tbuckley/cabot-search huggingface dataset:
Differential effect of erlotinib on survival of patients with non-small cell lung cancer in terms of EGFR status: A meta-analysis.
Authors: Nay Min Tun, Asha Nayak
Journal: Journal of Clinical Oncology (2012)

e18024 Background: Erlotinib is a small-molecule tyrosine kinase inhibitor that inhibits the protein kinase activity of epidermal growth factor receptor (EGFR). The primary objective of this meta-analysis is to compare the response of patients with EGFR-positive versus EGFR-negative advanced non-small-cell lung cancer (NSCLC) to erlotinib in terms of overall survival (OS) and progression-free survival (PFS). Methods: A Medline search using the MeSH terms “erlotinib” and “lung” in the title field, filtered by ‘clinical trial’, yielded 108 articles. Clinical trials involving erlotinib with available survival data on EGFR-positive versus EGFR-negative NSCLC were searched for. The intervention effect estimate and standard error of each study was derived from the hazard ratio (HR) and p value. Generic inverse variance method was applied to compute the overall effect size and HR with 95% confidence interval (CI). Fixed or random effects model was used according to the level of between-study heterogeneity. Results: 3 studies including 504 patients were eligible for the analysis. All patients received erlotinib in a single arm. EGFR gene mutation was tested in 326 patients (35 mutation-positive, 188 wild-type, 103 indeterminate). EGFR gene amplification by fluorescent in-situ hybridization (FISH) was studied in 353 patients (100 positive), and EGFR protein expression by immunohistochemistry (IHC) in 368 patients (290 positive). Patients with EGFR gene mutation had significantly longer PFS (HR = 0.4, CI 0.25-0.64, p = 0.0001) but not OS (HR = 0.59, CI 0.18-1.95, p = 0.39). In contrast, EGFR FISH-positivity was associated with better PFS as well as OS (HR = 0.52, CI 0.39-0.71, p &lt; 0.00001 and HR = 0.65, CI 0.47-0.88, p = 0.006, respectively). Conclusions: Results of EGFR gene amplification by FISH rather than EGFR gene mutation by PCR may be a better predictor of survival for advanced NSCLC patients receiving erlotinib. Subgroup analyses of erlotinib's differential effect on NSCLC patients with regard to their EGFR status (as measured by PCR, FISH or IHC) are further warranted in randomized controlled trials.
Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells
Authors: Ping-Hsien Lee, Tori N. Yamamoto, Devikala Gurusamy, Madhusudhanan Sukumar, Zhiya Yu, Jane Hu-Li, Takeshi Kawabe, Arunakumar Gangaplara, Rigel J. Kishton, Amanda N. Henning, Suman K. Vodnala, Ronald N. Germain, William E. Paul, Nicholas P. Restifo
Journal: The Journal of Experimental Medicine (2019)

Host conditioning has emerged as an important component of effective adoptive cell transfer–based immunotherapy for cancer. High levels of IL-1β are induced by host conditioning, but its impact on the antitumor function of T cells remains unclear. We found that the administration of IL-1β increased the population size and functionality of adoptively transferred T cells within the tumor. Most importantly, IL-1β enhanced the ability of tumor-specific T cells to trigger the regression of large, established B16 melanoma tumors in mice. Mechanistically, we showed that the increase in T cell numbers was associated with superior tissue homing and survival abilities and was largely mediated by IL-1β–stimulated host cells. In addition, IL-1β enhanced T cell functionality indirectly via its actions on radio-resistant host cells in an IL-2– and IL-15–dependent manner. Our findings not only underscore the potential of provoking inflammation to enhance antitumor immunity but also uncover novel host regulations of T cell responses.
Abstract 13723: Does Presence of Fluoroscopic Coronary Artery Calcification Affect the Clinical Outcome of Patients Undergoing Percutaneous Coronary Intervention? Results from the Intermountain Heart Collaborative Study Registry
Authors: Shadi Karabsheh, Brigham Smith, Heidi T May, Jeffrey L Anderson, Tami L Bair, Qunyu P Li, Donald L Lappé, Anwar Tandar, Joseph B Muhlestein
Journal: Circulation (2012)

