tbuckley/cabot-search huggingface dataset:
Abstract 140: Knockdown of Nucleosome Assembly Protein 1-like 1 Promotes Cardiomyocytes Differentiation by Mesoderm induction through Notch Signaling in Mouse Induced Pluripotent Stem Cells
Authors: Hui Gong, Yuan Yan, Yuanyuan Xue, Peipei Yin, Guoping Zhang, Zhidan Chen, Yong Ye, Chunjie Yang, Jie Yuan, Junbo Ge, Yunzeng Zou
Journal: Circulation Research (2013)

Recently, we used a functional proteomic analysis to screen out nucleosome assembly protein 1-like 1 (Nap1l1) which was downregulated during the differentiation of P19CL6 cells into cardiomyocytes. Here, we attempted to study the role of Nap1l1 in the cardiogenesis of mouse iPSCs. We observed Nap1l1 was downregulated during the differentiation of iPSCs. Knockdown of Nap1l1 dramatically enhanced the differentiation of iPSCs to cardiomyocytes characterized by the increased number of beating embryonic bodies (EBs), the larger alpha-myosin heavy chain (α-MHC)-stained area and the upregulation of cardiac transcription factors (Nkx2.5, GATA4, Mef2c, Tbx5). The effects were sharply inhibited by Nap1l1 overexpression in iPSCs. Cardiomyocytes derived from Nap1l1-knockdown-iPSCs exhibited proper cell biological characteristics. Further study revealed that Nap1l1 knockdown in iPSCs promoted mesoderm (Flk-1, Brachyury and Mesp1) development, but Nap1l1 overexpression inhibited the effect. To explore whether Nap1l1 knockdown in iPSCs enhances cardiomyocytes differentiation by mesoderm induction. Mesoderm cells (Flk-1 positive cells) from iPSCs development were sorted by fluorescent-assisted cell sorting (FACS) and recultured to induce cardiomyocytes differentiation. The result revealed that the same number of Flk-1(mesodermal marker) positive cells from Nap1l1 knockdown, Nap1l1 overexpression or their control iPSCs didn’t show obvious difference in cardiomyocyte differentiation. Loss of Notch signaling in ES cells has been reported to favor commitment to a mesoderm and to induce cardiogenesis. The present study revealed that NICD and downstream genes (Hes1, Hes5, Hey1 and Hey 2) were positively regulated by Nap1l1 expression during differentiation of iPSCs. Notch signaling inhibitor greatly rescued the inhibitory effects of Nap1l1 overexpression on mesoderm induction and cardiogenesis. These findings demonstrate that downregulation of Nap1l1 significantly enhances mesodermal induction and subsequently promotes cardiogenesis from mouse iPSCs via regulating Notch signaling, which will facilitate application of iPSCs for heart diseases.
Is RECIST-defined progression free-survival a meaningful endpoint in the era of immunotherapy?
Authors: Sukhvinder Johal, Irene Santi, Justin Doan, Saby George
Journal: Journal of Clinical Oncology (2017)

488 Background: Progression-free survival (PFS) is often used as a primary endpoint in oncology clinical trials as a surrogate for overall survival. Traditionally, the Response Evaluation Criteria in Solid Tumors (RECIST) have defined disease progression as a significant increase in the size of tumor lesions and the development of new lesions. However, some patients starting immunotherapy have shown initial increased size of tumor lesions followed by tumor regression, due to the unique mechanism of action of immunotherapies. This initial “pseudo-progression” could be classified inaccurately as disease progression, as evidenced by benefit from the treatment beyond progression approach ( JAMA Oncol 2016). The phase III CheckMate 025 trial of nivolumab versus everolimus in patients with advanced renal cell carcinoma allowed treatment beyond progression if there was investigator-assessed clinical benefit and tolerability. The purpose of our study was to test if treatment duration for an immunotherapy was different from RECIST-defined PFS, and as such, could potentially explain the apparent lack of correlation between RECIST progression and overall survival shown in CheckMate 025. Methods: Using 1-year data from CheckMate 025, Kaplan–Meier methodology was used to estimate the median duration of PFS and time to treatment discontinuation (TTD). Stratified log-rank test was used to assess the difference in treatments. Results: For all patients, the median PFS with nivolumab was 4.6 months (95% CI, 3.7–5.4 months) and median TTD was 6.2 months (95% CI, 5.6–7.7 months). For everolimus, the median PFS was 4.4 months (95% CI, 3.7–5.5 months) and median TTD was 3.9 months (95% CI, 3.7–4.6 months). Conclusions: Patients in CheckMate 025 had significantly longer survival with nivolumab than with everolimus, but with similar PFS. Our analysis demonstrated that while PFS was similar to TTD with everolimus, there was a significant difference between the 2 measures for nivolumab, suggesting that RECIST-defined PFS may not be the proper endpoint to define progression for immunotherapies. Further evaluation of the association of TTD and other immune-related progression endpoints with overall survival is warranted. Clinical trial information: NCT01668784.
Trastuzumab beyond first progression in cases of HER2-positive advanced gastric or gastro-esophageal junction cancer: Initial results from KSCC1105, a trastuzumab observational cohort study.
Authors: Akitaka Makiyama, Mototsugu Shimokawa, Tomomi Kashiwada, Ikuo Takahashi, Yasunori Emi, Tetsuya Kusumoto, Kazuharu Yamamoto, Hiroshi Ishikawa, Yuji Negoro, Eiji Oki, Hiroshi Saeki, Yoshihiro Kakeji, Hideo Baba, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2017)

