tbuckley/cabot-search huggingface dataset:
Sunitinib (SU) treatment (trx) patterns and toxicity in patients (pts) with advanced renal cell carcinoma (RCC) in United Kingdom (UK).
Authors: J. Wagstaff, R. E. Hawkins, P. D. Nathan, S. P. Sarda, F. Vekeman, C. Korves, S. Dasgupta, S. O'Mara, S. Fitton, J. Hayers, C. Tham, A. Luka, R. Wei, A. Mykletun, M. Neary, M. S. Duh
Journal: Journal of Clinical Oncology (2011)

e15150 Background: This study evaluated the rates of and reasons for trx modifications and occurrence of adverse events (AEs) amongst pts treated with the angiogenesis inhibitor (AI) SU in UK clinical practice. Methods: Data from medical records were retrospectively abstracted at three large UK oncology centers for advanced RCC pts who were ≥18 years and received SU (N=132) as 1st-line AI trx from 1/1/2005 to 11/15/2010; prior cytokine therapy was permitted. The proportion of pts and reasons for trx modification, i.e. discontinuation, interruption, or dose change were determined. Timing of trx modifications and the proportion of pts with all grade and grade 3/4 AEs were also determined. Data on clinician assessed response rates were collected. Results: 91% of pts had not received cytokine therapy. Mean daily dose over initial cycle was 31.23 mg; 73.5% of pts started trx with dosing of 50 mg QD 4/2. Tumor response assessments were available for 96 pts among which 38.5% had an objective response (complete or partial response). 85.6% of pts treated experienced AEs (grades 3/4 24.2%). The 3 most commonly reported all grade AEs were mucositis/stomatitis (42.4%), diarrhea (38.6%), and fatigue (28.0%). 87.1% of pts experience ≥1 trx modification. Among pts who discontinued trx, 34.5% discontinued within 18 weeks (w), 14.8% within 0-6 w, 6.6% in 7-12 w, and 13.1% in 13-18 w. Median 1st-line AI trx duration was 6.5 months among those who discontinued trx. Conclusions: This study of 132 advanced RCC pts treated with SU revealed that a large proportion of pts experienced AEs and trx modifications due to AEs. Dose reduction was the most commonly used form of trx modification for AEs in comparison to trx interruption or trx discontinuation. The results from this study suggest that SU tolerability is a challenge for clinicians in the treatment of advanced RCC pts. Validation of these results using a larger sample is warranted. Trx patterns, n (%) SU N=132 Pts with trx discontinuation 61 (46.2) Due to progressive disease 27 (20.5) Due to AEs 25 (18.9) Pts with trx interruption 48 (36.4) Due to AEs 34 (25.8) Pts with dose reduction 63 (47.7) Due to AEs 56 (42.4) Pts with ≥1 any of the above trx modifications due to AEs 82 (62.1)
The Upper Age Limit for a Pediatric-Inspired Therapy in Younger Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL)? Analysis of the Graall-2005 Study
Authors: Françoise Huguet, Thibaut Leguay, Xavier Thomas, Nicolas Boissel, Martine Escoffre-Barbe, Patrice Chevallier, Mathilde Hunault, Norbert Vey, Caroline Bonmati, Stéphane Leprêtre, Jean-Pierre Marolleau, Thomas Pabst, Philippe Rousselot, Agnès Buzyn, Jean-Yves Cahn, Véronique Lhéritier, Marie C Béné, Vahid Asnafi, Eric Delabesse, Elizabeth Macintyre, Yves Chalandon, Norbert Ifrah, Hervé Dombret
Journal: Blood (2016)
Presence of frequent underlying <i>RAS</i> mutations in cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC/KA) that develop in patients during vemurafenib therapy.