BACKGROUND: The technical approach to, and difficulty of, percutaneous coronary intervention (PCI) among pts with CAD may be profoundly affected by the amount of coronary calcification (CAC) presen...
Human VP8* mAbs neutralize rotavirus selectively in human intestinal epithelial cells
Authors: Ningguo Feng, Liya Hu, Siyuan Ding, Mrinmoy Sanyal, Boyang Zhao, Banumathi Sankaran, Sasirekha Ramani, Monica McNeal, Linda L. Yasukawa, Yanhua Song, B.V. Venkataram Prasad, Harry B. Greenberg
Journal: Journal of Clinical Investigation (2019)

We previously generated 32 rotavirus-specific (RV-specific) recombinant monoclonal antibodies (mAbs) derived from B cells isolated from human intestinal resections. Twenty-four of these mAbs were specific for the VP8* fragment of RV VP4, and most (20 of 24) were non-neutralizing when tested in the conventional MA104 cell-based assay. We reexamined the ability of these mAbs to neutralize RVs in human intestinal epithelial cells including ileal enteroids and HT-29 cells. Most (18 of 20) of the "non-neutralizing" VP8* mAbs efficiently neutralized human RV in HT-29 cells or enteroids. Serum RV neutralization titers in adults and infants were significantly higher in HT-29 than MA104 cells and adsorption of these sera with recombinant VP8* lowered the neutralization titers in HT-29 but not MA104 cells. VP8* mAbs also protected suckling mice from diarrhea in an in vivo challenge model. X-ray crystallographic analysis of one VP8* mAb (mAb9) in complex with human RV VP8* revealed that the mAb interaction site was distinct from the human histo-blood group antigen binding site. Since MA104 cells are the most commonly used cell line to detect anti-RV neutralization activity, these findings suggest that prior vaccine and other studies of human RV neutralization responses may have underestimated the contribution of VP8* antibodies to the overall neutralization titer.
Quantification of p16 methylation in serum DNA as a new diagnostic tool for colorectal cancer
Authors: G. Nakayama
Journal: Journal of Clinical Oncology (2006)

10050 Background: The incidence of colorectal cancer (CRC), one of the commonest malignancies worldwide, is still increasing. Despite advances in the diagnostic procedure, a large number of patients with CRC still presents with advanced disease. More sensitive and efficient diagnostic technique would make an impact on the prognosis of CRC patients through improving their compliance to the screening program, hence allowing earlier detection of the disease. To test the hypothesis that p16 methylation may serve as a marker for the diagnosis of CRC, we quantified the methylation levels of p16 in the serum DNA of CRC patients. Methods: Fresh specimens of 168 CRC and corresponding noncancerous tissues were obtained surgically at the Department of Surgery II, Nagoya University Graduate School of Medicine, together with the corresponding serum samples obtained 1 week prior to surgery. We defined the p16 methylation rate (p16 MR, in %) as follows: CM/(CM + CU) × 100%. CM is the concentration of methylated p16 sequences and CU is the concentration of unmethylated p16 sequences measured by quantitative methylation-specific PCR (Q-MSP) after bisulfite conversion. The relationship between the p16 MR and clinicopathologic findings were evaluated. Results: Aberrant p16 promoter methylation was found in 59% (99 of 168) of surgically resected CRC tissues. None of the corresponding normal tissues had methylated p16 sequences. 37% (37 of 99) serum samples of the CRC patients with tumoral p16 methylation had the same alterations. p16 MRs of 99 serum samples with tumoral p16 methylation were 0 to 68.9 (mean was 5.43±11.01). p16 MRs were significantly correlated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.001) and venous invasion (P=0.020) of CRCs. p16 MRs increased significantly with tumor stage [stage I : 0.94 ± 1.68, stage II : 2.33 ± 5.19, stage III : 8.49 ± 14.22, stage IV : 10.03 ± 14.27 (P = 0.021)]. Moreover, the survival of patients with low p16 MR was significantly superior to those with high p16 MR (P=0.006). Conclusions: These results suggest that quantification of p16 methylation in the serum DNA might be a novel diagnostic tool and a prognostic factor for CRC. No significant financial relationships to disclose.
Ghrelin in Alzheimer’s disease: Pathologic roles and therapeutic implications
Authors: Seong Gak Jeon, Sang Bum Hong, Yunkwon Nam, Jungyeon Tae, Anji Yoo, Eun Ji Song, Kun Il Kim, Dongje Lee, Junyong Park, Sang Min Lee, Jin-il Kim, Minho Moon
Journal: Ageing Research Reviews (2019)
Synergistic inhibition of EGFR tyrosine kinase activity and NSCLC cell growth by combination treatment with FUS1-nanoparticle and gefitinib
Authors: Hiroyuki Kawashima, Futoshi Uno, Jonathan Kurie, John D. Minna, Jack A. Roth, Lin Ji
Journal: Cancer Research (2005)

