tbuckley/cabot-search huggingface dataset:
Evaluation of the potential for QT/QTc interval prolongation for therapeutic biotechnology products.
Authors: Sarah J Schrieber, Hong Zhao, Patricia Keegan, Brian Booth, Nam Atiqur Rahman
Journal: Journal of Clinical Oncology (2014)

2600 Background: The implementation of the 2005 ICH E14 has included clinical evaluation of QTc prolongation for Therapeutic Biotechnology Products (TBPs). The ability of monoclonal antibodies (mAbs) to cause a QT effect via indirect mechanisms was uncertain. Therefore, we compiled a database of TBPs under development to assess the study designs and outcomes to guide future FDA regulatory recommendations on evaluation of the QT/QTc interval prolongation potential for TBPs. Methods: FDA reviews for QT/QTc study reports of TBPs were collected. Therapeutic drug class and molecular weight, study design features, ECG data analyses, study results, and regulatory recommendations were compiled and analyzed. Results: Fifteen TBPs with completed QT/QTc studies were identified including 13 mAbs and 2 antibody drug conjugates (ADCs). The study designs were varied by study population (patients vs. healthy subjects), dosing (single vs. multiple dosing), and active control (moxifloxacin was used in 2 studies). No large QT/QTc interval changes were observed for any of the mAbs evaluated. Conclusions: The available data suggest that mAbs are unlikely to cause QT/QTc interval prolongation. This finding supports our proposal that no dedicated QT assessment is necessary and clinical ECG monitoring may follow ICH E14 guidelines under negative ‘thorough QT’ (TQT) scenario except in cases where off-target cardiac-related adverse events are observed for specific mAbs. Conclusions cannot be made on the potential QT effect for other TBPs at this time, and the recommendations for well-designed QT studies to generate useful data for this assessment will continue.
E3 Ubiquitin Ligase UBR5 Drives the Growth and Metastasis of Triple-Negative Breast Cancer
Authors: Liqiu Liao, Mei Song, Xin Li, Lili Tang, Tuo Zhang, Lixing Zhang, Yihang Pan, Lotfi Chouchane, Xiaojing Ma
Journal: Cancer Research (2017)

Abstract Patients with triple-negative breast cancers (TNBC) are at high risk for recurrence and metastasis at an early time despite standard treatment, underscoring the need for novel therapeutic modalities. Here, we report for the first time a distinctive and profound role of the E3 ubiquitin ligase UBR5 in the growth and metastasis of TNBC. An analysis of primary TNBC specimen by whole-exon sequencing revealed strong gene amplifications of UBR5 associated with the disease. UBR5 overexpression in TNBC tissues was confirmed at mRNA and protein levels. CRISPR/Cas9-mediated deletion of ubr5 in an experimental murine mammary carcinoma model of TNBC dramatically abrogated tumor growth and metastasis in vivo, which could be reversed completely via reconstitution with wild-type UBR5 but not a catalytically inactive mutant. Loss of UBR5 caused an impairment in angiogenesis within the tumor, associated with increased apoptosis, necrosis, and growth arrest. Absence of UBR5 in the tumor triggered aberrant epithelial-to-mesenchymal transition, principally via abrogated expression of E-cadherin, which resulted in severely reduced tumor metastasis to secondary organs. Use of NOD/SCID mice revealed that tumor-derived UBR5 facilitated tumor growth in a manner completely dependent upon immune cells in the microenvironment, whereas it promoted metastasis in a tumor cell–autonomous fashion. Our findings unveil UBR5 as a novel and critical regulator of tumor growth, metastasis, and immune response and highlight the potential for UBR5 as an effective therapeutic target for the treatment of highly aggressive breast and ovarian cancers that fail conventional therapy. Cancer Res; 77(8); 2090–101. ©2017 AACR.
Does primary site of colorectal cancer become a prognostic factor of patients undergoing curative resection of liver metastases?
Authors: Rika Kizawa, Yasushi Ichikawa, Fumitaka Kumamoto, Yu Sawada, Ryusei Matsuyama, Noritoshi Kobayashi, Ayumu Goto, Motohiko Tokuhisa, Atsushi Ishibe, Masashi Momiyama, Yusuke Suwa, Yukihiko Hiroshima, Kenichi Matsuo, Mitsuyoshi Ota, Hirotoshi Akiyama, Takeharu Yamanaka, Kuniya Tanaka, Itaru Endo
Journal: Journal of Clinical Oncology (2017)