93 Background: The concept of using trastuzumab (Tmab) beyond progression (TBP) is currently accepted in HER2-positive metastatic breast cancer. However, TBP has never been investigated in cases of HER2-positive advanced gastric or gastro-esophageal junction (G/GEJ) cancer. KSCC1105 is an observational cohort study designed to investigate the clinical outcomes associated with Tmab combined with chemotherapy including TBP strategy in part, as used in clinical practice, for the treatment of advanced G/GEJ cancer. Methods: Patients (pts) with advanced HER2-positive G/GEJ cancer receiving Tmab between March 2011 and January 2014 were enrolled. Data regarding the baseline characteristics before Tmab plus chemotherapy, pre-specified Tmab-related adverse events, and effectiveness were collected retrospectively. Treatment outcomes were estimated using Kaplan-Meier method and compared using log-rank test. Results: Of 181 enrolled pts, 179 were eligible for analysis and 123 received Tmab as first-line chemotherapy. Among the 123 pts, 85 were able to undergo second-line therapy with or without Tmab. We divided these 85 pts into those treated with Tmab (TBP group, n = 59; 69%) and those treated without Tmab (non-TBP group, n = 26; 31%) in the second-line chemotherapy. The baseline characteristics were similar between the two groups. The median OS was significantly longer in the TBP group (12.8 months; 95% CI 9.0–16.5 months) than in the non-TBP group (7.9 months; 95% CI 5.1–10.7 months) (hazard ratio = 0.50; 95% CI 0.29–0.84; p = 0.010). Infusion-related events were more frequent in the TBP group (20.3%) than in the non-TBP group (11.5%); however, no significant difference was observed. No cardiac event-related death was observed in either group. Conclusions: TBP may be associated with a better prognosis, without severe toxicity. A randomized controlled trial to assess TBP (T-ACT trial; WJOG7112G) is currently being undertaken by the West Japan Oncology Group.
Survival effect of bi-shRNA<sup>furin</sup>/GMCSF DNA-based immunotherapy (FANG) in 123 advanced cancer patients to α-interferon-ELISPTOT response.
Authors: John J. Nemunaitis, Neil N. Senzer, Minal A. Barve, Jonathan Oh, Padmasini Kumar, Donald Rao, Beena O. Pappen, Gladice Wallraven, Frederick A. Fletcher
Journal: Journal of Clinical Oncology (2014)

3077 Background: Over the last 3 years, follow up in a series of Phase I (study # CL-PTL-101) and phase II studies (study # CL-PTL-105, -107, -114, -110, -112) involving FANG (BB-IND 14205) have been performed involving 123 advanced cancer patients, most of whom previously failed prior systemic therapy. ELISPOT assay which quantitatively measures responding mononuclear cell γIFN release to patient personal tumor was utilized to track immunotherapy activity. Methods: Sequential ELISPOT assessment utilizing patient blood mononuclear cells and autologous tumor tissue as antigen source (harvested prior to immune therapy) were measured at baseline and sequentially afterward. Results: Sixty-four advanced cancer patients received monthly intradermal injections of FANG and 53 had FANG constructed but elected other therapy (No FANG group). Median survival of FANG treated patients was 729 days vs. No FANG patients 260 days, p=0.001. Patients (4%) who were ELISPOT positive at baseline or before receiving FANG or who crossed over (1%) from No FANG to FANG as part of Phase II trial were excluded. Forty-seven patients received FANG and had sequential ELISPOT analysis. Thirty-five were ELISPOT positive, and 12 were ELISPOT negative. Median survival of the FANG ELISPOT positive patients was 995 days vs. 554 days of the ELISPOT negative patients (p=0.011). No significant toxic effect was demonstrated to FANG over the three year follow up period. Seventy-one percent of the ELISPOT positive FANG treated patients were alive at 2 years and 44% were alive at 3 years. By comparison, only 25% of the FANG treated patients who were ELISPOT negative were alive at 2 years and none have reached 3 year survival. Conclusions: Treatment with FANG demonstrates safety and suggests survival benefit in coordination with γ-interferon ELISPOT assessment. Randomized phase II assessment is ongoing. Updated results will be presented. Clinical trial information: NCT01061840, NCT01309230, NCT01505166, NCT01453361, NCT01867086, NCT01551745.
Pharmacogenetic analysis of toxicity after 5-fluorouracil (5FU) or 5FU/oxaliplatin therapy for metastatic colorectal cancer: Preliminary results in FFCD 2000–05 trial
Authors: M. Castaing, M. A. Loriot, M. Barrois, I. Miran, C. Mulot, P. Laurent-Puig, J. P. Pignon, M. Ducreux, V. Boige
Journal: Journal of Clinical Oncology (2007)

