tbuckley/cabot-search huggingface dataset:
Delivery of adjuvant FOLFOX for colon cancer: Insights from routine clinical practice.
Authors: Natasha Satkunam, Xuejiao Wei, James Joseph Biagi, Sulaiman Nanji, Christopher M. Booth
Journal: Journal of Clinical Oncology (2016)

e15110 Background: Oxaliplatin is now a standard component of adjuvant chemotherapy for colon cancer. Details regarding delivery of oxaliplatin and outcomes achieved in routine practice are not well described. Methods: All cases of colon cancer diagnosed in Ontario 2002-2008 were identified using the Ontario Cancer Registry. Pathology reports were obtained for a 25% random sample of cases to identify stage II and III cases; those treated with adjuvant oxaliplatin were included in this analysis. Chemotherapy treatment records were reviewed to identify oxaliplatin dose reductions or omissions. Modified Poisson regression was used to evaluate factors associated with dose reduction/omission. Cox proportional hazards model was used to explore factors associated with cancer-specific (CSS) and overall (OS) survival. Results: The study population included 532 patients; 88% (469/532) had stage III disease. Concomitant chemotherapy was identified as 5-FU in 75% (397/532) of cases and capecitabine in 5% (26/532); concomitant chemotherapy records were not available in 20% of cases (109/532). The mean/median number of oxaliplatin cycles delivered was 10/12. Fifty-four percent (288/532) of cases had a dose reduction/omission of oxaliplatin; the dose was subsequently escalated in 34% (97/288) of these cases. Women were more likely than men to have dose reduction/omission (RR 1.29, 95%CI 1.10-1.51). Dose reduction/omission was not associated with inferior CSS (HR 0.76, 95%CI 0.51-1.14) or OS (HR 0.81, 95%CI 0.59-1.13). Five year CSS and OS of all cases was 77% (95%CI 72-81) and 72% (95%CI 68-76) respectively. Conclusions: Dose reductions/omissions of adjuvant oxaliplatin are common in routine practice but do not appear to be associated with inferior survival. Outcomes achieved in the general population are comparable to the results of clinical trials.
A phase I study of oral SRA737 (formerly CCT245737) given in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer.
Authors: Alvaro Henrique Ingles Garces, Maxime Chenard-Poirier, Robert Hugh Jones, Amy Quinton, Elizabeth R. Plummer, Yvette Drew, Mark Marion Kowalski, Barbara J. Klencke, Udai Banerji
Journal: Journal of Clinical Oncology (2017)

TPS2613 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells. Chk1 is also believed to facilitate tumor cell resistance to chemotherapy or radiation-induced DNA damage and the combination of SRA737 with these standards-of-care may provide synergistic antitumor activity. SRA737 is being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation study of SRA737 in combination with gemcitabine/cisplatin (GC) or gemcitabine (G) alone (NCT02797977). Methods: Up to 70 patients will receive escalating doses of SRA737+GC in Stage 1 or SRA737+G in Stage 2 until a recommended Phase 2 dose (RP2D) is established, followed by expansion cohorts. Patients will receive a single SRA737 PK run-in dose followed by Gem on D1 and 8, Cis on D1, SRA737 on D2, 3, 9 and 10 of each 21-d cycle or Gem on D1, 8 and 15, SRA737 on D2, 3, 9, 10, 16, 17 of each 28-d cycle. Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of SRA737 combination therapy and to establish a RP2D. The PK profile and PD biomarkers (eg, phosphorylation of Chk1 at Ser296, Ser345 and γH2AX foci in PBMCs and tumor tissue) will be explored. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of an indication specific expansion cohort of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations (eg, gene mutations and amplifications/deletions), has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. Clinical trial information: NCT02797977.
P02.03 ALK expression can differentiate the WNT-activated type of medulloblastoma from choroid plexus carcinoma and ependymoma
Authors: A A Sobocińska, J Trubicka, A Karkucińska-Więckowska, M Kaleta, W Grajkowska, E Matyja, M Łastowska
Journal: Neuro-Oncology (2018)

