tbuckley/cabot-search huggingface dataset:
Results of a planned efficacy and safety analysis for a National Comprehensive Cancer Network sponsored phase II study of gemcitabine and irinotecan (GI) in metastatic breast cancer (MBC)
Authors: S. L. Moulder, P. Munster, S. Minton, N. Diaz, J. Horton, C. Rocha Lima, L. Hutson, D. Sullivan
Journal: Journal of Clinical Oncology (2005)

679 Background: Gemcitabine and irinotecan, have both demonstrated efficacy in patients with MBC. The incorporation of gemcitabine into DNA enhances cleavage complexes induced by a topo I inhibitor in vitro. Objectives: response, tolerability, and translational studies measuring topo I and PK. Methods: Inclusion criteria: male and female patients with MBC, prior anthracycline therapy, ECOG PS of ≤ 2, adequate organ function ≤ 3 prior chemotherapy regimens for MBC. 26 patients received gemcitabine at 1000 mg/m2 and irinotecan at 100 mg/m2 on days 1 and 8 of a 21 day cycle. Response evaluated by RECIST criteria. Topo I: Tumors were biopsied by fine needle aspiration (FNA) prior to initiation of therapy. Topo I was detected using immunofluorscence with a murine monclonal antibody against the protein’s C-terminus. PK: Irinotecan: A previously validated limited sampling strategy was used. Gemcitabine: Blood was collected over 24 hrs following the first dose. Intracellular nucleotides were also quantified in PBMCs using established techniques. Results: Of the 26 patients enrolled, 26 have been evaluated for response with an overall response rate of 31% (CR=0, PR=8 (1 unconfirmed), SD=4, PD=14). No febrile neutropenia was seen. Grade 3 non-hematologic toxicities included fatigue (1), N/V (3), dehydration (1) and diarrhea (1). Results from the 6 tumors assessed for topo I are listed in the table below. PK data will be available at presentation. Conclusion: Preliminary results indicate that GI is an active combination for metastatic breast cancer with acceptable toxicity; therefore accrual continues. Additionally, topo I levels and localization can be measured in breast tumors using FNA. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Lilly Oncology Lilly Oncology, Pfizer GlaxoSmithKline, Lilly Oncology, Pfizer AstraZeneca, Lilly Oncology
Phase I/II study of sorafenib concurrent with androgen deprivation and radiotherapy in treatment of intermediate- and high-risk localized prostate cancer.
Authors: S. Talwar, S. M. Cohen, N. A. Romas, R. D. Ennis
Journal: Journal of Clinical Oncology (2010)

TPS243 Background: Androgen-deprivation therapy (ADT) administered prior to and concurrent with radiotherapy (RT) improves outcomes in intermediate and high-risk prostate cancer (PCa). This study is designed to evaluate the safety and efficacy of a maximal tolerated dose of sorafenib, given concurrently with ADT and RT. Sorafenib is an oral multitargeted tyrosine kinase inhibitor with activity against Raf kinase, VEGFR, and PDGFR among others. It is active in renal and hepatocellular carcinoma, but its role in PCa is unknown. The targets of sorafenib promote tumor growth and progression in PCa cell lines with recent phase II data showing some activity in progressive androgen independent PCa. Sorafenib also has radiosensitizing effects in multiple cancer cell lines and preclinical work suggests that manipulation of the MAPK/ERK pathway increases radiation-induced apoptosis in a PCa cell line. This enhanced radiation sensitivity occurs only when sorafenib is given after RT. Methods: Eligibility criteria include intermediate-high risk localized PCa with normal organ function. Subjects with more than 4 weeks of ADT, recent thromboembolic disease, or significant bleeding within 4 weeks of first dose of study drug will be excluded. All subjects will receive LHRH analog and bicalutamide, for a total of 9 months. Sorafenib (400 mg p.o. b.i.d.) will be initiated after subjects have received 1 month of ADT and continue until maximal hormonal response has been achieved. After allowing for drug clearance, the initial cohort of concurrent sorafenib and RT will receive sorafenib 100 mg p.o. daily, administered following radiation (dose level 0), on the days that radiation is delivered. At least 3 patients will be studied at each dose level and evaluated for at least 4 weeks after completion of radiotherapy before starting additional patients on escalated doses. Dose escalation will continue through a planned maximum dose of 400 mg p.o. daily. Currently, there are 3 patients enrolled in the trial with a planned sample size of 12-18 in phase I and 30 during phase II. Subjects will be followed with clinical assessment, PSA, and testosterone levels. No significant financial relationships to disclose.
Diagnostic discrepancies between second-opinion and referring pathology reports of neuroendocrine tumors.
Authors: Hillary Lin, Teri A. Longacre, Vilay H. Khandelwal, Raymond R. Balise, Pamela L. Kunz
Journal: Journal of Clinical Oncology (2013)