772 Background: The comparison of prognosis between right and left-sided colon cancer (RC, LC) has recently attracted a lot of attention. We examined whether primary location of colo-rectal cancer represents a prognostic factor of patients received curative resection of liver metastasis. Methods: We reviewed all patients undergoing resection of liver metastasis of colo-rectal cancer from1992 to 2013 in the 2 YCU hospitals, and selected eligible 377 patients (59 [15.6 %] with RC, 318 [84.4 %] with LC) undergoing R0 or 1 resection of primary and metastatic lesions. Patients with transverse colon cancer were excluded. We stratified patients according to previously-reported prognostic factors of hepatic metastasis resection, and conducted univariate analysis by Log Rank test to compared overall survival (OS) in each stratum. Using those results, independent factors affecting OS were determined by multivariable Cox regression. Results: The median OS of 377 patients was 66 months, and disease free survival (DFS) was 11.6 months. Univariate analysis revealed that the number and maximum diameter of liver metastasis, existence of other metastasis apart from liver, CEA, and having pre- or post- operative chemotherapy showed significant difference of OS. Primary site did not show significant difference of OS (p = 0.547), but median OS of LC (67 months) was 24 months longer than of RC. As for DFS, there was no significant difference between RC and LC (10.75 vs. 11.6 months, p = 0.873). Multivariate Cox regression analysis was conducted using former factors showing significant difference and primary site. Then primary site was an independent prognostic factor (p = 0.047). LC showed a lower risk than RC (HR: 0.675). Conclusions: The primary site did not affect DFS, but could become a prognostic factor of OS with patients undergoing curative resection of liver metastases. It suggested that curative resection of liver metastases could contribute to prolong survival, regardless of RC or LC. And there is some possibility that the primary site affects prognosis after post-operative recurrence of colo-rectal cancer liver metastases.
Factors impacting the diagnosis of stage IV colorectal cancer: A National Cancer Database (NCDB) analysis.
Authors: Alison Emily Brandeis, Gaurav Goyal, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2015)