2707  New cancer treatments designed to restore functions of defect genes and gene products in tumor suppressing and apoptotic pathways by gene transfer and to target at the specific and frequently occurring molecular alterations in key signaling pathways by “smart drugs” such as protein tyrosine kinase inhibitors (PTKIs) are fundamentally changing cancer therapy and holding a promise for lung cancer treatment. FUS1 is a novel tumor suppressor gene (TSG) identified in the human chromosome 3p21.3 region that is frequently altered or deleted in many human cancers and has been shown to function as a key mediator in Apaf1-associated apoptotic pathway and as a potent tumor suppressor in vitro and in vivo. In light of our recent observations on the FUS1-mediated PTK inhibition and the direct interactions of FUS1 with PTK and Apaf1 proteins together with the current findings of activating mutations of EGFR gene in gefitinib-responders in NSCL patients and the role of these mutations in selectively activating cell survival signaling and blocking pro-apoptotic pathway by other researchers, in this study we explored the capability of using the multifunctional FUS1 as a modulator for enhancing chemotherapeutic potency of gefitinib and overcoming gefitinib-resistance by simultaneously inactivating cell survival and proliferation signaling and activating proapoptotic pathways in both gefitinib-sensitive and resistant NSCLC cells. We found that reactivation of wt-FUS1 by FUS1-nanoparticle-mediated gene transfer or treatment with a wt-FUS1-derived peptide (wt-FP) in 3p-deficeint and Gefitinib-resistant NSCLC H1299, H358, and H460 cells significantly sensitized these cells’ response to Gefitinib treatment, as demonstrated by a more than additive inhibitory effect on tumor cell growth and a synergistic induction of apoptosis. An enhance growth inhibition was also observed in gefitinib-sensitive HCC827(with an activating mutation of EGFR) and H1819 (with amplification of EGFR) cells co-treated with FUS1-nanoparticles and a very low dose of gefitinib (at a level of IC10). A marked inhibition on activities of phosphorylated EGFR and Erk proteins was also detected in cells treated by FUS1-nanoparticle or wt-FP alone or in combination with gefitinib, as demonstrated by Western-blot analysis with phosphor-EGFR or Erk-specific antibodies. Our results suggest that the wt-Fus1 may play a critical role in modulating the sensitivity of tumor cells to the chemotherapeutic agents such as PTKIs and that a combination treatment of the FUS1-nanoparticle-mediated molecular therapy with these small molecule chemotherapeutics may be an efficient treatment strategy for lung cancer. This abstract is supported by grants of NIH NCI (SPORE P50CA70907) and DOD (TARGET, DAMD17002-1-0706).
The ideal amount of physical activity to improve quality of life and symptoms in lung cancer patients: A systematic review.
Authors: Gilberto Castro, Alberto Codima, Willian das Neves, Ana Paula Souza Borges
Journal: Journal of Clinical Oncology (2019)