Authors: M. E. Lacouture, P. B. Chapman, A. Ribas, J. A. Sosman, G. A. McArthur, K. T. Flaherty, K. B. Kim, I. Puzanov, K. B. Nolop, A. K. Joe, O. Spleiss, A. Koehler, W. Wu, C. Robert, A. Hauschild, D. Schadendorf, J. L. Troy, M. Duvic, K. Trunzer
Journal: Journal of Clinical Oncology (2011)

8520 Background: Vemurafenib (V; RG7204, PLX4032), an oral inhibitor of oncogenic V600E mutant BRAF, was evaluated for safety, efficacy, and pharmacokinetics in dose escalation and melanoma extension cohorts from the Phase I study (n=87; Flaherty, et al. NEJM, 2010). Development of cuSCC/KA was observed in melanoma patients (pts). Here we describe further molecular characterization of confirmed cases of cuSCC/KA. Methods: Pts receiving V therapy were monitored for toxicity including development of skin lesions. Suspicious lesions were excised and sent to central laboratories for confirmation of cuSCC/KA histology and for molecular analysis. Analyses included genetic analysis of H/K/N-RAS, CDKN2A and TP53, as well as P53 protein expression. Results: 35 cuSCC/KA lesions developed in 15 pts during therapy—34/35 (97%) were diagnosed as SCC, KA type or SCC, with features of KA and 1/35 (3%) were diagnosed as SCC, without features of KA. All lesions were histologically well differentiated and were managed with complete local excision. No lesions recurred and therapy was not interrupted. The majority of lesions developed within 8–21 wks after initiation of therapy. Genetic analyses were performed on 21 cuSCC/KA from 10 melanoma pts. 15/21 (71%) had mutations at codons 12, 13 or 61 of H-, K- or NRAS (with 14/15 having an HRAS mutation). No specimens had BRAF mutations in exon 15. A CDKN2A mutation was observed in 1/21 (5%) lesions (A73V) and 4/18 (22%) had exonic TP53 mutations. P53 nuclear expression varied, but was highest in the samples with P53 mutations (C176W and Y236C). Conclusions: CuSCC/KA lesions that developed during V therapy had a high incidence of RAS mutations in codons commonly mutated in sporadic cuSCC/KAs in the general population (HRAS mutation rate 12–46%, Nouri K., Skin Cancer, 2008). Given the short latency between exposure to V and the development of cuSCC/KA, these preliminary findings suggest that skin cells with pre-existing RAS mutations may develop into these lesions upon exposure to V. Further investigation and larger sample size is needed to determine if RAS alone or additional factors are required to induce cuSCC/KA.
Impact of pulmonary vascular volume on mortality in IPF: is it time to reconsider the role of vasculature in disease pathogenesis and progression?
Authors: Joseph Jacob, Andrew G. Nicholson, Athol U. Wells, David M. Hansell
Journal: European Respiratory Journal (2017)

We were pleased to read the letter from E. Puxeddu and co-workers, written in response to our observation that an increased pulmonary vessel volume, derived using quantitative computed tomography (CT) analysis, strongly predicts mortality in patients with idiopathic pulmonary fibrosis (IPF) [1]. E. Puxeddu and his team highlight a selection of studies that have identified pulmonary vascular alterations in IPF, similar to those seen in pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) [2–4]. They suggest that when considered in the light of these previous reports, our findings add support to the idea that vascular alterations might be the first pathological lesion in IPF preceding, and leading to, fibrogenesis. Understanding the complexities of the pulmonary vasculature is an important but neglected field of study in IPF <http://ow.ly/anqV307U5rA>
Survival impact of surgical resection of primary tumor (SRPT) in metastatic colorectal cancer (mCRC): A population-based cohort study.