Medulloblastoma is the most common malignant paediatric brain tumour located in the posterior fossa region. The disease consists of at least four molecular subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4 medulloblastoma. Patients with the WNT tumours have a favourable outcome and therefore accurate identification of this type of tumours is essential because of clinical consequences. Our previous analyses indicate that expression of ALK at the RNA and protein levels correlates with the WNT-activated type of medulloblastoma and differentiates WNT-activated tumours from other molecular types of medulloblastoma. However, other paediatric malignant brain tumours, which also may occur in the posterior fossa location, were not examined for presence of ALK expression. Therefore, in this work we investigated if immunohistochemical detection of ALK protein may distinguish WNT medulloblastoma from other paediatric brain tumours, namely choroid plexus carcinoma (CPC) and ependymoma. Overall, 36 patients diagnosed in The Children’s Memorial Health Institute (CMHI) in Warsaw, Poland, were included in the analysis. Five patients were diagnosed previously as the WNT-activated type of medulloblastoma. The remaining patients included 15 patients diagnosed with CPC and 16 patients with ependymoma G II or G III, all not analyzed so far. Tumour analysis was performed on formalin-fixed paraffin-embedded tissue collected at diagnosis. Expression of ALK protein levels was performed by immunohistochemistry using ALK antibody, clone D5F3 (Cell Signaling, Denver, MA, dilution 1:250). Antigen retrieval was performed at 99.9°C for 20 minutes. ALK scoring was applied as the following: 0 (negative) for 0–10%, 1+ for >10–50%, 2+ for >50–100% of positive tumour cells. Whole preparations were scanned in Hamamatsu NanoZoomer 2.0 RS scanner at original magnification 40x. All 5 WNT medulloblastoma tumours, which showed presence of mutation in exon 3 of CTNNB1 gene, had a positive ALK expression present in >50% of tumour cells (score 2+). By contrast, all 15 CPC tumours showed a negative reaction in tumour cells (score 0, < 10% of tumour cells) regardless of tumour location in supratentorial or infratentorial region. Negative reaction was also characteristic for infratentorial ependymoma tumours, both for G II or G III tumour grades (11 tumours with G II and 5 tumours with G III). The results indicate that immunohistological detection of ALK expression at the protein level may serve as a marker for a differential diagnosis for the WNT-activated type of medulloblastoma when compared with CPC and ependymoma tumours. Funded by National Science Centre, Poland (2016/21/B/NZ2/01785).
Daratumumab, lenalidomide, and dexamethasone (DRd) vs lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (POLLUX).
Authors: Nizar J. Bahlis, Philippe Moreau, Hareth Nahi, Torben Plesner, Hartmut Goldschmidt, Kenshi Suzuki, Robert Z. Orlowski, Neil Rabin, Merav Leiba, Albert Oriol, Ajai Chari, Jesus San Miguel, Paul G. Richardson, Saad Zafar Usmani, Lisa Marie O'Rourke, Kaida Wu, Tineke Casneuf, Christopher Chiu, Xiang Qin, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2017)

8025 Background: Daratumumab (D) is a human CD38-targeting mAb that significantly prolongs progression-free survival (PFS) when added to standard-of-care regimens in patients (pts) with RRMM. We examined updated efficacy and safety data from POLLUX (NCT02076009), a randomized phase 3 study of DRd vs Rd in RRMM. Methods: Pts with ≥1 prior line of therapy (LOT) received Rd (25 mg PO lenalidomide on days 1-21 of each q4w cycle; 40 mg dexamethasone weekly) ± D (16 mg/kg IV qw for cycles 1 and 2, q2w for cycles 3-6, then q4w until disease progression). Pts refractory to lenalidomide were ineligible. Minimal residual disease (MRD) was assessed on bone marrow samples at time of suspected complete response (CR) and at 3 and 6 months post-suspected CR at sensitivities of 10 –4 , 10 –5 , and 10 –6 via next-generation sequencing (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 1 (1-11) prior LOT. 55% received prior IMiDs (18% lenalidomide). Based on previous median follow-up of 17.3 months, DRd significantly prolonged PFS (median: not reached vs 17.5 months; HR, 0.37; 95% CI, 0.28-0.50; P&lt; 0.0001) and significantly improved overall response rate (ORR; 93% vs 76%, P&lt; 0.0001) vs Rd. DRd induced higher rates of deep responses vs Rd (≥very good partial response [VGPR]: 78% vs 45%; ≥CR: 46% vs 20%; all P&lt; 0.0001) and included MRD negativity, which was &gt; 3-fold higher across all 3 sensitivity thresholds for DRd vs Rd (25% vs 6% at the 10 –5 threshold). MRD-negative pts demonstrated longer PFS vs MRD-positive pts. Follow up for overall survival (OS) is ongoing (OS events: 40 [14%] in DRd and 56 [20%] in Rd). No new safety signals were identified with longer follow up. Updated efficacy and safety data based on approximately 25-months follow up will be presented at the meeting. Conclusions: DRd provided significant benefits vs Rd in terms of PFS, ORR, and MRD negativity, and the favorable safety profile of DRd was maintained with longer follow up. These data further validate the use of DRd in RRMM pts who received ≥1 prior therapy. Clinical trial information: NCT02076009.
Final analysis of DECOG-SLT trial: Survival outcomes of complete lymph node dissection in melanoma patients with positive sentinel node.
Authors: Ulrike M. Leiter, Rudolf Stadler, Cornelia Mauch, Werner Hohenberger, Norbert Brockmeyer, Carola Berking, Cord Sunderkötter, Martin Kaatz, Kerstin Schatton, Percy Lehmann, Thomas Michael Martin Vogt, Jens Ulrich, Rudolf Herbst, Wolfgang Gehring, Jan-Christoph Simon, Ulrike Keim, Peter Martus, Claus Garbe
Journal: Journal of Clinical Oncology (2018)

