tbuckley/cabot-search huggingface dataset:
The relationship between pemetrexed exposure (AUC) and clinical outcome in Japanese NSCLC patients
Authors: S. Adachi, T. Tamura, K. Nakagawa, C. Falcoz, L. Musib, H. Calvert
Journal: Journal of Clinical Oncology (2007)

18041 Background: The efficacy of pemetrexed (PEM) 500 mg/m 2 administered with vitamin B 12 and folic acid (FS) has been established in previously treated NSCLC. The 500 mg/m 2 dose is based on the MTD determined for PEM without FS. Recently completed phase I studies have shown the recommended dose of PEM single agent with FS to be 900–1,000 mg/m 2 . A randomized phase II study conducted in Japan (ASCO 2007) showed PEM 500 mg/m 2 and 1,000 mg/m 2 with FS to have similar efficacy for patients with 2 nd and 3 rd line NSCLC. PEM is renally excreted and a PK model characterizing the relationship between CrCL and PEM AUC has been previously established. The exposure response relationships (ERRs) between AUC and progression free survival (PFS), individual patient’ tumor response, and toxicity were explored in these analyses. Methods: Eligible patients had a histologic or cytologic diagnosis of NSCLC, had been previously treated by 1 or 2 chemotherapy regimens, and were randomized to 500 mg/m 2 (N = 108 pts) or 1,000 mg/m 2 (N = 108 pts) of PEM once every 3 weeks. A previously established PK model was used to estimate AUC based on patient CrCL and dose administered. AUCs were linked to clinical outcome to identify ERRs. Efficacy models assumed a distribution of events with hazard dependent on prognostic factors and mean AUC at cycle over the treatment period. The AE model assumed probability of toxicity as a function of AUC at each cycle. Results: Median CrCL for patients in 500 mg/m 2 and 1,000 mg/m 2 groups were 85 ml/min (42–167) and 83 ml/min (38–146), respectively; median estimated PEM AUCs were 158 mg.h/L (107–221) and 318 mg.h/L (215–468). The relationship between model-estimated AUC and PFS was not significant. This is consistent with the clinical findings: PFS for the 500 mg/m 2 and 1,000 mg/m 2 groups of 3.0 months and 2.4 months, respectively; overall response rate (RR) of 18.5% and 14.8%, respectively. ERR analyses for individual patient tumor response, neutropenia and thrombocytopenia are ongoing at this time. Conclusions: Estimated PEM AUCs, based on CrCL, does not correlate with PFS for pretreated NSCLC at 500 mg/m 2 and 1,000 mg/m 2 . The ERRs for individual tumor response and toxicity are ongoing and will be presented at the meeting. No significant financial relationships to disclose.
Association of pharmacokinetics and germ-line mutations in EGFR and ABC transporters with erlotinib toxicity in patients with non-small cell lung cancer (NSCLC)
Authors: A. Hamada, J. Sasaki, S. Saeki, N. Iwamoto, M. Inaba, S. Ushijima, M. Urata, H. Kishi, S. Fujii, H. Semba, H. Saito
Journal: Journal of Clinical Oncology (2009)

2506 Background: Erlotinib demonstrates substantial inter-individual differences in response and the development of skin rash (grade≥2) was correlated with efficacy. Erlotinib interacts with its target EGFR and the efflux transporter ABCB1 and ABCG2. EGFR CA repeat is associated with incidence of skin rash. A 421C&gt;A SNP in ABCG2 and 1236C&gt;T, 2677 G&gt;(T/A), and 3435C&gt;T SNPs in ABCB1 are associated with reduced protein expression. The aim of this study was to evaluate the effects of these variants and pharmacokinetics of erlotinib on toxicity grade in Japanese patients treating single agent erlotinib. Methods: Twenty-two patients with NSCLC received erlotinib orally at 150 mg/day and plasma levels of erlotinib were measured on days 1(D1), 8(D8), and stable phase (&gt;day 14) by high-performance liquid chromatography. DNA from plasma was screened for SNPs in the EGFR, ABCB1, and ABCG2 genes using direct nucleotide sequencing or TaqMan assay. Eligibility criteria included: performance status (PS) &lt; 3, age &lt; 75, stage IIIB-IV, and written informed consent. Results: The mean Cmax (±SD) of D1 and D8 were 1.8 ± 1.0 and 3.1 ± 1.4 μg/ml, respectively. Trough concentration (Cmin) at D1 and steady state were 0.9 and 1.7 μg/ml, respectively. Grade 1–2 skin rash or diarrhea occurred in 95% of patients. One patient (Cmax at D1, 3.0 μg/ml) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The area under curves and Cmax on D1 were correlated with the severity of skin rash (p=0.05 and 0.01), however, Cmin were not correlated. Patients with homozygous variant and heterozygous for ABCB1 1236C&gt;T, 2677 G&gt;(T/A), and 3435C&gt;T genotype as compared to patients carrying the wild-type were associated with higher Cmin at steady state (2.4 vs 1.2 μg/ml, p=0.01). EGFR CA repeat and AGCG2 421C&gt;A genotype were not associated with any pharmacokinetic parameters. All Patients (n=4) with homozygous variant for ABCB1 1236TT- 2677TT/TA/AA-3435TT developed grade≥2 skin rash or diarrhea. Conclusions: The present study suggests that ABCB1 gene polymorphism is associated with the variable toxicity and pharmacokinetics to erlotinib treatment. No significant financial relationships to disclose.
Gene expression signature of circulating tumor cells (CTC) in patients with colorectal carcinoma (CRC)
Authors: S. Madajewicz, T. Fan, W. Zeng, M. Zarrabi, S. Zucker, Q. Zhao, J. Lu, M. Seibel, W. Chen
Journal: Journal of Clinical Oncology (2008)

