tbuckley/cabot-search huggingface dataset:
Quality of safety reporting in oncology-randomized controlled trials (RCTs).
Authors: R. C. Pezo, B. Seruga, M. K. Krzyzanowska, P. Bedard
Journal: Journal of Clinical Oncology (2011)

e13037 Background: Clinical trial reports often emphasize the efficacy of an investigational agent. Inadequate reporting of harms in published reports of RCTs may cause a misinterpretation of the risk to benefit ratio associated with new therapies. Our aim was to evaluate the quality of reporting of safety results in RCTs in oncology. Methods: We searched Medline to identify all RCTs with a sample size of at least 200 patients evaluating experimental medical therapies in breast and colorectal cancer published from 2000 to 2007. Each article was reviewed by a single investigator using a standardized data extraction form based on the harm reporting criteria developed by the CONSORT group. A random sample of articles was reviewed by a second investigator for quality assurance. Results: A total of 98 RCTs were identified through our search (breast n =68, colorectal n =30). The level of agreement between investigators performing data abstraction was high (kappa=0.737). Of these, 95.9% reported adverse events (AEs) in the body of the manuscript while only 39.8% of studies described AEs in the abstract. Information on only common and severe AEs was provided in 23.4% and 40.4% of reports respectively. The population group used for safety analysis was not identified in 19.4% of trials. No information on treatment discontinuation or dose reductions was provided in 24.5% and 53.1% of reports. Date of publication (before vs. after publication of the CONSORT harm reporting criteria), tumor site (breast vs colorectal), and treatment setting (early vs advanced disease) were not associated with quality of reporting severe adverse events, treatment discontinuation, and dose reduction. RCTs of advanced disease were more likely to report common adverse events than RCTs of early disease (41.3% vs 10.6% p=0.001). Conclusions: Most oncology RCTs fail to adequately report harm-related results. Adherence to reporting guidelines for adverse events is particularly important in oncology trials, where therapies often have a narrow therapeutic window.
Signatures of drug sensitivity in non-small cell lung cancer.
Authors: H. Gong, D. G. Beer, S. Singh
Journal: Journal of Clinical Oncology (2011)

10602 Background: We profiled receptor tyrosine kinase pathway activation and key gene mutations in eight human lung tumor cell lines and 50 human lung tumor tissue samples to define molecular pathways which may help to evaluate the efficacy of targeted therapies. Methods: A panel of eight kinase inhibitors was used to determine whether blocking pathway activation affected the growth of the tumor cell lines. Clustering the primary tumor samples with the corresponding tumor cell lines based on their signatures was used to predict treatment options for the patients based on the response of the selected tumor cell lines to the panel of kinase inhibitors. Results: Subsets of patients were identified as candidates for treatment with inhibitors of EGFR, c-Met, IGF-1R, MEK, and PI3K. The EGFR pathway in EGFR mutant cell lines HCC827, H1975 and H1650 were found to be highly activated and sensitive to inhibitors blocking EGFR signaling. Primary tumors were identified with similar profiles, and we predict that those patients would be candidates for anti-EGFR therapies. H1993 is a cell line containing c-Met amplification and with c-Met and EGFR pathway activation and patients sharing this genotype may respond to c-Met inhibitor treatment. IGF-1R pathway activated H358 and A549 cells are sensitive to IGF-1R inhibition and patients sharing a similar profile with these cells may be candidates for this type of therapy. The downstream PI3K inhibitor, BEZ-235, effectively inhibited tumor cell growth in most of the cell lines tested, except the H1993 and H358 cells, while the MEK inhibitor PD-325901 was effective in blocking the growth of KRAS mutated cell line H1734 but not in the other KRAS mutated cell lines, H358, A549 and H460. Patients with a similar signature may benefit from treatment with a combination of two kinase inhibitors. Conclusions: Thus, by combining pathway biomarker information, mutational status and clinical features, we were able to cluster the patient tumor samples to the corresponding lung tumor cell lines and propose treatment options for the patients based on their signature overlap with the tumor cell lines.
A phase I study of aflibercept, pemetrexed (P), and cisplatin (C) in patients with advanced solid tumors.
Authors: C. A. Townsley, L. L. Siu, M. San Pedro-Salcedo, L. Liu, H. A. Wakelee
Journal: Journal of Clinical Oncology (2010)

