tbuckley/cabot-search huggingface dataset:
The efficacy and safety of nivolumab in advanced non-small cell lung cancer in clinical practice in Japan: A multicenter analysis.
Authors: Keigo Kobayashi, Katsuhiko Naoki, Ichiro Nakachi, Yoshitaka Oyamada, Morio Nakamura, Takashi Inoue, Hiroki Tateno, Fumio Sakamaki, Koichi Sayama, Tsuyoshi Terashima, Hidefumi Ko, Makoto Nishino, Keita Masuzawa, Hanako Hasegawa, Tadashi Manabe, Daisuke Arai, Hiroyuki Yasuda, Ichiro Kawada, Kenzo Soejima, Tomoko Betsuyaku
Journal: Journal of Clinical Oncology (2017)

e20577 Background: Nivolumab, an immune checkpoint inhibitor, is now approved as standard treatment for pre-treated advanced non-small cell lung cancer (NSCLC) based on the results from mega clinical trials with carefully selected patients. We sought to clarify the real-world efficacy and safety of nivolumab and to identify the clinical factors influencing the efficacy. Methods: This study enrolled 142 patients with pre-treated advanced NSCLC who had been administered nivolumab (3mg/kg, Q2W) from January to July 2016 at Keio University and affiliated hospitals in Japan. We retrospectively evaluated objective responses, adverse events (AEs), and analysed clinical factors associated with the response. Results: The overall response rate and disease control rate were 17% and 62%, respectively. The rate of any grade AEs was 45%, while the rate of grade 3-4 AEs was 13%. Among patient’s clinical factors such as age, gender, ECOG performance status, types of carcinoma, epidermal growth factor receptor ( EGFR)/ anaplastic lymphoma receptor tyrosine kinase (ALK) mutation status, smoking status, number of previous treatment lines, presence of central nervous system (CNS) metastasis and presence of prior radiotherapy, “ EGFR/ALK mutation negative” and “administration of prior radiotherapy” were independently associated with the good response to nivolumab treatment by multivariate logistic regression analysis (OR NA/ p &lt; 0.01, OR 5.4/ p &lt; 0.01, respectively). None of the 19 EGFR/ALK mutation positive patients showed response. Although a significant difference was not recognized between “current, former smokers” and “never smokers” (chi-square test, p = 0.1), a subsequent analysis showed smoking pack years (PY) was significantly higher in responders than in non-responders ( t-test, p = 0.035). Conclusions: The objective responses and the profiles of AEs confirmed in our study were similar to those observed in Checkmate 057/017 trials. We can use nivolumab safely regardless of age or number of treatment lines. EGFR/ALK mutation and presence of prior radiotherapy were key clinical factors statistically associated with the nivolumab efficacy.
Clinico-epidemiologic characteristics and patterns of care in glioblastoma multiforme: Data from a single-institution series.
Authors: Andrew Samir Iskandar, Wesley Kerr, Andrew Hwang, Stephanie Farrell, Michael Del Rosario, Steven C. Plaxe, Constantin Dasanu
Journal: Journal of Clinical Oncology (2018)