e17605 Background: Studies have shown that ethnicity, insurance status and socioeconomic status all play a role in the stage at presentation of colorectal cancer. The purpose of this study is to use the National Cancer Database (NCDB) to evaluate disparities in presentation with stage IV colorectal cancer. Methods: This retrospective analysis surveys the NCDB data on demographic and insurance characteristics of 171,330 newly diagnosed stage IV colorectal cancer cases (18% of total cases) from 2000 to 2012. NCDB is a nationwide oncology outcomes database for ~70% of newly diagnosed cases from 1,658 American College of Surgeons accredited hospitals. Chi-square analysis was used to test statistical significance. Results: Uninsured, Medicaid, and patients age 20-49 had the highest likelihood of presenting with stage IV (each > 25% stage IV). Black and Hispanic patients presented with more than average stage IV disease (22%, 19%), as did patients with household income < $53,000. Medicare patients had less metastatic disease (16%) though they represent half of all colorectal cancers. Other groups presenting with less stage IV disease are those with household income > $53,000 (17%), patients with higher education status (17%), and patients 70-89 (15%) (Table 1). Conclusions: This is the largest epidemiological study analyzing the impact of this combination of factors in the diagnosis of metastatic colorectal cancer. This study shows that ethnic minorities, uninsured or Medicaid patients, those with household income less than $53,000, low education status and aged 20-49 are at greater risk of presenting with stage IV disease. Groups presenting with less metastatic disease include those with Medicare, higher household income, higher education status and age 70-89. Insurance status, race, and age have the biggest impact on stage of presentation. Stage IV colorectal cancer. Insurance % Stage IV Medicare 16 Private 19 Government 19 Uninsured 28 Medicaid 28 Income - $ <43,999 19 44,000-52,999 18 53,000-68,999 17 >69,000 17 Race White 17 Hispanic 19 Black 22 Age 20-49 26 50-69 20 70-89 15 Education – (% patients without HS degree) 23%+ 19 15-22.9% 18 11-14.9% 18 6-10.9% 17 <6% 17 Overall Stage IV 18 P < 0.001 for all comparisons.
Association of low expression of VEGF121 soluble isoform with prognostic impact and survival in patients with activated B-cell-like (ABC-like) diffuse large B-cell lymphoma (DLBCL) from the CORAL trial.
Authors: Catherine Thieblemont, Nicolas Mounier, Samia Mourah, Remi Houlgatte, Edouard Hirchaud, Wendy Cuccuini, Loic Ysebeart, Dominique Bron, Philippe Gaulard, Christian Gisselbrecht, Josette Briere
Journal: Journal of Clinical Oncology (2012)

8048 Background: Gene expression profiling (GEP) has demonstrated that survival of DLBCL is influenced by the origin of the tumor cells (COO), germinal center-like (GC-like) vs ABC-like (Alizadeh et al. 2000), but also by the tumor microenvironment, particularly the angiogenesis (Lenz et al., 2008). To further understand the prognostic impact of these tumoral characteristics, we analysed the prognostic impact of COO and the expression of biomarkers involved in angiogenesis, in a selected population of 36 patients with relapsed/refractory DLBCL included in CORAL (Gisselbrecht, ASCO 2011). Methods: Expression of 5 biomarkers including VEGF (isoforms 121, 165, and 189), and their receptors (VEGFR-1 and R-2) was assessed by quantitative qRT-PCR after total RNA extraction and cDNA synthesis of tumor samples. COO was determined by GEP, and progression free- (PFS) and overall- (OS) survivals were analysed. Results: In the study population, VEGF121 expression below the median was associated to a better outcome, with 4 year-PFS at 63% vs 33% (p=.053), and a 4-year-OS at 79% vs 37% (p = 0.032), respectively. VEGF-165 -189, VEGF-R1, -R2 did not have any significant impact. Eighteen patients were predicted as ABC-like DLBCL and 18 as GCB-like DLBCL. In patients with ABC-like DLBCL, low VEGF121 level was associated to a significantly better survival than in those with high VEGF121 level: 4-year OS at 100% vs 36% (p=.011). The type of induction treatment, R-ICE or R-DHAP, did not influence the outcome. The differences in outcome according to VEGF isoforms were not significant among CGB patients. Conclusions: Our data suggest that angiogenesis plays a central role in ABC-like DLBCL. VEGF121 seemed to be a key player in this context and should be proposed as a target in the treatment of patients with ABC-like DLBCL.
SELECT: Randomized phase III study of docetaxel (D) or pemetrexed (P) with or without cetuximab (C) in recurrent or progressive non-small cell lung cancer (NSCLC) after platinum-based therapy.
Authors: Edward S. Kim, Marcus A. Neubauer, Allen Lee Cohn, Lee Steven Schwartzberg, Lawrence E. Garbo, John Robert Caton, Francisco Robert, Terry Katz, Sreenivas Chittoor, Lorinda Simms, Scott Saxman
Journal: Journal of Clinical Oncology (2012)

