tbuckley/cabot-search huggingface dataset:
Preliminary pharmacokinetics of CT-2106 (polyglutamate camptothecin) in patients with advanced malignancies
Authors: M. V. McNamara, J. H. Doroshow, J. Dupont, D. Spriggs, E. Eastham, S. Pezzulli, S. Syed, A. Bernareggi, C. Takimoto
Journal: Journal of Clinical Oncology (2004)

2073 Background: CT-2106 is a novel camptothecin (CPT) conjugate in which CPT is bound to a biodegradable water soluble poly-L-glutamic acid-glycine polymer. Conjugation of CPT to the polymer allows for greater stability in circulation, increased potential for exclusion from normal tissue, and enhanced permeability and retention in tumor tissue. CT-2106 has demonstrated significant anti-tumor activity in multiple human tumor cell lines in vivo, including lung and colon cancers. This study was designed to determine the pharmacokinetics of CT-2106 in patients with advanced malignancies. Methods: Patients were treated with CT-2106 as a 10 minute intravenous infusion every 21 days. Blood and urine samples were collected during treatment cycles 1 and 2. Samples were analyzed for conjugated and unconjugated CPT with validated HPLC/FD methods. Noncompartmental PK analysis of plasma concentration-time data was made by WinNonLin (Ver. 4.01). Results: Twenty-four patients have been treated. Conjugated CPT doses were 12 mg/m2 (3 patients), 25 mg/m2 (7), 50 mg/m2 (3), 75 mg/m2 (8), and 105 mg/m2 (3). Data is currently available from blood and urine samples from 17 patients (mean age 62.8, range 46–77). Plasma Cmax and AUC values for conjugated and unconjugated CPT indicate CT-2106 PK linearity from 12 to 75 mg/m2. The apparent termination t1/2 of unconjugated CPT is quite long -approximately 40 hours. Five days after the first administration (cycle 1), the excretion in urine of CT-2106 and unconjugated CPT accounted for 27.9% and 5.1% of the administered dose, respectively. The excretion pattern did not change during cycle 2. A major CPT conjugated species found in urine was glu-gly-CPT. Dose-limiting toxicities include: grade 3/4 neutropenia with concomitant grade 3 thrombocytopenia in 3 patients (105 mg/m2); grade 2 hematuria in 1 patient (25 mg/m2). Most adverse events have been mild or moderate. Conclusions: CT-2106 generates prolonged systemic exposures to unconjugated CPT in plasma; also, urine excretion levels of conjugated camptothecin are substantial. This study is ongoing to determine the MTD and collect further pharmacokinetc data. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics, Inc.
Abstract P272: Physiological and Pathological Functions of Nox2 and Nox4 in Ischemia/Reperfusion Injury
Authors: Shouji Matsushima, Junya Kuroda, Tetsuro Ago, Peiyong Zhai, Junichi Sadoshima
Journal: Circulation Research (2011)

