tbuckley/cabot-search huggingface dataset:
First-line icotinib versus cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with sensitizing EGFR mutation (CONVINCE).
Authors: Yuankai Shi, Lin Wang, Baohui Han, Wei Li, Ping Yu, Yunpeng Liu, Cuimin Ding, Xia Song, Ma Zhi Yong, Xinling Ren, Ji Feng Feng, Helong Zhang, Gongyan Chen, Ning Wu, Xiaohong Han, Chen Yao, Yong Song, Shucai Zhang, Lieming Ding, Fenlai Tan
Journal: Journal of Clinical Oncology (2016)

9041 Background: Icotinib is an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which is non-inferior to gefitinib in treating unselected or EGFR-mutated advanced non-small cell lung cancer (NSCLC) patients as second-line therapy. We assess icotinib as first-line therapy in lung adenocarcinoma patients with EGFR mutation. Methods: This phase 3, open-label, randomized study (CONVINCE, NCT01719536) was conducted at 18 sites in China. Eligible patients (pathologically confirmed lung adenocarcinoma, 19/21 EGFR mutation, treatment naive) were 1:1 randomized to receive icotinib (125 mg, three times daily) or pemetrexed (500 mg/m2, day 1) plus cisplatine (75 mg/m2, day 1), non-progressive patients after 4-cycle chemotherapy continue to receive pemetrexed (500 mg/m2, day 1) as maintenance therapy until disease progression or intolerable toxicity. Randomization was stratified by performance status, smoking status, disease stage, and mutation type. The primary endpoint was progression free survival (PFS). Results: Six hundred and sixty-nine patients were screened (January, 2013 to August, 2014), in which 296 were enrolled and randomized (148 for each group), and 285 patients were treated (icotinib: 148, chemotherapy: 137). Baseline patients' characteristics were well balanced between groups. Icotinib significantly improved PFS (296 days [95% CI 255–355] vs 219 days [189–253]; HR 0.67, 95% CI 0.49-0.90, p = 0.008) compared with the chemotherapy group. Icotinib also showed better tumor response rate (64.8% vs 33.8%, p < 0.001). Significantly fewer adverse events (AEs) were seen in the icotinib group (104 [70.3%] vs 121 [88.3%], p < 0.001). The most common AEs were elevated transaminase (29.1%), rash (17.6%) and diarrhea (9.5%) in icotinib group,and were neutropenia (77.4%), erythropenia (76.6%), leukopenia (70.1%), nausea (54.7%), elevated transaminase (40.1%) in chemotherapy group. Conclusions: First-line icotinib is well tolerated and offers superior PFS compared with cisplatine/pemetrexed plus pemetrexed maintenance therapy in lung adenocarcinoma patients with sensitizing EGFR mutation. Clinical trial information: NCT01719536.
XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough
Authors: Maria G. Belvisi, Mark A. Birrell, Michael A. Wortley, Sarah A. Maher, Imran Satia, Huda Badri, Kimberley Holt, Patrick Round, Lorcan McGarvey, John Ford, Jaclyn A. Smith
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough.Objectives: XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough.Methods: XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig. Twenty patients with refractory chronic cough participated in a double-blind, randomized, placebo-controlled crossover study evaluating the effect of 14 days of XEN-D0501 (oral, 4 mg twice daily) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough, and patient-reported outcomes.Measurements and Main Results: XEN-D0501 was more efficacious and 1,000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus nerve. In vivo XEN-D0501 completely inhibited capsaicin-induced cough, whereas 100 times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline, XEN-D0501, −19.3 ± 16.4) coughs; placebo, −1.8 ± 5.8 coughs; P < 0.0001), but not spontaneous awake cough frequency (mean change from baseline, XEN-D0501, 6.7 ± 16.9 coughs/h; placebo, 0.4 ± 13.7 coughs/h; P = 0.41).Conclusions: XEN-D0501 demonstrated superior efficacy and potency in preclinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough frequency did not improve, ruling out TRPV1 as an effective therapeutic target for refractory cough.Clinical trial registered with www.clinicaltrialsregister.eu (2014-000306-36).
Improved prediction of PSA recurrence through systems pathology
Authors: C. Cordon-Cardo, A. Kotsianti, M. J. Donovan, P. Capodieci, D. A. Verbel, M. Teverovskiy, O. Saidi, J. Edelson, T. M. Wheeler, G. Ayala
Journal: Journal of Clinical Oncology (2004)