7502 Background: SELECT investigated whether the addition of C to standard chemotherapy improved progression-free survival (PFS) in patients (pts) with recurrent or progressive NSCLC after failure of platinum-based therapy. Methods: SELECT was a multicenter, open label, randomized phase III trial. Per investigator choice, pts received either P (500 mg/m 2 ) or D (75 mg/m 2 ) on day 1 and then were randomized within each group to chemotherapy plus C (400/250 mg/m 2 ) (initial/weekly) or chemotherapy alone. Therapy was given for up to six 3-week cycles; pts randomized to C continued weekly monotherapy until disease progression or unacceptable toxicity. The primary objective was PFS for PC vs. P as determined by an Independent Review Committee (IRC). Secondary endpoints included overall survival (OS), objective response rate (ORR) and duration of response (DOR) by IRC, and safety. Preplanned subgroup analyses for epidermal growth factor receptor (EGFR) staining intensity by immunohistochemistry and histology were performed. Results for PC vs. P only are presented. Results: Between Jan 2005 and Feb 2010, 938 total pts were randomized. Baseline demographics were comparable between PC (n=301) and P (n=304): median age 64 years; male 60%; Caucasian 88%; KPS 80-100/60-70 84%/16%; squamous/non-squamous 24%/76%. Median PFS (months) PC: 2.89 and P: 2.76 (hazard ratio [HR] =1.03 [95% confidence interval (CI)=0.87-1.21]; p=0.76). Median OS (months) PC: 6.93 and P: 7.79 (HR=1.01 [95% CI=0.86-1.20]; p=0.86). ORR PC: 6.6% and P: 4.3% (odds ratio =1.59 [95% CI=0.78-3.26]; p=0.20). Median DOR (months) PC: 4.17 and P: 6.93 (HR=1.58 [95% CI=0.74-3.36]; p=0.24). There were no statistical differences in efficacy based on histology or EGFR staining intensity. More drug-related AEs/SAEs were observed in the PC arm, with differences mainly attributable to skin toxicities, GI (diarrhea/stomatitis), and hypomagnesemia. Conclusions: The addition of C to P did not improve efficacy in this pt population. Further biomarker analyses are planned. The safety profiles for C and P were consistent with existing data and no new safety signals were observed.
Household secondhand smoke exposure among community-dwelling cancer survivors in the United States.
Authors: Oladimeji Akinboro, Odunayo Olorunfemi, Ian Robert Hantman, Prasanta Basak, Elizabeth Phillips, Daniel Pomerantz, Bernard Bernhardt, Rasim A. Gucalp, Stephen Jesmajian
Journal: Journal of Clinical Oncology (2015)

9568 Background: There is little extant data regarding the prevalence of secondhand smoke exposure among cancer survivors. We sought to estimate the prevalence of household secondhand smoke exposure, as well as its association with active smoking, among community-dwelling cancer survivors in the United States (US). Methods: We abstracted data from the US National Health and Nutrition Examination Survey for 1,742 community dwelling adults, aged 20 years and older sampled nationwide from 2005-2012, who had survived at least 2 years since their first cancer diagnosis. We calculated the age-adjusted population-based prevalence of household secondhand smoke exposure. Multivariable logistic regression was utilized in examining the association between household secondhand smoke exposure and survivors’ smoking status while controlling for age, gender, race, marital status, education, income, having a regular source of routine care, and cancer site. Survey weights were applied in estimating the population-based prevalence rates, odds ratios (OR), and 95% confidence intervals (CI). Results: The age-adjusted prevalence of household smoke exposure among adult cancer survivors was 22.4% (CI 17.5-27.3%). Among those exposed, 76% were females (CI 69.8-81.8%), 82% were active smokers (CI 75.5-87.1%), and 55% had survived a smoking-related cancer (CI 45.3-64.5%). Higher odds of household secondhand smoke exposure were seen with: i) active smoking (OR = 92.56, CI 46.31-185.01); ii) former smoking (OR = 2.07, CI 1.27-3.39); iii) living below federal poverty level (OR = 2.66, CI 1.29-5.48); and iv) cancers caused by active smoking (OR = 2.62, CI 1.70-4.04). Conclusions: The risk of household secondhand smoke exposure was highest among actively smoking adult cancer survivors but the direction of causality between active smoking and household secondhand smoking among cancer survivors cannot be inferred from this cross-sectional analysis. Nonetheless, these findings suggest that smoking cessation programs for smoking cancer patients may also need to target the households of such patients. Prospective studies are needed to parse out the effects of secondhand smoking on long-term outcomes among adult cancer survivors.
Nomogram for predicting breast-conservation surgery after neoadjuvant chemotherapy.
Authors: Min Kyoon Kim, Wonshik Han, Hyeong-Gon Moon, Jisun Kim, Soo Kyung Ahn, Jun Woo Lee, Dong Young Noh, Taeryung Kim, Ju yeon Kim
Journal: Journal of Clinical Oncology (2013)