2536 Background: Aflibercept (AF) (aka VEGF-trap) is a fully human recombinant protein inhibitor of vascular endothelial growth factor (VEGF) that also binds to placental growth factor. AF consists of the second immunoglobulin domain of VEGFR-1 and the third domain from VEGFR-2, the two most potent VEGF binding domains, attached to the Fc portion of IgG1. P plus C is a standard regimen for the treatment of NSCLC and mesothelioma. Methods: The objectives of this study were to assess dose-limiting toxicity (DLT), recommended phase II dose (RD), and pharmacokinetics (PK) of aflibercept administered intravenously (IV) every 3 weeks with P plus C in patients with advanced solid tumors. AF was administered over 1 hour at escalating doses of 2, 4, or 6 mg/kg in combination with fixed doses of P (500 mg/m2) plus C (75 mg/m2). Results: 18 patients (M/F 9/9), median age 64 yr. range (37-73), ECOG PS 0 (n=2); PS 1 (n=16) were enrolled at 2 (n=4), 4 (n=7), 6 (n=7) mg/kg cohorts. Primary tumors included: mesothelioma (5), NSCLC (4), GI (4), other (5). Prior therapy included: surgery (77%), chemotherapy (44%), and radiation (44%). Patients received a median number of 3 cycles (range 1-8). No DLT was observed in any cohort. Most common adverse events (AEs) of all grades included (#pts): fatigue (13), nausea (10), vomiting (8), constipation (8), dysphonia (6), stomatitis (5), and diarrhea (5). Grade ≥ 3 AEs commonly related to anti-VEGF therapy included: pulmonary embolism (2), deep vein thrombosis (1), and hypertension (1). Non-DLT grade 3 hypophosphatemia was observed in one patient at 4 mg/kg and one at 6 mg/kg. Fifteen patients are evaluable for efficacy: SD (13) and PD (2). Four patients remain on treatment at 6 mg/kg (3+, 6+, 7+, 7+ cycles). No drug–drug interaction was observed. Conclusions: Aflibercept in combination with P plus C was well tolerated. AF 6 mg/kg IV every 3 weeks was selected as the phase 2 RD in combination with P plus C and is consistent with AF dosing of 2 mg/kg/wk in all ongoing combination phase III studies. The phase II study in first-line NSCLC is ongoing. Updated phase I efficacy, safety, and PK data will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Regeneron Merck, Millennium, Ozmosis Research Regeneron AstraZeneca, Bayer, Bristol-Myers Squibb, Cyclacel Pharmaceuticals, Exelixis, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, Regeneron, Roche Regeneron
A divergent population of autoantigen-responsive CD4<sup>+</sup>T cells in infants prior to β cell autoimmunity
Authors: Anne-Kristin Heninger, Anne Eugster, Denise Kuehn, Florian Buettner, Matthias Kuhn, Annett Lindner, Sevina Dietz, Sibille Jergens, Carmen Wilhelm, Andreas Beyerlein, Anette-G. Ziegler, Ezio Bonifacio
Journal: Science Translational Medicine (2017)

A divergent autoantigen-responsive CD4 + T cell population is present in infancy, before autoimmunity in type 1 diabetes.
Retrospective study to evaluate interstitial lung disease secondary to oxaliplatin-containing chemotherapy at an NCI-designated comprehensive cancer center.
Authors: Vaibhav Sahai, Halla Sayed Nimeiri, Maxwell Thomas Vergo
Journal: Journal of Clinical Oncology (2013)