NADPH oxidases (Noxes) represent an enzyme system whose primary function is to produce reactive oxygen species (ROS). Both Nox2 and Nox4 play an important role in regulating oxidative stress and growth/death of cardiomyocytes (CMs). However, the role of Nox2 and Nox4 during ischemia/reperfusion (I/R) is poorly understood. In order to elucidate the function of the Nox isoforms, wild type (WT), Nox2 KO (Nox2-/-), and cardiac specific Nox4 KO (cNox4-/-) mice were subjected to 30 minutes ischemia followed by 24 hours reperfusion. Myocardial infarction size/area at risk (MI/AAR) as evaluated by TTC staining was significantly smaller in Nox2-/- and cNox4 -/- than in WT mice (32 ± 3.1% and 28.0 ± 6.1% vs. 40.3 ± 8.3%, p &lt; 0.05). O 2 - production in Nox2 -/- and cNox4 -/- hearts was significantly lower than in WT hearts, as evaluated with the lucigenin-chemiluminescence assay (433 ± 52, 580 ± 106 vs. 1250 ± 236 RLU, p &lt; 0.05). The I/R experiment was also conducted with mice in which both Nox2 and Nox4 are deleted (double KO mice). O 2 - production in the double KO heart was significantly lower than in the single KO ones (257 ± 42 RLU, p &lt; 0.05). The MI/AAR in double KO mice was, however, significantly greater than that in WT mice (58.0 ± 6.3% vs. 40.3 ± 8.3%, p &lt; 0.05). These results raised the possibility that marked suppression of ROS by combined downregulation of Nox2 and Nox4 exacerbates I/R injury. To elucidate the underlying mechanism, we examined expression of hypoxia inducible factor-1alpha (HIF-1 α ), using DN-Nox transgenic (Tg) mice, which we have shown also exhibited marked suppression of O 2 - and significantly greater MI/AAR after I/R. HIF-1 α is lower in DN-Nox Tg mice than in WT mice in both the ischemic and non-ischemic areas. A genetic cross between DN-Nox Tg and mice lacking prolyl hydroxylase 2, an enzyme mediating hydroxylation and downregulation of HIF-1 α , partially rescued I/R injury in DN-Nox mice (35.8 ± 5.9% vs 65.2 ± 10.3%, p&lt;0.05). Taken together, these data show that both Nox2 and Nox4 mediate increases in oxidative stress and myocardial injury in response to I/R. However, combined downregulation of Nox2 and Nox4 induces marked downregulation of ROS, which in turn exacerbates I/R injury possibly through downregulation of HIF-1α and consequent impairment of hypoxic adaptation.
A randomized phase II study of carboplatin/gemcitabine (CG) versus vinorelbine/gemcitabine (VG) in patients with advanced non-small cell lung cancer (NSCLC); mature results of West Japan Thoracic Oncology Group (WJTOG) 0104
Authors: T. Kashii, N. Yamamoto, Y. Takada, S. Negoro, K. Matsui, Y. Horio, M. Takada, Y. Nakanishi, T. Kato, M. Fukuoka
Journal: Journal of Clinical Oncology (2004)

7124 Background: Non-platinum regimen may improve efficacy with less toxicity than platinum-based combination. Newer platinum regimen, CG has shown activity in advanced NSCLC and a better toxicity profile than cisplatin/gemcitabine. A randomized phase II study was performed between 06/01 and 10/02 to compare the efficacy and safety of non-platinum regimen (VG) with newer platinum regimen (CG). Method: 128 chemotherapy-naive patients with stage IIIB/IV were enrolled in the study and randomized to vinorelbine 25 mg/m2 and gemcitabine 1000 mg/m2 both given on d1, 8, q3w or carboplatin at AUC 5 on d1 and gemcitabine 1000 mg/m2 on d1, 8, q3w. All patients had measurable disease, ECOG PS 0–1, and adequate organ function. The primary endpoint was 1-year survival and secondary were response rate, toxicity profile, and overall survival. Results: The median treatment cycles were 3 and 4 in CG and VG, respectively. The Median survival time and 1-year survival rate were 494 days and 64.4% for CG arm (42 patients censored) and 319 days and 47.8% for VG arm (41 patients censored), respectively (P=0.073). The median progression free survival was 208 days in CG (23 patients censored) and 160 days in VG (19 patients censored; P=0.06). Overall response rates were 20% in CG and 21% in VG. Hematologic toxicities were more common in CG arm; Grade 3/4 neutropenia, anemia, thrombocytopenia occurred in 79.7%, 50% and 81.3% CG, and 62.5%, 4.7% and 6.3% VG. Non-hematologic toxicities were moderate; Grade 2/3 liver dysfunctions, Grade 2 phlebitis and Grade 2/3 nausea occurred in 25%, 0% and 42.2% CG, and 42.2%, 29.7% and 20.3% VG, respectively. About 50% of CG patients required dose-reduction after the 1st cycle of chemotherapy due to the toxicity. Conclusion: CG combination chemotherapy showed a tendency towards more prolonged survival than VG, although there was no significant difference in response rate. A follow up results of the study will be presented at the meeting. No significant financial relationships to disclose.
Paclitaxel-induced severe sensory peripheral neuropathy is associated with NDRG-1 genetic variant and negative NDRG-1 expression in nerve tissue.
Authors: Raghav Sundar, Anand Jeyasekharan, Kar Tong Tan, Thomas Choudary Putti, Lay Mui Poh, Huiling Yap, Nur Sabrina Binte Sapari, Richie Chuan Teck Soong, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2014)

