tbuckley/cabot-search huggingface dataset:
A phase I study of capecitabine in combination with yttrium-90 labeled resin microspheres (SIR-Spheres) in patients (pts) with advanced cancer.
Authors: S. J. Cohen, A. A. Konski, S. Putnam, D. Ball, J. E. Meyer, J. Q. Yu, I. A. Astsaturov, K. Magalong, D. Cade, N. J. Meropol
Journal: Journal of Clinical Oncology (2011)

e14612 Background: Radioembolization (RE) with Yttrium-90 labeled resin microspheres (SIR-Spheres) is an emerging treatment for liver tumors, both alone and with chemotherapy. Concurrent use of capecitabine (cape) with RE has been contraindicated due to concerns for liver toxicity. This phase I study was initiated to formally evaluate the safety of concurrent cape and RE. Methods: Pts with unresectable metastatic or primary liver tumors were treated in a 3+3 design with escalating doses of cape (375, 600, 750, 900 mg/m2) bid x 14d q21d. RE was performed on the dominant diseased liver lobe on day 2 of chemotherapy. Repeat imaging was obtained after 2 cycles of cape. Pts with bilobar disease without progression in the treated lobe could receive a second RE with 2 additional cycles of cape. Inclusion criteria were liver only/dominant disease, any number of prior regimens, ECOG PS 0-1, bilirubin ≤ ULN, ALT and AST ≤ 1.5 x ULN, patent portal vein, < 20% lung shunt. Primary endpoints were safety and toxicity. Results: Pts (n=21) were enrolled in 4 cohorts. Pt characteristics: median age 61 (49-81), M/F (13/8), diagnoses (CRC 16, NET, biliary, HCC, small bowel, unknown, 1 each), median prior tx=2, prior TACE=2. Cohort 1 (375 mg/m2, n=8): Of the first 3, one pt with biliary cancer had gr 3 hyperbilirubinemia possibly related to tx. Of the next 2 pts, one with CRC had gr 4 hyperbilirubinemia related to disease. The cohort was expanded to 8 with no further DLTs. Cohort 2 (600 mg/m2, n=4 - one pt erroneously took 300 mg/m2 of cap): No DLTs were observed. Cohort 3 (750 mg/m2, n=6): One pt with mCRC and a large left lobe lesion had a partial antral perforation possibly related to tx and the cohort was expanded to 6, with no further DLTs. Cohort 4 (900 mg/m2, n=3): No DLTs were observed. No other gr 3/4 non-heme toxicities were noted. Common gr 1/2 non-heme toxicities included transaminitis/alk phos elevation (9), nausea (8), pain (7), fatigue (5), and hand/foot (5). Best response: cPR (3), uPR (1), SD (16), PD (1). Conclusions: Capecitabine can be safely administered with SIR-Spheres at doses typically utilized with combination chemotherapy (up to 900 mg/m2 twice daily). Further evaluation in CRC patients is planned.
Transglutaminase II expression in invasive ductal carcinomas.
Authors: Jasmeet Sunny Assi, Gunjan Srivastava, Ajay Matta, Martin Chang, Ranju Ralhan, Paul G. Walfish
Journal: Journal of Clinical Oncology (2013)

34 Background: Molecular markers for predicting breast cancer patients at high risk of recurrence are urgently needed for more effective disease management. The impact of alterations in extracellular matrix components on tumor aggressiveness is under intense investigation. Overexpression of Transglutaminase 2 (TG2), a multifunctional enzyme, in cancer cells impacts epithelial mesenchymal transition and cancer stem cell phenotype, growth, invasion and interactions with tumor microenvironment. The objective of our study is to determine the clinical relevance of stromal TG2 overexpression and explore its potential to identify which IDCs are at high risk of recurrence. Methods: This retrospective study is based on immunohistochemical analysis of TG2 expression in 168 invasive ductal carcinomas with clinical, pathological and follow-up data available for up to 12 years. TG2 expression was correlated with clinical and pathological parameters as well as disease free survival (DFS) of breast cancer patients. Results: Stromal TG2 overexpression was observed in 97/168 (57.7%) invasive ductal carcinomas (IDC). Notably, IDC patients showing stromal TG2 accumulation had significantly reduced disease free survival (mean DFS = 110 months) in comparison with patients showing low expression (mean DFS = 130 months), as revealed by Kaplan-Meier survival analysis (p &lt;0.001). In Cox multivariate regression analysis, TG2 accumulation in tumor stroma emerged as an independent risk factor for recurrence in IDC (p = 0.006, Hazard’s ratio, H.R. = 3.79). Conclusions: Accumulation of TG2 in tumor stroma is an independent risk factor for identifying breast cancer patients at high risk of recurrence. TG2 overexpression in tumor stroma may serve as a predictor of poor prognosis for IDC of the breast.