9501 Background: The multicenter DeCOG-SLT trial assessed in a randomized phase 3 trial whether complete lymph node dissection (CLND) resulted in increased survival compared with observation in patients with positive sentinel node biopsy (SLNB). This study now gives an update three years after inclusion of the last patient. Methods: Outcomes of 473 patients in the intent-to-treat population (ITT) randomly assigned into the DeCOG trial were evaluated with an additional 3 years follow-up observation after randomization has ended. A total of 233 patients was analyzed in the observation group, 240 in the CLND group. The primary endpoint was distant metastasis-free survival (DMFS); recurrence-free (RFS) and overall (OS) survival were secondary endpoints. Results: Patient enrolment was performed from January 2006 to December 2014 followed by an observation period from January 2015 to December 2017. The median follow-up time was 72 months (95% CI 67.2;76.8) No significant treatment-related difference was seen in the 5-years DMFS: 68% (90%CI: 62.1%;72.5%, 79 events) in the observation arm and 65% (90%CI: 59.3%;70.5%, 85 events) in the CLND arm (HR1.08 (90%CI 0.83; 1.39), P = 0.65). The 5 years RFS (HR 1.01 (90%CI 0.8; 1.28), P = 0.94) and OS (HR 0.99 (90%CI 0.74; 1.31), P = 0.93), also showed no differences with respect to the treatment arms. The 5-year DMFS differed according to the tumor load in the SLNB, but again not between CLND and observation arm (≤ 1.0 mm: 78.7% vs 72.5%, HR 1.12, P = 0.58 and > 1.0 mm 54.7% vs 51.7%, HR 0.98, P = 0.95) Regional lymph node metastases occurred in 10.8% of the CLND and in 16.3% of the observation arm (P = 0.11) The multivariate proportional hazard regression analysis revealed tumor thickness and tumor load in the SLNB to be independent prognostic factors for RFS, DMFS and OS. Conclusions: After a median follow-up time of 72 months there was no survival benefit in melanoma patients with positive SLNB undergoing CLND compared to observation only. Clinical trial information: NCT02434107.
Safety profile of nivolumab administered as 30-minute (min) infusion: Analysis of data from CheckMate 153.
Authors: David Michael Waterhouse, Leora Horn, Craig H. Reynolds, David R. Spigel, Jason Claud Chandler, Tarek Mekhail, Mohamed K. Mohamed, Ben C. Creelan, Kenneth Bruce Blankstein, Petros Nikolinakos, Michael McCleod, Ang Li, Ian M. Waxman, Nivedita Aanur, Shruti Agrawal
Journal: Journal of Clinical Oncology (2016)