4591 Improved prediction of PSA recurrence through systems pathology Background: Current tools in clinical practice which are used to predict PSA recurrence s/p radical prostatectomy have been limited to a consideration of clinical/pathological (clinpath) features. We evaluated whether integrating clinpath, biomarker (IHC), and bio-imaging (IMG) data in a systems pathology platform could improve the prediction of PSA recurrence. A cohort of patients s/p surgery from the Baylor College of Medicine was studied. High-density tissue microarrays (TMAs) were constructed from prostatectomy specimens. An H&E of each TMA was used for image analysis; IHC was performed with 14 biomarkers. A patented supervised multivariate learning approach was developed and from the 3 datasets' features, a predictive model for PSA recurrence was derived. Methods: Clinpath information was collected retrospectively. TMA cores with ≥ 80% tumor were analyzed using a proprietary automated image quantitation system. Serial sections were immunostained and double-read for intensity and percent positive cells. 132 patients with complete non-missing data in each domain were placed in a support vector machine for regression developed to handle censored data (SVRc). Predictive performance of the model was estimated using the concordance index (CI) and optimized with an ensemble of neural networks (NNci). Scores generated by the model were used to define risk groups of patients to explore differences in time to recurrence. Results: Using SVRc, clinpath features had a CI of 0.79; clinpath + IHC features had a CI of 0.81, and by integrating IMG the CI increased to 0.84. After optimization using NNci, the final CI was 0.88. A total of 41 features (17 clinpath, 14 IHC, 10 IMG) out of 562 were selected. Using the log-rank test, a significant difference in PSA recurrence was observed between risk groups (p < 0.0001). Conclusions: The study demonstrates an incremental trend of improved PSA recurrence prediction through the use of a new systems approach combining clinpath, IHC, IMG using SVRc and NNci. This systems pathology approach has the potential to form the basis of a new generation of predictive clinical tools. No significant financial relationships to disclose.
Contribution of microRNA-3646 to docetaxel resistance in human breast cancer cells by GSK-3β/β-catenin signaling pathway.
Authors: Jinhai Tang, Xiaohui Zhang, Shanliang Zhong, Jianhua Zhao
Journal: Journal of Clinical Oncology (2016)

e12501 Background: This study investigated whether mircoRNA profile and miR-3646 regulated sensitivity of breast cancer cells to Docetaxel (Doc). Methods: Doc-resistant MDA-MB-231 breast cancer cell line (MDA-MB-231/Doc) was successfully established in vitro by gradually increasing Doc concentration on the basis of parental MDA-MB-231/S. The potential miRNAs relevant to the drug-resistance was screened by miRNA microarray and confirmed by RT-qPCR. Cell transfection and survival experiments were performed to verify the effect of identified miRNAs on the drug resistance. The miRNA target gene and signal pathway were studied by bioinformatic analyses, RT-qPCR, Western blot and Immunofluorescence test. Results: IC50 of MDA-MB-231/Doc and MDA-MB-231/S to Doc were 22.89μM and 2.75μM, respectively. Compared with MDA-MB-231/S, there were 169 differentially expressed miRNAs in its variant MDA-MB-231/Doc, and miR-3646 was found to be obviously up-regulated. Transfection of miR-3646 mimics into MDA-MB-231/S remarkably increased their drug resistance; in contrast, transfection of miR-3646 inhibitors into MDA-MB-231/Doc resulted in significant reduction of the drug resistance. By the pathway enrichment analyses for miR-3646, we found that GSK-3β/β-catenin pathway was a significant pathway, in which GSK-3β was an essential member. Further studies demonstrated that miR-3646 could regulate GSK-3β mRNA and protein expressions. In miR-3646 mimics-transfected MDA-MB-231/S, GSK-3β mRNA and protein expressions were reduced along with miR-3646 increase; reversely in miR-3646 inhibitors-transfected MDA-MB-231/Doc, their expressions were increased along with miR-3646 decrease. Immunofluorescence staining result showed that a marked increase of both nuclear and cytoplasmic β-catenin expressions (with phosphorylated-β-catenin decrease) was observed in MDA-MB-231/Doc compared with MDA-MB-231/S, and their expressions were positively related to miR-3646 and negatively correlated with GSK-3β. Conclusions: MiR-3646-mediated drug resistance may be, at least in part, through suppressing expression of GSK-3β and resultantly resulting in activation of GSK-3β/β-catenin pathway.
Multiorgan Involvement of Chemotherapy-Induced Sarcoidosis Mimicking Progression of Lymphoma on FDG PET/CT
Authors: Prateek Sanan, Yang Lu
Journal: Clinical Nuclear Medicine (2017)

