. Clinical trial information: NCT01460875.
Survival of patients with gastrointestinal malignancies participating in phase 1 clinical trials.
Authors: Aaron Cleveland Denson, Nancy Burke, Barbara Bertels, Georgine Wapinsky, TzuHua Juan, Jae K Lee, Daniel Sullivan, Amit Mahipal
Journal: Journal of Clinical Oncology (2015)

e15205 Background: Limited data is available on the clinical outcomes of patients with gastrointestinal (GI) malignancies enrolled in phase 1 clinical trials. The aim of this study is to evaluate the clinical characteristics and survival of patients with GI cancers participating in phase 1 clinical trials. Methods: All consecutive patients with advanced GI tumors who participated in phase 1 clinical trials from 1/2007 to 12/2013 at Moffitt Cancer Center were included. Data was extracted from the OnCore database and clinical charts. Only patients who received at least one dose of the study drug were included. Cox regression model was used to estimate multivariable adjusted hazard ratios and 95% CI. Results: 243 pts with GI malignancies who participated in phase 1 clinical trials were included. Median age was 62 years (26-82 years) with 55% aged > 60 years. Disease types included pancreas (42%), colorectal (34%), gastro-esophageal (10%), hepatobiliary (13%) and others (2%). The baseline characteristics include: male (55%), DVT/PE (12%), ECOG ≥ 1 (72%), prior systemic therapies > 1 (58.8%), no. of metastatic sites > 2 (30.9%), lung metastases (40%), liver metastases (77%), prior radiation (30%), and prior surgery (53.9%). Lab values include Albumin < 3.5 (27.2%), ALT > 41 (35.4%), AST > 50 (25.2%), Bilirubin > 1.2 (9.1%), Glucose > 110 (44%), hemoglobin < 10 (16.5%), INR > 1.1 (27.1%), LDH > 618 (34.2%), neutrophil > 3.5 (47.9%), Platelet < 140 (22.6%), Sodium > 135 (83.1%), Total protein < 6.6 (23.5%), and WBC > 6 (49.4%). Treatments included chemotherapy only (14%), targeted therapy (41%), chemotherapy + targeted therapy (42%) and others (2%). The response rate was 4% with 38% achieving stable disease; 42% of pts had progressive disease. The median PFS was 2 months (0.2-30). The median OS was 5.8 months (0.2-52.4). ECOG score of 0, prior systemic therapies < 2, absence of liver metastasis, LDH < 619, Sodium > 135, and WBC < 7 were associated with better OS on multivariate analysis. Conclusions: This is the largest study to assess clinical outcomes in this patient population. ECOG score, prior number of therapy, absence of liver metastasis, LDH, Sodium, and WBC have prognostic value in this population of patients with GI malignancies.
Phase I trial of the polo-like kinase (Plk) inhibitor volasertib (BI 6727) combined with cisplatin or carboplatin in patients with advanced solid tumors.
Authors: Herlinde Dumez, Andrea Gombos, Patrick Schöffski, Thierry Gil, Christof Vulsteke, Marie-Anne Meeus, Jessica Cescutti, Gerd Michael Munzert, Korinna Pilz, Ahmad Awada
Journal: Journal of Clinical Oncology (2012)

3018^ Background: Volasertib (V) is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Plk. This phase I study evaluates dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety and pharmacokinetics (PK) of V combined with cisplatin (Cis) or carboplatin (Ca). Methods: Sequential cohorts of patients (pts) received a single 2h infusion of V with Cis (arm A) or Ca (arm B) every 3 wks. Cis and Ca were given for up to 6 cycles (Cy); V was continued until progression or intolerance. MTD was the highest dose at which ≤1/6 pts experienced a DLT in Cy 1. MTD cohorts were expanded to 12 DLT-evaluable pts to further characterize safety. Results: As of January 11 2012, 61 pts (arm A: 30; arm B: 31) were treated. Pt characteristics were (arm A/B): median age 55/58 yrs, male 16/18 pts, ECOG PS 0: 13/14 pts, PS 1: 17/17 pts. Tumors included (pts): non-small cell lung cancer (15); sarcoma (8); colorectal cancer (6); melanoma (4); urothelial cancer (4); other (24). Pts received V + Cis for a median [range] of 3.5 Cy [1-6], V + Ca for 2 Cy [1-6] and V for 3.5 Cy [1-20] in arm A and 2 Cy [1-14] in B. PK analyses are ongoing. MTD was reached at V 300 mg + Cis 100 mg/m 2 and V 300 mg + Ca AUC 6. Five partial responses (PR) were seen. 15/30 pts in arm A and 12/31 in B achieved stable disease (SD) or PR. PR or SD for &gt;6 Cy was observed in 6/30 pts and 5/31 pts in arms A and B, respectively. Conclusions: In this phase I study, V in combination with Cis or Ca at full single-agent doses was well tolerated. Furthermore, several objective responses and cases of sustained SD were observed in heavily pretreated pts with advanced solid tumors.[Table: see text]
An immune-related signature for prediction of risk of late recurrences beyond proliferation and ER-related genes in ER-positive breast cancer.
Authors: Giampaolo Bianchini, Gabriella Rossi, Maurizio Callari, Takayuki Iwamoto, Eugenia Galeota, Thomas Karn, Catherine Margaret Kelly, Milvia Zambetti, Libero Santarpia, Lajos Pusztai, Luca Gianni
Journal: Journal of Clinical Oncology (2014)

