tbuckley/cabot-search huggingface dataset:
Safety and tolerability of the combination of ATRA + arsenic trioxide (ATO) + gemtuzumab ozogamicin (GO) in high-risk acute promyelocytic leukemia (APL): Initial report of the SWOG/Alliance/ECOG S0535 trial.
Authors: Jeffrey E. Lancet, Megan Othus, Daniel J. DeAngelo, Steven Coutre, Rami S. Komrokji, Martin S. Tallman, Mark Robert Litzow, Frederick R. Appelbaum
Journal: Journal of Clinical Oncology (2015)

7016 Background: High-risk APL remains a therapeutic challenge, with significant rates of early mortality and relapse. Recent evidence confirmed excellent outcomes in low-risk APL with the combination of ATO and ATRA (Lo-Coco, NEJM 2013), and a previous pilot study indicated the efficacy of a combination of ATO + ATRA + GO in a subset of high-risk APL (Ravandi, JCO 2009). SWOG designed a larger phase 2 study to confirm the safety and efficacy of this combination in high-risk APL. Primary Objectives: 1) assessment of early (6 week) death rate; 2) assessment of 3-year continuous complete remission (CCR) Methods: Adult patients with newly diagnosed high-risk APL (WBC ≥ 10k/uL) were eligible. Induction therapy consisted of: ATRA (45 mg/m2/day) - day 1 until CR; ATO (0.15 mg/kg/day) – day 10 until CR; GO 9 mg/m2- day 1. Patients in CR received consolidation with ATO x 2 cycles, followed by ATRA + daunorubicin x 2 cycles, followed by GO x 2 cycles. Subsequent maintenance therapy consisted of ATRA + 6-MP + methotrexate for up to 1 year. Results: From 2008 to 2013, 73 patients were enrolled and evaluable for toxicity. Median age was 46.5 years, with 52% females and 48% males. Sixty-two (85%) patients completed induction therapy as planned, and 48 patients (66%) completed all planned consolidation. Six of 73 patients (11%) died within 6 weeks of treatment initiation (95% confidence interval 6-21%), supporting rejection of the null hypothesis (30% early death rate). The most common treatment-emergent grade 3-4 adverse events (AE) during induction included: febrile neutropenia (33%), AST/ALT elevation (12%), hypoxia/differentiation syndrome (11%), hyperglycemia (11%), headache (11%), prolonged QTc (11%). Amongst 59 patients receiving consolidation, the most common treatment-emergent grade 3-4 AEs included: febrile neutropenia (52%), headache (14%), fatigue (14%), and nausea (12%). The efficacy analysis of CCR is ongoing. Conclusions: The combination of ATO + ATRA + GO appears safe and well-tolerated in patients with high-risk APL, with an acceptable early mortality rate. 3-year CCR assessment is not yet mature. Clinical trial information: NCT00551460.
Predicting axillary lymph node involvement in breast cancer patients by ultrasonography
Authors: N. Rokutanda, J. Horiguchi, Y. Koibuchi, R. Nagaoka, Y. Iino, I. Takeyoshi
Journal: Journal of Clinical Oncology (2007)

11075 Background: About 20% of breast cancer patients eligible for sentinel node (SN) biopsy have axillary node metastases. The purpose of this study is to evaluate the sensitivity of preoperative ultrasonography (US) for SN involvement. Methods: Between October 2004 and May 2006, a total of 141 breast cancer patients without clinically node involvement were eligible for SN biopsy. The size (length and height) and cortical thickness of lymph nodes (LN) was measured by US before surgery. Results: Twenty-four (20%) of 141 patients had pathologically involved LN (Positive Group), and 118 (80%) were negative for LN metastases (Negative Group). No LN was detected in 25 patients (21%) of the negative group by US. The number of detected LN was more in the positive group than the negative group (1.59 vs 1.13, p&lt;0.05). There was no significant difference in the size of LN between the two groups. The cortical layer of LN was thicker in the positive group than the negative group (3.11 vs 2.12, p&lt;0.05). Eighteen patients had the LN with more than 4mm of cortical thickness, nine (50%) of which revealed pathologically LN involvement. Conclusions: The measuring of cortical thickness is useful for predicting axillary LN involvement by US. This approach may improve the selection of patients for SN biopsy. No significant financial relationships to disclose.
Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation
Authors: Xinlu Ding, Sanxiong Liu, Miaomiao Tian, Wenhao Zhang, Tao Zhu, Dongdong Li, Jiawei Wu, HaiTeng Deng, Yichang Jia, Wei Xie, Hong Xie, Ji-Song Guan
Journal: Nature Neuroscience (2017)
Evolocumab reduces cardiovascular events in patients with heart disease, finds study
Authors: Susan Mayor
Journal: BMJ (2017)

Evolocumab reduced the risk of major cardiovascular events by 15% in patients with atherosclerotic cardiovascular disease who were already taking statins, a study has found . 