e23158 Background: The symptoms which burden lung cancer patients contribute to a vicious cycle of physical inactivity as the disease progresses. Some studies have shown that exercise is feasible and safe for this population, and it improves their symptoms and quality of life. However, the current recommendations are non-specific, and little is known about the optimal amount and type of exercise in this scenario. Here we aimed to identify a specific recommendation of physical activity that could work more efficiently, benefiting lung cancer patients, in terms of diminishing their symptom burden and improving quality of life. Methods: A systematic review was undertaken through structured searches on PubMed, Medline, Embase, Scopus, Web of Science and SciELO. The search protocol was registered on the Prospero platform. Rayyan QCRI was used for data extraction and determining eligible studies after a blind screening of titles and abstracts by the three authors. The Physiotherapy Evidence Database (PEDro) scale was used for quality assessment of each eligible trial in regards of risk of bias. Trials which had clear eligibility criteria and a summary score equal or superior than 6 were considered to have low risk of bias, and accepted for full text review. Results: From September/1998 to January/2019, a total amount of 1998 studies were returned from the aforementioned databases, and 17 studies were established to be eligible for quality assessment. All the 17 quality-assessed studies were randomized clinical trials. However, two of them did not clearly report the eligibility criteria and were immediately excluded. Five other studies were considered to have high risk of bias. Therefore, we considered only 10 trials to be fully reviewed, including 843 patients. Only 3 trials found significant improvement in the quality of life after their interventions, and included 243 patients. Two studies associated aerobic exercise and resistance training from 10 to 20 weeks post surgery, while the other studied intervention was Tai Chi for 10 days after each chemotherapy cycle. Conclusions: Evidence from this review suggests that exercise may improve quality of life of lung cancer patients. However, we could not identify an ideal amount nor type of physical activity given the limited available data and the heterogeneity of methods. Further studies are warranted.
In vitro and in vivo evaluation of a novel recombinant immunotoxin of ranpirnase fused to a humanized anti-EGP-1 antibody, hRS7, for the potential treatment of prostate and lung cancers.
Authors: Chien-Hsing Chang, Thomas Cardillo, Michele Losman, Meiyu Loo, David Goldenberg
Journal: Cancer Research (2007)

4795  Introduction: We have generated a novel immunotoxin by fusing ranpirnase (Rap), an amphibian RNase, to hRS7, an internalizing humanized anti-EGP-1 antibody, using the method described previously (Blood 2005; 106: 4308-4314). Since EGP-1 is expressed abundantly in certain human cancer cell lines such as PC-3 of prostate cancer, Calu-3 of NSCLC, and ME180 of cervical cancer, the immunotoxin is a potential therapeutic for these solid tumors. Methods: The Rap gene was inserted at the N-terminus of the light chain in the expression vector of hRS7. SP2/0 mouse myeloma cells were transfected, and positive clones identified by ELISA screening. The fusion protein (Rap-hRS7) was purified by protein A and characterized by a variety of in vitro techniques. In vivo therapeutic efficacy was evaluated in SCID mice bearing either PC-3 or Calu-3 xenografts. Results: Rap-hRS7 was shown to be a single peak by SE-HPLC and have binding affinity to PC-3 or Calu-3 similar to hRS7. Whereas the EC50 of RNase activity, as measured in cell-free systems by the IVTT assay, was 1400 pM for Rap-hRS7 compared to 30 pM for free Rap, the in vitro cytotoxicity of the immunotoxin on Calu-3 and PC-3, as measured by the MTS assay, was 50-and 30-fold higher than free Rap. When given a single dose of 50 μg, the immunotoxin was able to extend the median survival time of treated animals to 96 days from 55 days of the untreated group (P
Geographic variation in the adjuvant treatment of NSCLC over time.
Authors: Mary C. Schroeder, Yu-Yu Tien, Thorvardur Ragnar Halfdanarson, Taher Abu Hejleh, Matthew Nattinger, John Brooks
Journal: Journal of Clinical Oncology (2013)