530 Background: In ER+ tumors, a dentritic metagene (DM) predicts for lower risk of relapse (Bianchini G JCO 2010; Bianchini G ASCO 2012). We investigated if other immune metagenes provided additional prognostic information and their involvement in early and late (after 5 years) relapses. Methods: We evaluated public available Affymetrix-based gene expression profiles from ER+ untreated (n=599) and adjuvant tamoxifen (TAM)-treated pts (n=683). Four previously defined immune metagenes were evaluated: CD8, MHC1, STAT1 and interferon inducible (IF.I) (Gianni L SABCS 2012). Multivariate analyses were adjusted by estrogen-related genes, proliferation (Bianchini G Breast Cancer Res 2013) and HER2 status. Median cut-off points were used to define low and high expression groups. Outcome was assessed according to distant relapse. Results: In untreated breast cancer, adjusting for other markers only IF.I metagene retained independent prognostic value [HR 1.19 (1.00-1.41), p=0.043], with higher risk for higher expression value. This effect was driven by its prognostic value in the late period [HR 1.50 (0.99-2.28), p=0.057]. Low and high expression groups of DM and IF.I were combined. The lowDM/highIF.I group had a higher risk of recurrences in the overall period [HR 3.68 (1.96-6.91), p<0.0001], with a similar trend in the late period [HR 2.98 (0.85-10.5), p=0.08]. In tamoxifen treated patients, adjusting for other markers, IF.I was confirmed as prognostic in the overall period [HR 1.25 (1.05-1.49), p=0.01] with an even stronger time varying effect [late period: HR 1.51 (1.14-2.01), p=0.004 and early period: HR 1.12 (0.90-1.39), p=0.29]. From 5 to 10 years, the lowDM/highIF.I group had the highest risk [HR 7.26 (1.78-33.9), p=0.006] with a corresponding relapse rate of 22.8% compared to 3% in the highDM/lowIF group. Conclusions: In ER+ breast cancer, high expression of interferon inducible-related genes predicts for higher risk of late recurrences in untreated and tamoxifen-treated patients. Immune related-functions contribute to tumor dormancy and late relapses. Assessment of immune markers might contribute in tailoring extended adjuvant endocrine treatment.
Unilateral Adrenal Cryptococcosis on FDG PET/CT
Authors: Jinxin Zhou, Jing Lv, Yu Pan, Jing Xie, Yifan Zhang
Journal: Clinical Nuclear Medicine (2017)

A 70-year-old man with T-cell deficiency experienced continuous right waist pain and a low degree of fever. Abdominal CT found a large right adrenal mass. FDG PET/CT imaging was acquired to identify the nature of this likely malignant mass and search for potential metastases. The images revealed increased FDG activity in the mass. The patient received right adrenalectomy. Postsurgical pathological and microbial examination demonstrated adrenal cryptococcosis.
Levels of circulating natural killer T and natural killer cells in breast cancer patients.
Authors: Mya Sanda Thein, Saranya Chumsri, James Eeast, Junxin Li, Susan Kesmodel, Ting Bao, Steven J. Feigenberg, Katherine Hanna Tkaczuk, Tonya Webb
Journal: Journal of Clinical Oncology (2013)

e22034 Background: Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that express markers characteristic of both T cells and natural killer (NK) cells. Following activation, iNKT cells rapidly produce a variety of cytokines and activate many other immune cells, thus iNKT cells are key mediators of innate immune responses (IIR) against tumors. The aim of this study was to assess the percentage (%) of iNKT, NKT-like, and NK cells in the peripheral blood of healthy volunteers (HV) and breast cancer (BC) patients. Methods: The % of circulating iNKT (Va24Ja18 + CD3 + ), NKT-like (CD3+CD16CD56+), and NK (CD3-CD16CD56+) cells was analyzed by standardized flow cytometry in 22 newly diagnosed stage 0-3 BC patients and 27 HV. Luminal A BC was defined as ER/PR+≥1%, HER2- Ki67&lt;20%. Differences between groups were assessed using the Mann-Whitney U test for nonparametric data and ANOVA for ≥ 3 groups. Results: iNKT cells % in BC patients (ages: 37-75) was significantly lower compared to HV (ages: 21-64) (Mean: 0.32 vs 0.12, p=0.0036). Among BC patients, NK cells were lower in patients aged ≥50 yrs (p=0.003) and with BMI ≥ 30 (p=0.0036). NK cell % was higher in Asians compared to other races. Patients with luminal A BC, which generally have the best prognosis, have a significantly higher % of NKT-like cells. Conclusions: Interestingly our data shows that older and obese BC patients have lower % of circulating NK cells, while patients with luminal A tumors have a higher % of NKT-like and a lower % of iNKT cells. Further studies on the effects of BMI and aging on IIR as well as functional studies are needed to better understand immunosenescence-related increasing incidence of cancers and IIR-mediated anti-tumor activity in BC patients. [caption]iNKT, NKT-like, and NK cells (% lymphocytes) by age, BMI, race, and pathology in BC patients.[/captions] [Table: see text]