The study randomised 27 564 patients with clinically evident atherosclerotic cardiovascular disease to evolocumab (either 140 mg every two weeks or 420 mg monthly by subcutaneous injection) or to placebo.1 Study participants had fasting concentrations of low density lipoprotein (LDL) cholesterol of ≥1.8 mmol/L on moderate or high intensity statin therapy, and 81% had a …
Treatment of advanced gastrointestinal stromal tumors (GIST): Are results of second-line sunitinib therapy related to duration of response of first-line imatinib?
Authors: Daniela Katz, Sari Greenberg-Dotan, Ilan Feldhamer, Haim Bitterman, Ariel Hammerman
Journal: Journal of Clinical Oncology (2015)

10538 Background: Imatinib (IM) revolutionized the outcome of patients with advanced GISTs; however, disease progression eventually occurs due to IM resistance or intolerance. Sunitinib (SU) is an oral multi-targeted tyrosine kinase inhibitor, approved for second line treatment of advanced GIST after IM failure. Clinical trials have shown that clinical activity of SU after IM failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases. However, since mutational status is not mandatory in the workup of GIST patients, it is difficult to predict response to second line SU. The aim of this study was to explore whether results of SU therapy after IM failure, might be related to the duration of IM treatment. Methods: All patients with advanced GIST that are insured by Clalit Health Services, Israel's largest health-care organization were identified. Only patients, who progressed on second-line SU, after receiving IM as first-line therapy, were included. Last date of patient recruitment was Dec 31, 2014. A linear regression model was used to identify the relation between first-line IM duration of response (the independent variable) and duration of response of second line SU. Results: We identified 31 consecutive patients with advanced GIST treated with IM and SU, consequently. There were 18 male and 13 female patients, with median age at the start of SU therapy 63.5 years (range: 34-85). Only 7% of patients (n = 3) received adjuvant IM therapy, prior to their metastatic disease. Median duration of response was 25.8 months (2.3-67.4) for IM and 5.2 months (0.8-32.7) for SU. The linear model predicted duration of second-line SU therapy (Y) in relation to duration of IM first-line therapy (X) best with: Y = 2.36+0.282X, (R2= 20.6%, p < 0.01). Conclusions: In our study, results of SU therapy in advanced GIST patients were found to positively relate with the duration of first line IM treatment. This relation may serve as a handy estimate for SU duration in the clinic. However, further studies in wider cohorts of patients are needed to confirm this observation.
Role of <i>miR-21</i>, <i>miR372</i>, and<i> E2F1</i> as biomarkers predicting outcome in cisplatin-treated bladder cancer patients.
Authors: Chensheng Willa Zhou, Stephanie A. Mullane, Lillian Werner, Mary-Ellen Taplin, Andre Poisl Fay, Toni K. Choueiri, David Yoshio Takeda, Michaela Bowden, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2015)

4530 Background: Cisplatin based chemotherapy is the gold standard for first line metastatic/locally advanced urothelial carcinoma (aUC). Variant expression of selected miRNAs and transcription factors (TF) are shown to correlate with and predict cisplatin efficacy in many types of cancers. In this study we aimed to confirm the role of selected miRNAs and TFs in patients receiving first line cisplatin combination therapy in aUC Methods: 82 clinically annotated patients with aUC (including N1 resected patients), with available tumor tissue, were identified, and total RNA was extracted from FFPE specimen. MicroRNA (miR21, miR106b, miR10b, miR146a, miR146b, miR371, miR372, miR373, miR1224, miR1248, miR200c, Let7i, miR27b, and miR26b) and TF panels (RELA, SMAD4, FOXO3, E2F1 and TWIST1) were identified using in silico data mining based on their roles in UC or in cisplatin response. Time to progression (TTP) was defined as time from chemotherapy start date to date of progression or censored on the last known without progression. For the TTP analysis, median miRNA expression levels were dichotomized and a cox regression model was used. For the extreme TTF phenotype, correlations were assessed by Wilcoxon’s test (P < 0.05). Multivariate analysis was performed for all miRNAs, adjusting for ECOG status and visceral disease. Results: The median TTP was 12 mo, with 43 patients experiencing disease progression. In the TTP multivariate analysis, increased levels of E2F1 [p = 0.02, HR:0.49, (0.27, 0.89)], miR21 [p = 0.03, HR:0.53, (0.29, 0.97)] and miR372 [p = 0.02, HR: 0.49, (0.26, 0.90)], were associated with a shorter TTP. For the extreme phenotype, only miR21 and E2F1 were shown to be associated with TTP (p = 0.055). Conclusions: In this retrospective cohort of patients treated with cisplatin based therapy, higher levels of E2F1, miR21, and miR372 correlated with a shorter TTP. Biological validation of cisplatin effect on 6 bladder cancer cell lines that express different miR21 levels, from Cancer Cell Line Encyclopedia, is ongoing and results will be presented.
Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma.
Authors: Henk M Lokhorst, Torben Plesner, Peter Gimsing, Hareth Nahi, Monique Minnema, Ulrik Niels Lassen, Jakub Krejcik, Jacob Laubach, Steen Lisby, Linda Basse, Paul Gerard Guy Richardson
Journal: Journal of Clinical Oncology (2013)