Authors: Shahid Ahmed, Anne Leis, Selliah Kanthan, Safiya Karim, Thomas Perron, Kamal Haider, Bruce Reeder, Punam Pahwa
Journal: Journal of Clinical Oncology (2013)

456 Background: Currently there is very low quality evidence available regarding survival benefit of SRPT in patients with mCRC. In the absence of randomization the reported benefit may reflect selection of younger and healthier patients with good performance status (PS). We have undertaken a retrospective cohort study to determine the survival benefit of SRPT in mCRC. Methods: A cohort of 1,378 patients with mCRC diagnosed between 1992-2005 in the province of Saskatchewan was evaluated. Kaplan-Meier curves were used to determine survival. Log-Rank test was done to compare survival between the two groups. Cox regression model was used to adjust survival for important prognostic variables. Results: Median age was 70 yrs (22-98) and M:F was 57:43. 27% had ECOG PS of &gt;1 and 62% had a comorbid illness. 944 (69%) patients underwent SRPT. Among 1,378 patients, 40% were operated for tumor related symptoms (33% obstruction, 6% perforation, and 4% heavy bleeding, mutually nonexclusive). Median follow up time for whole cohort was 7.1 months (inter-quartile range 2.5-17.5). 42.3% received chemotherapy and 19.1% received 2 nd generation therapy. Median survival of patients who received chemotherapy was 15.9 months. Patients who underwent SRPT had median overall survival of 18.3 months vs. 8.4 months if they did not have surgery (p&lt;0.0001).On multivariate analysis 5FU-based chemotherapy (HR 0.53; 95%CI: 0.45-0.61), metastesectomy (HR 0.54; 95%CI: 0.45-0.64), SRPT (HR 0.55; 95%CI: 0.48-0.62), and 2 nd generation chemotherapy (HR 0.65; 95%CI: 0.54-0.77) were correlated with a better survival whereas, elevated CEA level (1.56; 95%CI: 1.30-1.90), leukocytosis (HR 1.54; 95%CI: 1.33-1.80), ECOG PS &gt;1 (HR 1.48; 95%CI: 1.30-1.69), low albumin (HR 1.44; 95%CI: 1.26-1.64), age ≥ 65 yrs (HR 1.21; 95%CI: 1.10-1.38), anemia (HR 1.16; 95%CI: 1.03-1.31), and symptomatic disease (HR 1.12; 95%CI: 1.0-1.26) were correlated with poor survival. Comorbid illness, smoking, and gender did not correlate with survival. Conclusions: This is the first large cohort study that reveals that SRPT in patients with mCRC improves survival independent of chemotherapy, age, functional status and comorbid illness.
Chemotherapy outcomes for the treatment of unresectable intrahepatic and hilar cholangiocarcinoma: A retrospective analysis.
Authors: J. Weatherly, K. Eckmann, D. Patel, A. N. Landgraf, J. H. Slade, R. A. Wolff, E. Lin, M. M. Javle
Journal: Journal of Clinical Oncology (2011)

271 Background: Recent clinical trials for biliary cancers include a heterogenous group of patients with cholangiocarcinoma, gallbladder, and ampullary cancers. There are limited data regarding the relative effectiveness of known chemotherapeutic regimens specifically in intrahepatic or hilar cholangiocarcinoma. Methods: M. D. Anderson Cancer Center patients with unresectable intrahepatic and hilar cholangiocarcinoma who received first-line chemotherapy from January 1, 2005 to October 31, 2009 were reviewed. Eighty-five patients met inclusion criteria and were eligible for analysis. The primary objective of this project was to determine the overall tumor control rates with the chemotherapeutic regimens used for first-line treatment of unresectable intrahepatic and hilar cholangiocarcinoma. Secondary objectives included duration of response, overall survival, and prognostic factors. Results: The most commonly used regimen was gemcitabine/cisplatin (gem/cis; 53 patients, 62%), followed by oxaliplatin and capecitabine (14 patients, 16%). There was no significant difference between tumor control rates with gem/cis (72% PR/SD, 28% PD) and other regimens (69% PR/SD, 31% PD). There was also no significant difference between overall survival with the use of gem/cis (15.2 months) or alternative regimens (13.9 months). A decrease in overall survival was seen with elevated baseline CA 19-9 (p&lt;0.0001), an initial diagnosis of unknown primary tumor (p=0.0001), and prior treatment with chemoradiation (p=0.0018). Conclusions: In this retrospective review, both gem/cis and alternative doublets (including capecitabine/oxaliplatin, gemcitabine/capecitabine, and gemcitabine/oxaliplatin) were effective regimens in maintaining disease control in the intrahepatic and hilar population. No significant financial relationships to disclose.