1128 Background: The indications for neoadjuvant systemic treatment (NST) have broadened to early breast cancer patients and more patients can undergo breast conservation with results in better cosmetic outcomes. However, a significant number of patients with operable breast cancer still require mastectomy after NST with a small number of patients experiencing disease progression which may hinder complete surgical resection. Therefore, accurate prediction of each patient’s likelihood of achieving breast conservation after NST is important for establishing a treatment plan for patients with operable breast cancers. Methods: We identified 534 women from the Seoul National University Hospital Breast Care Center, who were stage II and III, and treated with neoadjuvant chemotherapy and surgery from Jan. 2001 to Dec. 2010. Breast conservation surgery (BCS) and tumor size reduction to less than 3cm were clinical outcome variables for nomograms, and we analyzed the various clinicopathologic factors best predicting these outcomes. To develop well-calibrated and exportable nomograms for BCS and for residual tumor size, we built each model in a training cohort and validated it in an independent validation cohort. Results: Of the 513 patients, pCR was observed in 10.5% and BCS was performed in 50.1%. The nomogram for predicting BCS and tumor size reduction to less than 3cm were constructed using logistic regressing model. Initial tumor size(p&lt;0.001), the distance between the lesion and the nipple (p &lt; 0.001), the presence of suspicious calcifications in the mammography (p = 0.0127) and multicentricity (p = 0.0146) were independently associated with breast conservation surgery. ER status (p = 0.001), initial tumor size (p &lt; 0.001), histologic type (p = 0.012) were independently associated with a residual tumor size &lt;3cm. Mastectomy rate in the larger than 3cm tumors were 72.7%, and breast conservation surgery in smaller than 3cm tumors were 63.2%. (p &lt; 0.001). Conclusions: In conclusion, we have established a new model to predict BCS and residual tumor size after NST. The model showed the outperformed prediction accuracy compared with previous similar models with reflecting novel factors impacting on surgical decision making.
Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study
Authors: Joshua Bauml, Tanguy Y. Seiwert, David G. Pfister, Francis Worden, Stephen V. Liu, Jill Gilbert, Nabil F. Saba, Jared Weiss, Lori Wirth, Ammar Sukari, Hyunseok Kang, Michael K. Gibson, Erminia Massarelli, Steven Powell, Amy Meister, Xinxin Shu, Jonathan D. Cheng, Robert Haddad
Journal: Journal of Clinical Oncology (2017)

