tbuckley/cabot-search huggingface dataset:
Evaluation of nutritional parameters in prechemotherapy of oncology patients in a service of the Unified Health System.
Authors: Silvia Regina Graziani, Carolina Graziani Vital, Hezio Jadir Fernandes, Fauzia de Fátima Naime, Ricardo Oliveira Da Fonseca, Carla Andressa Rodrigues Dias, Ligia Rabello De Almeida, Raphael Francisco Azuaga Neto, Karina Emi Yamada, Maria Stella Sa Granja De Abreu, Tatiana Caldeira Pontes, Thiago D'Alvia, Rafael Sanches Ferreira, Arianne Renata Eyzaguirre Velasquez, Valéria Urresti Orias, Fabiano Garcia Vanderlinde, Leandro Maritan de Almeida, Paula Calixto Batistela Diniz, Brigitte M. Van Eyll, Cassia Costa
Journal: Journal of Clinical Oncology (2017)

e21628 Background: Pre-chemotherapy nutritional evaluation is fundamental strategy as predictive factor for the possibility of response to oncological treatment and treatment-related toxicity. As in the Unified Health System patients usually arrive for evaluation with advanced disease, we believe that medical evaluation of the nutritional parameters is important in the therapeutic decision. Methods: From October 2015 through July 2016, we evaluated 210 patients referred for cancer treatment at the Arnaldo Vieira de Carvalho Cancer Institute in São Paulo (Brazil), which is an Institution that exclusively serves the Unified Health System. We evaluated the clinical parameters of weight and height, for estimation of BMI; evaluation the muscle of the fold of the thumb; and laboratory parameters as hemoglobin, lymphocytes, albumin, PCR (C-reactive protein) levels. We included 54 patients with gastrointestinal tract carcinoma; 32 colorectal carcinoma, 14 gastric carcinoma, 8 esophageal carcinoma, 12 lung carcinoma, 16 head and neck carcinomas, 38 breast carcinoma, 6 cervical carcinoma, 4 uterine carcinoma, 6 ovarian carcinoma, 4 malignant melanoma carcinoma, 2 soft tissue sarcomas, 10 prostate carcinoma, and 4 bladder carcinoma. Results: We found significant changes in the clinical nutritional parameters in patients with gastric, esophageal, lung and head and neck carcinomas, whose hemoglobin levels were among the mean normal values of 8.9 g/dL (6.5-10.3 g/dL), the lymphocytes levels were 850/mm 3 (450-1200/mm 3 ), the albumin levels were 3.2 g/dL (2.3-3.8 g/dL), the PCR levels were 126 mg/L (80-620 mg/L) and the Adductor muscle of the thumb were &lt; 1 mm. Although all the evaluated patients presented advanced stages in diagnosis, the tumors of breast, prostate, uterine body, malignant melanoma and bladder did not present any significant alterations in the nutritional state. Conclusions: Our strategy shows that nutrition evaluation is an easy-to-use instrument, and opens the possibility of using in the therapeutic decision in patients with severe mal nutrition and compromising the general condition, since palliative chemotherapy has no impact on the overall survival of this population.
Inhibition of EGFR nuclear translocation attenuate radioresistance through decreased p-DNA-PK expression in cervical cancer cells.
Authors: Yunxiang Qi, Jinyi Lang, Lu Li, Mei Feng, Yecai Huang
Journal: Journal of Clinical Oncology (2017)

e17011 Background: The commonly used treatment for cervical cancer is radiotherapy. However, the resistance to irradiation and metastasis at the advanced stage is a common reason for the poor prognosis and high mortality. This study was designed to elucidate the role of epidermal growth factor receptor (EGFR) nuclear translocation in radioresistance, and its correlation with DNA damage repair pathway in the cervical cancer cells. Methods: The dynamic expression of EGFR, DNA-dependent protein kinase (DNA-PK), PDK-1, PKN1 and their phosphorylation level in irradiated cervical cancer cell line CaSki at 0 10 20 40 minutes was determined by western blotting. Besides, nuclear localization signal (NLS) peptide inhibitor and control peptides was synthesized and treated cells before irradiation to elucidate the correlation between EGFR nuclear translocation and DNA damage repair after irradiation. Results: Expression of EGFR, protein kinase N1 (PKN1), and DNA-PK in nucleus was increased after irradiation in CaSki cells. Irradiation also enhanced the phosphorylation level of EGFR at Thr654, PKN1 at T774 and DNA-PK at T2609. Inhibition of EGFR nuclear translocation by NLS peptide decreased the expression level of EGFR and DNA-PK in the nucleus, and attenuated their phosphorylation process. Conclusions: EGFR nuclear translocation riggered by irradiation promoted DNA damage repair in irradiated cervical cancer cells. This work facilitated us to understand the possible molecular mechanism of the resistance to irradiation in the treatment of cervical cancer, providing a potentially potent clinical method to cancer therapy.
The prevalence of <i>TP53</i> mutation and primary resistance mechanisms in short-term responders to EGFR tyrosine kinase inhibitors in non-small cell lung cancer.
Authors: Yun Fan, Xiaoling Tong, Junrong Yan, Xue Wu, Yang Shao, Yanjun Xu
Journal: Journal of Clinical Oncology (2018)