2508 Background: The FFCD 2000–05 randomized trial compared simplified LV5FU2 followed by FOLFOX6 (arm 1) to FOLFOX6 followed by FOLFIRI (arm 2) in the treatment of metastatic colorectal cancer. The aim was predicting the toxicity profile of oxaliplatin after the first line treatment using pharmacogenetic data. Methods: Patients (pts) with available blood samples were compared to the other pts for clinical prognostic factors (chi2 test). A logistic model was computed to test the association between polymorphisms and toxicity in each arm. An interaction test was used to assess a differential effect according to treatment (predictive effect), in order to identify a predictive effect of oxaliplatin. Grade 3–4 hematological and non-hematological toxicities (H-tox and NH-tox) at 4 months and grade 2–4 neurological at 6 months were the endpoints of the study. Thirteen genetic variants in 10 candidate genes were selected for pharmacogenetic analysis: ERCC1_04 (rs3212961), ERCC1_05 (rs11615), ERCC1_06 (rs3212948), ERCC1_24 (rs3212955), ERCC2_02 (rs1799793), ERCC2_03 (rs13181), ERCC2_06 ( rs238406 ), ERCC2_09 (rs1799787), GSTM1 (null/present), GSTT1 (null/present), TS (TSER, Ins/del6bp) and UGT1A1 (rs8175347). Genotyping was performed using Taqman probes, QMPSF and fragment analysis. Results: 327 pts (156/171) out of 410 were included (61 had no blood samples, 16 had less than 2 cycles, 3 had incomplete data on toxicity, 3 had insufficient DNA). No difference was found between included and excluded pts in the analysis for gender, age, OMS, number of metastatic organs and adjuvant chemotherapy. Pts received similar 5FU doses in both arms. Number of patients with at least one toxicity in arms 1/2 were as followed: 5/54 grade 3–4 H-tox, 28/47 grade 3–4 NH-tox, and 0/103 grade 2–4 neurological. The genotype CC of ERCC2_02 correlated with higher NH-tox at 4 months in arm 2 (p=0.0008, OR=0.31, 95%CI=[0.15–0.62] versus p=0.87, OR=0.93, CI=[0.39–2.21] in arm 1) compared to genotypes CT and TT, with borderline interaction (p=0.05). Conclusions: These preliminary results on early toxicity in first-line are in favour of an effect of ERCC2_02 on NH-tox of FOLFOX6 and a predictive effect on NH-tox of oxaliplatin. [Table: see text]
Ipilimumab in treating Asian patient with advanced melanoma: The preliminary report of Taiwan ipilimumab extended access program group.
Authors: Chun-Feng Wu, Wen Kuan Huang, Jun-Huang Liu, Chen-Yuan Lin, Ta-Chih Liu, Chia-Chi Lin, Wu-Chou Su, Yumin Yeh, Shih-Tsung Cheng, Sheng-Fung Lin, Ruey-Long Hong, John W. C. Chang
Journal: Journal of Clinical Oncology (2015)

