tbuckley/cabot-search huggingface dataset:
Can hippocampus be spared in patients with small cell lung carcinoma (SCLC) during cranial radiation therapy (CRT)?
Authors: Vijayananda Kundapur, Tasha Ellchuk, Shahid Ahmed
Journal: Journal of Clinical Oncology (2013)

7596 Background: Although CRT is a standard therapy for prevention and treatment of brain metastases (BM) in patients with SCLC, neurocognitive impairment (NI) following therapeutic whole brain radiation treatment (WBRT) or prophylactic cranial irradiation (PCI) is a major problem and can cause impairment in quality of life. A RTOG study is assessing various outcomes by avoiding the hippocampus (AH) during WBRT in different malignancies. The estimated risk of hippocampal avoidance region metastases (HM) in patients with SCLC before &amp; after WBRT/PCI is not known. AH during CRT may delay the onset of NI in such patients. Our study aims to determine risk of HM in patients with SCLC and to assess clinical factors correlate with it. Methods: A patients cohort of SCLC diagnosed and treated at the Saskatoon Cancer Center between 2005 and 2012 were followed. All MRI and/or CT scans were independently reviewed by a neuroradiologist. HM was defined as BM within 5 mm of hippocampus. Binary Logistic regression analysis was done to assess correlation between various clinical variables and HM using SPSS. Results: 162 patients with SCLC were identified, 60 (37%) have developed BM. The preliminary data of 39/60 patients is presented here. All 39 patients received CRT and 17 patients received upfront chemotherapy. Their median age was 63 yrs (range: 41-82) &amp; M:F was 22:17. 30 (77%) had extensive stage SCLC and 30 (77%) had de novo BM before CRT. A total 198 (range: 1-33) BM were identified among these patients with a mean BM of 6.6 per patient. 4 (13.3%) of 30 patients had HM involvement with mean BM of 1.3 per patient. Median follow up was 13.5 months (range: 1-69). Post-CRT 13 (33%) of 39 patients (4 PCI, 9 WBRT) developed central nervous system (CNS) progression. None of 13 patients with CNS failure following CRT developed HM. Overall 4 (10.2%) of 39 patients developed HM. No clinical factors significantly correlated with HM. Conclusions: The preliminary result revealed that overall incidence of HM before and after WBRT/PCI is low. AH in such patients may consider during CRT to avoid NI. The study is ongoing and final analysis will be presented.
A Neutrophil Activation Biomarker Panel in Prognosis and Monitoring of Patients With Rheumatoid Arthritis
Authors: Mary Bach, Jeonghun Moon, Richard Moore, Tiffany Pan, J. Lee Nelson, Christian Lood
Journal: Arthritis & Rheumatology (2019)

Objective Exaggerated neutrophil activation and formation of neutrophil extracellular traps ( NET s) are linked to inflammation and autoimmunity, including rheumatoid arthritis ( RA ). However, whether NET s are present in the circulation of RA patients and contribute to inflammation and disease progression has not been carefully addressed. We undertook this study to assess markers of neutrophil activation and NET formation in plasma samples, investigating whether they add clinical value in improving the determination of prognosis and monitoring in RA patients. Methods Markers of neutrophil activation (calprotectin) and cell death ( NET s) were analyzed, using enzyme‐linked immunosorbent assay, in serum and plasma obtained from patients in 3 cross‐sectional RA cohorts and sex‐matched healthy controls. A longitudinal inception cohort (n = 247), seen for a median follow‐up of 8 years, was used for predictive analyses. Results Markers of neutrophil activation and cell death were increased in RA patients compared to healthy individuals ( P &lt; 0.0001). Calprotectin levels correlated with the Clinical Disease Activity Index (r = 0.53, P &lt; 0.0001) and could be used to distinguish between patients with disease in remission and those with active disease, an observation not seen when examining C‐reactive protein levels. A biomarker panel consisting of anti–citrullinated protein antibody and calprotectin could predict erosive disease (odds ratio [ OR ] 7.5, P &lt; 0.0001) and joint space narrowing ( OR 4.9, P = 0.001). NET levels were associated with markers of inflammation ( P = 0.0002). Furthermore, NET s and a “neutrophil activation signature” biomarker panel had good predictive value in identifying patients who were developing extraarticular nodules ( OR 5.6, P = 0.006). Conclusion Neutrophils undergo marked activation and cell death in RA . Neutrophil biomarkers can provide added clinical value in the monitoring and prognosis of RA patients and may allow for early preventive treatment intervention.
Design of a “Lean” Case Report Form for Heart Failure Therapeutic Development
Authors: Mitchell A. Psotka, Mona Fiuzat, Peter E. Carson, David P. Kao, Jeffrey Cerkvenik, Daniel E. Schaber, Patrick Verta, Robert T. Kazmierski, Meir Shinnar, Norman Stockbridge, Ellis F. Unger, Bram Zuckerman, Javed Butler, G. Michael Felker, Marvin A. Konstam, JoAnn Lindenfeld, Scott D. Solomon, John R. Teerlink, Christopher M. O'Connor, William T. Abraham
Journal: JACC Heart Failure (2019)

