tbuckley/cabot-search huggingface dataset:
The role and regulatory mechanism of NFIB in the metastasis of colorectal cancer.
Authors: Zhi-hang Zhou
Journal: Journal of Clinical Oncology (2018)

e24009 Background: Distant metastasis is the main cause of colorectal cancer (CRC)-related mortality, but the underlying mechanism remains largely elusive. It has been revealed that acidic microenvironment in solid tumors promoted invasion and metastasis of tumors. Methods: CRC cell lines SW620 and HCT116 cells were cultured in pH 6.5 medium for more than 3 months to get acid-adaptive (AA) cells. Gene knock-down was achieved by lentivirus transfection. CRC cells were injected into the spleen of nude mice to evaluate the metastatic capacity of CRC cells. Results: SW620-AA and HCT116-AA cells have stronger invasive capacity and metastatic potential than normal cells. Microarray analysis showed that the expression of nuclear factor NFIB was significantly elevated in SW620-AA and HCT116-AA cells. Knock-down of NFIB in SW620 cells dramatically inhibited proliferation, invasion in vitro and liver metastasis in vivo. Moreover, we found that NFIB was over-expressed in CRC tissues in comparison with adjacent normal tissues. High expression of NFIB correlated with lymph node metastasis, differentiation degree and overall survival of CRC patients. Immunoprecipitation and mass spectrum assay revealed that the proteasome activator subunit 3 (PSME3) could bind to NFIB. Knock-down of PSME3 in SW620 cells significantly reduced the stability of NFIB protein, which did not influence the transcription of NFIB gene. Conclusions: All together, these results demonstrated that NFIB promoted invasion and metastasis of CRC cells, which was stabilized by PSME3.
The expression profile of biomarkers in squamous cell carcinoma of the anal canal and their influence on treatment outcomes: Preliminary results.
Authors: Camila Motta Venchiarutti Moniz, Rachel Pimenta Riechelmann, Suilane Coelho Ribeiro, Giovanni Mendonca Bariani, Thomas Giollo Rivelli, Cintia Ortega, Allan Andresson Lima Pereira, Sibele Inacio Meireles, André Chen, Caio Nahas, Jorge Sabagga, Renata A. Coudry, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2016)

e15059 Background: Chemoradiation (CRT) is the standard curative treatment for Squamous Cell Carcinoma of the Anal Canal (SCCAC). However, some patients develop progressive disease and ultimately die from this cancer. There is need to identify potential clinical and molecular predictors of response to treatment of SCCAC. Methods: Prospective cohort study aimed to evaluate whether specific molecular tumor markers and/or Human papillomavirus (HPV) status could be associated with response to definitive CRT among patients with localized SCCAC. Eligible patients had T2-4/N0-3/M0 disease and were candidates to full CRT. Radiological response at 6 months measured by RECIST 1.1 was the primary endpoint. All patients underwent HIV test. Tumor samples were collected before treatment. Presence of mutations was analyzed by next-generation TruSight Tumor26 panel (Illumina) and HPV positivity was tested by Papillo Check(Greiner Bio-One GmbH). Results: 77 patients were recruited from 2011 to 2015; 4 awaits imaging evaluation. 71 were evaluable for response: 67 by RECIST and 4 by clinical examination because they did not have measurable disease. Median age was 56 years, 71% (n = 51) were female, 11% (n = 8) presented positive serology for HIV and 65% (n = 46) had clinical stage III. At 6 months 65% (n = 46) presented complete response (CR), 24% (n = 17) partial response, 11% (n = 8) progression of disease. HPV test was performed in 62 samples, 65% were positive (n = 40), with the majority with HPV16. 22 tumor samples were sequenced for mutations: 14 had at least one pathogenic or undetermined mutation, with the most common mutated genes being PIK3CA (n = 5) and MET (n = 5). HIV+ patients experienced lower CR rate, although this was not statistically significant (37% vs 68%. Chi2: p = 0.086; Fisher test p = 0.12). HPV status did not predict for CR (65% vs 68%, Chi2 test p = 0,064). Also there was no differences in CR rates according to either MET (60% vs 47%, Fisher test p = 1) or PIK3CA (40% vs 53%, Fisher test p = 1) mutational status. Conclusions: Our prospective study shows that there were no significant associations between the presence of HIV+, HPV+, PIK3CA or MET mutation and CR rate at 6 months after treatment.
A phase 1 adaptive dose-escalation study to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of ADCT-402 in patients with relapsed or refractory B-cell lineage non Hodgkin lymphoma (B-NHL).
Authors: Ki Y. Chung, Mehdi Hamadani, Brad S. Kahl, Leonard T. Heffner, Paolo Fabrizio Caimi, Jay Marshall Feingold, Owen A. O'Connor
Journal: Journal of Clinical Oncology (2016)