e15011 Background: The nomenclature and histologic classification schemes for neuroendocrine tumors (NETs) have historically been heterogeneous and inconsistent. However, clinicians require specific descriptors to determine treatment plans for patients. In 2010, Klimstra, et al. published a set of NET pathology reporting guidelines. Using these guidelines, we undertook a systematic evaluation of discrepancies between referring versus Stanford second-opinion NET pathology reports. Methods: We developed a cohort ofall NET cases seen at Stanford University Hospital between April 1998 and December 2012 with available Stanford and referring pathology reports for the same specimen to identify the discrepancies between their clinical diagnoses. Results: Of 170 cases, histological diagnoses were discrepant in 79% of the reports; 89 (66%) of which were clinically insignificant, and 46 (34%) clinically significant. Stanford used 14 unique terms for histological description, and referring institutions used 49 unique terms. Grade, mitotic index (MI), and Ki67 were among the variables examined; they were not reported (NR) from the majority of cases in one or both reports, yet more likely to be included in the Stanford report. Grade was NR in one or both reports in 152 cases (89%); of the 18 cases reporting grade in both reports, 3 (2%) were discrepant. MI was NR in one or both reports in 128 cases (75%); of the 42 cases reporting MI in both reports, 27 (16%) were discrepant. Ki67 was NR in one or both reports in 153 cases (90%); of the 17 cases reporting Ki67 in both reports, 12 (7%) were discrepant. Reporting was found to improve over time for these variables (five-year blocks from 1998-2012). There was a trend towards improved reporting from academic hospitals (vs. non-academic hospitals) and by Stanford NET pathology experts (vs. general pathologists). Conclusions: Clinically relevant differences were frequently found between Stanford and referring pathology reports for NETs. Future studies of NET pathology discrepancies are warranted to allow additional time for adoption of the 2010 guidelines.
Switching From Romiplostim to Eltrombopag or Vice Versa for Immune Thrombocytopenia: Efficacy and Safety in 46 Patients
Authors: Mehdi Khellaf, Jean-François Viallard, Mohamed Hamidou, Stephane Cheze, Francois Lefrere, Olivier Fain, Sylvain Audia, Fabrice Jardin, Emmanuel Gyan, jean Marc Durand, Corinne Haioun, Philippe Bierling, Marc Michel, Bertrand Godeau
Journal: Blood (2012)
<i>EGFR, KRAS, PIK3CA </i>mutations and response to tyrosine kinase inhibitors (TKIs) in advanced NSCLC patients
Authors: S. Darwish, V. Ludovini, L. Pistola, F. Bianconi, M. Betti, R. Chiari, A. Sidoni, D. Giuffrida, F. R. Tofanetti, A. Flacco, L. Crinò
Journal: Journal of Clinical Oncology (2008)

22003 Background: Molecular alterations of the EGFR pathway are considered the major determinant of clinical outcome in response to EGFR TKIs in non small cell lung cancer (NSCLC) patients (pts).The aim of this study was to determine the clinical implication of EGFR, KRAS, PIK3CA gene mutations in pts with advanced NSCLC who had been treated with gefitinib or erlotinib after failure of 1st or 2st-line platinum-based chemotherapy. Methods: Genomic DNA was isolated from paraffin- embedded tumor specimens, amplified for EGFR (exons 18, 19, 20 and 21), PIK3CA (exons 9 and 20) KRAS (exon 2) by nested polymerase chain reaction and sequenced in both sense and antisense directions. RECIST criteria were used to assess response to TKIs. Results: From July 2002 to December 2007 128 pts have been treated with TKIs in our Institution. EGFR mutations were detected in 25.4% of pts; 16.4% had deletional mutations in exon 19, 4.7% point mutations in exon 20 and 4.7% in exon 21. KRAS and PIK3CA mutations were detected in 5.7% and in 2.7% of pts, respectively. Overall, pts with EGFR mutations had a response rate (RR) of 58.4% vs 19.7% (p=0.001), disease control rate of 74.2% vs 49.4% (p=0.02) median time to progression of 8 months vs 3 months (p=0.06), with respect to EGFR non mutated pts. No difference in overall median survival was observed. However when we considered 25 pts with TKI-sensitive EGFR mutations (deletion in exon 19, missense L858R) we observed a significant longer TTP (p=0.008, median 8 vs 3 months in non mutants) and a better OS (p=0.07, median not reached vs 11 months in non mutants). In this setting the RR was 88% (22 of 25) and TTP was significantly better also the multivariate analysis (p=0.03). All pts with KRAS mutations did not responded to TKIs treatment as the pts with PIK3CA mutations. Conclusions: In this experience we confirmed that EGFR mutations (deletion in exon 19, missense L858R) are the most important predictor of TKI sensitivity. In addition the evaluation of KRAS and PIK3CA mutations could contribute to identify lung cancer patients who are most suitable for TKIs treatment. No significant financial relationships to disclose.
Validation of NF-kappaB p65 as a prostate cancer prognostic marker on a large cohort of European patients
Authors: L. Lessard, L. R. Bégin, T. Schlomm, J. Köllermann, M. Graefen, P. I. Karakiewicz, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2008)