A 35-year-old woman with biopsy-proven recurrent Hodgkin lymphoma in the neck lymph nodes received salvage chemotherapy of brentuximab/insulin growth factor-methotrexate. Although the patient continued doing well clinically with no constitutional symptoms or significant laboratory abnormalities following the second recurrence, subsequent FDG PET CT examinations over the next 2 years revealed multiple new FDG-avid foci including lymph nodes above/below the diaphragm, liver, spleen, lungs, and bone. An alternate diagnosis of chemotherapy-induced sarcoidosis was suggested and confirmed on both bone marrow and right inguinal node biopsy.
Pathogenic germline mutations in emerging cancer genes: What happens after panel testing?
Authors: Evan Thomas Hall, Divya Ahuja Parikh, Tanya Gupta, Jennifer Lee Caswell, Meredith Mills, Kerry Kingham, Rachel Koff, James M. Ford, Allison W. Kurian
Journal: Journal of Clinical Oncology (2017)

1528 Background: Next-generation sequencing technology enables more comprehensive germline genetic testing, including genes whose cancer risks are less well-characterized (particularly among patients with less striking family histories). Little is known about patient outcomes, particularly adherence to risk-reducing recommendations and family testing. Methods: We attempted a phone interview ≥3 times with each adult patient who had a germline pathogenic or likely pathogenic mutation found in an emerging cancer gene (defined as any gene other than BRCA1/2 or the Lynch Syndrome genes MLH1, MSH2/6, PMS2) at a single academic cancer genetics clinic from January 2013-July 2016. Results: Of 143 eligible patients, 53 (37%) were successfully contacted and all consented to participate. Median follow-up was 677 days (range 247–1401) and age was 52 years (21-82). Two-thirds (68%) had personal cancer history and 93% had a first-degree relative with cancer. Mutations in genes associated with named syndromes ( APC=5 , CDH1=3 , TP53=3, PTEN=2) were found in 23% (many of whom lacked family history typical of these syndromes) whereas 77% had mutations in less well-characterized genes ( MYH=10, CHEK2=10, ATM=6, PALB2=6 , NBN=3, RAD51C=2, RAD51D=2, SDHB=1, CDKN2A=1, MRE11A=1, RAD50=1, FLCN=1). Conclusions: Two years after panel testing, patients with germline mutations in less well-characterized genes reported high rates of adherence to recommendations, family communication and testing. Limitations include a relatively low response rate and a single academic center; this may bias toward a “best-case” scenario. Larger, population-based studies will be crucial to understand the real-world outcomes of germline multiple-gene panel testing and its contribution to precision oncology. [Table: see text]
Second primary cancer in survivors of locally advanced NSCLC treated with concurrent chemoradiation followed by surgery.
Authors: Go Makimoto, Toshio Kubo, Yuka Kato, Takashi Ninomiya, Isao Oze, Kadoaki Ohashi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Nagio Takigawa, Shinichi Toyooka, Kuniaki Katsui, Mitsune Tanimoto, Katsuyuki Kiura
Journal: Journal of Clinical Oncology (2016)

10100 Background: Mediastinal lymph node metastasis is associated with a poor prognosis in non-small cell lung cancer (NSCLC). The standard treatment for unresectable stage III NSCLC is concurrent chemoradiotherapy (CRT). Institutions worldwide have experienced good overall survival with surgical resection after induction CRT. Our institute reported the long-term outcome of induction CRT followed by surgery for NSCLC. The 3- and 7-year overall survival (OS) rates were 72.7 and 63.6%, respectively, both much longer than for CRT alone. Nevertheless, patients treated with CRT for NSCLC remain at risk of developing a second primary cancer (SPC). This study assessed the incidence of SPC in survivors with locally advanced NSCLC after CRT followed by surgical resection. Methods: Between October 1997 and October 2013, 112 NSCLC patients were treated with tri-modal therapy in our hospital. The main regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40–46 Gy followed by surgery after 4–6 weeks. We searched for SPC using our medical record database. Results: The median patient age was 61 [range 31–78] years, with 71% stage IIIA and 29% stage IIIB. The median follow-up time was 4.5 [range 0.38–16.6] years. The 5-year overall survival rate was 71.8% and the median survival time was 13.0 years (95% confidence interval 9.7–). SPC developed in 10 of the 112 patients 0.60–15.0 years (median 5.49) after the initiation of CRT. The SPC lesions involved the lungs, stomach, and colon in two patients each and esophagus, urinary bladder, thyroid, and sarcoma in one case each. Among these 10 cases, three cases occurred inside the original radiation field. Eight patients are alive now after treating these cancers. Conclusions: The observed incidence of SPC was 1.8 per 100 patient-years (95% CI 1.6–2.1) and was slightly lower than our previously reported value of 2.4 per 100 patient-years for patients treated with CRT alone (total radiation dose ≥ 60 Gy). The reduction in RT dose by adding surgery may decrease the incidence of SPC. NSCLC patients need to be followed carefully for the long-term to avoid overlooking SPC.
A single-institution phase II trial of radiation (RT), temozolomide (TMZ), erlotinib, and bevacizumab for initial treatment of glioblastoma (GBM).
Authors: Jennifer Leigh Clarke, Annette M Molinaro, Nicholas A. Butowski, Susan Marina Chang, Joanna J Phillips, Bruno M Costa, Joseph F Costello, Jane E Rabbitt, Valerie A Kivett, Ashley A DeSilva, Michael Prados
Journal: Journal of Clinical Oncology (2012)

