tbuckley/cabot-search huggingface dataset:
Prognostic significance of new glioma marker, laminin-411, and its inhibition by targeted nanobiopolymer in vivo.
Authors: J. Y. Ljubimova, S. Inoue, S. I. Bannykh, S. Phuphanich, J. Rudnick, A. V. Ljubimov, K. L. Black
Journal: Journal of Clinical Oncology (2011)

e13008 Background: Increased expression of α4 and β1 chain-containing vascular protein laminin-411 (α4β1γ1) correlated with tumor invasion and progression and was associated with glioma patients’ poor prognosis and survival. Therefore, laminin-411 may be a promising target for glioma diagnosis and treatment. Methods: 1. A clinical trial for laminin-411 vs. a normal laminin-421 is underway at Cedars-Sinai Medical Center for evaluating laminin-411 overexpression in gliomas. The clinical material used comprises 194 primary gliomas: 106 glioblastomas multiforme, 28 anaplastic astrocytoma, 7 anaplastic oligoastrocytoma, 20 astrocytoma grade II, 19 oligodendroglioma grade II, 4 ependymomas grade I-II, pilocystic astrocytoma I-II, 4 microglial activation tissues. 2. Targeted nanobiopolymer for angiogenesis inhibition of gliomas was synthesized for systemic treatment in vivo. The drug is based on polymalic acid for efficient and specific delivery of antisense oligonucleotides and monoclonal antibodies. The mechanism of PMLA nanoconjugate tumor delivery through blood tumor barrier was studied. Results: New tumor vascular marker, laminin-411, was overexpressed in 75% of patients with glioblastoma, 14% anaplastic astrocytoma, 28% of 7 anaplastic oligoastrocytomas. Low-grade glial tumors and non-tumor glial tissues did not overexpress laminin-411, but predominantly expressed laminin-421 (α4β2γ1). Systemic treatment of mice bearing intracranial U87MG glioma with nanobioconjugate resulted in a significant inhibition of tumor growth 4 mm3 compared to 47 mm3 in saline-treated control group, p<0.001). On immunostained tumor sections, the signal for laminin-411 chains diminished after treatment with nanobioconjugate and morphometric analysis showed significant decrease in the tumor vascular area. Conclusions: Laminiin-411 appears to be a marker of high-grade gliomas. 2. Biodegradable, nontoxic and nonimmunogenic delivery system was designed for systemic treatment of brain tumors. The new nanomedicine drug was able to increase brain tumor bearing animal survival and decrease tumor size 10 fold by inhibiting laminin-411, a structural component of newly formed tumor vessels.
NGR-hTNF in previously treated patients with malignant pleural mesothelioma (MPM) .
Authors: F. De Vincenzo, G. Rossoni, A. Santoro, V. Gregorc, P. A. Zucali, G. Citterio, M. Simonelli, G. Petrella, F. Caligaris-Cappio, A. Lambiase, C. Bordignon
Journal: Journal of Clinical Oncology (2011)