e20069 Background: Ipilimumab is proved effective in treating patient with advanced melanoma. However, the clinical experiences of ipilimumab have been limited in Asia. In this preliminary report of Taiwan extended access program (EAP) cohort, the efficacy and safety of ipilimumab in Asian patient with advanced melanoma was accessed. Methods: Patients with advanced melanoma which progressed after at least one line of systemic therapy are eligible in our EAP. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumor assessments were conducted at baseline and week 12. Results: In the Taiwan EAP cohort, 31 were evaluable for response. Of these, 9.6% had an objective immune response, and the immune-related disease control rate was 29.1%. The median duration of follow up were 6.2 (95% CI, 5.3 to 7.5) months. Median progression-free survival was 4.14 (95%CI, 2.8 to 4.5) months and the overall survival was not reached yet, respectively. The 1-year survival rate is 51%. Overall, 79.4% of patients reported an immune-related adverse event (irAE) and 9.6% patients reported grade 3/4/5 irAE. The most frequent irAEs were skin rashes (73.5%), pruritus (51.3%), and diarrhea (25.7%). Conclusions: In this preliminary report, ipilimumab is a feasible treatment option for patients with metastatic melanoma in Asian after previous treatment failed. The efficacy is consistent with previous clinical trials and EAPs in western countries and the toxicities were generally manageable.
Predictive factors and the important role of detectable prostatic specific antigen for the detection of clinical recurrence following robot-assisted radical prostatectomy.
Authors: Silvia Garcia Barreras, François Rozet, Igor Nunes-Silva, Victor Srougi, Mohammed Baghdadi, Rafael Sanchez-Salas, Eric Barret, Marc Galiano, Dominic Prapotnich, Xavier Cathelineau
Journal: Journal of Clinical Oncology (2017)

e567 Background: To evaluate predictive factors associated with detectable prostate-specific antigen (PSA) and clinical recurrence (CR) after robot assisted radical prostatectomy (RARP). Methods: The study included 2500 patients who were treated with RARP between 2000 and 2016. Patients were divided into two groups according to PSA value at 6 weeks after surgery: undetectable PSA (PSA &lt; 0.1 ng/dl) and PSA persistently elevated (PSA ≥ 0.1 ng/dl). Logistic regression analysis was used to evaluate association between covariates and: (1) detectable PSA, (2) CR (positive imaging during follow up) in persistently elevated PSA group. Kaplan-Meier analyses were used to assess CR and cancer-specific mortality (CSM) rates according to PSA persistence after surgery. Results: Overall, 229 patients (9.16%) experienced PSA persistence and from them, 38 (16.5%) had CR. Inside the group of detectable PSA ,146 men (63.75%) received adjuvant treatments and 44 (19.21%) salvage therapies. Gleason ≥ 7, ≥ pT3a, PSA &gt; 10 ng/dl and positive margins were found as significant predictive factors of detectable PSA after surgery (all p &lt; 0.001). Within patients with detectable PSA, stage ≥ pT3a (HR: 2.71; 95% CI, 1.10-6.67; p &lt; 0.029) and to received adjuvant ADT (HR: 13.36; 95% CI, 5.18-34.48; p &lt; 0.001) were associated with CR. CR-free survival in Gleason ≤ 6 at 3-year was 100% vs 60% for Gleason 7(4+3) and 20% for Gleason ≥ 8, (p 0.02). Men aged &lt; 65 years had higher 3-year CR-free survival than older (35% vs 20%, p 0.05). 10-year CSM rates were higher for patients with CR (25% vs 0% no CR; p &lt; 0.001), for men with Gleason ≥ 8 (10% at 10-y; p 0.003) and pathological stage ≥ pT3a (9% at 10-y; p 0.05). CSM rate for patients who received adjuvant ADT+ RT was 20%, 10% for men with ADT and 0% for patients without adjuvant treatment at 10-year (p 0,03). Conclusions: A detectable PSA is clearly affected by factors associated with high risk prostate cancer. Stage pT3 and adjuvant ADT have an important prognostic value in the prediction of CR. Patients with CR , Gleason ≥ 8, pathologic stage ≥ pT3 and those who are treated with adjuvant ADT+ RT must have a close monitoring due to the high rate of mortality.
Methotrexate, rituximab, and temozolomide in CNS lymphoma: The Mayo Clinic experience.
Authors: Vinay Gupta, Robert C. Wolf, Patrick B. Johnston
Journal: Journal of Clinical Oncology (2013)