e21237 Background: Non-small cell lung cancer (NSCLC) with activating EGFR mutations in exon 19 or 21 usually responds to EGFR tyrosine kinase inhibitors (TKIs), but sometimes the responses can only be maintained for a few months. The underlying mechanisms of such short responses have not been fully revealed. Methods: The mutation profiles of 16 short-term responders (SR) whose progression free survival (PFS) less than 6 months on the first generation EGFR TKIs were interrogated, in comparison to 15 long-term responders (LR) that had more than 12 months of PFS. All patients were diagnosed with advanced lung adenocarcinoma and harbored EGFR 19del or L858R mutation. Paired tumor samples collected before treatment and after relapse were subjected to next-generation sequencing of 416 cancer-relevant genes. Results: SR patients were significantly younger than LR patients (p<0.001). 88% of SR patients have TP53 variants compared to 13% in LR patients (p<0.001). The TP53 mutations in SR were scattered in exons 4-8, 10, 11 with 35% of them in exon 5, while mutations in LR were in exons 6-8. Meanwhile, 13 SR patients (81%) were identified with potential primary resistance mechanisms, including BIM deletion polymorphism, primary EGFR T790M, amplifications of EGFR, ERBB2, MET, HRAS and AKT2, and PTEN loss, which present much more common than LR patients (p<0.01), and 6 SR patients have more than one primary resistance mechanism. Other genetic alterations that might also render the resistance were the amplifications of DDR2 and IKBKE. DDR2 is correlated to cancer epithelial mesenchymal transitions (EMT) and IKBKE is suggested to activate NF-κB pathway to bypass PI3K pathway. After treatment of SR patients, 1 patient acquired AKT1 amplification and 3 (19%) acquired EGFR T790M at a much lower frequency than the historical reports. Conclusions: TP53 mutations were more prevalent in SR patients than LR patients, especially the exon 5 mutations. The diversified pre-existing resistance mechanisms in SR patients revealed the complexity of treatment decision-making even for patients with the same EGFR-sensitive mutation.
P01.095 The use of TTFields for newly diagnosed GBM patients in Germany in routine clinical care (TIGER: TTFields in Germany in routine clinical care)
Authors: O Bähr, G Tabatabai, R Fietkau, R Goldbrunner, M Glas
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common malignant primary brain tumor. Survival in GBM has remained essentially unchanged since 2005 despite numerous clinical Phase 3 trials conducted. Tumor treating fields (TTFields) are low-intensity, intermediate frequency, alternating electric fields that inhibit cancer cell division. In a phase 3 newly diagnosed GBM trial (EF-14), adding TTFields to adjuvant temozolomide (TMZ) demonstrated significant extension of median overall, progression-free and long-term survival. There is enormous interest among prescribing physicians in Germany to further validate these results in routine clinical care. The goal of this study is to evaluate safety and efficacy of TTFields in routine clinical care as well as reasons for patients refusing TTFields treatment, changes in quality of life within 4 months after start of therapy, treatment duration and compliance. The TIGER study is a multi-centre, prospective, non-interventional study in Germany (NCT03258021, opened in August 2017). Patients with newly-diagnosed GBM who are eligible for treatment with TTFields are asked for consent for study participation and comprehensively introduced to the therapy to allow them to make a conscious positive or negative therapy decision. At baseline and 2–4 months after treatment start in the scope of clinical care routine, demographic data as well as the QoL and reasons for therapy decision are assessed applying the EORTC-QLQ-C30/BN-20 and TTFields questionnaire, respectively. Planned number of patients is about 1000 (500 in each arm with positive and negative treatment decision, respectively) with a follow-up period of 18 months. First results on current enrollment status, patient’s baseline characteristics, compliance and acceptance as well as a safety analysis will be presented at the congress. The TIGER study generates systematic and prospective data for the use of TTFields in routine clinical care including patient’s therapy decision. In addition the study supports the evaluation of treatment duration and compliance, which could play a role in future assessment of TTFields treatment duration.
A pilot study of lactoferrin in patients with self-reported, chemotherapy-induced taste and smell abnormalities.
Authors: Glenn Jay Lesser, Doug Case, Aili Wang, Andrea Dietrich, Susan Duncan
Journal: Journal of Clinical Oncology (2017)