7089 Background: NGR-hTNF exploits the tumor-homing peptide NGR for selectively targeting tumor necrosis factor to tumor blood vessels. Methods: Here we report the long-term results of a phase II trial testing NGR-hTNF in 57 MPM patients (pts) who had failed a pemetrexed-based regimen. NGR-hTNF was given as 1-hour infusion at 0.8 µg/m2 every 3 weeks (q3w; n=43) or weekly (q1w; n=14) in a subsequent cohort. Moreover, we assessed the impact on outcome of the systemic neutrophil-to-lymphocyte ratio (NLR), an index of the host immune response to tumor. Median baseline NLR was 3 (range 1-23). Results: In the whole study population (n=57), one grade 3 drug-related toxicity was observed and common grades 1-2 were transient chills (75% of pts). There was no higher toxicity using the q1w schedule. Median progression-free survival (PFS) was 2.8 months (95% CI 2.2-3.3). The disease control rate was 46% (26/57 pts; 95% CI 33-60%) and was maintained for a median time of 4.7 months (95% CI 4.0-5.4). With a median follow up of 28.6 months, the overall survival (OS) rates at 1 and 2 years were 47% and 15%, respectively. The 6-month PFS and 2-year OS rates were 11% and 10% in q3w cohort vs 36% and 29% in q1w cohort, respectively. In pts with disease control (n=26), median PFS and 2-year OS rate were 4.4 months and 11% in q3w cohort vs 9.1 months and 57% in q1w cohort, respectively. In a landmark analysis set at 2 months (1st restaging), median OS was longer in pts who had achieved disease control compared with those who had progressed (14.7 vs 6.8 months; p=0.03). By multivariate analyses, a PS of 0 (HR=0.38; p=0.02) and a baseline NLR ≤ 3 (HR=0.40; p=0.005) were associated with longer survival, while no associations were detected between OS and age, sex, histology, EORTC score and treatment-free interval on prior therapy. Median OS were 17.4 vs 8.0 months in pts with PS 0 or PS 1-2 and 15.7 vs 5.6 months in pts with NLR ≤ or > 3, respectively. Conclusions: Based on these results, NGR-hTNF 0.8 µg/m2 q1w is currently tested in a placebo-controlled phase II trial as a maintenance treatment in MPM pts who did not progress after 6 cycles of first-line chemotherapy and in a double-blind phase III trial evaluating best investigator’s choice ± NGR-hTNF in relapsed MPM.
MLL-AF9 and FLT3 Cooperation during Myeloid Leukemogenesis: Development of a Model for Rapid Testing of New Therapeutics.
Authors: Matthew C. Stubbs, Andrei Krivtsov, Yong-mi Kim, Renee D. Wright, Zhaohui Feng, Jyoti Agarwal, Andrew L. Kung, Scott A. Armstrong
Journal: Blood (2005)
Early discussion of advance directives for patients with newly diagnosed cancer.
Authors: Sekwon Jang, Suvarna Sundaram, Andrea Finlay, Natalia Romanova, Laura Knopp, Chiara Pierattini, Jenny Fuentes, Emily Hidalgo, Marian Daye, Megan Kokon, Christina Gustavson, Pamela Radomsky, Josefina Buras, Jennifer DeSimone, Suraj S. Venna, John F. Deeken, Donald L. Trump
Journal: Journal of Clinical Oncology (2016)

91 Background: Although advance care planning and the completion of advance directives (ADs) are important methods to prevent unwanted aggressive care once patients have lost their decision-making capacity, only a minority of patients have ADs at the time of cancer diagnosis. Methods: We established a new multidisciplinary outpatient clinic to provide comprehensive care to patients with newly diagnosed cancer at the Inova Dwight and Martha Schar Cancer Institute in Northern Virginia. Improvement in advance care planning was chosen as one of the first quality improvement initiatives for 2015. We started the first PDSA cycle after creating the team, establishing the problem and goal statement, and reviewing the process map. We had three measures including: 1. Inquiring whether the patient has advance directives or not at the time of scheduling their first appointment, 2. Provide written information about advance directives at the patient’s first visit, 3. Obtain advance directives by the third office visit. The goal for each measure was 90%, 90%, and 50% by the end of 2015. Results: Between May-June 2015, 65 patients were evaluable. Baseline rates were 26%, 2%, and 12%, respectively for measures 1, 2, and 3. In July 2015, we convened a staff meeting to review each staff’s role in the process of advance care planning. The new patient schedulers had training and created a telephone script to effectively communicate advance directives information with patients. The front desk staff included written information about advance care planning in the new patient information folders. Clinical staff were asked to address any questions or concerns that patients have and to encourage patients to complete the ADs by next visit. After this intervention, the rates increased to 100%, 44%, and 33%, respectively for measures 1, 2, and 3 in August and September, 2015 (n = 45). Conclusions: Early discussion about the ADs for newly diagnosed cancer patients at our outpatient clinic showed improvement in the rate of completed ADs by a third office visit.
Melphalan and whole-blood stem cell reinfusion in castration-resistant prostate cancer (CRPC): A phase I/II study.
Authors: J. Shamash, J. Jacob, T. Powles, S. Agrawal, K. Mutsvangwa, N. Saunders, P. Wilson, J. Stebbing
Journal: Journal of Clinical Oncology (2011)