Prospective phase I study of nab-paclitaxel plus gemcitabine with concurrent MR-guided IMRT in patients with locally advanced or borderline resectable pancreatic cancer.
Authors: Jeffrey R. Olsen, Parag J. Parikh, Todd A. DeWees, Lindsey Olsen, William G. Hawkins, Steven M. Strasberg, Kian-Huat Lim, Preet Paul Singh, Rama Suresh, Benjamin R. Tan, Lee Ratner, Ryan C. Fields, Manik A. Amin, Andrea Wang-Gillam
Journal: Journal of Clinical Oncology (2016)

TPS480 Background: Radiotherapy (RT) for locally advanced and borderline resectable pancreatic cancer (LABPC) is controversial as potential local control benefits are often obscured by high rates of distant progression. However, local failure remains a significant cause of morbidity among patients without distant progression after initial chemotherapy, although toxicity concerns may limit delivery of optimal systemic therapy concurrent with RT. Given known systemic efficacy and radiosensitization effects of nab-paclitaxel (A) with gemcitabine (G), we initiated a phase I study of nab-paclitaxel with gemcitabine (AG) and concurrent intensity modulated radiation therapy with magnetic resonance guidance (MR-IMRT) for LABPC. Methods: A planned 24 patients with LABPC will be enrolled to a phase I dose escalation trial using the Time-to-Event Continual Reassessment Method (TITE-CRM) design. Following one lead-in cycle of GA, MR-IMRT is administered daily with concurrent weekly GA for a total of 25 fractions in 5 weeks. The initial dose levels for RT and AG, respectively, are: 40 Gy MR-IMRT, 75 mg/m 2 A and 600mg/m 2 G. The maximum possible dose level is 60 Gy MR-IMRT, 100mg/m 2 A and 1000mg/m 2 G. To reduce toxicity risk, MR-IMRT volumes include the primary tumor only, with cine-MR used for intra-fraction tumor tracking in place of fiducial markers. The primary endpoint is determination of the maximum tolerated dose level, with secondary endpoints including rate of conversion to resectable disease, progression- free survival, overall survival, and patient reported quality of life. Clinical trial information: NCT02283372.
Physician decisions related to maintenance therapy for advanced non-small cell lung cancer (NSCLC) in the United States (US).