e21643 Background: Taste and smell abnormalities (TSA) are common in patients receiving chemotherapy and may lead to food avoidance, altered nutritional intake, treatment delay or withdrawal, diminished socialization and impaired overall quality of life. Lipid peroxidation of mucosal cell membranes in the oral cavity is one cause of TSA and lactoferrin (LFN), an iron-binding protein normally present in saliva, is an effective scavenger of lipid byproducts that can decrease metallic flavor in healthy volunteers. Methods: Eligible patients with colorectal or pancreatic adenocarcinoma and self-reported TSA while on an oxaliplatin-containing chemotherapy regimen were treated with LFN 250mg three times daily for 4 weeks and then followed for an additional 4 weeks off study drug. A second identical IRB-approved pilot trial enrolled patients with solid tumors, lymphoma or myeloma with self-reported TSA while receiving chemotherapy. The primary outcome was the change in self-reported TSA following 4 weeks of LFN as measured by a validated taste and smell questionnaire (TSQ) consisting of taste (score 0-10) and smell (score 0-6) subscales, which are combined to yield a total composite score (0-16, 0 = no TSA). The TSQ was assessed at 0, 4 and 8 weeks along with the FAACT (FACT–G + anorexia subscale), salivary protein and metals analyses, and the Brief Smell Identification test (B-SIT). Results: 26 total pts were enrolled (14 Males; mean age 60.5 years; range 32-79), and 19 and 17 pts remained on study with analyzable data at 4 and 8 weeks. Baseline mean taste, smell and composite TSQ scores for the 26 enrolled patients were 6.5, 3.1 and 9.6 units. After 4 weeks of LFN treatment, the mean overall TSQ score improved by 1.7 units (p = .018) while the taste and smell subscales improved by 0.6 (p = .062) and 1.1 units (p = .042) respectively. At 8 weeks, the mean TSQ score improved from baseline by 3.8 units (p &lt; .0001) while the taste and smell subscales improved by 1.9 (p = .001) and 1.8 (p = .003) units. No significant change from baseline was recorded in the FAACT or the B-SIT at 4 or 8 weeks. Conclusions: These pilot data suggest that further evaluation of LFN in patients with self-reported TSA is warranted. A randomized trial is in development. Clinical trial information: NCT01941810, NCT01596634.
Effect of bavituximab in combination with nivolumab on tumor immune response in a 3D ex vivo system of lung cancer patients.
Authors: Melanie Mediavilla-Varela, Melba Marie Page, Jenny Kreahling, Bruce D Freimark, Joseph Shan, Nikoletta Lea Kallinteris, Scott Joseph Antonia, Soner Altiok
Journal: Journal of Clinical Oncology (2017)

e23091 Background: Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Our previous studies showed that bavituximab enhances the activation of CD8+ TILs that correlates with increased cytokine production by lymphoid and myeloid cells in lung cancer with low PD-L1 expression suggesting that the interruption of the PD-1/PD-L1 axis by nivolumab may enhance the bavituximab effect in tumors. Methods: Fresh tumor tissues obtained from consented patients with NSCLC at the time of surgical resection were utilized in a 3D ex vivo tumor miscrosphere assay, where 3D tumor microspheres were treated with bavituximab or nivolumab alone or in combination at 10 mg/ml for 36 hours. At the end of the treatment, a multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines, including human IFNg, in culture media as a surrogate of TIL activation. In addition, a gene expression analysis using a NanoString platform containing probes to quantitate 770 immune function genes. Results: Preliminary results indicate the combination treatment with bavituximab and nivolumab led to increased expression of genes involved in M1 polarization of tumor associated macrophages in a subpopulation of lung tumors that closely correlated with release of cytokines such as MIP1b (CCL4) which is a chemoattractant for natural killer cells, monocytes and a variety of other cells involved in tumor immune response. Conclusions: This lung patient derived ex-vivo approach indicates that bavituximab in combination with nivolumab may enhance immune response. This response likely involves M1 polarization of tumor associated macrophages and suggests potential clinical implications in the treatment of lung cancer.
Tuberous sclerosis complex–mediated mTORC1 overactivation promotes age-related hearing loss
Authors: Xiaolong Fu, Xiaoyang Sun, Linqing Zhang, Yecheng Jin, Renjie Chai, Lili Yang, Aizhen Zhang, Xiangguo Liu, Xiaochun Bai, Jianfeng Li, Haibo Wang, Jiangang Gao
Journal: Journal of Clinical Investigation (2018)