Racial disparities in chemotherapy for breast cancer: Are delays explained by hospital quality and volume?
Authors: R. A. Freedman, Y. He, N. L. Keating
Journal: Journal of Clinical Oncology (2011)

6034 Background: Black women experience more delays to initiation of adjuvant chemotherapy for breast cancer than white women. Research also suggests that hospital quality and volume may influence receipt of cancer care. In a large population-based cohort, we examined racial differences in chemotherapy delay and whether hospital quality or volume explained any observed disparities. Methods: We used Surveillance Epidemiology and End Results-Medicare data to examine time to chemotherapy for black and white women who were diagnosed with stage I-III breast cancer during 1992-2005 and received neo/adjuvant chemotherapy. We used multivariate logistic regression to assess the probability of chemotherapy delay (first dose of chemotherapy >90 days after surgery) by race, controlling for patient, tumor, and area-level characteristics. Sequential models included hospital quality (defined based on rates of recommended chemotherapy for eligible women), volume, or both. Results: Among the 676 black and 5,905 white women who received adjuvant chemotherapy, 7% had a delay in treatment. Black women (vs. white) were less likely to be treated in higher quality hospitals (24% vs. 30%) and higher volume hospitals (62% vs. 73%) (both p<.05) and were more likely to have delayed chemotherapy (6.6% vs. 10.2%, p<.05). In adjusted analyses, black women (vs. white) had higher odds of treatment delay (Table). In sequential models, hospital quality but not hospital volume was associated with timely chemotherapy. Addition of both hospital variables had minimal effects on observed differences by race (Table). Conclusions: Racial differences in delay to chemotherapy were not explained by measures of hospital quality or volume, despite lower rates of treatment in high quality and high volume centers for black women. Adjusted odds of chemotherapy delay by race and hospital factors (95% CI). Model with race and patient, tumor, and area variables Black (vs. white) 1.4 (1.0-1.9) Model above, also including hospital quality and volume Black (vs. white) 1.3 (0.9-1.8) High quality (top quartile vs. other) 0.8 (0.6-1.0) Highest volume (top quartile vs. lowest) 1.1 (0.3-3.7)
A dose-escalation and pharmacodynamic study of AT9283 in patients with refractory solid tumours
Authors: E. R. Plummer, H. Calvert, H. Arkenau, K. H. Mallett, M. Squires, D. Smith, S. Lewis, I. Judson
Journal: Journal of Clinical Oncology (2008)

2519 Background: AT9283, a multitargeted kinase inhibitor, inhibits tyrosine and serine/threonine kinases with an IC50 of <10 nM including Aurora A and B, JAK 2 and 3 Tyk2, RSK2, Ret, Mer, Yes and GSK3 beta. Exposure of solid tumor cell lines to AT9283 induces an “aurora inhibitory” phenotype creating large aneuploidal cells with limited replication potential. Cell survival decreases with increased duration of exposure. Methods: A phase I dose escalation study was performed using a 72 hour iv infusion every 3 weeks using a standard “3+3” design. Epidermal skin biopsies were performed for immunohistochemistry at screening and 48 hours into first infusion. Serum samples were taken during and post infusion for quantification of the apoptosis marker cleaved cytokeratin. Results: Twenty-two patients (pts) have been treated with a median age of 63 (range 33–77 years) (6 F). Biological evidence of activity was seen across all dose levels with a dose dependent reduction in histone H3 phosphorylation, incomplete inhibition in 2/3 pts at dose level 1, complete inhibition in 2/3 pts at dose level 2 and inhibition in 3/3 pts (2 complete) at dose level 3. Reduction in phosphohistone H3 was accompanied by stabilisation of p53 which was more marked in pt samples exhibiting complete inhibition. Reduction