e14069 Background: Glioblastoma multiforme (GBM) is a brain tumor with dismal prognosis. Current standard treatment consists of maximal surgical excision followed by adjuvant chemoradiotherapy. Methods: With IRB approval, we performed a retrospective chart review of all consecutive GBM patients seen at our institution between 2007-2017. Clinico-epidemiologic data including age, gender, tumor location/size at diagnosis, and disease course were collected. Therapy and survival were analyzed. Our findings were compared to data obtained from the surveillance, epidemiology, and end results program (SEER). Statistical analysis: Survival analysis was performed using multivariate Cox proportional hazard regression with censoring to calculate hazard ratios (HR) and time to death (TTD). Fisher exact statistics were used to compare frequencies of binary events across age ranges and Chi squared tests were used to compare categorical descriptors. Results: We identified 156 patients with GBM (n = 156). The mean age at diagnosis was 68 years; 61% (95/156) were male. A total of 56% (88/156) patients had surgical excision, 72% (112/156) received radiation therapy, and 62% (97/156) received chemotherapy. Longer survival correlated with younger age at diagnosis (HR 0.97 per year, p = 0.002), surgical excision (TTD 1138 vs 733; HR 0.56, p = 0.003) and chemotherapy use (TTD 935 vs 729; HR 0.57, p = 0.027). Tumor size was not shown to correlate with survival (HR 1.01 per cm, p = 0.88). Neither gender nor radiation therapy were shown to correlate with survival (HR 1.18; p = 0.39 & HR 1.17; p = 0.57, respectively). Conclusions: Younger patients and those treated with surgical resection and chemotherapy displayed a better overall survival. Tumor location, size, patient gender, and use of radiation therapy were not associated with survival in our cohort. Subgroup analysis in older ( > 70 years of age) vs younger (£70 years of age) GBM patients showed a significantly shorter survival in the former group. Final statistical analysis, including survival analysis, comparison to SEER data and significance will be presented.
Prognostic value of tumor heterogeneity evaluated by FDG-PET/CT imaging in lung cancer patients.
Authors: Nicola Marie Hughes, Tian Mou, Kevin N O'Regan, Peter Murphy, Janet N O'Sullivan, Eric Wolsztynski, Jian Huang, Marcus Kennedy, Janet F. Eary, Finbarr O'Sullivan
Journal: Journal of Clinical Oncology (2016)

11564 Background: FDG-PET/CT (FDG) scans are routinely used for staging lung cancer. More detailed analysis of these scans may be fruitful. The present study reviews a sample of scans to evaluate the association between the heterogeneity of FDG and patient survival. Methods: A retrospective random sample of 104 lung cancer patients, who underwent staging using clinical FDG scanning prior to treatment, was considered. The volume of interest (VOI) for the primary tumor site was extracted for image analysis. Heterogeneity was defined as the degree to which the 3-D FDG-PET uptake within the VOI deviates from a centrally concentrated, radially diminishing spatial pattern. This technique was originally proposed and validated in the context of FDG sarcoma data. Patient survival was analyzed using standard multivariate Cox proportional hazard regression. The variables used included PET stage, age and gender, as well as the heterogeneity and maximum FDG uptake (SUVmax) within the VOI. Results: 104 patients (mean age 67, range 32-86; 61% male) were available for analysis. The PET staging distribution had 27 Stage IA/B, 14 Stage II A/B, 52 Stage III/IV and 11 Unknown. Mean tumor heterogeneity was 9.06% with a range 0.56%- 36%. In univariate analysis PET Stage, SUVmax and Heterogeneity were all found to be strongly associated with survival; age and gender were not. Multivariate analysis found that heterogeneity and PET stage were both significant but SUVmax, age and gender played no significant role. An increase of 7% (1 standard deviation) in the heterogeneity is associated with a 30% increase in risk of death (p = 0.023). Conclusions: Quantitative assessment of tumor heterogeneity based on FDG-PET/CT scan data may provide a potential refinement of the PET staging process. The study motivates consideration of heterogeneity as an indicator of treatment response. Funding support SFI 11/PI/1027. Hazard Ratio p-value Pet Stage IIA/B 4.428 0.005 Pet Stage III/IV 7.223 0.000 Heterogeneity 1.331 0.023 Age 1.010 0.519 Gender 1.638 0.076 SUVmax 0.992 0.968
Attitudes of breast cancer patients and oncology staff towards randomized clinical trials in southwest Nigeria.
Authors: Jim Leng, Abiola Falilat Ibraheem, Anthonia Chima Sowunmi, Adeyinka Francis Ademola, Atara Ntekim, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2018)