2058 Background: We present a tertiary center experience with high-dose methotrexate, rituximab and temozolomide (MRT) chemotherapy in both primary and secondary CNS lymphoma. Methods: A retrospective analysis was performed for a total of 27 patients (20 male, 7 female) who underwent treatment at Mayo Clinic, Rochester between November 2010 and October 2012. The median age was 63 years (range 23-73). Of these, 12 patients were diagnosed with primary CNS lymphoma, while 15 patients had secondary CNS lymphoma. All patients received at least 1 cycle of MRT. The most common histological subtype was diffuse large cell lymphoma (23 of 27 patients). Other histological subtypes were high grade lymphoma (2 patients), Burkitt’s lymphoma (1 patient) and Mantle cell lymphoma (1 patient). Results: Of 26 patients, who underwent imaging studies for response assessment after MRT, 14 patients achieved complete response (CR), 4 patients achieved partial response (PR), 2 patients had stable disease, while 6 patients had evidence of disease progression. Overall, the median number of chemotherapy cycles with MRT was 3 (range 1-6). For patients, who achieved CR, the median number of MRT cycles was 4 (range 2-6). MRT was well tolerated. Of 27 patients, who underwent their entire treatment at Mayo Clinic, grade 3 or higher treatment related toxicity were noted to be as follows – neutropenia (9/27), thrombocytopenia (4/27), anemia (7/29), and transaminitis (10/27). 16 of 27 patients proceeded to high dose chemotherapy and autologous stem cell transplant. Out of 16 patients, 14 received BCNU/Thiotepa as conditioning regimen, while 2 patients underwent BEAM conditioning. All 16 patients who underwent transplantation remain in CR at this time. Of the remaining 11 patients, 4 are being planned for autologous transplantation, 2 received and responded to salvage chemotherapy, while 5 patients died of progressive disease. Conclusions: Overall, the MRT regimen was well tolerated. Overall response rate was noted to be 67% (18 of 27 patients) and achieved CR in 54% patients (14 of 26 patients). Patients who underwent autologous stem cell transplantation as consolidation therapy continue to do well at a median followup of 12.5 months (range 2-20 months).
ERCC1 as a predictor of response to induction therapy for stage III non-small cell lung cancer.
Authors: Alessandro Marra, Dirk Kemming, Thomas Krueer, Ulrich Bosse, Maria Netchaeva, Wolfgang Wagner, Olaf M. Koch, Ulf Vogt, Ludger Hillejan
Journal: Journal of Clinical Oncology (2013)

e18511 Background: Neoadjuvant platinum-based chemotherapy in stage III NSCLC offers the chance to eradicate occult metastases and decrease tumor volume, thus improving curative surgical resection rates. A remission after induction therapy is correlated with prolonged survival. However, only 40-50% of patients respond to therapy since there is still no validated predictor for the benefit of platinum based chemotherapy. As DNA repair mechanisms are related with resistance of lung cancer cells to platinum-based chemotherapy, aim of the study was to compare ERCC1 level in lymph node metastases with the degree of pathologic tumor regression after induction treatment and surgery. Methods: From July 2004 to June 2009, 46 NSCLC patients with clinically staged IIIA (N = 32) or IIIB (N = 14) NSCLC underwent at least two cycles of platinum-based induction chemotherapy and combined radio-chemotherapy. After restaging radical surgery was performed. ERCC1 was determined from pretreatment samples of metastatic nodes taken on mediastinoscopy. Real time RT-PCR assays were performed to determine ERCC1 mRNA expression. Tumor regression has been classified on surgical specimen using an score system ranging from grade I (pCR) to grade VI (non-responder). The samples were categorized into three groups according to their ERCC1 expression values and in two groups according to their chemotherapy response (either pCR or non-pCR). Results: A significant correlation between the ERCC1 expression level and the chance to achieve a pCR during a platinum-based chemotherapy could be demonstrated in our samples (P&lt;0.05). Furthermore, the median overall survival in the pCR group was 44 vs. 29 month in the non-pCR group (HR 0.33 [95%-CI: 0.02-1.15]; P=0.06). However, no direct correlation between ERCC1 expression and local or distant metastasis formation could be found. Conclusions: Assessment of ERCC1 mRNA expression in pretreatment tumor tissue is feasible in the clinical setting and predicts response to platinum-based induction therapy. Additional studies are warranted to optimize methodologies for ERCC1 analysis in small tumor samples and to redefine induction protocols on an individual basis, thus enhancing response rates and perhaps outcome.
EGR2 Mutations in Chronic Lymphocytic Leukemia: A New Bad Player
Authors: Daniel Noerenberg*, Emma Young*, Viktor Ljungström, Larry Mansouri, Karla Plevova, Panagiotis Baliakas, Stuart Blakemore, Davide Rossi, Ruth Clifford, Veronika Navrkalova, Lesley-Ann Sutton, Karin E Smedby, Gunnar Juliusson, Chrysoula Belessi, Panagiotis Panagiotidis, Nicholas Chiorazzi, Frederic Davi, Anton W. Langerak, Anna Schuh, Gianluca Gaidano, Jonathan C Strefford, Paolo Ghia, Kostas Stamatopoulos, Sarka Pospisilova, Thorsten Zenz, Richard Rosenquist**, Frederik Damm**
Journal: Blood (2015)