6542 Background: Adjuvant chemotherapy (ACT) and postoperative radiotherapy (PORT) are used in the treatment of resected NSCLC to reduce risk of relapse, but guideline-based recommendations for these treatment modalities have varied over time. ACT is now recommended for stage II-IIIA NSCLC following resection based on phase III trial results which, starting in 2003, showed improved survival. Conversely PORT recommendations have been rescinded due largely to a 1998 Lancet meta-analysis. In this study we explore the rates of these two adjuvant treatment modalities across areas over time. Methods: Using SEER-Medicare data we identified 18,410 patients diagnosed 1992-2007 with resected NSCLC. Adjuvant treatment was defined as the first treatment received within 4 months of surgery. The study period was divided into 3 eras: 1992-1998, 1999-2003, and 2004-2007. Area treatment rates were calculated using the 50 patients closest to each zip code, adjusting for patient and area characteristics. Areas were then ranked and divided into quintiles. Percent differences were calculated to measure the variation between the highest and lowest quintiles. Results: Between 1992-1998 when the results of the phase III ACT trials were still unknown and utilization of ACT was low, areas with the highest treatment rates were 35 times more likely than areas with the lowest rates to administer ACT. After 2003 ACT use increased swiftly and geographic variation fell. In contrast, PORT utilization rates have declined and become more geographically dispersed since 1998. Receiving no adjuvant treatment was highest between 1999-2003, after the Lancet PORT meta-analysis and before the major ACT trials. Conclusions: NSCLC adjuvant treatment has been shifting from PORT to ACT. The positive results of the ACT trials and publication of treatment guidelines have increased usage and reduced geographic variation in ACT use. Geographic variation in PORT use however has increased over time, although overall usage has decreased. [Table: see text]
Use of cetuximab (CTX) in first-line therapy of metastatic colorectal cancer (mCRC): Patient characteristics, safety, and effectiveness in the EREBUS cohort.
Authors: Denis Smith, Magali Rouyer, Emmanuel Mitry, Eric François, Alain Monnereau, Antonio Sa Cunha, Emmanuelle Bignon, Alise Le Monies, Jeremy Jove, Pernelle Noize, Nicholas Moore, Annie Fourrier-Réglat
Journal: Journal of Clinical Oncology (2012)

e14168 Background: CTX has demonstrated improved survival outcomes in mCRC but information in real-life is sparse. Methods: EREBUS is a French multicentre (n=92) cohort. Patients (pts) initiating CTX 1 st -line therapy for unresectable mCRC in 2009 and 2010 were identified from dispensation registries and followed 12 months. Presented here is preliminary data for those included in 2009. Results: A total of 205 pts were included, all had wild-type (wt) KRAS gene. Median age: 64 yrs, 67.3% male, 65.8% ECOG=0-1, 61% cardiovascular history, 78.5% colon primary site, 55.6% primary tumor resection, 73.7% synchronous metastasis, single metastatic site: 52.7% (39% exclusively liver). A multidisciplinary team considered 1 st -line as palliative for 61.5% of pts, and 37.1% as potentially resectable. CTX was combined with oxaliplatin-based regimens: 37.6%, irinotecan-based regimens: 55.6%, and other regimens: 6.8%. For those receiving CTX+oxaliplatin (n=77): median duration of CTX use was 3.6 months and 63.6% were treated every 2 weeks. For those receiving CTX+irinotecan (n=114): it was 4.7 months and 81.6% treated every 2 weeks. Response rate (CR+PR) according to physician evaluation was 48.6% for CTX+oxaliplatin and 46.8% for CTX+irinotecan. 1-yr OS was 59.9% (95%CI 47.6-70.2) and median PFS was 8.6 months (6.3-10.5) for CTX+oxaliplatin. 1-yr OS was 69.1% (59.6-76.7) and median PFS was 9.3 months (7.4-10.5) for CTX+irinotecan. Incidence of any grade 3/4 event was 58% for CTX+oxaliplatin and 57% for CTX+irinotecan: neutropenia (18.2% and 19.3%, respectively), skin reaction (11.7% and 14%), asthenia (11.7% and 14.9%), hypokalaemia (13% and 4.4%), diarrhoea (6.5% and 10.5%) and infusion-related reactions (1.3% and 0.9%). Surgical evaluation was performed in 27.8%: 31.2% CTX+oxaliplatin and 24.6% CTX+irinotecan Conclusions: In France, CTX was frequently combined with irinotecan-based regimens in 1 st -line wt KRAS mCRC. These results indicate a high proportion of exclusive liver metastases, and a high proportion of patients undergoing surgery. Effectiveness and safety profile of CTX in real life were in line with pivotal trials
Abstract 18909: Progressive Myocardial Injury is Associated With Mortality in Patients With Non-cardiac Respiratory Failure
Authors: Thomas S Metkus, Eliseo Guallar, Lori Sokoll, David A Morrow, Gordon Tomaselli, Roy Brower, Steven Schulman, Frederick K Korley
Journal: Circulation (2017)