11055 Background: In recent years, NF-kB p65 has become a candidate molecular marker of prostate cancer progression. We and others have shown that the nuclear expression of p65 can predict biochemical recurrence and lymph node invasion in small cohorts (i.e. < 100 patients). Methods: The goal of this study was to assess the clinical relevance of NF-kB (p65 subunit) in a large cohort. Immunohistochemical analysis of p65 was performed on a tissue micro-array (TMA) of radical prostatectomy specimens from 1161 patients treated at the Department of Urology, University Medical Center Hamburg-Eppendorf between 1992 and 2005. The frequency of nuclear staining (%) and the intensity of nuclear expression (0–1-2–3) were evaluated for each sample. Results: Kaplan-Meier analysis of the 1161 patients revealed that the presence of nuclear p65 staining (>1%) predicts biochemical recurrence (Log Rank 6.7, p = 0.01). Interestingly, the intensity of p65 nuclear expression (2–3) appears to be an even stronger predictor (Log Rank 10.3, p = 0.001). Nuclear p65 positivity and strong nuclear p65 intensity increased the risk of biochemical recurrence by 30% (RR 1.3, CI 1.1–1,7; p = 0.01) and 40% (RR 1.4, CI 1.1–1.8; p = 0.001) respectively. In addition, strong p65 nuclear staining was associated with a 2.1-fold higher risk of biochemical relapse in patients with lymph node metastases (95% CI 1.1–3.9; p = 0.02). Conclusion: The prognostic relevance of NF-kB p65 to predict biochemical recurrence was validated on a large patient cohort with long time follow-up. Our centers are in the process of developing clinico-molecular nomograms. The addition of NF-kB and other molecular markers to current clinical markers will facilitate the identification of high risk patients and guide clinicians in the choice of an appropriate therapeutic approach. No significant financial relationships to disclose.
Incidence, Prevention and Management of Anti-Drug Antibodies Against Therapeutic Antibodies in Inflammatory Bowel Disease: A Practical Overview
Authors: Pieter Hindryckx, Gregor Novak, Niels Vande Casteele, Reena Khanna, Debby Laukens, Jairath Vipul, Brian G. Feagan
Journal: Drugs (2017)
Characteristics and survival in patients with metastasic uveal melanoma: Analysis of a referral center cohort.
Authors: R. Schuster, K. Sorgatz, E. Thiel, U. Keilholz
Journal: Journal of Clinical Oncology (2011)

e21036 Background: Reported median survival in metastatic uveal melanoma ranges between 6 and 12 months. We here evaluated characteristics and survival of an unselected patient cohort of a major referral center for this rare condition. Methods: All patients with metastatic uveal melanoma reported to the Charité between 2004 and 2007 were identified from our database (n=124). We recorded date of initial diagnosis, date of metastatic disease, site and extension of first metastases, age, sex, aspartate (AST) and alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), bilirubin, lactate dehydrogenase (LDH), therapy, and outcome. Results: Follow-up information was available for 114 patients. The estimated median survival analyzed was 8.4 months (range 0 to 76). 10% of patients survived more than 2 years. 89% of patients had diffuse organ metastases, and in 96% the liver was involved. In 5 patients surgical resection of single metastases was performed. 54% of patients received at least two different systemic therapies. The following factors correlated with survival in univariate analysis: liver involvement, AST, ALT, AP, GGT, bilirubin, and LDH. Multivariate cox analysis revealed AP (HR: 3.5), bilirubin (HR: 2.7), and LDH (HR: 2.0) as independent prognostic factors for survival. 22% of patients had elevated bilirubin values at time of initial presentation and a median survival of 3.1 months as compared to 9.2 months in patients with normal bilirubin. Conclusions: The overall patient cohort still had poor outcome, but a proportion of patients was included in one or several subsequent experimental treatment protocols. Only very few patients were candidates for surgery. Despite of ultrasonography screening, more than 20% of patients still presented with evidence for liver failure, which rendered them unsuitable for testing of novel therapies.
Advanced-stage colon cancer prior to the screening age: Association with age, race, and insurance status.
Authors: Y. N. You, Y. Xing, B. W. Feig, M. A. Rodriguez-Bigas, J. M. Skibber, G. J. Chang, J. N. Cormier
Journal: Journal of Clinical Oncology (2011)