TPS7580 Background: In normal human tissue, expression of cluster of differentiation 19 (CD19) is limited to the developmental stages of the B cell and is lost in terminally differentiated plasma cells. Expression of CD19 is maintained in hematologic B-cell malignancies, including B-NHL. ADCT-402 is an antibody drug conjugate (ADC) composed of a humanized monoclonal antibody (RB4v1.2), directed against human CD19, conjugated to SG3199, a pyrrolobenzodiazepine (PBD) dimer cytotoxin, through a protease-cleavable valine-alanine linker. The PBD dimer cytotoxin (SG3199) attached to the linker is designated as SG3249. Methods: This is a Phase 1, open-label, dose escalation (Part 1) and expansion (Part 2) study of the safety and tolerability of ADCT-402, used as monotherapy, in patients with relapsed or refractory B-NHL. The study will determine the maximum tolerated dose, as well as evaluate the preliminary activity, PK, pharmacodynamics (PD), and other exploratory assessments of ADCT-402. Patients will be assigned to treatment according to a modified continual reassessment method (mCRM) with oversight by a Dose Escalation Steering Committee (DESC). In Part 2, all patients will be assigned to the dose level of ADCT-402 identified in Part 1. Clinical trial information: NCT02669017.
Heestermans M, Salloum-Asfar S, Salvatori D, Laghmani EH, Luken BM, Zeerleder SS, Spronk HMH, Korporaal SJ, Wagenaar GTM, Reitsma PH, van Vlijmen BJM. Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice. Blood. 2016;127(21):2630-2637.
Journal: Blood (2018)
Adverse event (AE) incidence rates with cobimetinib (C) plus vemurafenib (V) treatment: Extended follow-up (f/u) of the phase III coBRIM study.
Authors: Brigitte Dréno, Paolo Antonio Ascierto, Grant A. McArthur, Antoni Ribas, Susan Eng, Jessie J. Hsu, Isabelle Anne Rooney, James M. G. Larkin
Journal: Journal of Clinical Oncology (2016)

9533 Background: coBRIM (Larkin J et al. N Engl J Med 2014;371:1867-1876.) showed significant improvement in PFS and OS with C+V treatment for advanced BRAF-mutated melanoma patients (pts) but was associated with higher AE frequency. This exploratory analysis evaluates incidence rates of specific AEs over the C+V treatment course with extended f/u. Methods: AE rates for diarrhea, serous retinopathy (SR), photosensitivity, liver laboratory value abnormalities (LFTs), and left ventricular (LV) dysfunction were analyzed between May 9, 2014 (initial) and Sept 30, 2015 (updated). Pt-year (PY) is total treatment time between the start and end of C/placebo (P) treatment + 28 d. Rates were calculated by the number of AEs/total PY exposure. Results: At the updated data cutoff, safety population = 247 C+V pts and 246 P+V pts. Median duration of treatment: C+V arm, C = 274 d (range, 4-915) and V = 281 d (9-922), 253 PY; P+V arm, P = 173 d (5-892) and V = 175 d (5-892), 197 PY. Although incidence of diarrhea, SR, and LFTs was higher in the C+V arm, it decreased over time, suggesting that fewer new AEs of these types are reported later in treatment (Table). The photosensitivity incidence rate in the C+V arm was similar to that in the P+V arm and decreased over time in both. LV dysfunction incidence rate remained unchanged in both arms. Conclusions: Decreased AE rates over time suggest that these select AEs occur early and are managed during treatment. Updated photosensitivity rates were similar in both arms. Longer total exposure with C+V compared to P+V show that patients can tolerate treatment and derive benefit without stopping therapy. Clinical trial information: NCT01689519.Incidence rates of select AEs. AE C+V (n = 247) P+V (n = 246) Initial Updated Initial Updated Events/PY (95% CI) Events/PY (95% CI) Events/PY (95% CI) Events/PY (95% CI) Diarrhea 1.59 (1.39-1.80) 1.09 (0.96-1.22) 0.71 (0.57-0.86) 0.69 (0.57-0.80) SR 0.54 (0.42-0.66) 0.36 (0.29-0.44) 0.04 ( < 0.01-0.08) 0.05 (0.02-0.08) Photosensitivity 0.93 (0.77-1.09) 0.76 (0.65-0.86) 0.87 (0.70-1.03) 0.73 (0.61-0.85) LFTs 1.63 (1.42-1.84) 1.10 (0.97-1.23) 1.23 (10.3-1.42) 0.85 (0.72-0.98) LV Dysfunction 0.13 (0.07-0.19) 0.15 (0.10-0.20) 0.06 (0.02-0.11) 0.08 (0.04-0.11)
Urbanicity and Psychosis
Authors: Jeremy W. Coid, Yamin Zhang, Tao Li
Journal: JAMA Psychiatry (2018)