e18663 Background: Clinical trials have continued to improve treatments for breast cancer in the United States and other developed countries. In Nigeria, there is an urgent need to develop trials that could bring novel treatments and reduce global disparities in survival. Apart from infrastructure deficits, practical and cognitive barriers to clinical trial participation present additional challenges. We aim to characterize these barriers to identify points for intervention. Methods: This cross-sectional study was conducted in two teaching hospitals in Ibadan and Lagos, Nigeria. Breast cancer patients and oncology staff (including physicians, residents, and nurses) in the surgical and radiation oncology clinics were surveyed to assess their knowledge, attitudes, and perceived barriers related to randomized clinical trials (RCTs) for cancer therapy. Results: 30 breast cancer patients and 36 oncology staff were surveyed. Among patients, 93% have never heard of clinical trials before. When given a description of clinical trials, many patients expressed concerns over serving as research subjects in RCTs (63%), citing treatment risks (54%). Amongst 7 potential barriers to clinical trials, treatment side effects and lack of patient understanding were the factors mostly commonly cited by both patients and staff. In comments, patients most frequently reported “potential benefit from trial treatment” (n = 6) and “desire to help future patients” (n = 4) as reasons to participate in clinical trials. 89% of oncology staff were very interested in clinical trials, and 92% would recommend RCTs to patients. Most patients (86%) agreed that those who participate in clinical trials make an important contribution to society, and providers strongly agreed (mean 4.7 on a 5-point Likert scale) that clinical research in oncology is important for improving future cancer care. Conclusions: Lack of patient understanding and concerns over treatment side effects are major cognitive barriers to participation. With a high level of interest among oncology staff, targeted educational programs could be developed to improve patient understanding and willingness to participate in cancer clinical trials.
Chronic tracheoesophageal fistula successfully treated using Amplatzer septal occluder
Authors: Mario Traina, Michele Amata, Lavinia De Monte, Antonino Granata, Dario Ligresti, Ilaria Tarantino, Caterina Gandolfo
Journal: Endoscopy (2018)

Tracheoesophageal fistula (TEF) is a serious life-threatening condition that appears in critically ill patients with a prolonged history of mechanical ventilation. Enteral feeding and dietary support combined with surgery is the gold standard. In selected patients, TEF healing can be ensured by a mini-invasive approach using an Amplatzer septal occluder (AGA Medical Corporation), intended for cardiac septal defect closure [1]. The Amplatzer septal occluder, which is composed of a nitinol mesh, has two self-expandable disks connected by a thin diameter waist ([Fig. 1]) and ensures mechanical closure of the two sides of the fistula, making a potential platform for subsequent tissue ingrowth [2].
Genetic Variants Associated with Circulating Fibroblast Growth Factor 23
Authors: Cassianne Robinson-Cohen, Traci M. Bartz, Dongbing Lai, T. Alp Ikizler, Munro Peacock, Erik A. Imel, Erin D. Michos, Tatiana M. Foroud, Kristina Akesson, Kent D. Taylor, Linnea Malmgren, Kunihiro Matsushita, Maria Nethander, Joel Eriksson, Claes Ohlsson, Daniel Mellström, Myles Wolf, Osten Ljunggren, Fiona McGuigan, Jerome I. Rotter, Magnus Karlsson, Michael J. Econs, Joachim H. Ix, Pamela L. Lutsey, Bruce M. Psaty, Ian H. de Boer, Bryan R. Kestenbaum
Journal: Journal of the American Society of Nephrology (2018)