Authors: Suzanne Lane, Sarah Goring, Kerstin Mueller, Lisa M. Hess, Ana Belen Oton, Catherine Muehlenbein, Yajun Zhu, Himani Aggarwal, Mohamed K. Mohamed, Benjamin Philip Levy, Katherine B. Winfree
Journal: Journal of Clinical Oncology (2016)

182 Background: In 2006, maintenance therapy was added as a treatment guideline for patients with advanced non-squamous (nsq) NSCLC. This study aimed to identify patient- and disease-related factors that impact maintenance therapy decision making. Methods: An online discrete choice survey was administered to physicians currently managing patients with advanced nsq NSCLC in the US. Physicians viewed 12 patient profiles differing in levels of the following attributes: 1st line treatment response (complete, partial, stable, progression), adverse events during 1st line therapy (none, mild, moderate, severe), comorbidities (none, mild renal, severe renal, other), patient motivation/convenience (+/+, +/-, -/+, -/-), patient insurance co-pay rate (0, 5, 10, 20%), and age (45, 58, 68, 80 years). No specific maintenance treatments were stated. For each profile, physicians indicated if they would recommend maintenance therapy. Recommendations were analyzed using a mixed-effects logistic regression model. Odds ratios (ORs) were calculated to estimate the relative odds of a maintenance therapy recommendation for levels of each attribute. Results: The survey was completed by 100 physicians (81% male; mean years of experience: 15.4). The study design was balanced and orthogonal. Maintenance therapy was recommended for 75% of the profiles; 98% of physicians recommended maintenance therapy for at least 1 profile, with 26% recommending it for all profiles. The odds of recommending maintenance therapy were significantly lower when the patient profile included disease progression relative to stable response (OR: 0.17; p&lt;0.01), severe renal impairment relative to no comorbidities (OR: 0.38; p&lt;0.01), or low motivation/convenience relative to high motivation/convenience (OR: 0.25; p&lt;0.01). The odds also decreased with increasing age (OR: 0.97 per year increase in age; p&lt;0.01). Conclusions: Treatment response, age, motivation/convenience, and comorbidities were relevant factors for physicians when recommending maintenance therapy. Physicians report recommending maintenance even in the presence of less desirable patient and disease characteristics indicative of a real world setting.
Long-term bother profiles in patients with locally advanced prostate cancer treated with radiotherapy compared to men with localized prostate cancer treated with high-dose radiotherapy.
Authors: Wolfgang Lilleby
Journal: Journal of Clinical Oncology (2015)

104 Background: We compared the long-term the bother profiles in patients with prostate cancer (T1-3 M0) consecutively referred to the OUS to definitive radiotherapy encompassing the prostate and pelvic lymph nodes (RT+IMRT) (N=90) or radiotherapy to the prostatic gland only (RAD) (N=180), applied with adjuvant androgen deprivation in all patients. Methods: After 36months 206 (76%) of the eligible men (RT+IMRT = 64 and RAD = 142) had completed the UCLA-PCI questionnaire at baseline, 12, 24 and 36 months. The bother scores were adjusted for significant differences in quality of life measured by the SF-12 instrument. Differences in the mean scores between the treatment groups were evaluated by the Mann-Whitney U test for skewed samples. Patients were similar in age and by the distribution of prognostic risk factors in both cohorts. Results: The longitudinal bother mean scores up to 36 months post-treatment for the main domains are reported. Significantly more RAD patients had less urinary bother at baseline compared to RT+IMRT patients. In both groups sexual bother was significantly increased over time. Thus, at 36 months mean scores for urinary, bowel and sexual bother appeared to be stable in both groups. However, despite of increased bowel bother at one year (p= 0.02) in the RT+IMRT group, bowel bother score improved in these patients compared to RAD at last observation (p= 0.25). Conclusions: The long-term bother profiles are similar in the RT+IMRT and RAD groups at 36 months follow-up. Modern radiotherapeutic techniques allow targeting of high-risk patients. Differences in organ function and bother can only be accomplished for by long-term health care assessment.
Heterogeneity of circulating tumor cells isolated from bladder cancer patients using ApoStream and biomarkers of epithelial-mesenchymal transition.