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.
Concomitant chemoradiotherapy phase II study comparing pemetrexed/carboplatin with paclitaxel/carboplatin in patients with unresectable stage III non-small cell lung cancer.
Authors: Shenglin Ma, Yaping Xu, Yongling Ji, Xiaojiang Sun, Yuanda Zheng
Journal: Journal of Clinical Oncology (2012)

e17527 Background: Concomitant chemoradiotherapy is the standard treatment of unresectable stage III non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial. We have conducted a phase II study to evaluate concomitant treatment using pemetrexed/carboplatin or paclitaxel/carboplatin in these patients. The purpose of this study is to compare the feasibility and activity, and also assess its impact on progression-free survival (PFS). Methods: A total of 37 patients were enrolled between January 2008 and May 2011. Patients received concomitant chemoradiotherapy [thoracic radiotherapy and pemetrexed 500mg/m 2 , carboplatin AUC 5 every 3 weeks for 2 cycles; or paclitaxel 50mg/m 2 , carboplatin AUC 2 weekly for 6 weeks. ] Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. The Kaplan–Meier method was used to evaluate patient survival. Univariate analysis of patient characteristics and tumor responses was conducted using the Chi-square and Fisher's exact test. Results: The overall response rate for pemetrexed/carboplatin was statistically superior to paclitaxel/carboplatin (P &lt;0.05). In patients with adenocarcinoma, there was a signiﬁcant improvement in PFS with pemetrexed/carboplatin versus paclitaxel/carboplatin (11.6 vs. 9.3 months, respectively). For pemetrexed/carboplatin, rates of grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia were signiﬁcantly lower (P &lt;0.05), whereas grade 3 or 4 fatigue (P = 0.08) was more common. Conclusions: This data suggests that concomitant chemoradiotherapy with pemetrexed/carboplatin was better tolerability and more efficacy than paclitaxel/carboplatin in a Chinese population with unresectable stage III NSCLC. Better outcomes were observed in patients with adenocarcinoma in pemetrexed/carboplatin. Although the data presented herewith appears more promising in pemetrexed/carboplatin, this study is relatively small, and more data from randomized trials are needed to further validate this regimen.
EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR C797S Respond to First-Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR T790M/C797S in Preclinical Models and Clinical Samples
Authors: Deepa Rangachari, Ciric To, Jason E. Shpilsky, Paul A. VanderLaan, Susumu S. Kobayashi, Mierzhati Mushajiang, Christie J. Lau, Cloud P. Paweletz, Geoffrey R. Oxnard, Pasi A. Jänne, Daniel B. Costa
Journal: Journal of Thoracic Oncology (2019)