Background Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences. Methods We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR&lt;30 ml/min per 1.73 m 2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log–transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR. Results We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 ( P =3.0×10 −24 ), lies upstream of CYP24A1 , which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO , the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level. Conclusions Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
Therapeutic response monitoring using digital PCR for patient-specific circulating tumor DNA identified by an esophageal squamous cell carcinoma-specific sequencing panel.
Authors: Takeshi Iwaya, Fumitaka Endo, Yasushi Sasaki, Yuji Akiyama, Akira Sasaki, Mari Masuda, Tesshi Yamada, Takashi Tokino, Satoshi Nishizuka
Journal: Journal of Clinical Oncology (2018)

e24089 Background: Esophageal squamous cell carcinoma (ESCC) is belligerent cancer with a poor prognosis. At present, no specific ESCC biomarkers for therapeutic monitoring have been established. This study aimed to monitor ESCC therapeutic response using circulating tumor DNA (ctDNA) by digital PCR (dPCR) with individual ESCC tumor-specific mutations identified from an originally-designed ESCC-specific sequencing panel. Methods: Twenty-six ESCC patients were enrolled (Stage I/II/III/IV: 5/3/12/6). A mutation screening of primary ESCCs was performed by amplicon sequencing using the ESCC panel targeting 31 genes. The ctDNAs level was evaluated by dPCR using 41 originally-designed primer/probe sets based on uniquely-identified mutations for individual patient. First-line therapies included surgery, chemoradiotherapy, and chemotherapy (docetaxel/CDDP/5-FU) for 6, 1, and 20 patients, respectively. With the median follow-up was 459 days, 288 blood samples were examined for ctDNA. Results: The ESCC panel revealed nine mutations per sample. Mutations were present in TP53 (26 of 26, 100%) and NFE2L2 (8 of 26, 31%). The patients with NFE2L2 mutation were more resistant to chemotherapy than those of wild-type (P = 0.0001). Among 41 mutations identified from primary tumors were analyzed in pre-treatment blood, 34 (83%) were detectable as a ctDNA. In 35 mutations from Stage II or higher cases, ctDNA was detectable in 97% (34/35). The Stage-stratified average mutant allele frequencies (MAF) of ctDNA were 0, 0.53, 5.03, and 12.74 in Stage I, II, III, and IV, respectively. The MAF of good responders could decrease to 0.00 after one cycle of chemotherapy, whereas the MAF of non-responders stayed high levels throughout multiple cycles. Of note, a patient who had a recurrence with a lymph node metastasis after 1.5 years of resection with curative intent for stage II ESCC showed that ctDNA had been detected six months before the recurrence was noticeable by CT scan. Conclusions: With the ESCC panel and dPCR, the patient-specific ctDNA monitoring readily indicates the disease Stage and possibly facilitates an early recurrence detection of ESCC.
Ubiquitin ligase RNF8 suppresses Notch signaling to regulate mammary development and tumorigenesis
Authors: Li Li, Kiran Kumar Naidu Guturi, Brandon Gautreau, Parasvi S. Patel, Amine Saad, Mayako Morii, Francesca Mateo, Luis Palomero, Haithem Barbour, Antonio Gomez, Deborah Ng, Max Kotlyar, Chiara Pastrello, Hartland W. Jackson, Rama Khokha, Igor Jurisica, El Bachir Affar, Brian Raught, Otto Sanchez, Moulay Alaoui-Jamali, Miguel A. Pujana, Anne Hakem, Razq Hakem
Journal: Journal of Clinical Investigation (2018)

The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.
The reasons why re-biopsies were not performed after failure with EGFR-TKI.
Authors: Tomoyo Oguri, Atsushi Horiike, Ryo Ariyasu, Junji Koyama, Masafumi Saiki, Tomoaki Sonoda, Natsuki Takano, Shingo Nishikawa, Satoru Kitazono, Noriko Yanagitani, Fumiyoshi Ohyanagi, Makoto Nishio
Journal: Journal of Clinical Oncology (2017)