Authors: Colin P. N. Dinney, Vladislava O. Melnikova, Shanna M. Pretzsch, Miguel Garza, Weiguo Wu, Darren W. Davis, Kenna Lynn Anderes
Journal: Journal of Clinical Oncology (2014)

349 Background: Elucidating the molecular pathways that drive the progression of metastatic bladder cancer (BC) from local disease to metastatic may provide insight into prognosis and potentially treatment. The frequency of detection of circulating tumor cells (CTCs) in metastatic BC patients is only 30% using EpCAM based methods. Reports have shown that EpCAM based methods detect only a fraction of CTCs and miss the heterogeneous subpopulations of CTCs related to epithelial to mesenchymal transition (EMT). EMT is a hallmark of cellular invasion and metastasis and CTCs undergoing EMT may have prognostic value in BC if reliable detection and characterization methods were developed. Here we used ApoStream, a novel antibody-free CTC isolation device to isolate CTCs and perform molecular characterization. Methods: Blood samples from 13 early stage or metastatic BC patients were collected and processed using ApoStream. Isolated cells were immunophenotyped using a multiplexed immunofluorescence assay for CK, CD45, DAPI, uroplakin, vimentin and Twist. Laser scanning cytometry analysis was applied to identify subsets of CK + CD45 - DAPI + or CK - CD45 - DAPI + cells for the expression and distribution of uroplakin, vimentin and Twist. Urovysion FISH analysis was performed on CTCs from 6 BC patients. Results: CK + CD45 - DAPI + cells were detected in 4/13 (31%) of patients with vimentin detected in this subset. CK - CD45 - DAPI + cells were detected in 9/12 (75%) of patients with Twist expression detected in this subset. Uroplakin expression was not detected. Chromosomal abnormalities were detected in CK - CD45 - DAPI + cells isolated from the blood of 3/6 (50%) BC patients. Conclusions: ApoStream isolated cells from the blood of BC patients with phenotypic and genotypic characteristics of CTCs. The CK +/- CD45 - DAPI + Twist and vimentin phenotype indicates a population of circulating cells with relevant biomarkers of EMT and may represent an important population of CTCs mediating disease progression. Detection of chromosomal abnormalities on non-canonical CTCs highlights heterogeneity and underscores the need for expanded definitions of CTCs in BC.
Coordination of care: Lessons learned from a pilot study in head and neck cancer.
Authors: S. S. Baxi, C. Monether, R. J. Wong, J. Miransky, D. G. Pfister, J. F. Kelvin
Journal: Journal of Clinical Oncology (2011)

e16607 Background: The Institute of Medicine highlighted coordination of care (COC) as a target for improving health care quality. COC is important in oncology, where patients (pts) are treated with combined modality therapy (CMT). Head and neck squamous cell cancer (HNSCC) is treated with CMT and delays in treatment can be detrimental to disease control. Methods: A multidisciplinary team reviewed the pretreatment process for HNSCC pts treated with concurrent chemoradiation at our center. Potential delays were identified; action plans to address them (e.g, expedited pathology review; reserved appointments for feeding tube placement) were implemented. Primary outcome/goal: to reduce the days from first contact to the start of radiation by 25%. Secondary outcome/goal: to reduce the number of pretreatment trips to the center. Results: We measured baseline data and then repeated measurements for 3 quarters after implementation of COC action plans. There was wide variability in primary and secondary outcome measures at baseline. The COC action plans did not achieve our prespecified primary goal in a durable way; nor was there a clear impact on the number of trips. Review of the study experience/data identified the following factors as important when planning similar COC initiatives: careful selection of pt/setting, as complexity and unpredictability—common in pts with HNSCC—complicate any standardization of work flow; participation of all involved staff, facilitating their investment in the process/project goals, and encouraging their receptivity to standardization of practice; use of valid metrics, including ones sensitive to changes caused by smaller component processes; use of metrics that lend themselves to ease of measurement to facilitate timely feedback. Conclusions: Although our primary goal was not met, many lessons were learned from this pilot study. COC is an important goal but is a complicated health care delivery concept. Careful attention to several methodological factors is required to effect improvement and document change in the setting of CMT in oncology. No. of days to start RT No. of trips N Median Mean Median Mean Baseline 81 47 (18-84) 47 8 (4-18) 9 Q1 18 39 (18-73) 42 7 (4-10) 7 Q2 20 36 (25-66) 32 8 (4-13) 9 Q3 19 49 (18-69) 46 7 (3-14) 9
Molecular profiling of infiltrating urothelial carcinoma of the bladder.