2573 Background: Repeated cycles of chemotherapy supported by lenograstim and whole blood re-infusion (WBR) allows escalation of dose and increased frequency of therapy. Fixed doses of high dose lenograstim may facilitate predictable recovery following WBR. Alkylating drugs have shown activity in CRPC. We investigated the role of melphalan and WBR in metastatic CRPC. Methods: Twenty-two patients were recruited into this phase I/II study. High dose lenograstim was given for 3 days followed by venesection and subsequent iv melphalan. The autologous blood was returned 12 -24 hours later. Nine days later high dose lenograstim was restarted for 4 days then the procedure was repeated every 14 days. A total of 4 cycles was planned. Dose was escalated in 7 cohorts of 3 patients to a maximum of 60 mg/m2 cycle 1 and 40 for cycle 2-4. Results: There was 1 toxic related death leading to cohort expansion. Dose limiting toxicity was platelet recovery after the 4th cycle (100%). A median of 6 platelet transfusions were given per patient. Other grade3/4 toxicities included infection 35% and neutropenia 100%. The median intercycle time was 14 days (range 12-21 days). Lenograstim failed to mobilise in 2 patients and were taken off study. The PSA response rate (50% reduction) was 43%. Circulating tumour cells were measured in 15 (68%) patients, normalization occurred in 7/9 (77%)of those where they were elevated. Conclusions: Escalated melphalan with WBR is feasible in CRPC and results in responses. A formal phase II study is planned.
The initial report of RTOG 0524: Phase I/II trial of a combination of paclitaxel and trastuzumab with daily irradiation or paclitaxel alone with daily irradiation following transurethral surgery for noncystectomy candidates with muscle-invasive bladder cancer.
Authors: M. Dror Michaelson, Chen Hu, Huong T. Pham, Douglas M. Dahl, Chin-Lee Wu, Richard M. Whittington, Gregory P. Swanson, Jacqueline Vuky, R. Jeffrey Lee, Luis Souhami, Brian K. Chang, Asha George, Howard Mark Sandler, William U. Shipley
Journal: Journal of Clinical Oncology (2014)

LBA287 Background: Most patients (pts) with muscle-invasive bladder urothelial carcinoma (UC) undergo definitive local treatment with radical cystectomy. Up to 50% of pts with UC overexpress HER2/neu, which may be associated with reduced responsiveness to chemoradiation and reduced survival. Many pts with UC have comorbidities that preclude surgery, creating a traditionally underserved population with worse outcomes. RTOG 0524 evaluated the safety and efficacy of trimodality, organ-preserving therapy in pts not suitable for cystectomy. Methods: Pts with invasive bladder UC (stages T2-T4a, N0-1, M0) underwent cystoscopic tumor resection. Tumors were analyzed by HER2/neu immunohistochemistry (IHC) and assigned to chemotherapy group I (IHC 2+ or 3+; paclitaxel and trastuzumab) or II (IHC negative or 1+; paclitaxel alone). Concurrent weekly paclitaxel (50 mg/m2), weekly trastuzumab (group I only) and daily radiation (64.8 Gy total in 36 fractions) were given for seven consecutive weeks. Results: 21 eligible patients were entered in group I and 47 in group 2, with median ages of 80 and 73, respectively. The primary endpoint was acute protocol-defined toxicity related to treatment. Acute toxicity was observed in 7/21 pts (33%) in group I and 14/47 pts (30%) in group II. Most common grade &gt; 3 adverse events in groups I and II were marrow suppression (43% and 17%), diarrhea (33% and 30%), and hyponatremia (14% and 4%). Three deaths on study were attributed to colonic perforation, pneumonia, and sudden death. Radiation completion rates were 72% and 85% in the two groups, and full-dose chemotherapy completion rates were 52% and 51%. Evaluation by cystoscopy and/or tumor biopsy at 12 weeks noted complete response in 9/13 pts (69%) in group I, in 19/33 pts (58%) in group II, and was not performed in the remaining pts. Conclusions: Trimodality bladder-preserving therapy is an appropriate treatment in noncystectomy candidates with invasive UC. The response rate for HER2/neu-targeted therapy is encouraging but may increase certain adverse events in this challenging population. Clinical trial information: NCT00238420.
Evaluation of the prognostic value of UBE2C mRNA levels in early breast cancer.
Authors: D. Psyrri, R. Kronenwett, E. Timotheadou, R. M. Wirtz, A. Onyenadum, G. E. Pentheroudakis, C. A. Papadimitriou, E. Razis, T. Economopoulos, G. Fountzilas
Journal: Journal of Clinical Oncology (2010)