8512^ Background: Daratumumab (DARA) is a human CD38 monoclonal antibody (mAb) with broad-spectrum killing activity. Preliminary safety and efficacy data from this first-in-human dose-escalation study of DARA in pts with relapsed or refractory (RR) multiple myeloma (MM) have previously been published. Here, we present safety and efficacy data from the finalized part 1 and preliminary safety data from the ongoing part 2 of the study. Methods: Pts ≥18 years requiring systemic therapy and considered RR to at least 2 prior lines of therapy and ineligible for ASCT were enrolled. In part 1, a 3+3 dose-escalation design was applied and DARA was administered over a 9-week period as 2 pre- and 7 full doses. The phase II dose was determined to 8mg/kg and these pts receive DARA weekly for 8 weeks followed by dosing every 2nd week for 16 weeks and every 4th week until disease progression, toxicity or for max. 24 months. Results: Data from 32 pts included in part 1 are presented. In part 2, 7/16 pts have been recruited: all available data will be presented at the meeting. In part 1, the median number of prior treatment lines was 6. PK analysis showed plasma peak levels as expected but relatively rapid clearance at low dose levels. At doses ≥4mg/kg, observed PK values approximated model-predicted values. Efficacy evaluation from part 1 was based on IMWG guidelines. In the ≥4mg/kg groups (n=12), 5 PRs and 3 MRs were observed. 7 of these pts had a 50-100% concomitant reduction in bone marrow plasma cells. Median PFS in the ≥4mg/kg dose groups was not reached (median follow-up at data cut-off was 3.8mths (range: 0-9.6mths). No ADA responses were detected. In part 1, the most common adverse events reported were infusion related (IRE) which occurred predominantly during the first full infusion. 44% of subjects across all dose groups had IREs grade 1-3, of which 2 were grade 3. Six related SAEs (1 anemia, 1 thrombocytopenia, 2 bronchospasm, 1 cytokine release, 1 AST increase) were reported. Conclusions: DARA induced a marked reduction in paraprotein and bone marrow plasma cells at doses ≥4mg/kg in heavily pretreated RR MM pts. In addition, high response rates and encouraging PFS data were observed. This is unprecedented for single-agent mAb treatment of MM. Clinical trial information: NCT00574288.
Lipogenesis and resected colorectal liver metastases.
Authors: Hinda Boutrid, Richard J. Barth, William B Kinlaw, Arief A. Suriawinata, Tor Tosteson, Zhongze Li, Mary D. Chamberlin
Journal: Journal of Clinical Oncology (2015)