377 Background: Stage-at-diagnosis is a major determinant of outcome in colon cancer. Population-based screening is currently only recommended after age 50, but the number of colon cancers diagnosed before 50 is increasing. We aimed to identify risk factors associated with advanced-stage disease (stage III or IV) among colon cancers diagnosed before 50. Methods: Between 2003 and 2007, 248,716 colon adenocarcinomas (25,383 diagnosed before age 50) were reported to the National Cancer Database. Patients with familial adenomatous polyposis were excluded. Among the cases diagnosed before 50, independent predictors for presenting at advanced stages (stage III or IV) were identified using multivariate logistic regression. Results: 10.2% of all colon cancers occur prior to age 50. Stage III or IV disease accounted for 62.2% of the cases before age 50, and 46.9% of those diagnosed at or after age 50 (p&lt;0.001). Among colon cancers diagnosed before 50, independent risk factors for advanced-stage disease included: very young age groups (age 18-30 and age 30-40 vs. age 40-50), African American race (vs. Caucasian), and having Medicaid, non-Medicare government insurance or no insurance (vs. private insurance), after adjusting for gender, tumor location, geographic region, and treatment facility type (Table). Conclusions: In the unscreened population of patients before age 50, disparities in age, race, and insurance are associated with the stage at presentation. The risk factors identified help alert the treating clinicians toward patients most vulnerable to delays in their cancer diagnosis. [Table: see text] No significant financial relationships to disclose.
OLIGOPELVIS – GETUG P07, a multicentre phase II trial of combined salvage radiotherapy and hormone therapy in oligometastatic pelvic node relapses of prostate cancer: Preplanned analysis of acute toxicity.
Authors: Stephane Supiot, Gilles Crehange, Xavier Buthaud, David Pasquier, Ali Hasbini, Guy De Laroche, Pascal Pommier, Genevieve Loos, Veronique Beckendorf, Paul Sargos, Emmanuel Rio, Loic Campion
Journal: Journal of Clinical Oncology (2016)

173 Background: We explored the role of salvage pelvic radiotherapy combined with LH-RH agonists in pelvic oligometastatic patients (pts) detected by 18 F-choline positron-emission tomography (FCH-PET) imaging in biochemically relapsing prostate cancer patients following radical therapy. We report a preplanned analysis of acute toxicity and quality of life after the first 20 pts. Methods: Biochemically relapsing prostate cancer pts with 1-5 FCH-PET positive oligometastatic pelvic lymph nodes received high-dose image-guided intensity-modulated radiation therapy (RT: pelvic lymph nodes 54 Gy, 30 f; FCH-PET-positive lymph nodes 66 Gy, 30 f; prostate bed 66 Gy, 33 f; if FCH-PET-positive prostate bed relapse 72 Gy, 36 f) combined with 6 months LH-RH agonists. Primary objective was biochemical-clinical failure-free survival. After the first 20 pts, a preplanned analysis of toxicity at 1 months after RT completion was conducted. Stopping criteria were more than 10 or 2 pts experiencing grade 2 or 3 toxicity respectively. Changes in toxicity (NCI-CTC AE v4), and quality of life (EORTC QLQ-C30 and PR25 questionnaires) over time were analyzed by the Wilcoxon signed-rank test. Results: 20 pts (median age 62) presenting oligometastatic pelvic lymph nodes (mean 1.7) received RT to lymph nodes in all pts and to the prostate bed in 8 pts with a boost to a local relapse in 2 pts. Grade 2 gastrointestinal and genitourinary toxicity was noted in 4/20 and 0/20 pts respectively during radiotherapy that resolved completely in all pts one month after treatment. No grade 3 toxicity was noted. At 1 month, significant worsening was reported by pts for 4/21 QoL items but the worsening was clinically relevant ( &gt; 10 points) for 2 items only: fatigue and dyspnea. However, there was significant - but clinically non-relevant ( &lt; 10 points) - worsening of physical functioning and hormonal-treatment related symptoms. Conclusions: High-dose RT to the pelvis and oligometastatic lymph nodes did not increase acute toxicity. As per protocol, the study resumed and is now recruiting 50 more patients. Clinical trial information: NCT02274779.
Survival trends in chemorefractory unresectable intrahepatic cholangiocarcinoma (ICC) and the effect of yttrium-90 (Y90) radioembolization: SEER versus tertiary cancer center.
Authors: Minzhi Xing, Hasmukh J. Prajapati, Nima Kokabi, Juan C. Camacho, Bassel F. El-Rayes, Hyun Sik Kim
Journal: Journal of Clinical Oncology (2014)