2026 Background: Standard treatment for GBM includes surgery followed by RT and TMZ, rarely a curative treatment. Both the EGFR and VEGF pathways are frequently overactive in GBM; we previously added erlotinib, an EGFR inhibitor, to RT and TMZ, with modest improvement in survival. The present study combined bevacizumab, a VEGF inhibitor, and erlotinib with RT and TMZ, with the goal of improving overall survival (OS). Methods: Treatment consisted of fractionated RT to 60 Gy with daily TMZ at 75 mg/m2/d and erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzyme-inducing antiepileptic drugs [EIAEDs]). Bevacizumab was given at 10 mg/kg every 2 wks, starting ≥ 4 wks after surgery. After RT, adjuvant TMZ was given at 200 mg/m2/d x 5d per 28d cycle, with unchanged erlotinib and bevacizumab doses. Treatment was continued until progression or for 12 mo, with an option to continue for up to 24 mo. OS and progression-free survival (PFS) from initial diagnosis were compared against institutional historical controls (recent prior up-front clinical trials including RT and TMZ). Results: 59 pts were enrolled; 12 were receiving EIAEDs. Median age was 54 yrs; median KPS was 90. 33% underwent gross total resection and 53% subtotal resection. 16 pts had tumors with methylated MGMT (mMGMT), 26 with unmethylated MGMT (umMGMT), and 17 with unknown status. The most frequent related grade 3/4 AEs were lymphopenia (68%) thrombocytopenia (24%), neutropenia (10%), diarrhea (14%), weight loss (14%), and fatigue (12%). 1 pt died of aspergillosis. Median OS and PFS were 19.8 mo and 13.5 mo, respectively, vs. 18 mo and 8.6 mo for the historical control. The hazard ratio (adj for age, KPS, and extent of surgery) for PFS was 0.7 (95% CI 0.49-0.99, p=0.04). Median OS in pts with mMGMT was 20.9 mo, vs. 17.5 mo in pts with umMGMT; median PFS was 14 mo vs. 12.4 mo, respectively. Conclusions: The combination of bevacizumab, erlotinib, TMZ, and RT showed improved PFS but not OS vs. historical controls. Though the numbers were small, PFS and OS for pts with umMGMT were not significantly different from pts with mMGMT, suggesting that this combination may be more effective than standard therapy alone for pts with unMGMT tumors.
Abstract 116: Slit-Robo Signaling Regulates Lipopolysaccharide-induced Endothelial Inflammation and Expression of Slit/Robo is Dysregulated During Endotoxemia
Authors: Helong Zhao, Appakkudal Anand, Ramesh Ganju
Journal: Circulation Research (2013)