IntroductionOsimertinib is approved for advanced EGFR-mutated NSCLC, and identification of on-target mechanisms of resistance (i.e., EGFR C797S) to this third-generation EGFR inhibitor are evolving. Whether durable control of subsequently osimertinib-resistant NSCLC with the EGFR-sensitizing mutation (SM)/C797S is possible with first-generation EGFR inhibitors (such as gefitinib or erlotinib) remains underreported, as does the resultant acquired resistance profile.MethodsWe used N-ethyl-N-nitrosourea mutagenesis to determine the profile of EGFR SM/C797S preclinical models exposed to reversible EGFR inhibitors. In addition, we retrospectively probed a case of EGFR SM lung adenocarcinoma treated with first-line osimertinib, followed by second-line erlotinib in the setting of EGFR SM/C797S.ResultsUse of N-ethyl-N-nitrosourea mutagenesis against the background of EGFR L858R/C797S in conjunction with administration of gefitinib revealed preferential outgrowth of cells with EGFR L858R/T790M/C797S. A patient with EGFR delE746_T751insV NSCLC was treated with osimertinib with sustained response for 10 months before acquiring EGFR C797S. The patient was subsequently treated with erlotinib, with response for a period of 4 months, but disease progression ensued. Liquid biopsy disclosed EGFR delE746_T751insV with T790M and C797S present in cis.ConclusionEGFR SM NSCLC can acquire resistance to osimertinib through development of the EGFR C797S mutation. In this clinical scenario, the tumor may respond transiently to reversible first-generation EGFR inhibitors (gefitinib or erlotinib), but evolving mechanisms of on-target resistance—in clinical specimens and preclinical systems—indicate that EGFR C797S along with EGFR T790M can evolve. This report adds to the growing understanding of tumor evolution or adaptability to sequential EGFR inhibition and augments support for exploring combination therapies to delay or prevent on-target resistance.
Gab3 is required for IL-2– and IL-15–induced NK cell expansion and limits trophoblast invasion during pregnancy
Authors: Anna Sliz, Kathryn C. S. Locker, Kristin Lampe, Alzbeta Godarova, David R. Plas, Edith M. Janssen, Helen Jones, Andrew B. Herr, Kasper Hoebe
Journal: Science Immunology (2019)

NK cells require Gab3 for peripheral expansion, tumor eradication, and resistance to trophoblast invasion during pregnancy. See the related Focus by Colucci .
Treatment response and survival outcome of patients with late relapse (LR) from renal cell carcinoma (RCC) in the era of targeted therapy.
Authors: Nils Kroeger, Jae-Lyun Lee, Georg A. Bjarnason, Jennifer J. Knox, Mary J. MacKenzie, Ulka N. Vaishamayan, Lori Wood, Sandy Srinivas, Sun Young Rha, Sumanta Kumar Pal, Takeshi Yuasa, Frede Donskov, Neeraj Agarwal, Min-Han Tan, Aristotelis Bamias, Christian K. Kollmannsberger, Scott A. North, Brian I. Rini, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2013)

4578 Background: A small subset of localized RCC patients will experience disease recurrence ≥5 years after nephrectomy. Clinical outcome of patients with LR has not been well characterized. Methods: Patients with mRCC treated with targeted therapy were retrospectively characterized according to time to relapse. Replase was defined as diagnosis of recurrent metastatic disease &gt;3 months after initial diagnosis. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as Early Relapsers (ER) if they recurred within 5 years while Late Relapsers (LR) recurred after 5 years. Demographics and outcomes were compared. Results: 1210 mRCC patients were identified; 903 (74.6%) with relapse within the first 5 years, 200 (16.5%) within &gt;5-10 years, and 107 (8.8%) after 10 years (range 10-35 years). Baseline characteristics are presented in the Table. Overall response rates to targeted therapy were better in LR vs. ER (35% vs. 24%; p=0.009). LR patients had significant longer progression free- (10.7 vs. 8.5 months; log rank p=0.004) and overall survival (34.0 vs. 27.3 months; log rank p=0.003). Conclusions: One quarter of patients that eventually developed metastatic disease treated with targeted therapy relapsed over 5 years from initial diagnosis. The proportion of patients that relapse after five years is substantial. mRCC patients presenting with LR have more favorable prognostic features, treatment response, and overall survival. [Table: see text]
Effect of weekly administration of bevacizumab, gemcitabine, and oxaliplatin in patients with heavily pretreated ovarian cancer.
Authors: Yuji Ikeda, Yoshihiro Kikuchi, Masashi Takano, Tomoko Goto, Hiroko Kouta, Naoki Sasaki, Kazuya Kudoh, Katsutoshi Oda, Tsuneki Nagasaka, Tsunekazu Kita
Journal: Journal of Clinical Oncology (2012)