3059 Background: Nivolumab,aprogrammed death-1 (PD-1) immune checkpoint inhibitor, is approved in the US for previously treated metastatic NSCLC and renal cell carcinoma, and for advanced melanoma, and in the EU for previously treated squamous NSCLC and advanced melanoma. Here, we assess the impact of infusion time on nivolumab safety from an ongoing, predominantly community-based trial. Methods: Patients who progressed during or after receiving ≥ 1 prior therapy were enrolled. The primary outcome of this study is incidence of grade (gr) 3–4 and 5 and select treatment-related adverse events (TRAEs). Patients received nivolumab 3 mg/kg IV Q2W; infusion time was shortened from 60 min to 30 min following an amendment to the study protocol. A comparison of toxicities by infusion time is reported in this analysis. Data for the overall population and elderly/poor performance status patient subgroups are presented in separate abstracts. Results: A total of 322 and 355 patients, respectively, received nivolumab by 30-min or 60-min infusion; demographics for these patients are comparable to the overall population (median follow-up, 6 mo). Any gr (gr 3–4) TRAEs occurred in 53% (11%) and 51% (12%) of patients with 30-min or 60-min infusions, respectively. Gr 3-4 select AEs in ≥ 2% of patients given 30-min or 60-min infusions occurred in pulmonary (3% and 2%), hepatic (2% and 3%), and gastrointestinal (2% and 2%) categories. Any gr (gr 3–4) infusion reaction occurred in 3% and 2% ( < 1% and < 1%) of patients given 30-min or 60-min infusions, respectively (Table). Additional data by infusion time for this subgroup will be presented, including safety (use of steroids, incidence of discontinuation) and pharmacokinetics. Conclusions: Nivolumab3 mg/kg can be safely infused over 30 min, with a safety profile comparable to 60-min infusion and with a low incidence of infusion-related reactions. Clinical trial information: NCT02066636. Nivolumab 3 mg/kg Q2W 30-min infusion n = 322 60-min infusion n = 355 Any gr Gr 3–4 Any gr Gr 3–4 Infusion reaction, n (%) 9 (3) 2 ( < 1) 6 (2) 3 ( < 1) Hypersensitivity 5 (2) 0 1 ( < 1) 0 Infusion-related reaction 2 ( < 1) 0 5 ( < 1) 3 ( < 1) Anaphylaxis 1 ( < 1) 1 ( < 1) 0 0 Bronchospasm 1 ( < 1) 1 ( < 1) 0 0
All‐Cause and Cause‐Specific Mortality Trends of End‐Stage Renal Disease Due to Lupus Nephritis From 1995 to 2014
Authors: April Jorge, Zachary S. Wallace, Yuqing Zhang, Na Lu, Karen H. Costenbader, Hyon K. Choi
Journal: Arthritis & Rheumatology (2018)

A prior study showed that premature mortality among patients with end-stage renal disease (ESRD) due to lupus nephritis (LN) persisted in the US between 1995 and 2006. The present study was undertaken to extend this analysis through 2014 to examine more recent trends, including key cause-specific mortality trends.Using the national registry of patients with ESRD, we identified all patients with incident ESRD due to LN between January 1, 1995 and December 31, 2014, divided into four 5-year cohorts of ESRD onset by calendar year (1995-1999, 2000-2004, 2005-2009, 2010-2014). We assessed mortality within each cohort. Temporal trends in all-cause mortality and cause-specific mortality were examined, adjusting for covariates.We identified 20,974 individuals with incident ESRD due to LN from 1995 through 2014. The mortality rate per 100 patient-years declined from 11.1 (95% confidence interval [95% CI] 10.4-11.8) in 1995-1999 to 6.7 (95% CI 6.2-7.2) in 2010-2014 (P for trend < 0.01). Adjusted mortality hazard ratios in 2010-2014, compared with 1995-1999, were 0.68 (95% CI 0.58-0.78) for white patients, 0.67 (95% CI 0.57-0.78) for African American patients, and 0.51 (95% CI 0.38-0.69) for Hispanic patients. Deaths from cardiovascular disease (CVD) and infection declined by 44% and 63%, respectively, from 1995-1999 to 2010-2014 (P for trend < 0.01 for both).In the more recent years of the period 1995-2014, there was a considerable reduction in all-cause mortality among white, African American, and Hispanic patients, with reduced risk of death from CVD and infection. Collectively, these trends provide an important benchmark of improving care in this high-risk population.
Blood exosomes regulate the tissue distribution of grapefruit-derived nanovector via CD36 and IGFR1 pathways
Authors: Qi-long Wang, XiaoYing Zhuang, Mukesh K. Sriwastva, Jingyao Mu, Yun Teng, Zhongbin Deng, Lifeng Zhang, Kumaran Sundaram, Anil Kumar, Donald Miller, Jun Yan, Huang-Ge Zhang
Journal: Theranostics (2018)