10570 Background: Ubiquitin-dependent proteolysis by the 26S proteasome plays a pivotal role in cell cycle progression as well as in tumorigenesis. The Ubiquitin Proteasome System (UPS) consists of ubiquitin, ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin-ligating enzymes (E3), and the 26S proteasome. Components of the UPS have been implicated in breast cancer progression. In the present study, we sought to explore the prognostic significance of UBE2C on disease-free survival (DFS) and overall survival (OS) in high-risk operable breast cancer patients. Methods: 595 high-risk breast cancer patients were treated in a two-arm trial (HE10/97) investigating postoperative dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel. RNA was extracted from 315 formalin-fixed paraffin-embedded primary tumor tissue samples followed by kinetic one-step RT-PCR for assessment of mRNA expression of UBE2C. Values above the 25th percentile were considered high expression. Results: With a median follow-up of 8 years the total number of events (disease relapses) was 111 (35%), and the total number of deaths 81 (26%). Escalating values of UBE2C were associated with significantly inferior DFS (Wald, p = 0.016) and OS (p = 0.005). High UBE2C mRNA expression was associated with poor DFS (log-rank, p = 0.002) and OS (p = 0.003), as well. This remained unchanged when adjusted for treatment group. Results of the Cox multivariate regression analysis revealed that, in the presence of treatment group, high UBE2C mRNA expression was associated with a significantly increased risk for relapse (HR = 1.77, 95% CI: 1.04-3.00, p = 0.035) and a significantly increased risk for death (HR = 2.12, 95% CI: 1.07-4.20, p = 0.030). Finally, higher tumor grade was more likely to be present in the high expression group of UBE2C than in the low expression group (58.2% vs 24.4%, p < 0.001), as was negative ER/PR status (26.4% vs 9.1%, p = 0.001). Conclusions: High UBE2C mRNA levels were found to be of adverse prognostic value in high-risk breast cancer patients treated with dose-dense sequential chemotherapy. Our findings however, need to be validated in larger prospective cohorts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Siemens AG, Siemens Healthcare Diagnostics Products Siemens AG, Siemens Healthcare Diagnostics Products
Is there a relationship between self-reported healthy days and comorbidity medication adherence among oncology patients?
Authors: Adrianne Waldman Casebeer, Dana Drzayich Jankus, Sari Hopson, Raya Khoury, Aparna Parikh, Alisha Stein, Todd Michael, Stephen Stemkowski, Mikele Bunce
Journal: Journal of Clinical Oncology (2016)

189 Background: Previous studies established the link between comorbidities and Health Related Quality of Life (HRQoL) for cancer patients. Adherence to comorbid medications has been found to be predictive of HRQoL in other disease states, but this has not been established for patients with cancer. This study sought to investigate the association between healthy days (HDs) and comorbidity medication adherence (CMA) for cancer patients. Methods: A survey was mailed to 5,098 patients with metastatic breast, lung or colorectal cancer who received treatment in 2014 and had at least one comorbid condition. Survey responses were merged with Humana claims data for analysis. The CDC’s Healthy Days measure was used to identify self-reported overall, physical and mental unhealthy days in the past 30 days and the number of days that poor physical or mental health limited usual activities. The Morisky Medication Adherence 8-point scale was used to differentiate high CMA ( &gt; 6) and low CMA ( &lt; 6). P-values are from chi-square and t-tests. Results: The survey response rate was 32% (N = 1,629). Respondents were mostly female (66%), and Medicare beneficiaries (90%) with mean age of 69.7 years. Patients with lung cancer experienced more overall unhealthy days than those with either breast or colorectal cancer (mean: 16.2 vs 12.6 and 13.5, p &lt; 0.0001). The number of overall unhealthy days was higher among patients with low CMA compared to high CMA (mean: 15.4 vs 13.5, p = &lt; 0.0001). Patients with low CMA had more mentally unhealthy days than those with high CMA (mean: 6.0 vs 8.2, p = 0.0128). There was no difference in physically unhealthy days by CMA. Patients with low CMA had 3.7 more unhealthy days that kept them from doing their usual activities (12.0 vs 8.3, p&lt; 0.0001). Conclusions: Surveyed oncology patients with high comorbidity medication adherence reported fewer unhealthy days, in particular mentally unhealthy days, in the past 30 days. The complex interplay between comorbidity medication adherence and HDs for cancer patients warrants further investigation. These results suggest that increasing patients’ level of comorbidity medication adherence may be an avenue for improving the number of healthy days they experience.
Dihydropyrimidine dehydrogenase (DPD) evaluation in 5-fluorouracil (5FU)-based therapies for gastrointestinal (GIC) and breast cancer (BC) patients (pts)
Authors: P. Marchetti, I. Paris, G. Antonini Cappellini, A. Romiti, P. Malaguti, A. Viterbo, A. De Blasi, A. M. Lostia, L. Lionetto, M. Simmaco
Journal: Journal of Clinical Oncology (2008)