5037 Background: The combination therapy of gemcitabine with oxaliplatin (GEMOX) has high activity in patients with ovarian cancer. Bevacizumab (B), a vascular endothelial growth factor specific antibody, enhances chemotherapeutic efficacy through its anti-angiogenic function in various types of tumors. We evaluated the effect of weekly administration of B and GEMOX in heavily-pretreated patients with recurrent or refractory ovarian cancers (ROC). Methods: Nineteen patients with ROC received at least three or more cycles of weekly-B and GEMOX consisting of B (2mg/kg), gemcitabine (300mg/m 2 ) and oxaliplatin (30mg/m 2 ). The treatment was continued until the development of progressive disease. The response and adverse effects (AE) were evaluated using the response evaluation criteria in solid tumors (RECIST), CA125 Gynecologic Cancer Intergroup (GCIG) criteria, and common terminology criteria for adverse events (CTCAE) version 3.0. Results: Seventeen (89%) of the 19 patients were primarily stage 3 or 4. Fifteen patients (79%) had received more than three regimens of chemotherapy. All patients were pretreated with a platinum-containing regimen within 6 months and 16 of these patients (84%) were pretreated within 3 months. According to the RECIST evaluation, 2 patients (11%) had a complete response (CR), 6 patients (32%) had a partial remission (PR) and 5 patients (26%) had a stable disease (SD). The response rate (RR; CR+PR) and clinical benefit rate (CBR; CR+PR+SD) were 42% and 68%, respectively. In 10 patients with serous adenocarcinoma, RR was 60%. In 6 patients pretreated with weekly B and pegylated liposomal doxorubicin (PLD), RR was 50%. Median progression-free survival was 5 months (range: 2-11 months). Hematological adverse effects (AE) with grade 3/4 were leukopenia (16%), neutropenia (10%), thrombocytopenia (5%), however, all AE were manageable. Conclusions: Weekly B and GEMOX administration had significant activity with mild AE in patients with ROC especially in serous adenocarcinoma. Notably, the activity was also observed in patients pretreated with weekly B and PLD. These results warrant further prospective study.
Cetuximab + FOLFOX6 as first line therapy for metastatic colorectal cancer (An International Oncology Network study, I-03–002)
Authors: S. Dakhil, T. Cosgriff, D. Headley, R. V. Boccia, S. Badarinath
Journal: Journal of Clinical Oncology (2006)

3557 Background: Cetuximab, an IgG1 monoclonal antibody targeting the EGFR, is currently approved for second line treatment of metastatic colorectal cancer (CRC). This phase II trial was designed to evaluate the safety and efficacy of cetuximab combined with FOLFOX6 as first line therapy in this patient population. Promising results have been reported at ESMO in a similar small pilot study. Methods: Eligibility: Age ≥ 18, locally advanced or metastatic CRC, no prior therapy for advanced disease, EGFR expression positive or undetectable. Regimen: Cetuximab 400 mg/M 2 (2 hour infusion) day 1; 250 mg/M 2 day 8 (and 250 mg/M 2 for all subsequent doses); and modified FOLFOX 6 (2 hour infusion); and 5FU bolus 400 mg/M 2 day 1 followed by 5FU-CI 2400 mg/M 2 over 46 hours (days 1 and 2). Cycles were repeated every 14 days. Results: 82 patients were enrolled in the study. The median number of treatment cycles administered was 8. (range 1–28) At the time of this report, 23 patients are still on study. Reasons for discontinuation of therapy included: Toxicity (14 patients), disease progression (20), investigator /patient decision (11), planned therapy completed (3). Five patients (6%) died on study. Causes of death included: PD (2 patients), acute MI (1), respiratory failure secondary to pneumonia (1), sudden death of unknown cause (1). The most frequently observed toxicity was neutropenia. Grade 3/4 toxicities are listed in the table below. At this early analysis time point, 32 of 60 patients evaluable for response have documented CR/PR (3 CR, 29 PR, overall response rate of 53%). A pre-meeting update is planned for presentation purposes. Conclusion: These findings suggest that the combination of cetuximab with FOLFOX6 is safe and active in first line treatment of patients with metastatic CRC. Updated efficacy and safety data will be presented. [Table: see text] No significant financial relationships to disclose.
Phase 1 dose-escalation study of 17-allylamino-17-demethoxygeldanamycin (17AAG) in combination with irinotecan in patients with solid tumors
Authors: A. N. Tse, R. Carvajal, M. Shah, H. Dials, M. Fogel, E. O’Reilly, K. Chung, R. Maki, N. Wu, M. Egorin, G. K. Schwartz
Journal: Journal of Clinical Oncology (2007)