e14610 Background: Activation of lipogenesis in cancer cells is known to correlate with a poorer prognosis for many tumor types. Colorectal cancer (CRC) tumors have been shown to express increased levels of molecules involved in the de novo synthesis and hepatic uptake of lipids (S14, LPL, FASN, CD36). However, the expression of these molecules in CRC liver metastases compared to adjacent uninvolved liver has not been assessed. This study evaluates the expression of lipogenic molecules in CRC liver metastases in comparison with both the primary CRC tumors and the surrounding liver tissue. It further explores the effect of a low fat, low calorie diet on these levels of expression. Methods: A retrospective study was performed using available tissue specimens collected from patients with metastatic CRC who were randomized into a group which received a low calorie, low fat diet for one week prior to surgery or to a group with a regular diet. Tissue samples from primary CRC tumors as well as resected CRC liver metastases and liver tissue adjacent to the metastases prior to and following a one week diet were evaluated by immunohistochemistry (IHC) for Sp14, LPL, FASN and CD36. IHC scores for these proteins were compared using Fisher’s exact test. Results: CRC liver metastases in the control group expressed S14 (70%), LPL (50%) and FASN (100%). There was a statistically significant decrease in expression of LPL in CRC liver metastases (50%) in comparison to adjacent liver tissue samples (100%,p = 0.0096) and primary tumor samples (100%,p = 0.0124) in the control group. No statistically significant difference was seen in expression of S14, LPL and FASN between control and low calorie diet groups. Conclusions: CRC liver metastases express molecules involved in lipogenesis, suggesting this is a mechanism for metastasis. However, these tumors may have a decreased ability to hydrolyze fatty acids from triglycerides present in circulating lipoprotein particles, as indicated by decreased levels of LPL expression. In addition, a short term low fat, low calorie diet, does not appear to have an effect on CRC liver metastases. A longer term diet may be needed. This information provides a better understanding of the CRC liver metastatic tumor microenvironment and may lead to new therapeutic targets.
Symptomatic response to a non-platinum doublet in performance status 2 (PS 2) patients (pts) with non-small lung cancer (NSCLC)
Authors: H. Spiridonidis, M. Tao, L. Laufman, H. Laufman, M. Weiss, P. Ganz
Journal: Journal of Clinical Oncology (2004)

7303 Background: Because PS 2 NSCLC pts have poor outcomes with platinum-based chemotherapy, we tested the palliative effects and safety of a non-platinum doublet in a phase II study. Methods: Docetaxel 60 mg/m2 Day 1 and Gemcitabine 800 mg/m2 Days 1, 8 and 15, were given q 4 weeks. Symptomatic responses were assessed q cycle and radiographic tumor responses q 2 cycles. Lung cancer-specific symptom burden and quality of life (QOL) were assessed by patient and observer using the Lung Cancer Symptom Scale (LCSS) and the Subjective Health Estimation (SHE). Results: 30 pts were entered: 17 males, median age 69 yrs, 22 stage IV, 13 with severe cardiorespiratory co-morbidities. Pts received a median of 2 cycles. Toxicities were grade 4 neutropenia (5), febrile neutropenia (1), grade 3 anemia (2), grade 3 asthenia (11). Ten (33%) of pts had partial responses. 21 pts completed baseline QOL assessments with at least one follow-up (F/U). There was no significant difference in age, rate of severe co-morbidities, baseline scores, best tumor response or days to death between those with baseline only QOL assessments vs. those with F/U. For these 21 pts with F/U QOL forms, the baseline average symptom burden (average score of 6 items on a 0–100 scale in the LCSS) was 35.9 (STD= 15.3, range 8–59) and improved an average of 8 points. The median time to best symptomatic response was 1.9 months. The SHE and observer LCSS scores paralleled these results. Those who improved at least one point in average symptom burden score were younger with fewer baseline symptoms (t-test p-value <.04); however, best tumor response, rate of severe morbidities, and days to death were no different. Median survival was 4.1 months (1-year 14%, 2-year 7%); 11 of 28 deaths were due to cardiorespiratory causes other than cancer progression. Conclusions: PS 2 patients derive symptomatic benefit from non-platinum chemotherapy regardless of tumor response, co-morbidities and prognosis. Survival however remains short due to the burden of co-morbidities Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis; Eli Lilly Eli Lilly; Aventis
Phase I trial of cetuximab, intensity modulated radiotherapy (IMRT), and the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab in previously untreated, locally advanced head and neck squamous cell carcinoma (PULA HNSCC).
Authors: Julie E. Bauman, William E. Gooding, David Andrew Clump, Seungwon Kim, Brian J Karlovits, Dwight Earl Heron, Umamaheswar Duvvuri, James Ohr, Karen Holeva, Robert L. Ferris
Journal: Journal of Clinical Oncology (2014)