in Ki67 staining and increases in the levels of cleaved cytokeratin in serum was seen in pts receiving a dose of 6 mg/m2/day. A plateaux steady state plasma concentration was achieved at all dose levels, exposure increased linearly with dose. The maximum tolerated dose is 27 mg/m2/72 hours and dose limiting toxicity observed to date has been febrile neutropenia. The best response to date is stable disease with three pts receiving at least six cycles of therapy (squamous cell carcinoma of the lung, colorectal adenocarcinoma [2]). Conclusions: The MTD of AT9283 administered as a 72 hour infusion is 9 mg/m2/day. Febrile neutropenia is the dose limiting toxicity and treatment results in significant disease stabilisation in a proportion of patients. Dosing Summary Dose level (mg.m2.day) Number of patients treated Number of cycle (median) Dose limiting toxicities 1 (1.5) 3 2–7 (2) None 2 (3) 3 1–4 (4) None 3 (6) 3 1–2 (2) None 4 (12) 6 1–6 (ongoing) (1) Febrile neutropaenia (3) 5 (9) 7 1–2 (ongoing) (tbc) None Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Astex Therapeutics Limited
Independent central review of progression in randomized phase II/III oncology trials: Is it needed?
Authors: W. Wu, L. I. Lin, D. J. Sargent
Journal: Journal of Clinical Oncology (2011)

e16558 Background: Time to progression (TTP) or progression free survival (PFS) are increasingly being used as the primary endpoint for phase II/III trials in advanced disease trials in oncology. To minimize the potential bias introduced by subjectivity in radiographic interpretation, an independent review committee (IRC) has often been required in randomized phase II/III studies. However, limited information is available demonstrating the necessity of IRC review. Methods: Data from 2 randomized studies in metastatic cancers, AVF2119g (open-label phase III of capecitabine alone vs. capecitabine + bevacizumab for pre-treated metastatic breast cancer, n=462) and AVF2192g (double-blind phase II of 5-FU/leucovorin alone vs. 5-FU/leucovorin + bevacizumab for metastatic colorectal cancer, n=209) were included. TTP was defined as the time from randomization/registration till tumor progression. Agreement between local and IRC measurements was assessed using a mixed effect model combined with generalized estimating equations, and was de-composed into precision (equivalent to Pearson’s correlation coefficient) and accuracy (measures location shift with 1 representing no shift), and agreement is defined as the product of precision and accuracy. Agreement measurements in both relative and absolute scales were considered, and the results were adjusted for treatment and study effects. Results: Estimated concordance correlation coefficient between local and IRC was 0.87 with a 90% lower confidence limit of 0.86, indicating very good agreement. The source of disagreement is mainly due to imprecision as compared to inaccuracy. 80% of local TTP were within 2.8 months of their corresponding IRC measures. The colorectal cancer study has better agreement for all measurements. The difference of agreement between control and experimental groups is negligible. Conclusions: Based on data from these two studies, local measurement of TTP have good agreement with IRC, with disagreement almost entirely due to precision (or variance) as opposed to accuracy (or bias). Analyses of additional datasets are needed to further assess the necessity of IRC.
ALOX5AP Gene Variants and Risk of Coronary Artery Disease in Italy. An Angiography-Based Study.
Authors: Domenico Girelli, Nicola Martinelli, Elisabetta Trabetti, Oliviero Olivieri, Ugo Cavallari, Giovanni Malerba, Fabiana Busti, Simonetta Friso, Francesca Pizzolo, PierFranco Pignatti, Roberto Corrocher
Journal: Blood (2006)
Accuracy of clinical staging with EUS for early stage esophageal cancer: Are we denying patients beneficial neoadjuvant chemo-radiation?