1054 Background: N-myc downstream regulated gene (NDRG)-1 has been implicated in Charcot Marie Tooth disease, a peripheral nerve hereditary disorder and in the development and maintenance of the myelin sheath. We hypothesize that NDRG-1 may be implicated in paclitaxel-induced peripheral neuropathy. Methods: Breast cancer patients who received adjuvant weekly paclitaxel were genotyped for 10 single nucleotide polymorphisms (SNPs) in 9 genes, including rs2233335 in NDRG-1 using MassArray (Sequenom) technology. Immunohistochemical (IHC) staining of NDRG-1 was performed on normal nerve tissue in archival lumpectomy/mastectomy specimens. Clinical data including paclitaxel dose intensity and density, onset and severity of neuropathy was correlated with genetic and IHC data. Results: Of the 122 patients that were evaluated, 67% were Chinese, median age was 51 (26 – 79) years and 9% had diabetes. Mean total paclitaxel dose administered was 924 (240 – 960) mg/m2. Median duration of treatment was 12 (3 – 18) weeks, with 36% completing full dose intensity (960mg/m2 in 12 weeks). 57.4% developed all grade neuropathy, with 20.5% having ≥grade 2 severity. Severe neuropathy, defined as those requiring dose delay, dose reduction or early termination of chemotherapy, occurred in 9.8%. Expectedly, presence of diabetes correlated with severe neuropathy (36% vs 7%; p=0.01). Of the 10 SNPs evaluated, NDRG-1 (rs2233335) CC/CA genotype was significantly associated with severe neuropathy compared to the AA genotype (28% vs 7%, p=0.016). Of note, patients with the CC/CA genotype and who were younger than 50 years of age had a higher incidence of ≥grade 2 (80% vs 14%, p=0.005) and severe neuropathy (80% vs 6%, p=0.001) than those with the AA genotype. Patients with severe neuropathy were more likely to stain negative for NDRG-1 in nerve tissues compared to those who had no neuropathy (80% vs 0%, p=0.047). Conclusions: Absence of NDRG-1 expression on nerve tissue and NDRG-1 rs2233335 SNP is associated with paclitaxel-induced severe neuropathy, and may guide selection of patients who should avoid paclitaxel. Correlation of NDRG-1 SNP with expression and functionality requires further study.
Carcinoid Syndrome Impact Survey: Evaluation of the burden of illness and the gap between patient and oncologist perceptions.
Authors: Grace Goldstein, Kathleen Evans, Arpan Shah, Pablo Lapuerta
Journal: Journal of Clinical Oncology (2017)

151 Background: Patients with advanced neuroendocrine tumors (NETs) may develop carcinoid syndrome, a rare condition characterized by debilitating symptoms including diarrhea, flushing and valvular heart damage that can greatly affect patient social and physical functioning. Limited information is available on the physician perceptions of carcinoid syndrome and areas that differ from patients. The Carcinoid Syndrome Impact Survey probed potential gaps in oncologist, patient and caregiver perception and the overall burden of the disease. Methods: The survey designed in collaboration with patient advocacy groups was conducted (June-October 2016) among 538 patients with carcinoid syndrome, 94 caregivers, and 151 oncologists. The online, anonymous survey consisted of demographic and disease-related questions including symptom frequency, and impact to daily living of carcinoid syndrome. Each group of respondents was given mirrored questions whenever possible to allow for comparison across groups. Questions were based primarily on a 4-level Likert scale. Results: Differences in perception of symptom frequency, syndrome severity and impact of carcinoid syndrome on daily living were observed between patients, caregivers, and oncologists. Patients and caregivers were more likely to report symptom frequency as &gt; 21 days a month (39% caregivers vs 38% patients vs 4% oncologists). Most oncologists cited symptom frequency as 1-7 days a month (50% of oncologists). Patients were more likely to report carcinoid syndrome affecting them ‘a great deal’ (62% patients vs 23% oncologists). Caregivers were most likely to report the highest category of severity compared to patients and physicians (39% caregivers vs, 25% patients vs 17% oncologists). Conclusions: Oncologists may not be fully aware of the impact of carcinoid syndrome on patient daily living. Furthermore, caregivers may perceive aspects of disease burden to which patients have habituated and may not report as frequently. Tools to encourage more explicit dialogue between patients with carcinoid syndrome and oncologists are needed to narrow the information gap and subsequently improve treatment outcomes.
An evaluation of the breast cancer Well Follow-up Care Initiative using administrative databases: A new model of analysis.
Authors: Nicole Mittmann, Craig Earle, Hasmik Beglaryan, Ning Liu, Julie Gilbert, Farah Rahman, Soo Jin Seung, Dominique LeBlanc, Stefanie De Rossi, Jacqueline Liberty, Victoria Zwicker, Jonathan Sussman
Journal: Journal of Clinical Oncology (2017)