TPS6104 Background: Concurrent therapy for PULA HNSCC using the EGFR-specific mAb cetuximab (C) plus IMRT is an accepted standard, however disease control in intermediate or high risk disease could be improved. Our recent data indicate that C induces Ab-dependent, cell-mediated cytotoxicity and cross-priming of cytotoxic T lymphocytes. However, C also induces immunosuppressive regulatory T cells (Treg) expressing the checkpoint receptor CTLA-4; Treg correlate negatively with clinical outcomes to C. We hypothesize enhanced C-induced antitumor cellular immunity and clinical activity by targeting Treg with the anti-CTLA-4 mAb ipilimumab (ipi). We are conducting a phase I study adding ipi to C-IMRT in patients (pts) with intermediate or high risk PULA HNSCC. Methods: Eligible pts have stage III-IVb PULA HNSCC (pharynx, larynx). “High risk” pts are HPV(-). “Intermediate risk” pts are HPV(+) and have either: 1) ≥ 10 pack-year tobacco and ≥N2 disease; or 2) T4 or N3 disease, irrespective of tobacco status. A phase I (3+3) dose escalation trial is evaluating the addition of ipi to standard concurrent C (250 mg/m2weekly after loading dose) + IMRT (66-70 Gy daily fractionation over 7 weeks). See table for dose cohorts and schedule. Dose limiting toxicity (DLT) is defined as any grade 4 toxicity (except in-field radiation dermatitis or asymptomatic, correctable lab abnormality), or any toxicity which delays IMRT ≥ 10 fractions. The DLT observation period ends 4 weeks after completing IMRT. As of Jan 2014, 3 pts have enrolled in the first cohort, receiving ipi at 3mg/kg. The next dose tier, assuming no DLTs, will increase ipi to 10 mg/kg. In the event of DLT at 10 mg/kg, ipi dosing will de-escalate to 6 mg/kg. Extensive immune monitoring is underway using baseline tumor tissue, including characterization of tumor-infiltrating lymphocytes, and serial monitoring of circulating lymphocytes and cytokines. Clinical trial information: NCT01935921. Week of Treatment 1 2 3 4 5 6 7 8 11 14 IMRT X X X X X X X Cetuximab X X X X X X X X Ipilimumab X X X X Cohort -1: 1 mg/kg Cohort 1 (start): 3 mg/kg Cohort 2 (de-escalation only): 6 mg/kg Cohort 3: 10 mg/kg Immune Biomarkers X X X X X
Stereotactic body radiotherapy for high-risk prostate cancer (5 treatment days): Toxicity results of a phase II trial.
Authors: Amar Upadhyaya Kishan, Donald B. Fuller, Michael L. Steinberg, Victoria Ramirez, Nzhde Agazaryan, Dan Ruan, Minsong Cao, Patrick Kupelian, Christopher R. King
Journal: Journal of Clinical Oncology (2017)

46 Background: Stereotactic body radiotherapy (SBRT) for high-risk prostate cancer (CaP) remains investigational not only due to undetermined efficacy but also due to concerns for the potential toxicity when the treatment volumes extend beyond the prostate gland itself. Methods: Men with high-risk CaP, as defined by Gleason score &gt; = 8, clinical stage T3-T4, or initial PSA &gt; = 20 ng/mL, were enrolled on a multicenter phase II trial and were treated with 40 Gy to prostate and 25 Gy to pelvic nodes in 5 fractions and 9 months neoadjuvant and concurrent ADT. Treatment with ADT and pelvic nodal radiation was at the discretion of the treating physician. Follow-up assessment was with CTCAE v4 and Expanded Prostate Composite Index (EPIC). Results: A total of 61 patients were treated, with a median follow-up of 12 months. Forty (64.4%) received ADT and 23 (37.1%) received nodal radiation. The median initial PSA was 8.1 ng/mL and 8% of patients had clinical T3-T4 disease; 45.9% and 39.3% had Gleason score 8 and 9-10 disease, respectively. No grade 3 or higher toxicities were seen. Rates of acute and late grade 2 genitourinary toxicities were 13.1% and 6.7%, respectively; rates of acute and late grade 2 gastrointestinal toxicities were 6.6% and 8.2%, respectively. Mean changes in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -0.35, +1.44, and -2.38, respectively. For the 32 patients with evaluable EPIC scores at 12 months, mean changes on EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were -1.04, -2.70, and -6.76, respectively. The percentages of patients with minimum clinically important change in EPIC urinary incontinence, urinary obstructive, and bowel domain scores at 4 months were 11.9%, 21.4%, and 26.2%, respectively. At 12 months, these figures were 13.9%, 30.6% and 27.8%. The receipt of ADT and/or nodal radiation had no significant effect on either physician- or patient-reported toxicity profiles (p &gt; 0.1, Fisher’s exact test). Conclusions: SBRT regimens can be safely utilized to deliver the entire course in 5 treatment days in patients with high-risk localized CaP. Clinical trial information: NCT02296229.