To the Editor The study findings of DeVylder et al1 on associations between urban settings and psychosis in low- and middle-income countries show heterogeneity. For some countries, risk is increased; for some, it is not. No attempt is made to investigate this heterogeneity.
Association of epithelial-mesenchymal transition with an immunosuppressive tumor microenvironment with elevated levels of PD-L1 in esophageal carcinoma.
Authors: Eiji Oki, Hiroshi Saeki, Satoshi Tsutsumi, Yuichiro Nakashima, Ryota Nakanishi, Masahiko Sugiyama, Junji Kurashige, Koji Ando, Yoshinao Oda, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2017)

e15585 Background: Programmed death-ligand 1 (PD-L1) plays a crucial role in the host immune system in cancer progression and is has become a new target for cancer therapy. PD-L1 gene promoter region contains a binding site of ZEB1, a transcription factor related to epithelial-mesenchymal transition (EMT). The purpose of this study is to clarify relationships between PD-L1, EMT and its clinical importance in esophageal squamous cell carcinoma (ESCC). Methods: We conducted preclinical studies using cell lines and clinical specimens. ZEB1, PD-L1 expression in TE8 cell line, demonstrating EMT phenotype, was determined following ZEB1 knockdown by siZEB1. TE5, 6 and 11 cell lines with non-EMT phenotype were also used for studies of TGF-β1-dependent EMT induction and ZEB1, PD-L1 expression. PD-L1 and ZEB1 expression at the tumor invasive front was examined in resected specimens from 90 patients with ESCC who underwent surgery without preoperative therapy by immunohistochemistry and their expression and clinicopathological factors were compared. Results: A correlation was observed between PD-L1 and ZEB1 expression. In TE8 cells which express EMT character , siZEB1 suppressed PD-L1 and promoted E-cadherin mRNA and protein expression. In TE5, 6 and 11 cell lines which are not EMT phenotype, TGF-β1 induced EMT and surface expression of PD-L1. In cases of high PD-L1 expression at invasive front, greater depth of tumor invasion, EMT, less CD8 expression were significantly observed. High PD-L1 expression was also associated with worse overall and relapse-free survival. Conclusions: PD-L1 expression at the invasive front was related to ZEB1 expression, EMT and poor prognosis in ESCC. We suggest that cooperative mechanism between tumor immune avoidance and EMT contributes to tumor malignancy. Whether or not ZEB1-PD-L1 signal pathway could be a target in treatment for ESCC requires further investigations.
Incidence of germline BRCA1 and BRCA2 mutations among Filipinos.
Authors: Frances Victoria Fajardo Que, Daphne Ang, Jose Jasper Andal, Manuelito Madrid, Raymundo Lo, Marcelo Imasa, Ma. Luisa Enriquez, Francisco Tria, Loraine Kay Cabral, Rosil Dimalibot, Rubi Khaw Li
Journal: Journal of Clinical Oncology (2018)