1 Background: Cancer Care Ontario (CCO) implemented the Well Follow-up Care Initiative (WFCI) to transition low-risk breast cancer (BC) survivors from oncologist to primary care providers. The objective of this work was to compare both the health system resources utilized and their associated costs, among women in the WFCI (cases) and women who were not transitioned (controls). Methods: Cases were linked to provincial administrative databases and matched to a control group based on year of diagnosis, cancer stage, age, comorbidity, income, geographic area of residence, and prior health system use. Health system resource utilization (physician, hospitalization, diagnostics, medication, and homecare) was ascertained per group. The annual mean and median costs (CAD 2014) per patient were determined. Annualized incremental costs between cases and controls were estimated using generalized estimating equations, accounting for matched pairs. Results: Results are based on 2,324 cases and 2,324 controls (mean age 64.4 and 64.9 years, respectively). During an average of 2.5 years of follow-up since the transition date, there were significant differences between the two groups for mean annual visits per patient with a medical oncologist (0.4 vs. 1.3, p&lt;0.001) and radiation oncologist (0.2 vs. 0.4, p&lt;0.001). There was no significant difference in mean annual family physician visits per patient (7.4 vs. 7.9, p=0.082). The intervention group had fewer inpatient hospitalizations (75.6% vs. 79.9%) and cancer clinic visits (84.9% vs. 94.0%). While there was a higher number of mammograms for cases compared to controls, other diagnostic tests (bone scan, CT, MRI, ultrasound, and x-rays) were done less frequently. The model was associated with a 39.3% reduction in mean annual costs ($6,575 among cases and $10,832 among controls) and a 22.1% reduction in median annual costs ($2,261 among cases and $2,903 among controls). Conclusions: Transitioning BC survivors to primary care was associated with fewer health system resources and had a lower annual mean cost per patient than women who were not transitioned.
Antiemetic efficacy of transcutaneous electrical nerve stimulation (TENS) at pericardium 6 acupuncture point (P6) in the treatment of chemotherapy-induced delayed nausea and vomiting (CINV) in stage I to III breast cancer patients during adjuvant/neoadjuvant chemotherapy (Ad/nAd).
Authors: Jean Yared, Melody Hu, Ting Bao, Saranya Chumsri, Emily Catherine Bellavance, Susan Kesmodel, Steven J. Feigenberg, Nancy Tait, Katherine Hanna Tkaczuk
Journal: Journal of Clinical Oncology (2013)

TPS648 Background: CINV remain major adverse effects of highly emetic chemotherapy for breast cancer patients (BC). Patients (PT) rate nausea &amp; vomiting as the most feared chemotherapy-related symptoms. There is substantial evidence that P6 (located in the region in the middle of the wrist 3 finger breaths from the juncture of the hand &amp; wrist) acupuncture is an effective antiemetic treatment in a variety of PT including the post-anesthesia, obstetrical, and motion sickness PT. We hypothesized that application of TENS at P6 point will reduce:1) the overall incidence of CINV episodes in stage 1-3 BC PT, 2) the severity &amp; duration of CINV, 3) the requirement for rescue antiemetics 4) &amp; that TENS is well tolerated &amp; feasible. Maxima III Transcutaneous Electrical Nerve Stimulation unit is utilized in this study &amp; is self-administered by PT. Patients and Methods: We are conducting a prospective, randomized, double-blinded, controlled trial to determine if self-stimulating P6 may decrease the incidence and severity of delayed CINV in stage 1-3 BC treated with the initial dose of highly emetic Ad/nAd (AC, AC-T, TAC, TC, TCH) and reduce PT' need for rescue oral antiemetic medications. PT will be randomized in a 1:1 ratio to the active treatment group (TENS self-stimulation at P6) &amp; the control group (TENS self-stimulation at a point on the lateral side of the elbow that does not conform to any known acupuncture points). The assignments are blinded to the PT &amp; the investigators. Subjects self-administer TENS at home q4 hours for 20 minutes during days 2-5 postchemotherapy. The use of conventional antiemetic therapy (corticosteroids, setrons, aprepitant, phenergan &amp; prochlorperazine) is similar for both treatment groups. The severity of nausea symptoms, episodes of emesis, use of rescue antiemetics, and compliance are recorded daily by the PT in diaries. A brief questionnaire is also administered to evaluate PT tolerability of TENS &amp; their ability to comply with the treatment regimen. Twenty six out of 70 planned PT have been enrolled. Recruitment is ongoing.
Off-label immunotherapy prescription: Financial implications for payers and patients.
Authors: Jonas A. De Souza, Yen Yvonne Duong
Journal: Journal of Clinical Oncology (2017)