547 Background: Oxaliplatin-induced interstitial lung disease (ILD) in gastric and colorectal cancer (CRC) patients is rarely reported and its clinical features remain to be clarified. Methods: Using a computerized database, we retrospectively identified 621 patients with gastric or CRC treated with oxaliplatin-containing regimen from February 2003 to September 2011 at an NCCN institution. Out of 621 patients, chart review was done for 135 patients who developed lung toxicity during or post-chemotherapy. For purpose of data collection, lung toxicity was defined as pulmonary fibrosis, pneumonitis, ARDS, pneumonia-organism unspecified and acute respiratory failure. Imaging data was reviewed for all patients until death or at least 1 year after diagnosis. Results: Of 621 patients, 4 patients developed ILD (0.64%) and of those 2 died due to the toxicity (0.32%). Of the 4 patients, three were symptomatic, three had high Brinkman Index (BI) (≥600) and two showed pulmonary opacities other than lung metastases before chemotherapy. All developed ILD during or within 30 days of oxaliplatin-containing chemotherapy. Extensive work-up in 3 of 4 patients was negative for infection. Chemotherapy regimens included 5-fluorouracil/oxaliplatin (n=2; 85 mg/m2), epirubicin/5-fluorouracil/oxaliplatin (n=1; 130 mg/m2) and capecitabine/oxaliplatin (n=1; 130 mg/m2) with a median of 4.5 cycles (range 2–17 cycles) and a median dose of administered oxaliplatin of 473 mg/m2 (range 260–1445 mg/m2). Conclusions: This is the first retrospective review of patients who received oxaliplatin-containing chemotherapy to determine the incidence and significance of lung toxicity in U.S. and the first to include gastric cancer patients. ILD following oxaliplatin-containing regimen is an uncommon but life-threatening complication. The incident population is too small to infer correlation with BI but it does not seem to correlate with dose or intensity of oxaliplatin. Oncologists should consider chemotherapy-induced hypersensitivity pneumonitis in their differential diagnosis when assessing patients with new onset shortness of breath during or shortly after chemotherapy.
Results of adjuvant chemoradiation for gall bladder carcinoma: An institutional experience.
Authors: Supriya Mallick, Sudeep Das, Ajeet Gandhi, Nikhil Purushottam Joshi, Renu Madan, B. K Mohanti, Atul Sharma, Pramod Kumar Julka, Goura Kishor Rath
Journal: Journal of Clinical Oncology (2013)

288 Background: Adjuvant chemoradiation for gall bladder carcinoma is not a well established treatment modality. Methods: We retrospectively analysed our database between 2000 and 2011. All patients underwent surgery followed by adjuvant chemoradiation. The radiation dose was 45 Gy in 25 fractions planned by either conventional (2D) or 3 dimensional conformal radiation therapy (3D). Adjuvant chemotherapy was either Gemcitabine or 5 FU/leucovorin based. Log-rank test was used to compare survival distribution. The data was analysed using SPSS 16. Results: 75 patients were analysed. The median age was 48 years (range: 22 to 75 years). 16 males &amp; 59 females were noted. 37 had well differentiated carcinoma while 38 had moderately differentiated carcinoma. The stage was IIIA or less in 45 patients and IIIB or more in 25 patients while it was unknown in 5. No patient had metastatic disease at presentation. 17 patients had a simple cholecystectomy, 57 had a radical cholecystectomy while status was unknown for 1. 25 patients had node negative disease while 50 had node positive disease. All patients received the prescribed radiation. 18 patients had 2D while 57 patients had 3D radiation. 13 patients had Gemcitabine based chemotherapy while 36 patients had 5 FU/leucovorin based chemotherapy. The status of chemotherapy was unknown for 26 patients. The median follow up was 12.7 months (range: 0 to 99 months). 22 patients relapsed. 2 patients had locoregional failure, 18 had distant failure while 2 had both locoregional &amp; distant failure. The relapse free survival at 2 years was 57% and at the end of 6 years was 34%. Relapse free survival was significantly better for radical cholecystectomy vs. simple cholecystectomy (relapse free survival at 2 years 59.2% vs. 30.2 %; p = 0.054 on univariate analysis and relapse free survival at 2 years, 60% vs. 30%; p = 0.035 on multivariate analysis). Gender, tumor differentiation, nodal status, radiation technique and type of chemotherapy did not correlate with relapse free survival. Conclusions: Adjuvant chemoradiation resulted in excellent locoregional control. Radical surgery is an important factor for relapse free survival.
Trimodality treatment for advanced esophageal cancer: Impact of minimally invasive esophagectomy.
Authors: D. G. Williams, S. Carpenter, H. J. Ross, H. Paripati, J. B. Ashman, M. D. Callister, K. L. Harold, D. E. Jaroszewski
Journal: Journal of Clinical Oncology (2011)