e13628 Background: The Philippines has the highest reported incidence of breast cancer (BC) in Southeast Asia, with a rate of 47.7 per 100,000 per year. 5 to 10% of BC results from a hereditary predisposition with majority caused by BRCA1/2 mutations, conferring a lifetime risk of 55-85% and 35-60%, respectively. Little is known about the contribution of BRCA mutations to cancer incidence in the Filipino population. Methods: Patients from St. Luke’s Medical Center-Quezon City were enrolled with written informed consent. DNA samples were obtained from a total of 192 subjects (181 females, 11 males; 18-76 years old) who met the National Comprehensive Cancer Network (NCCN) criteria for BRCA genetic testing: 89 patients had BC, 18 had ovarian cancer, 6 had DCIS, 1 had fallopian tube carcinoma, 4 had both ovarian and BC; 78 had no known cancer diagnosis but with strong family history. Next generation sequencing (NGS) approach for diagnostic mutation screening of the BRCA1/2 gene using the Miseq Illumina platform was performed, followed by confirmation of identified variants by Sanger sequencing. Results: Among 192 patients, 12 (6.25%) had pathological/presumably pathological variants: 6 with BRCA1 mutations (c.5314C > T, c.2213_2214dupTT, 2 cases of c.5398delC, 2 cases of c.4148C > G) and 6 with BRCA2 mutations (c.3362C > G, c.8009C > T, 2 cases of c.2176delG, 2 cases of c.5851_5854dupAGTT). Eight out of 12 patients with pathological variants had breast carcinoma, 1 had DCIS, 1 had ovarian carcinoma, 1 had fallopian tube carcinoma, and 1 was a healthy individual. Among 114 patients with a cancer diagnosis, 11 (9.6%) had BRCA1/2 mutations. A total of 22 (11.5%) variants of unknown significance identified, which would require further co-segregation analysis. Conclusions: This is the first local study to apply NGS of BRCA1/2 mutation analysis in a Filipino population. This study prompts further investigation of unique variants to enable better understanding of the genetic predisposition to cancer among Filipinos. Benefits of BRCA1/2 mutation testing include optimal treatment tailored for BRCA-positive patients and, more importantly, extending testing to family members and helping them take measures for early detection of cancer.
Quality of life (QoL) analysis in HPV positive oropharynx cancer (HPVOPC) patients in a randomized deintensification trial.
Authors: Michael Hwang, Marcelo Raul Bonomi, Krzysztof Misiukiewicz, Isaiah Selkridge, Elizabeth Roy, John-Tod Surgeon, Eric Michael Genden, Vishal Gupta, Richard Lorne Bakst, Marshall R. Posner
Journal: Journal of Clinical Oncology (2018)

e18068 Background: One method of therapy deintensification in locally advanced (LA) HPVOPC is to reduce total radiation dose during concomitant chemoradiation (CRT) in a sequential therapy plan. We prospectively assessed differences in patient reported QoL in LA HPVOPC patients receiving reduced dose CRT versus standard dose CRT in a small randomized trial. Methods: From 2012 to 2015, out of 23 patients identified with LA HPVOPC, 20 received induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (TPF) and responders were randomized to standard CRT (70 Gy, 7 weeks) or reduced CRT (56 Gy, 5.5 weeks) each with weekly carboplatin (one did not meet inclusion criteria, two withdrew consent). Five validated QoL surveys were taken at baseline, and 3, 6, 12, and 24 months post treatment: MD Anderson Dysphagia Inventory and Symptom Inventory (MDADI, MDASI), Xerostomia Questionnaire (XQ), European Organization for Research and Treatment of Cancer Questionnaire (EORTC) with head and neck module (EORTC HN). Five were excluded in QoL analysis (three had disease progression, two with insufficient surveys). 3 and 6 month results were grouped by using the score denoting a worse QoL due to lack of survey responses (five patients missing from 3 months, one patient from 6 months). Survival data was previously reported (ASCO 2017). Results: Out of 15 patients, six received standard CRT and nine received reduced CRT. No difference was noted in baseline QoL. At 3-6 month follow up, patients receiving reduced CRT had significantly less changes in QoL from their baseline in EORTC global health score and functional scale (1.85 vs -31.67, P= 0.0363; 3.51 vs -25.8, P= 0.003), MDADI (-10.44 vs -38, P= 0.0307), XQ (2.78 v 5.8, P= 0.047), EORTC HN (0.45 vs 23.37, P= 0.029), and MDASI symptom interference (-0.22 vs 4.07, P= 0.014). Change in MDASI symptom severity approached significance (0.84 vs 2.95, P= 0.051). Change in EORTC symptom scale did not show any significant difference (0.48 vs 13.95, P= 0.101). Differences in QoL disappeared at 12 and 24 month follow up. Conclusions: Reduced dose CRT in a TPF based sequential therapy program in LA HPVOPC is feasible and results in significantly quicker improvement in QoL post therapy. Clinical trial information: NCT01706939.
PD-L1 immunohistochemistry in clinical diagnostics: Inter-pathologist variability is as high as assay variability.
Authors: Patrick Micke, Anna Johansson, Anna Westbom-Fremer, Max Backman, Dijana Djureinovic, Annika Patthey, Martin Isaksson-Mettävainio, Miklos Gulyas, Hans Brunnstrom
Journal: Journal of Clinical Oncology (2017)