Tumor-specific delivery of therapeutics is challenging.One of the major hurdles for successfully delivering targeted agents by nanovectors is the filtering role of the liver in rapidly sequestering nanovectors from the circulation.Exosomes, a type of endogenous nanoparticle, circulate continuously in the peripheral blood and play a role in intercellular communication.The aim of this study was to determine whether the level of endogenous exosomes has an effect on nanovector delivery efficiency of targeted agents.Methods: Exosomes were isolated from peripheral blood and intravenously (I.V.) injected into tumor-bearing mice.Subsequently, 1,1-dioctadecyl-3,3,3'3'-tetramethylindotricarbocyanine-iodide (DiR) fluorescent dye-labeled nanoparticles, including grapefruit nanovectors (GNV) and standard liposomes, were I.V. injected in the mice.The efficiency of redirecting GNVs from liver to other organs of injected mice was further analyzed with in vivo imaging.The concentration of chemo drugs delivered by GNV was measured by HPLC and the anti-lung metastasis therapeutic effects of chemo drugs delivered by GNVs in mouse breast cancer and melanoma cancer models were evaluated.Results: We show that tail vein-injected exosomes isolated from mouse peripheral blood were predominately taken up by liver Kupffer cells.Injection of peripheral blood-derived exosomes before I.V. injection of grapefruit-derived nanovector (GNV) decreased the deposition of GNV in the liver and redirected the GNV to the lung and to the tumor in breast and melanoma tumor-bearing mouse models.Enhanced therapeutic efficiency of doxorubicin (Dox) or paclitaxel (PTX) carried by GNVs for lung metastases was demonstrated when there was an I.V. injection of exosomes before therapeutic treatment.Furthermore, we found that CD36 and IGFR1 receptor-mediated pathways played a critical role in the exosome-mediated inhibitory effect of GNV entry into liver macrophages.Conclusions: Collectively, our findings provide a foundation for using autologous exosomes to enhance therapeutic vector targeted delivery to the lung.
Abstract 13133: Coronary Artery Calcium and Cardiovascular Events in Diabetes: Implications for Primary Prevention Therapies: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Michael G Silverman, Michael J Blaha, Matthew J Budoff, Ron Blankstein, Roger S Blumenthal, Harlan M Krumholz, Juan J Rivera, Arthur Agatston, Nathan D Wong, Steven Shea, John McEvoy, Khurram Nasir
Journal: Circulation (2012)

Background: Patients with Diabetes Mellitus (DM) are at an increased risk for cardiovascular disease (CVD); however, not all individuals with DM carry the same elevated risk. We sought to evaluate ...
Trial in progress: A phase 2 study of intratumor pil-12 plus electroporation in combination with intravenous pembrolizumab in patients with stage III/IV mealanoma progressing on either pembrolizumab or nivolumab treatment (PISCES).
Authors: Robert Hans Ingemar Andtbacka, Tom Van Hagen, Phillip Parente, Victoria Atkinson, Igor Puzanov, Gregory A. Daniels, Sajeve Samuel Thomas, Anne Poh Long, Andrew Mark Haydon, Arkadiusz Z. Dudek, Sharron Erna Gargosky, Chris Twitty, John M. Kirkwood
Journal: Journal of Clinical Oncology (2018)

TPS9601 Background: Immunotherapy and targeted therapies have significantly changed the treatment landscape for advanced melanoma over the past few years. However, despite the addition of these new therapeutic strategies, a lack of response or disease progression continues to occur in a significant fraction of patients (˜60%). Pembrolizumab (anti-PD-1 antibody) for the treatment of advanced melanoma confers a 33% objective response rate (ORR). Intratumoral plasmid IL-12 (tavokinogene telseplasmid; tavo) with electroporation (IT-tavo-EP) is a gene-based immunotherapeutic approach that forces localized expression of the proinflammatory cytokine IL-12, which converts both treated and untreated lesions from poorly immunogenic/low T-cell infiltrating tumors unlikely to respond to anti-PD-1 therapy into highly inflamed immunologically active lesions. The purpose of this study is to evaluate the tolerability and efficacy of pembrolizumab plus IT-tavo-EP in Stage III/IV melanoma patients who have progressed or are progressing on approved checkpoint inhibitors, and to assess the immunomodulatory effects of therapy Methods: OMS-I103 (PISCES) is a phase 2, multicenter, open-label trial of IT-tavo-EP with pembrolizumab in patients with stage III/IV melanoma who are progressing on either pembrolizumab or nivolumab. The primary objective is best ORR by RECIST v1.1 at 24 weeks determined by independent reviewers. A Simon 2-stage minimax design is employed. In Stage 1, up to 23 eligible patients will be enrolled and treated with IT-tavo-EP to the accessible lesions on Days 1, 5 and 8 every 6 weeks with IV pembrolizumab (200 mg) on Day 1 of each 3-week cycle for 24 weeks. If the predesignated threshold is reached in Stage 1, (N > 3 /23) enrollment for Stage 2 will include an additional 25 patients (total of 48 patients). The study is enrolling in the US and Australia. Clinical trial information: NCT03132675.