Authors: Carrie Luu, Norbert Garcia-Henriquez, Jason Klapman, Cynthia L. Harris, Khaldoun Almhanna, Sarah E. Hoffe, Jose Mario Pimiento, Jacques Fontaine
Journal: Journal of Clinical Oncology (2016)

163 Background: Esophagectomy alone has been considered the standard of care for early stage esophageal cancer (EC) while neoadjuvant therapy is now standard for locally advanced disease. The choice of treatment therefore hinges on accurate locoregional staging by endoscopic ultrasound (EUS). Our objective is to evaluate the accuracy of EUS performed in a high-volume tertiary cancer center in clinical stage T1N0 (cT1N0) and T2N0 (cT2N0) esophageal cancer patients undergoing esophagectomy without neoadjuvant therapy. Methods: A retrospective review of the esophageal cancer database at a single institution was performed. Patients with cT1N0 and cT2N0 esophageal cancer based on EUS undergoing esophagectomy without neoadjuvant treatment were evaluated. Patient demographics, tumor characteristics, and treatment were reviewed. Surgical pathology was compared to EUS staging. Results: Between 2000 and 2015, 139 patients were identified. There were 25 (18%) female and 114 (82%) male patients. The tumor location included the middle 1/3 of the esophagus in 11 (8%) and lower 1/3 and gastroesophageal junction in 128 (92%) patients. Eighty-one percent of patients had adenocarcinoma, 9% had squamous cell carcinoma, 9% had Barrett’s dysplasia, and 1% had mixed histology. Clinical staging were as follows: 110 (79%) patients had cT1N0 and 29 (21%) patients had cT2N0 tumors. For the entire cohort, preoperative EUS matched the final surgical pathology in 76/139 patients for an accuracy rate of 53%. Twenty-nine patients (21%) were under-staged by EUS; of those, 19 (14%) had unrecognized nodal disease. This included 12/109 (11%) of cT1N0 and 7/29 (24%) of cT2N0 patients. Conclusions: The accuracy of preoperative EUS staging in early esophageal cancer remains sub-optimal. Interestingly, a significant proportion (24%) of cT2N0 EC patients were found to have positive lymph nodes on surgical pathology, and perhaps these patients could have benefitted from neoadjuvant therapy. In light of these findings, the current management of cT2N0 esophageal cancer should be reconsidered.
Multiomics profiling for gastric cancer using high-tech omics-based patient evaluation (HOPE).
Authors: Masanori Terashima, Keiichi Oshima, Masatoshi Kusuhara, Kennichi Urakami, Masanori Tokunaga, Yutaka Tanizawa, Etsuro Bando, Taiichi Kawamura, Rie Makuuchi, Yuichiro Miki, Keiichi Hatakeyama, Ken Yamaguchi
Journal: Journal of Clinical Oncology (2015)

95 Background: The Project HOPE (High-tech Omics-based Patient Evaluation) is an ongoing comprehensive platform that analyzes genome and transcriptome of fresh surgical specimens and blood samples obtained from cancer patients using whole-exome sequencing (WES, AmpliSeq Exome kit, Life Technology) and gene expression profiling (GEP, DNA microarray, Agilent Technologies). The research plan was approved by institutional review board (IRB) in Shizuoka Cancer Center, and total number of patients evaluated in this plan was about 3000 during the 3-year period of the research. Here, we focused on gastric cancer to investigate its characteristic profile. Methods: Tumor sample and peripheral blood was obtained from a total of 19 gastric cancer patients. At the initial stage of the study, the known mutation sites were analyzed by the WES, and expression level of cancer-related genes was evaluated by GEP. Results: Fourteen patients out of 19 patients (74 %) were categorized as advanced gastric cancer. The patients with single nucleotide variations (SNVs) in tumor protein P53 (TP53) accounted for 37% (7/19), and 21% (4/19) of patients had multiple SNVs in the known mutation sites. Furthermore, in two patients with gene amplification of ERBB2 or EGFR, mRNA expression corresponding these genes was markedly up-regulated. Conclusions: WES and GEP analyses may play an important role in interpretation of genetic changes of cancer tissues and personalized medicine.