e20637 Background: Several checkpoint inhibitors targeting the PD1 axis are now approved for the treatment of non-small cell lung cancer (NSCLC). The best predictor for therapy response is PD-L1 expression on tumor cells assessed by immunohistochemistry (IHC). However, the PD-L1 assays have been developed independently for each available drugs. In this study, we evaluated the different assays to determine the comparability between the assays and the concordance between pathologists under conditions reflecting the clinical situation. Methods: We tested four IHC assays (28-8, 22C3, SP263 and SP142) and one in-house protocol (28-8 on the Ventana system) on a tissue microarray (TMA) including 55 resected tissue specimens of NSCLC patients. The TMAs were independently annotated by seven pathologists with regard to the percentage of tumor cell membrane staining using a six-grade scale ( &lt; 1%; 1-≤5%; 5%-≤10%; 10-≤25%; 25-≤50%; ≥50%). Results: The staining scores were comparable for the three assays with clones 28-8, 22C3 and SP263 as well as the in-house 28-8 protocol (κ-value: 0.75-0.91). The use of the SP142 clone resulted in a lower percentage of positive tumor cells and positive cases (κ: 0.44-0.63). When a reference score was defined based on the majority of scores, the proportion of positive cases (≥1%) were 38% for 28-8, 29% for 22C3, 42% for SP263, 37% for 28-8 in-house and 16% for SP142%. With ≥1% cut-off 3-8 of the 55 cases (5-15%) were differently classified as positive or negative when comparing any two assays excluding SP142. Analysing the scoring of the seven pathologists a clear inter-rater variability (κ: 0.71-0.96) was observed independent from the assay. With a ≥1% cut-off, 20% of cases were annotated differently by at least one pathologist. Conclusions: The concordance between the three antibody clones 28-8, 22C3 and SP263 was acceptable and was in the similar range as inter-rater variability of different pathologists. The results suggest that assessment of tumor cell staining for Nivolumab, Pembrolizumab and Durvalumab might be performed with only one of these assays. The assessment of the pathologist presents an intrinsic source of error that should be considered especially at low PD-L1 scores.
Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma
Authors: Zhikui Liu, Yufeng Wang, Changwei Dou, Meng Xu, Liankang Sun, Liang Wang, Bowen Yao, Qing Li, Wei Yang, Kangsheng Tu, Qingguang Liu
Journal: Theranostics (2018)

Rational: Patients with hepatocellular carcinoma (HCC) have a poor prognosis mostly due to intrahepatic as well as distal metastasis. Vasodilator-stimulated phosphoprotein (VASP), a regulator of actin cytoskeleton and cell migration, is overexpressed in HCC and correlated with its malignant features and poor prognosis. Very little is known about its function in HCC. Methods: qRT-PCR, Western blot and IHC were used to detect the VASP expression in tissues and cells. Transwell and wound healing assays were used to measure the migration and invasion of HCC cells. Immunoblotting and immunofluorescence were used for detection of epithelial-to-mesenchymal transition (EMT) progression in HCC cells. A lung metastasis mouse model was used to evaluate metastasis of HCC in vivo. The putative targets of miR-204 were disclosed by public databases and a dual-luciferase reporter assay. IP was used to show the interaction between VASP and CRKL. ChIP was used to analyze the binding of HIF-1α to VASP promoter region. Results: Our data involving both gain- and loss-of-function studies revealed that VASP activated AKT and ERK signaling and promoted HCC migration and invasion in vitro and in vivo by altering the EMT phenotype and expression of MMPs. We investigated the positive correlation between VASP and an adapter protein, CRKL. VASP dynamically co-localized at the SH3N domain of CRKL and mediated its function. Mechanistically, VASP overexpression at the transcriptional level was mediated by HIF-1α through direct binding to two hypoxia response elements (HRE) in the VASP promoter region. Furthermore, we identified hypoxia-induced down-regulation of miR-204, which functioned as the regulator of VASP overexpression at the post-transcriptional level. Also, hypoxia-activated p-Smad3 dependent TGF-β signaling indirectly promoted VASP expression. Conclusion: A variety of hypoxia-induced molecular mechanisms contributed to the upregulation of VASP at transcriptional and post-transcriptional levels. These mechanisms involved CRKL, HIF-1α, miR-204, and TGF-β activating the AKT and ERK signaling to promote EMT and expression of MMPs. Taken together, our results defined VASP as an oncogene of HCC pathogenesis and metastasis with the potential to serve as a prognostic biomarker.