13535 Background: DPD plays a key role in the metabolism of 5FU and pts with deficiency of DPD suffer from severe toxicity. We developed a specific LC-MS/MS method to measure the DPD enzymatic activity in PBMC from pts treated with 5FU, as prescreening method. We measured the rate of 5FU degradation in PBMC. Materials and Methods: 10 μg/l of 5FU was added to PBMC and incubated at 37°C up to 2.0h. Concentration of 5FU was measured by a LC-MS/MS system and results were expressed as pg/min/106 cells of degraded 5FU. Blood samples were obtained from consecutive pts with GIC and BC treated with 5FU-based schedules. Toxicities were assessed according to NCI CTC 3. Results: 59 pts included, median age of 69y (40–84), M/F 37/22 (62.7/37.3%); neoplasms were colorectal/pancreatic-biliary/gastric/oesophageal/breast 44/9/4/1/1 (74.6/15.2/6.8/1.7/1.7%). 5FU based therapies: chemotherapy (CT) alone as adjuvant in 22/59 pts (37.3%), I line and ≥ II line in 22 and 4 pts (37.3 and 6.8%), 59.3% were polyCT; CTRT in 11/59 pts (18.6%). The DPD values were divided into 4 groups: values ≤0.68, ≥0.68 <1.12, ≥1.12 <1.36 identified a severe (SD), mild (MD), minimal (MIND) deficiency, respectively; values ≥1.36 identified a normal activity (N). None patient had SD of DPD. MD/MIND was shown in 5/8/43 pts (8.5/13.6/72.9%) with a median value of 0.9 (SD ± 0.11, 0.75–1.02)/1.27 (SD ± 0.05, 1.20–1.34)/4.40 (SD ± 2.36, 1.38–13.72), respectively. In the MD group, Haematological, Diarrhoea, Vomiting, Mucositis, Neurotoxicity G0–2/G3 toxicities were showed in 80/20, 60/40, 100/0, 80/20 and 20% of pts, respectively; in MIND group maximum toxicities were all G1 and, in the N group, G3–4 toxicities were Haematological/Diarrhoea/Vomiting/Mucositis/Neurotoxicity/Acute Renal Failure (ARF) in 11/9/4.7/4.7/7/2% of pts, respectively. ARF and G4 haematological toxicities were reported in 2 pts with high values of DPD (13.72 and 7.45). Conclusions: pts with normal-high DPD has been shown to be at risk of developing mild toxicity by 5FU; the analysis showed a trend toward greater toxicity in those pts with normal values of DPD than those with lower values. Higher toxicities rates have been shown in pts with very high levels of DPD. Recruitment is still ongoing. No significant financial relationships to disclose.
Gemcitabine (gem) as salvage therapy in metastatic colorectal adenocarcinoma (mCRC).
Authors: A. Cercek, M. Gollub, L. Saltz
Journal: Journal of Clinical Oncology (2011)

e14135 Background: When unresectable mCRC becomes refractory to standard therapies, physicians will at times resort to non-standard palliative therapies such as gem plus a fluoropyrimidine. The activity of gem in this setting, however, has not been well established. The limited data available are largely from abstracts that were not followed up by manuscripts, and are thus of limited utlility. Methods: After obtaining an IRB waiver of authorization we searched our institutional database to retrospectively identify all mCRC patients at MSKCC who received gem in combination with either capecitabine or intravenous 5FU after progression on all standard therapies from 1/1999 through the present. We reviewed the patients' (pts) medical records including pathology reports, progress notes, imaging studies and radiology reports to assess for suggestion of partial response (PR), stable disease (SD) and progression (POD) on gem-based chemotherapy. In all cases in which tumors were felt to have been stable or responding, actual CT scans were reviewed and formal response criteria (RECIST 1.1) were applied. Results: A total of 98 patients (pts) were identified. Two patients were determined to be uninterpretable due to inadequate scanning to permit assessment, and so were removed from the analysis. A total of 96 pts (42 females and 54 males) were evaluated. The median age was 62 (range 25-80). All pts had progressed by report on all standard therapies. No PRs were seen on gem-based therapy (0/96, 0%). A total of 9 pts (9%) experienced SD for ≥ 4 months. Overall, 82% of pts had overt tumor progression at the time of first on-treatment scan. Interestingly, one additional pt (not included in this analysis) with metastatic goblet cell carcinoid/adenocarcinoma of the appendix was found to have an unconfirmed PR. Conclusions: In this retrospective analysis, the antitumor activity of gem in combination with capecitabine or intravenous 5FU in chemotherapy-refractory mCRC was extremely limited. Our findings are consistent with the non-endorsement of gem-based chemotherapy in NCCN colorectal guidelines.