6 Background: Pembrolizumab (PEM) and nivolumab (NIV) are FDA-approved immunotherapy agents for specific indications. These drugs are extremely costly to the health care system, payers, and ultimately, patients, and little is known about their utilization for non-FDA labeled indications (off-label). Methods: We reviewed claims for PEM and NIV using the focalPoint database by onPoint oncology, which provides access to clearinghouse data for 168 community oncology practices and 2000+ providers throughout the US. Clearinghouse data is unique as it links claims data with remittance (payer response) data. ICD codes representing malignancies other than head and neck cancer, melanoma, non-small cell lung cancer ,and claims for 3 indications prior to their FDA-approval were considered off-label. Primary insurance for the patients, as well as patients’ financial responsibility and amounts paid by the insurance were evaluated. Results: A total of 1,570 patients received PEM or NIV from January 1st 2015 to September 1st 2016 for a cumulative total of 7,687 distinct claims. Of these patients, 285 (18%) received these agents for off-label indications for a total of 978 distinct claims. The total cost for the insurance for off-label claims was $13.36 million with the following breakdown: $7.74 million for 111 patients with commercial insurance, $125 thousand for 5 patients with Medicaid, $3.85 million for 126 patients with Original Medicare, and $1.90 million for 43 patients with Medicare Advantage. The patient responsibility for the off-label immunotherapy agents, which included the co-insurance and co-pay, totaled to $1.06 million or $3,731 per patient. Patient responsibility for off-label therapy per payer was as follows: $657 per patient for commercial insurance, $0 for Medicaid, $7,436 for Original Medicare, and $1,248 for Medicare Advantage. Conclusions: A substantial number of patients received unsupported off-label immunotherapy treatment. The costs of these therapies to the health care system, payers, and patients warrant increased efforts to regulate their use in off-label settings lacking sufficient scientific evidence or while clinical trials are in progress.
Cognitive functioning before chemotherapy treatment in women with breast cancer
Authors: F. A. Tager, P. S. McKinley
Journal: Journal of Clinical Oncology (2004)

548 Background: Many women with breast cancer (BC) undergoing chemotherapy report trouble with attention, concentration and memory. A small body of research suggests that attention, processing speed,and memory tend to be the areas most affected. However,most of the studies have looked at women only after treatment,with no pre-treatment assessment. As part of a longitudinal study, we report here pre-chemotherapy assessments of postmenopausal BC patients. Methods: Thirty-two pre-chemo BC patients (DCIS, Stage I and Stage II) were assessed with a battery of neuro-psychological tests and self-report forms measuring: intelligence, memory, attention, language, visuo-spatial and motor functioning, and mood. Results: Thirteen (40%) women were rated as cognitively impaired based on scoring >1 standard deviation below the mean on two or more tests. When we compared this group to the non-impaired patients, significant differences were seen on a number of tests assessing visual-motor function (Pegboard {P=.001 and .004}, Trailmaking A and B {P=.031, 006},Digit Symbol (P=.015) and Rey {P=.038}), visual memory (BVRT; P=.002)and visual attention(Conner's Continuous Performance Test {Commissions, P=.010; Detectability,P=.022}) independent of age, ethnicity, educational level, and stage of cancer. Conclusions: The results of this study indicate that a significant number of postmenopausal women with BC exhibit objective cognitive deficits pre-treatment in many of the same areas as seen in women after chemotherapy. Thus, to truly understand the cognitive effects of chemotherapy it is necessary to measure pre-treatment functioning in this population to compare with post-treatment changes. In addition,these results may suggest that women with cognitive deficits before chemotherapy may be more vulnerable to the possible effects of chemotherapy and thus be more prone to notice more pronounced changes in their cognitive abilities. No significant financial relationships to disclose.