Purpose There are no approved treatments for recurrent/metastatic head and neck squamous cell carcinoma refractory to platinum and cetuximab. In the single-arm, phase II KEYNOTE-055 study, we evaluated pembrolizumab, an anti-programmed death 1 receptor antibody, in this platinum- and cetuximab-pretreated population with poor prognosis. Methods Eligibility stipulated disease progression within 6 months of platinum and cetuximab treatment. Patients received pembrolizumab 200 mg every 3 weeks. Imaging was performed every 6 to 9 weeks. Primary end points: overall response rate (Response Evaluation Criteria in Solid Tumors v1.1, central review) and safety. Efficacy was assessed in all dosed patients and in subgroups on the basis of programmed death ligand 1 (PD-L1) expression and human papillomavirus (HPV) status. Results Among 171 patients treated, 75% received two or more prior lines of therapy for metastatic disease, 82% were PD-L1 positive, and 22% were HPV positive. At the time of analysis, 109 patients (64%) experienced a treatment-related adverse event; 26 patients (15%) experienced a grade ≥ 3 event. Seven patients (4%) discontinued treatment, and one died of treatment-related adverse events. Overall response rate was 16% (95% CI, 11% to 23%), with a median duration of response of 8 months (range, 2+ to 12+ months); 75% of responses were ongoing at the time of analysis. Response rates were similar in all HPV and PD-L1 subgroups. Median progression-free survival was 2.1 months, and median overall survival was 8 months. Conclusion Pembrolizumab exhibited clinically meaningful antitumor activity and an acceptable safety profile in recurrent/metastatic head and neck squamous cell carcinoma previously treated with platinum and cetuximab.
Predicting colorectal cancer recurrence by utilizing multiple-view multiple-learner supervised learning.
Authors: Jason Castellanos, Qi Liu, R. Daniel Beauchamp, Bing Zhang
Journal: Journal of Clinical Oncology (2017)

635 Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality in the United States. A key therapeutic dilemma in the treatment of CRC is whether patients with stage II and stage III disease require adjuvant chemotherapy after surgical resection. Attempts to improve identification of patients at increased risk of recurrence have yielded many predictive models based on gene expression data, but none are FDA approved and none are used in standard clinical practice. To improve recurrence prediction, we utilize a machine learning approach to predict recurrence status at 3 years after diagnosis. Methods: A dataset was curated from six publically available microarray datasets, and multiple views were generated to include information from non-tumor tissue gene expression patterns, gene set structure, protein-protein interaction network structure, previously curated molecular signatures, and identified tumor suppressor/driver mutations. These views were used to train a diverse pool of base learners using 10x 10-fold cross-validation. Stacked generalization was used to train an ensemble model, also known as a meta-learner, from the predictions of these base learners. Results: The performance of microarray trained models was significantly better compared to models trained on clinical data (Paired Wilcoxon signed rank test, p = 1.49 x 10 -8 ), demonstrating that molecular data predicts recurrence significantly better than basic clinical data. Review of the model training performances revealed that non-linear classifiers often outperform linear classifiers, and that ensemble methods can also enhance performance. We also demonstrate the feasibility of the multiple-view multiple learner (MVML) supervised learning framework to generate and integrate predictions across a diverse set of learners, with the performance of the meta-learner exceeding or matching that of the best base learners across all performance metrics. Conclusions: This work represents the first effort to use ensemble learning to predict CRC recurrence and highlights the promise of ensemble learning to improve the performance of predictive models in order to realize the goals of precision medicine.
Corrigendum to “An “all 5 mm ports” technique for laparoscopic day-case anti-reflux surgery: A consecutive case series of 205 patients” [Int. J. Surg. 35 (2016) 214–217]
Authors: L.M. Almond, V. Charalampakis, P. Mistry, M. Naqvi, J. Hodson, G. Lafaurie, J. Matthews, R. Singhal, P. Super
Journal: International Journal of Surgery (2017)
Reply to Tan et al.
Authors: Hironori Yamamoto, Yoshimasa Miura, Satoshi Shinozaki, Yoshikazu Hayashi, Hirotsugu Sakamoto, Alan Lefor
Journal: Endoscopy (2017)

We thank Tan et al. for their interest in our article. I totally agree with their opinion that the pocket-creation method (PCM) mimics the submucosal tunneling method. Actually, the PCM originated from the tunneling method, which I first described in colorectal endoscopic submucosal dissection (ESD) in 2010 [1].