125 Background: Esophageal cancer is best managed by multimodality therapy, frequently with chemotherapy (C) or chemo- radiotherapy (CRT) preceding resection. Minimally invasive esophagectomy (MIE) is increasingly accepted, but studies of MIE in advanced esophageal and gastroesophageal junction cancer after induction CRT are lacking. This report presents the data on MIE as part of tri-modality therapy for esophageal cancer at Mayo Clinic in Arizona (MCA). Methods: Patients (pts) who underwent CRT before or after MIE for cancer at MCA between November 2006 and May of 2010 were reviewed retrospectively. Results: 46 pts (40 males, and 6 females) met study criteria and were reviewed. Median age was 62 years (41-88 years). 45 pts (98%) had adenocarcinoma and one pt had squamous carcinoma. Initial clinical stage was IIA in 10 pts (22%), IIB in 3 pts (7%), III in 26 pts (55%), and IVA in 7 pts (15%) with positive celiac nodes. 43 pts (93%) underwent preoperative CRT with additional intra-operative radiotherapy in 4 pts. Median operating time was 354 min (range 211-567 min), median blood loss was 225 ml (range 50-1,400 ml), and median hospital stay was 8 days (range 5-48 days). 19 pts (41%), including the 3 who did not undergo preoperative CRT, received postoperative C or CRT due to either residual disease at resection or to local recurrence. 30 of 43 pts undergoing MIE after CRT were down staged (11 CR [25.6%], 10 near CR [23.3%]) demonstrating a major response to neoadjuvant therapy in 48.9% of pts. One pt died in hospital (from ARDS and sepsis subsequent to aspiration pneumonia) and two pts died within 30 days of surgery (one from pulmonary embolism, and the other from unknown causes) for a 30 day surgical mortality of 6.5%. 29 pts (63%) had a complication of surgery including 11 (24%) minor and 18 (39%) major complications. After a median follow-up of 13 months (range 0.9-43 months) 16 pts were diagnosed with recurrent disease and 10 of these pts have died of their disease. Conclusions: CRT with MIE is associated with an acceptable morbidity and mortality level for pts with locally advanced esophageal cancer. These results compare favorably with morbidity, mortality, and recurrence rates in open esophagectomy pts. No significant financial relationships to disclose.
A novel, cost-effective strategy for the screening of colorectal cancer with higher patient compliance.
Authors: Afsaneh Motamed-Khorasani, Andrea Lee Small-Howard
Journal: Journal of Clinical Oncology (2012)

407 Background: Routine screening methods for colorectal cancer (CRC) have poor patient compliance and low sensitivity for early stages. The sensitivity rates are 19, 71, 76, and 83% for Fecal Occult Blood test (FOBT), stool DNA test, colonoscopy/sigmoidoscopy, and double-contrast barium enema; respectively. Biological markers have also been tested including CEA (sensitivity of 38.7%); however, its utility in CRC screening is limited due to low sensitivity. Onko-Sure is an FDA-cleared blood test for monitoring of CRC treatment/recurrence. It measures the accumulation of Fibrin/Fibrinogen Degradation products in the serum using anti-DR-70 antibody. The objective was to determine whether DR-70 and CEA combination can improve the sensitivity such that it can be used as a cost-effective alternative to current screening methods yet with a higher patient compliance. Methods: A total of 564 serum samples were retrospectively obtained from a serum bank in two arms: confirmed healthy control (n=298) and biopsy-confirmed CRC (n=266) groups. The samples were tested for DR-70 and CEA. Results: The results showed sensitivity of 58.2% and specificity of 59.83% for DR-70 and CEA combined. The sensitivity for the combined test was 55.5% higher than that of CEA alone. A consistent improvement of sensitivity for the combined usage relative to CEA alone was observed with an increase of 73%, 108%, 58% and 18% in CRC stage I, II, III and IV; respectively. The sensitivity of the combined test was 48%, 47%, 57% and 98% for stages I, II, III and IV. Conclusions: Combining DR-70 and CEA tests showed a significant clinical advantage in CRC screening over using each marker alone. The sensitivity improvement was highest for stages I/II, which has important implications in patient treatment options, prognosis and survival rate due to this early detection. With a 3 times higher sensitivity for early stage CRC compared to using FOBT, this approach should improve the CRC early stage diagnosis. Such early stage detection is less likely using routine approaches for CRC screening because of low sensitivity and low patient compliance.
Functional characterization of an oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth.
Authors: K. Streicher, W. Zhu, K. Lehmann, R. W. Georgantas, C. Morehouse, P. Brohawn, R. Carrasco, Z. Xiao, D. Tice, B. W. Higgs, L. Richman, B. Jallal, Y. Yao
Journal: Journal of Clinical Oncology (2011)