Authors: Sherri Z. Millis, David Bryant, Gargi Dan Basu, Ryan Bender, Semir Vranic, Zoran Gatalica, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2014)

311 Background: Infiltrating urothelial carcinoma (UC) is the most common variant of urinary bladder cancer. The prognosis for muscle infiltrating or metastatic UC of the bladder is poor with no major advances made in the last 20 years. We investigated a large cohort of such patients for specific genetic/biomarker alterations and compared them to other, less common urothelial malignancies. Methods: We reviewed 602 cases; 518 cases (86%) were locally advanced or metastatic UCs of the bladder and the remaining 84 cases (14%) were non-bladder UCs. Multiple methodologies for optimal assessment of biomarker expression (Caris Molecular Intelligence, Caris Life Sciences, Phoenix, AZ) were employed: Mutation analysis (Next-generation sequencing, Sanger, pyrosequencing, qPCR, RFLP), in-situ hybridization (fluorescent and chromogenic), immunohistochemistry, and RNA fragment analysis. Results: Bladder UC showed slightly higher rates of HER2/neu gene amplification (12% in bladder vs. 6% non-bladder, p=0.32) and EGFR gene amplification (22% vs. 12%, p=0.25). HER2/neu and EGFR protein expressions were more common in the bladder than in non-bladder sites (10% vs. 1%, p=0.03, and 77% vs. 60%, p=0.5, respectively). Pathogenic mutations in HER2/neu and EGFR were rare. Although c-Kit and c-Met receptor kinases were more frequently overexpressed in bladder than in non-bladder cancers (10% vs. 6% and 25% vs. 8%, respectively), activating mutations were also rare. PIK3CA and/or PTEN mutations were more frequently observed in non-bladder (27%) than in bladder UCs (21%). Non-bladder UC harbored high FGFR3 gene mutation (33%), which was not observed in any of the UC of the bladder (p=0.02). TP53 gene mutations were frequently identified in both bladder and in non-bladder cancers (49% vs. 27%, respectively, p=0.15), while KRAS was frequently mutated in the bladder adenocarcinomas (56%, p&lt;0.001). Other therapeutically targetable biomarkers over-expressed in bladder UC compared to non-bladder UC included androgen receptor (16% vs. 8%, p=0.07) and MGMT (63% vs. 47%). Conclusions: Comprehensive molecular profiling of urothelial carcinoma identifies a number of potentially actionable targets, which can be managed by the novel treatment modalities.
Regular aspirin use and the risk of lethal prostate cancer in the Physicians' Health Study.
Authors: Christopher Brian Allard, Mary K Downer, Mark A Preston, J. Michael Gaziano, Meir J. Stampfer, Lorelei A. Mucci, Julie Batista
Journal: Journal of Clinical Oncology (2016)

306 Background: Aspirin exerts chemopreventive effects against several malignancies. An inverse association between regular aspirin intake and advanced prostate cancer is suggested by previous reports, but potential effects on lethal prostate cancer have not been characterized. Methods: The study population comprised 22,071 male physicians enrolled in the prospective Physicians' Health Study followed from 1982-2009. We evaluated the relationship between regular aspirin intake ( &gt; 3 tablets per week) and lethal prostate cancer (metastases or prostate cancer death). Secondary outcomes included the incidence of total, high-grade (Gleason 8-10), and advanced (T3b-T4 or N1 or M1) cancers. Cox proportional hazards models estimated age- and multivariate-adjusted hazard ratios (HR) for the incidence of primary and secondary outcomes and survival among participants with prostate cancer. Results: Over 27 years of follow-up (533,261 person-years), 3,183 men were diagnosed with prostate cancer, of whom 402 developed lethal disease. Decreased multivariate-adjusted risks of lethal prostate cancer were observed for regular aspirin users (HR: 0.67, 95%CI: 0.55-0.82). Recent regular use (within 12 months) was protective, with effects diminishing with time since last regular use (p for trend = 0.007). Among men with prostate cancer, regular aspirin use after diagnosis was associated with decreased prostate cancer mortality (HR: 0.79, 95%CI: 0.64-0.98), whereas pre-diagnostic use did not confer a measurable benefit. Regular aspirin use was not significantly associated with the incidence of total, high-grade, or advanced cancers. Conclusions: Regular aspirin use was associated with a decreased risk of lethal prostate cancer in this cohort of American physicians. An inhibitory effect of regular aspirin use on prostate cancer progression is suggested.