e20540 Background: Repeat biopsy becomes important to determine subsequent treatment after failure of EGFR-TKI. However, some patients did not receive re-biopsy in real world. Here we retrospectively analyzed the reasons why the patients did not receive re-biopsy. Methods: We reviewed medical records of 235 patients treated with EGFR-TKI at our institution between January 2014 and September 2016 and analyzed the treatment, the progression site after failure of EGFR-TKI and the reasons why they did not receive re-biopsy. Results: 127 of 235 (54%) patients had tumor progression after treatment with EGFR-TKI and 93 (73.2%) of 127 patients received re-biopsy and 34 (26.8%) patients didn’t. The characteristics of 34 patients who did not received re-biopsy were; the median age, 67 years (29-83), male/ female: 12/22, PS0-1/2 ≥:27/7, stage IV/recurrence/other:20/10/4, smoking history never/ex/current: 15/17/2, histology : adeno/other 34/0, EGFR mutation type; 19del/L858R/Other = 13/15/6, prior EGFR-TKI; Gefitinib/Erlotinib/Afatinib/other: 22/9/2/1. The commonest reason why they did not receive re-biopsy was no target lesion to get biopsy (n = 13,38%). CT scans of these patients were retrospectively evaluated and it was confirmed that there were no lesions that could be accessed safely at that time. Central nervous system lesions, multiple small pulmonary lesions and bone metastasis were unaccessible lesions. Although 21 patients had accessible lesions including lung, superficial lymph nodes, pleural effusion, liver, they did not receive re-biopsy because of patient refusal (n = 9), worsening of general condition (n = 3), need for other therapy immediately (ex: chemotherapy, radiotherapy) (n = 3), old age (n = 2), existence of de novo T790M (n = 2), complications (n = 1) and physician’s choice (n = 1). Conclusions: Some patients who did not recieve re-biopsy had some target lesions and it could be increase the re-biopsy rate.
Whole genome and transcriptome sequencing of lung cancer: Options for personalized cancer treatment.
Authors: Negar Chooback, Cheryl Ho, Yaoqing Shen, Erica S Tsang, Yongjun Zhao, Andrew J. Mungall, Richard Moore, Howard John Lim, Daniel John Renouf, Karen A. Gelmon, Stephen Yip, Steven Jones, Janessa J. Laskin, Marco Marra
Journal: Journal of Clinical Oncology (2017)

e20567 Background: Targeted therapy against driver mutations has revolutionized lung cancer management. The Personalized OncoGenomics (POG) program uses whole genome and transcriptome derived information to build pathways and identify potential therapeutic targets. We examined the lung adenocarcinoma (LUAD) patients enrolled in POG in order to identify novel cancer drivers and correlate the findings with clinical characteristics. Methods: Patients with advanced LUAD and survival &gt; 6 months were eligible. Blood, archival and fresh tumour specimens were subjected to comprehensive DNA and RNA sequencing. SNV data were compared to the TCGA-LUAD cohort using the cBioPortal platform. Whole tumor transcriptome data were compared to matched normal blood specimens. Clinical characteristics were collected by chart review. Results: 30 POG LUAD cases were analyzed. Baseline characteristics; 47% female, median age 60, 57% never/light smokers, biopsy site - 50% lung, 50% metastatic lesion. High mutations rates in TP53, KRAS, NF1 were comparable to the TCGA-LUAD cohort. Four genes ( GOLGA6L2, FAM186A, ARMCX4 and RBMXL3), were mutated 17-27% of the time in POG patients, while the rate in TCGA-LUAD was &lt; 1%. Driver mutations ( KRAS and EGFR) and known fusions (ROS1 and RET) were present in 63%.Other potential drivers included ERBB3, ERBB2, SDC:NRG1 fusion were identified. Copy number alterations and expression data revealed variations in cell cycle, mTOR, androgen receptor,HSP90, MET and Wee1 proteins, all potential targets for therapy. PD-L1 over-expression and a strong smoking signature were not mutually exclusive to EGFR copy gain and FGFR3 overexpression. Conclusions: The molecular signature of NSCLC is complex and involves multiple key oncogenic drivers. Whole genome sequencing and transcriptome data should be used together to map out the pathways of carcinogenesis and reliably identify targets for therapy.