Abstract Introduction: Lipopolysaccharide (LPS) is one of the critical factors which induce endothelial inflammation during the pathogenesis of atherosclerosis, endocarditis and sepsis shock induced heart injury. The secretory Slit2 protein and its endothelial receptors Robo1 and Robo4 have been shown to regulate mobility and permeability of endothelial cells, which could be functional in regulating LPS induced endothelial inflammation. Hypothesis: We hypothesized that in addition to regulating permeability and migration of endothelial cells, Slit2-Robo1/4 signaling might regulate other LPS-induced endothelial inflammatory responses. Methods and Results: Using Human Umbilical Vein Endothelial Cells (HUVEC) culture, we observed that Slit2 treatment suppressed LPS-induced secretion of pro-inflammatory cytokines (including GM-CSF), cell adhesion molecule upregulation and monocyte (THP-1 cell) adhesion. With siRNA knock down techniques, we further confirmed that this anti-inflammatory effect is mediated by the interaction of Slit2 with its dominant receptor in endothelial cells, Robo4, though the much lesser expressed minor receptor Robo1 is pro-inflammatory. Our signaling studies showed that downstream of Robo4, Slit2 suppressed inflammatory gene expression by inhibiting the Pyk2 - NF-kB pathway following LPS-TLR4 interaction. In addition, Slit2 can induce a positive feedback to its expression and downregulate the pro-inflammatory Robo1 receptor via mediation of miR-218. Moreover, both in in vitro studies using HUVEC and in vivo mouse model studies indicated that LPS also causes endothelial inflammation by downregulating the anti-inflammatory Slit2 and Robo4 and upregulating the pro-inflammatory Robo1 during endotoxemia, especially in mouse arterial endothelial cells and whole heart. Conclusions: Slit2-Robo1/4 signaling is important in regulation of LPS induced endothelial inflammation, and LPS in turn causes inflammation by interfering with the expression of Slit2, Robo1 and Robo4. This implies that Slit2-Robo1/4 is a key regulator of endothelial inflammation and its dysregulation during endotoxemia is a novel mechanism for LPS induced cardiovascular pathogenesis.
Differential response of oesophageal carcinoma cells to 5-fluorouarcil, cisplatin and taxol
Authors: AA Raouf, DA Evoy, MM Griffin, JV Reynolds
Journal: Endoscopy (2005)

Aims: Anticancer agents mediate cell death by activating elements of the apoptosis program. This study assesses the effect of the chemotherapeutic agents 5-fluorouracil, cisplatin and taxol on cell growth, apoptosis and levels of p53 and bcl-2 proteins in oesophageal carcinoma cells.
La minisonde (MS) d'échoendoscopie 3D permet t'elle d'améliorer l'exploration des voies biliaires et pancréatiques?
Authors: B Napoléon, C Lefort, B Pujol, T Ponchon
Journal: Endoscopy (2005)

Nous avons déja rapporté nos résultats d'exploration échoendoscopiques intracanalaires avec les MS 2D (Nantes 2002). Les indications principales et les limites techniques avaient été étudiées. Les MS 3D, récemment développées, pourraient permettre d'améliorer les résultats des MS 2D dans les voies biliaires et pancréatiques en simplifiant la procédure (un seul franchissement des sténoses) et en améliorant le diagnostic (association aux coupes radiales de coupes linéaires et de reconstruction 3D). La MS 3D est plus rigide et plus large que la MS 2D ce qui pourrait limiter son utilisation. But: Evaluer les limites techniques liées à l'utilisation de cette MS et son apport en comparaison avec la MS 2D.
Genetic counseling and testing in endometrial cancer: Are we capturing high-risk women?
Authors: Jessica Lee, Lindsay Gubernick, Jing-Yi Chern, Deanna Gerber, Stephanie V. Blank, Bhavana Pothuri
Journal: Journal of Clinical Oncology (2017)

1503 Background: Lynch syndrome accounts for the majority of inherited endometrial cancers and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. This is now even more relevant with the potential of novel immunotherapy agents for women with germline mutations. The diagnosis of endometrial cancer (EC) can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates. Methods: All women with EC between 2012 and 2015 were identified. Statistical analyses were performed to evaluate risk factors including age, body mass index (BMI), positive family history defined as two or more family members with Lynch-related cancers, and tumor mismatch repair (MMR) protein expression loss. Results: A total of 447 women were diagnosed with EC and of these, 107 (24%) were given GCR by their gynecologic oncologist based on their discretion. Compared to non-GCR, GCR women were significantly younger (median 54 vs 65, p &lt; 0.0001) and had lower BMI (median 28.2 vs 30.8, p= 0.007). Of the 107 GCR women, 71 (66%) underwent GT. Of the 71 GT women, 8 (11%) were found to have a germline mutation in one of the MMR genes. Table 1 lists GCR, GT and positive germline mutations among specific high-risk cohorts. Of these cohorts, 56% under 50 years of age, 28% with family history, and 61% with loss of tumor MMR proteins had GCR. Conclusions: Many young, thin EC women with a family history or a tumor MMR deficiency are not given GCR. Among GCR women, 66% underwent GT, despite there being a high rate of germline mutations among these women. It is imperative that high-risk women receive GCR with subsequent GT to capture the maximum number with Lynch syndrome to screen and prevent additional cancers as well as enable cascade testing in family members. Facilitated pathways may be helpful in increasing GCR, as well as GT in EC women. [Table: see text]