The GLOBE score identifies PBC patients at increased risk of liver transplantation or death during follow-up
Authors: Jorn C Goet, Willem J Lammers, Harry L Janssen, Gideon M Hirschfield, Christophe Corpechot, Keith D Lindor, Pietro Invernizzi, Marlyn J Mayo, Pier Maria Battezzati, Frederik Nevens, Annarosa Floreani, Albert Pares, Andrew Mason, Kris Kowdley, Cyriel Y Ponsioen, Tony Bruns, George N Dalekos, Douglas Thorburn, Xavier Verhelst, Henk R van Buuren, Bettina E Hansen
Journal: Hepatology (2016)
Objective response of the dual CYP17-Lyase (L) inhibitor / androgen receptor (AR) antagonist, VT-464, in patients with CRPC.
Authors: Luke T. Nordquist, Neal D. Shore, Johann S. De Bono, Shilpa Gupta, William R. Berry, Silke Gillessen, Glenn Liu, Nicholas J. Vogelzang, Eleni Efstathiou, Mark T. Fleming, Daniel J. George, John C. Araujo, Jingsong Zhang, Michael R Kurman, Joel Robert Eisner, William R. Moore
Journal: Journal of Clinical Oncology (2016)

273 Background: VT-464 is an oral, CYP17-L inhibitor and non-clinically an antagonist of the AR and its variants associated with clinical resistance to enzalutamide (ENZ) and abiraterone (AA). The safety, tolerability and initial pharmacodynamic effects (tumor responses, PSA and testosterone (T) decreases) of VT-464 given without steroid supplementation either bid with food or QD at night with dinner were evaluated in the Phase (Ph) 1/2 studies INO-VT-464-CL-001 (NCT02012920) and INO-VT-464-CL-004 (NCT02361086), respectively. Patients were either treatment-naïve (TN), or had failed AA or ENZ or AA/ENZ/chemotherapy (at least 2 out of the three). Preliminary objective response results from both studies are presented herein. Methods: Target lesions were assessed at baseline and during therapy using CT or MRI. Target lesion responses were categorized as a complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) using RECIST 1.1. Patients with ≥ 1 target lesion and ≥ 1 post-baseline scan following VT-464 BID (INO-VT-464-CL-001) or QD (INO-VT-464-CL-004) were included in the analysis. Results are reported through a data cutoff of 01 Sep 2015. Results: Combined, 23 patients (8 TN, 4 AA, 7 ENZ, 4 AA/ENZ/chemotherapy) from both Ph 1/2 studies had ≥ 1 target lesion and ≥ 1 post-baseline scan. Of 15 patients included who were treated BID (Study 001), 1 had PD, 12 had SD and 2 had a PR. Of 8 patients who were treated QD (Study 004), 2 had PD, 5 had SD and 1 had a PR. No patient had a CR in either study. For the 3 patients with PRs one patient had a prior response to ENZ but failed taxane-based chemotherapy, another was de novo resistant to ENZ, while the third was TN. For the 3 PRs, one was confirmed with a repeat scan 8-weeks later and the others have repeat scans pending. Conclusions: Potent and selective CYP17-L inhibition, PSA reductions, and objective tumor responses in TN and ENZ-failure patients have been observed with oral VT-464 administered bid (de Bono et al, GU ASCO 2015) or QD (Shore et al, GU ASCO 2016). Preliminary results demonstrate that the QD regimes are as efficacious as BID regimens. All Ph 2 CRPC studies now utilize a 750 mg QD regimen. Clinical trial information: NCT02012920 and NCT02361086.