342 Background: Survival in patients with chemorefractory unresectable ICC treated with Y90 radioembolization vs. best supportive care has not been investigated in large-scale population studies. Methods: Under IRB approval, our institute’s cancer registry was queried for Y90-treated patients with chemorefractory unresectable ICC diagnosed from Jan 2002 to Nov 2011. Eighteen registries of U.S. Surveillance, Epidemiology and End Results (SEER) database were queried for patients with advanced ICC not amenable to surgery/radiation diagnosed in the same period. Baseline characteristics, median overall survival (OS) from ICC diagnosis and median OS from first Y90 were stratified by national/state cohorts. Survival analysis and 95% confidence intervals (CI) were calculated using Kaplan-Meier estimation. Results: A total of 24 patients who received Y90 therapy for chemorefractory unresectable ICC (Group A) and 2757 patients with unresectable ICC who received neither radiation nor cancer-directed surgery (Group B) were included. Both groups were similar for mean age at diagnosis, gender, race, bilobar disease, portal vein thrombosis and mean largest tumor size (p&gt;0.05). Median OS from ICC diagnosis was 20.8 months (Group A; 95% CI, 11.2-30.5) and 3.0 months (Group B; 95% CI, 2.7-3.3), p&lt;0.001. Median OS from first Y90 was 11.5 months (Group A; 95% CI, 4.8-18.2). Interval survival rates from ICC diagnosis for Group A vs. B were: 100% vs. 77% (1 month), 100% vs. 63% (3 months), 92% vs. 30% (6 months), 67% vs. 17% (1 year), 42% vs. 6% (2 years), and 17% vs. 3% (3 years). Conclusions: Y90 radioembolization in patients with chemorefractory unresectable ICC demonstrated significantly greater median OS and favorable long-term survival rates compared to best supportive care. [Table: see text]
Biomarker patterns of localized and metastatic prostate cancer.
Authors: Rebecca Feldman, Sandeep K. Reddy, Zoran Gatalica, Joanne R. Mahanes, Charles E. Myers
Journal: Journal of Clinical Oncology (2015)

192 Background: Presence or absence of metastases is a determining factor for prostate cancer prognosis. Common sites of metastasis include bone (B), lymph nodes (LN) or visceral organs (V). We sought to determine theranostic biomarker differences between primary (P) and metastatic (M) specimens, with subset analysis for differences between metastatic sites. Methods: 497 prostate cancer cases referred to Caris Life Sciences between 2009 thru 2014 were evaluated. Specific testing was performed and included a multiplatform approach: sequencing (Sanger, NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: 58% (287/497) were M specimens, of which 23% (66), 24% (68) and 52% (149) were from B, LN and V, respectively. Significant differences for EGFR amplification/overexpression, low MGMT expression, TOPO1/2A overexpression and higher PTEN mutation rate were found in the M subgroup. These alterations indicate a role for EGFR/PTEN in progression of prostate cancer, and potential role of MAPK/PAM-targeted therapies, alkylating agents and topoisomerase inhibitors in M disease. Mutational profiles of the M subgroup are more genetically unstable exhibiting mutations in 60% of genes tested (notable events include APC &amp; β-Catenin, PTEN, TP53 and BRCA1/2) vs. 30% observed in the P subgroup (p=0.0067). In the subset analysis, EGFR amplification was higher in B (29%) and V (24%) compared to LN (13%); (not significant). Low TS expression was more frequent in B vs. LN (p=0.004), TOPO2A overexpression was higher in V vs. B (p=0.0001) and there was a trend for PD1 positive infiltrating lymphocytes being more abundant in LN vs B (p=0.09). Interestingly, cMET overexpression (7/230) and amplification (1/162) were rarely observed across the cohort, providing support for the surprising failure of cabozantinib in castration-resistant prostate cancer. Conclusions: Our data indicate a role for multiplatform profiling to identify therapeutic options that are appropriate for subsets of patients. Molecular changes associated with M disease including EGFR, PTEN, MGMT and TOPO1/2A, present opportunities for developing therapeutic strategies which may include a combination of targeted therapies, as well as traditional cytotoxic chemotherapies.