3533 Background: 17AAG is an inhibitor of the molecular chaperone Hsp90. Pre-clinical studies from our laboratory showed that treatment of cancer cells with 17AAG caused depletion of two critical checkpoint kinases, Chk1 and Wee1, resulting in abrogation of the G 2 /M checkpoint triggered by topoisomerase I poison, and selective induction of apoptosis in p53-defective cells. Methods: We initiated a phase 1 study of irinotecan (CPT) and 17AAG to determine the maximally tolerated doses (MTD) and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. During the dose-escalating phase, patients (Pts) received CPT over 30 min followed by 17AAG over 2 hrs once weekly for two weeks in a 21-day cycle. At the MTD, Pts underwent post-treatment tumor biopsy for PD biomarker analysis after CPT only during week 1 and after the combination during week 2. Results: 22 Pts (median age 53; range 32–73; median KPS 80) with a wide spectrum of solid tumor types were enrolled. Four Pts developed dose-limiting toxicity in cohort 4 (100 mg/m 2 CPT and 375 mg/m 2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The PKs of 17AAG and its metabolite 17AG were not affected by the co-administration of CPT. Although no CR/PR’s by RECIST criteria have been seen, minor responses were observed in CPT-naive Pts with pancreas (2), breast (1), and high grade neuroendocrine tumor (1). Pts are currently enrolled to the MTD expanded cohort for further assessment of tolerability and PD analysis. So far, paired tumor biopsies have been successfully obtained in 8/8 Pts and samples will be analyzed for p53 status, Hsp90 client protein depletion, G 2 /M checkpoint abrogation, and apoptosis. Conclusions: The combination of 17AAG and CPT can be given to Pts with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m 2 CPT and 300 mg/m 2 17AAG. (Supported by ASCO CDA and NCI K08 awards) No significant financial relationships to disclose.
Global proteome analysis of germ cell tumor (GCT) cell lines under treatment with cisplatin (CDDP)
Authors: F. U. Honecker, S. Glaesener, S. Venz, R. Walther, T. H. Brummendorf, S. Balabanov, C. Bokemeyer
Journal: Journal of Clinical Oncology (2007)

15567 Background: GCTs are the most common malignancy in young Caucasian males aged 20–40. With CDDP-based chemotherapy, highly effective treatment has been developed for the majority of patients with GCT. However, the molecular mechanisms underlying treatment response remain elusive. Therefore, we used a global proteomics approach to screen for changes induced in GCT cell lines by CDDP. Material and Methods: Global protein expression analysis of three GCT cell lines, NTERA2, 2102EP, and NCCIT, both untreated and treated with CDDP for 48 hours at the IC50, was performed using 2-dimensional gel electrophoresis. Differentially expressed proteins were analyzed using matrix-assisted laser desorption/ionization - time of flight (MALDI TOF) and Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Identification of proteins was performed using peptide mass-fingerprinting and NCBI/SwissProt and The Global Proteome Machine database search. Results: In total, 66 proteins were found to be differentially expressed comparing untreated and treated cells. Numbers of proteins showing upregulation under CDDP were 18 in NTERA2, 10 in NCCIT, and 9 in 2102EP, whereas 17 proteins were downregulated in NTERA2, 5 in NCCIT, and 7 in 2102EP. Identification of corresponding proteins was successful in 44 out of 66 spots (67%). Differential expression of 5 proteins was found in more than one cell line. One protein (Enolase 1) was consistently up-regulated in all three cell lines under CDDP. The identified proteins can be grouped into different categories: 15 are involved in DNA-binding/transcription, 8 in metabolism, 8 in protein folding/binding/chaperone, 6 in cell signaling/differentiation, 4 in apoptosis, and 3 in cytoskeleton/cell movement. Conclusion: The results of this screening approach identify factors differentially regulated during response to CDDP in GCTs, and reveal a specific response pattern for each cell line. This knowledge can help to identify therapeutic targets and factors potentially involved in treatment sensitivity and resistance. No significant financial relationships to disclose.