The underlying molecular mechanisms of age-related hearing loss (ARHL) in humans and many strains of mice have not been fully characterized. This common age-related disorder is assumed to be closely associated with oxidative stress. Here, we demonstrate that mTORC1 signaling is highly and specifically activated in the cochlear neurosensory epithelium (NSE) in aging mice, and rapamycin injection prevents ARHL. To further examine the specific role of mTORC1 signaling in ARHL, we generated murine models with NSE-specific deletions of Raptor or Tsc1, regulators of mTORC1 signaling. Raptor-cKO mice developed hearing loss considerably more slowly than WT littermates. Conversely, Tsc1 loss led to the early-onset death of cochlear hair cells and consequently accelerated hearing loss. Tsc1-cKO cochleae showed features of oxidative stress and impaired antioxidant defenses. Treatment with rapamycin and the antioxidant N-acetylcysteine rescued Tsc1-cKO hair cells from injury in vivo. In addition, we identified the peroxisome as the initial signaling organelle involved in the regulation of mTORC1 signaling in cochlear hair cells. In summary, our findings identify overactive mTORC1 signaling as one of the critical causes of ARHL and suggest that reduction of mTORC1 activity in cochlear hair cells may be a potential strategy to prevent ARHL.
Abstract 14698: Self-Complementary AAV9 Provides No Advantage Over Single-Stranded AAV9 in shRNA Knockdown of Ubiquitously Expressed GFP in Heart or Liver after Systemic Delivery
Authors: Bryan A Piras, Brent A French
Journal: Circulation (2014)

Introduction: AAV9 is a potent gene delivery system that has been shown to preferentially transduce the heart over other tissues. We previously used AAV9 to achieve highly-efficient knockdown of GFP in heart but not liver of transgenic mice that express GFP from the human ubiquitin C promoter, and hypothesized that lack of liver knockdown was due to inefficient conversion of the single-stranded genomes into double-stranded DNA after AAV9-mediated delivery. Methods: An expression cassette containing a mouse U6 promoter driving shRNA against GFP was constructed using wild-type AAV2 ITRs (ssAAV) or a mutated 5’ ITR for packaging of self-complementary (scAAV) genomes into AAV9 capsids. ssAAV9 or scAAV9 vectors were administered to 10-day old mice via intraventricular chamber injection at a dose of 8х10^10 vg/g. Uninjected mice were used as controls. Cardiac and liver tissues were collected 7 weeks after injection for protein, RNA and genomic DNA. GFP expression was analyzed by qRT-PCR and western blotting. Results: Compared to controls (n=5) in cardiac tissue, the ssAAV group (n=8) demonstrated an 82% decrease in GAPDH-normalized GFP mRNA (p&lt;0.0001) while the scAAV group (n=7) provided a 79% knockdown (p&lt;0.0001) (Panel A). In liver, the ssAAV group showed a 35% reduction in GFP mRNA versus controls (p&lt;0.01) and the scAAV group showed a 27% knockdown (p&lt;0.05). Western blot analysis showed that GAPDH-normalized GFP expression was reduced by 51% in the ssAAV group (p&lt;0.0001) and by 45% in the scAAV group (p&lt;0.001) compared to controls in heart, but there was no reduction in GFP in the liver (Panel B, n=4 for all groups). Genomic DNA analysis demonstrated a 6-fold and 1.9-fold increase in viral genomes in liver vs. heart for the ssAAV group (p&lt;0.0001) and scAAV group (p&lt;0.05), respectively. Conclusions: AAV9 vectors expressing shRNA provide similar knockdown in cardiac and liver tissues regardless of whether they are packaged as single-stranded or self-complementary genomes.
A preclinical study of a PI3K/mTOR dual inhibitor in the treatment of esophageal adenocarcinoma.
Authors: Ashten N. Omstead, Ali Hussainy Zaidi, Juliann E. Kosovec, Daisuke Matsui, Moses S. Raj, Robert W.W. Biederman, Gene Grant Finley, Ronan Joseph Kelly, Blair A. Jobe
Journal: Journal of Clinical Oncology (2016)