8514 Background: Malignant melanoma is the most aggressive form of skin cancer and its incidence has doubled in the last two decades. It represents only 4% of skin cancer cases per year, but encompasses as many as 74% of skin cancer deaths. If diagnosed early, the 5-year survival rates are encouraging—90% at Stage I and 60% at Stage II; however, this decreases substantially to 10% at stage III and nearly 0% at stage IV. Dysregulation of microRNA (miRNA) expression has been linked to tumor progression by functioning either as a tumor suppressor, an oncogene, or a metastasis regulator in multiple cancer types. Methods: To understand the role of miRNA in the pathogenesis of melanoma and identify putative biomarkers, miRNA expression profiles in skin punches from 36 melanoma patients and 15 healthy donors were compared. Mutational status of B-RAF and N-RAS was also determined. Primary melanocytes and multiple melanoma cell lines were transfected with miRNA mimics or hairpin inhibitors to manipulate levels of miRNAs of interest and determine the functional consequences. Results: From the miRNA analysis, we identified a novel miRNA cluster (comprised of miRs-506-510, -513, and -514) on the X chromosome, termed the miR-506-514 cluster, that is uniformly over-expressed in nearly all melanomas tested, regardless of mutational status. Inhibiting the expression of this cluster as a whole, or one of its sub-clusters (Sub-cluster A, containing miRs-506-508, and -513), led to significant functional alterations, including reduced cell growth, increased apoptosis, decreased invasiveness, and decreased colony formation in soft agar across multiple melanoma cell lines. Sub-cluster A was critical for maintaining the cancer phenotype, but the over-expression of the full miR-506-514 cluster was required for melanocyte transformation and cancer initiation. Conclusions: To our knowledge, this is the first report on the functional role of the miR-506-514 cluster in melanoma. Further work is needed to evaluate this cluster as a therapeutic target or a potential diagnostic marker; however, these results significantly impact our understanding of the critical role of miRNAs in oncogenesis.
Discontinuation of Dasatinib or Nilotinib in Chronic Myeloid Leukemia (CML) Patients (pts) with Stable Undetectable Bcr-Abl Transcripts: Results From the French CML Group (FILMC)
Authors: Delphine Rea, Philippe Rousselot, Franck E. Nicolini, Laurence Legros, Michel Tulliez, Stephane Giraudier, Pascale Cony-Makhoul, François Guilhot, Francois-Xavier Mahon
Journal: Blood (2011)
Clinical and pharmacodynamic (PD) results of TEL0805 trial: A phase II study of telatinib (TEL) in combination with capecitabine (X) and cisplatin (P) as first-line treatment in patients (pts) with advanced gastric or gastroesophageal junction (GEJ) cancer.
Authors: M. Alsina, A. H. Ko, M. Garcia De Paredes, F. Rivera, L. S. Schwartzberg, A. Fattaey, L. A. Kunkel, J. Tabernero, J. A. Ajani
Journal: Journal of Clinical Oncology (2011)

4122 Background: Angiogenesis is essential for tumor growth and plays an important role in metastasis in gastrointestinal (GI) cancers. TEL is a highly selective and potent oral kinase inhibitor with activity against VEGFR family, PDGFR and KIT receptor tyrosine kinases. TEL has been studies in 250 pts in Phase 1 and Phase 1b studies. TEL0805 is a multicenter phase II study that administered TEL with X and P in previously untreated advanced gastric or GEJ cancer pts. Methods: From June 2009 to August 2010, 48 pts were enrolled from the US and Spain. Treatment cycles were 21 days (d): TEL 900 mg p.o. bid continuously, X 1,000 mg/m2p.o. bid D1-14, P 80 mg/m2 D1. Results: The majority (94%) of pts were metastatic (52% with liver metastases). Tumor location was nearly equal between GEJ (54%) and gastric (46%) at presentation. 39 pts were evaluable for response per protocol (PP). The ORR was 67% (CR 2.6%, PR 64.1%); an additional 28.2% of pts had SD as best response. Responses were observed independent of tumor location. The onset of response was rapid, median 49 d. The median PFS was 140 d (range 46 to 341+). The median OS has not been reached (20 pts censored PP). The most common toxicities were G1/2 fatigue or GI; < 10% of pts discontinued treatment due to TEL AEs. Samples were available for PD in 28 patients. Reduction in plasma sVEGR2 levels up to 45% from baseline was observed with a median of 26% reduction in all participating pts. A statistically significant trend was observed between the degree of reduction in sVEGFR2 levels from baseline and clinical trial endpoints. Morphological changes in CT scans were noted that are consistent with potent anti-angiogenic activity. Conclusions: TEL in combination with X and P achieved a rapid and sustained tumor regression in 2/3 of metastatic gastric and GEJ cancer pts regardless of tumor location, histology, or presence of liver mets. TEL demonstrated potent on target activity as demonstrated by the sVEGFR2 levels, which appear to correlate with clinical benefit and may provide a potential biomarker of activity. A global randomized phase III study is planned.