Introduction: Myocardial injury is associated with adverse outcomes in the Acute Respiratory Distress Syndrome (ARDS), however the prognostic connotation of changes in cardiac troponin (cTn) levels...
18F-16β-fluoro-5α-dihydrotestosterone (FDHT) PET as a prognostic biomarker for survival in patients with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Karen A. Autio, Josef J. Fox, Xiaoyu Jia, Glenn Heller, Heiko Schöder, John Humm, Eric C. Haupt, Coursen Schneider, Howard I. Scher, Steven M. Larson, Michael J. Morris
Journal: Journal of Clinical Oncology (2012)

4517 Background: At present there is no imaging biomarker for patients with mCRPC as the disease primarily metastasizes to bone, which is difficult to visualize and quantify using standard techniques. We have conducted clinical trials in which patients with progressive mCRPC are scanned using FDG-PET to examine glucose metabolism, and FDHT-PET. FDHT is a novel tracer and structural analog of dihydrotestosterone that binds to the androgen receptor (AR) to demonstrate AR overexpression, a key biologic feature of mCRPC. We previously reported an association between baseline FDG-PET and overall survival in mCRPC. We now present the prognostic utility of baseline FDHT-PET. Methods: We prospectively scanned mCRPC patients with FDG and FDHT-PET prior to a change in therapy as part of imaging clinical trials. PET results were represented as the hottest lesion (SUVmax), or average of the five hottest lesions (SUVmaxavg). Five lesions per patient were recorded. If less than 5 lesions were captured, a value of 1 was imputed for the remaining lesions. Clinical and lab parameters were collected. Univariate analysis was performed on PET, clinical and lab variables for association with overall survival (OS). Multivariate models of prognostic factors were constructed. Results: 170 mCRPC patients were imaged with FDG and 116 also had FDHT-PET at baseline. Median survival was 21.2 months (95%CI: 19.1-24.0). On univariate analysis, FDHTmax, FDHTmaxavg, FDGmaxavg, PSA, hemoglobin, alkaline phosphatase, and LDH were associated with OS. FDHTmax and FDHTmaxavg were significantly correlated with one another. In a multivariate model, FDHTmaxavg and LDH were prognostic of survival. In a separate model assessing FDG, FDGmaxavg and LDH were also prognostic. Conclusions: FDHT not only allows for a visual assessment of the AR axis in prostate cancer, but appears to associate with overall survival in mCRPC. Increased AR activity as measured by FDHT SUVmaxavg held greater prognostic value than PSA or Gleason score. FDHT is also being evaluated as a clinical response indicator and pharmacodynamic measure with AR directed therapies.