e15554 Background: Esophageal adenocarcinoma (EAC) is a lethal cancer with limited treatment options. The PI3K/mTOR pathway is upregulated in EAC, and overexpression of p-mTOR is linked to poor prognosis. The modified Levrat model of esophagojejunostomy induces gastroduodenoesophageal reflux (GDER) in rats and reproduces the events central to human EAC carcinogenesis. The purpose of the present study is to determine the efficacy of a PI3K/mTOR dual inhibitor on established EAC in an in vivo model. Methods: Modified Levrat surgeries were performed on rats, and animals were randomized into control (n = 32) and treatment arms (n = 17) at 32 weeks post-surgery. Initial MRI was performed, and drug was administered to treatment animals intraperitoneally at 10 mg/kg for 5 weeks cyclically between 32-40 weeks. At 40 weeks, final MRI was performed on all animals to determine clinical response, and histological analysis was performed to refine the true extent of tumor response to drug treatment. Western blot, immunohistochemistry, and immunofluorescence were used to validate pathway expression, apoptosis by caspase-3, and proliferation by Ki67, respectively. Results: Mean MRI tumor volume increased by 109.2% in controls and decreased by 56.8% post-treatment (p < 0.01). During the treatment timeframe, MRI tumor volumes increased in 46.4% of control animals and 0% (p < 0.01) of treatment animals, decreased in 7.1% and 58.8% (p < 0.01), and showed stable volume in 46.4% and 41.2% (p = 0.77), respectively. EAC prevalence in controls increased by 25% between 32 and 40 weeks; whereas, EAC prevalence in the treatment group decreased by 29.4% (p < 0.01). Of treatment group animals presenting with partial or stable disease on MRI, 75% had a histological response greater than 50%. Increased apoptosis by caspase-3 (p = 0.03) and decreased proliferation by Ki67 (p < 0.01) was demonstrated in the treatment arm when compared to the control arm. Pathway inhibition was confirmed by PI3K-α (p = 0.04) and p-mTOR (p = 0.03) downregulation in treatment responsive residual tumors when compared to controls. Conclusions: The PI3K/mTOR dual inhibitor demonstrates efficacy against EAC in a preclinical model, establishing the rationale for clinical testing.
Co-occurrence of targetable aberrations in non-small cell lung cancer patients harboring <i>MAP2K1</i> mutations.
Authors: Alessandra Holzem, Lucia Nogova, Michaela A. Ihle, Claudia Wompner, Elisabeth Bitter, Sebastian Yves Friedrich Michels, Rieke Nila Fischer, Anna Kron, Ulrich Gerigk, Jens Kern, Britta Kaminsky, Winfried Randerath, Joachim Lorenz, Karl-Otto Kambartel, Sabine Merkelbach-Bruse, Reinhard Büttner, Matthias Scheffler, Juergen Wolf
Journal: Journal of Clinical Oncology (2017)

e20059 Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive with known driver mutations. Activation of the MEK1-cascade might play a pivotal role in resistance to targeted inhibition of BRAF V600E, EML4-ALK and EGFR T790M. So far, however, only MAP2K1 K57N could be identified and linked functionally to resistance in preclinical models. Clinical trials combining specific inhibitors for predefined NSCLC subgroups with MEK inhibitors are ongoing. We sought to characterize frequency and type of MAP2K1-mutated NSCLC regarding curated targetable aberrations. Methods: Tumor tissue collected consecutively from 4590 NSCLC patients within the German Network Genomic Medicine (NGM) between 07/2014 and 07/2015 was analyzed for MAP2K1 mutations using next-generation sequencing (NGS) with a set of 102 amplicons in 14 genes. Clinical and molecular characteristics of these patients were determined and compared with an internal control group of NSCLC patients and an independent control group of The Cancer Genome Atlas (TCGA). Results: We identified 21 (0.5%) patients with MAP2K1 mutations. They were frequently found in adenocarcinomas (n = 20) and were significantly associated with smoking. The most common MAP2K1 mutation was K57N. Most of the patients (n = 16) had additional oncogenic driver aberrations, including mutations in ALK, EGFR or BRAF, ROS1 rearrangements and MET amplification. TP53 mutations were found in 11 patients. In only five patients (23.8%) MAP2K1 occurred exclusively. TCGA analysis revealed additional 10 patients with MAP2K1 mutations, whereof 9 had additional TP53 mutations and one had BRAF mutation. Whereof most patients in our cohort had stage IV NSCLC, all patients in TCGA were systemic treatment naive. Compared with local stages in TCGA, our findings strongly suggest that targetable co-occurring mutations might occur more frequently in advanced stage NSCLC patients. Conclusions: MAP2K1 mutations co-occur frequently with targetable aberrations in smoking stage IV patients. Combination of targeted therapy against known driver aberrations with MEK inhibitors might be a promising therapeutic approach for such patients.