15061 Background: Accurate CTC detection may potentially serve as a diagnostic, prognostic and therapeutic cancer marker. Currently, CTC are identified using epithelial markers but some of these markers are also present in circulating hematopoetic cells of healthy individuals and down-regulated in CTC. The objective of this study is to define a CTC gene expression signature that exhibits high detection specificity and sensitivity for CRC patients. Methods: In a prospective two-center study, blood samples were collected from 12 CRC patients (4 stage II, 8 stage IV), 2 stage IV esophageal cancer (EC) patients, 7 breast cancer (BC) patients (1 stage I, 1 stage II, 3 stage III, 2 stage IV) and 6 healthy donors. A viable cell isolation system that utilizes the invasiveness of tumor cells to a cell adhesion matrix was used to enrich CTC. The enriched samples were examined for gene expression profiling (GEP) using the Affymetrix microarray Hu133A chip. Using GEP bioinformatics, 1874 genes differentially expressed (>3.5 fold, p<0.05) between 8 stage IV CRC patients and 6 healthy donors were selected to construct a CTC gene signature that consisted of 39 hematopoetic cell lineage and CRC genes. Results: CTC scores were established as the % of genes in each cell sample matching the signature. Using scores <40 as a cutoff for normal cells, the signature positively detected CTC in all stage IV CRC patients (scores 90–100; 100% sensitivity) and 2 out of 4 stage II CRC patients (scores 85–92: 50% sensitivity), but not in any healthy subjects (scores 0–3; 100% specificity). Using scores >80 as positive for CRC cells, negative CRC CTC scores (46–78) were detected in all 9 EC/BC patients suggestive of the signature‘s specificty for advanced CRC patients. Conclusions: We have identified a potentially specific CRC CTC signature. Further research is needed to confirm its diagnostic value, and the role as a prognostic and therapeutic marker. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Vitatex Inc. Vitatex Inc. Vitatex Inc. Vitatex Inc.
Phase I study to assess pharmacokinetics (PK), QT/QTc effect, and safety of amrubicin in patients (pts) with advanced solid tumors.
Authors: N. Chen, S. P. Chawla, E. G. Chiorean, W. L. Read, M. Gorbaty, A. C. Mita, L. Yung, R. McNally, M. F. Renschler, S. Sharma
Journal: Journal of Clinical Oncology (2011)

7073 Background: Amrubicin (AMR), a 3rd-generation synthetic anthracycline has shown promising activity in solid tumors, including small cell lung cancer (SCLC) without cardiotoxicity. This intensive PK and safety study also investigated the effect of AMR on QT interval. Methods: Pts with solid tumors and an ECOG PS score ≤ 1 were eligible. AMR 40 mg/m2 IV was given on days 1–3 of a 21-day cycle. Serial blood samples and time-matched triplicate ECG were collected on days 1–9, including an 11 h continuous ECG within 5 days prior to study initiation, and on days 1 and 3 of cycle 1. Urine was also collected for PK analyses. Results: 24 pts with different primary cancers (most common SCLC [5 pts]), median age 55 yrs; 46% male; 71% Caucasian) were enrolled. All received the intended AMR dose. AMR concentrations followed biphasic elimination with an initial 80% reduction within 10 min and a T1/2 of 4 h. The active metabolite of AMR, amrubicinol (AMROL), reached a peak concentration at 2–4 h. Blood AMROL had a terminal half-life of 51 h and an accumulation ratio of 1.7 after 3 doses. The AMROL to AMR molar ratio for AUC24 after 3 doses averaged 0.64. Mean urinary excretion of AMR or AMROL over 24 h was < 8% of the AMR dose. The upper 1-sided 95% CI for the time-matched, baseline-adjusted mean difference in QT interval (QTcF) on days 1 and 3 relative to the off-drug day (ΔΔQTcF) was below 10 ms at 20/21 time points, and was marginally above 10 ms at a single time point (day 1, 10 h). No correlation was observed between blood AMR or AMROL levels and ΔΔQTcF. No patients exceeded the clinically relevant thresholds of 480 ms for absolute QTcF or 60 ms for QTcF increase from the time-matched value on the off-drug day. There were no clinically significant findings in QTcF changes from baseline beyond day 3. The most common Gr 3/4 adverse events were neutropenia (45.8%), leukopenia (37.5%) and thrombocytopenia (37.5%). Gr 3/4 infections occurred in 16.7% of patients. Conclusions: The full AMR PK profile was defined for US patients. Therapeutic doses of AMR did not cause clinically significant prolongation of QTc interval in pts with solid tumors. The safety profile of AMR is consistent with earlier findings in SCLC.
A phase I/II study of docetaxel (D) and concomitant boost radiation (CBR) for patients with squamous cell cancer of the head and neck (SCCHN) following induction chemotherapy (IC)
Authors: R. B. Tishler, R. I. Haddad, C. M. Norris, C. Sullivan, A. Mahadevan, L. Wirth, L. Goguen, A. Nixon, S. Stowell, M. R. Posner
Journal: Journal of Clinical Oncology (2004)

5548 Background: We have previously reported the results of Sequential Therapy (ST) with IC followed by weekly D and concurrent daily XRT (Cancer, 2002). In this Phase I/II trial, we investigated concurrent weekly D and the more dose intensive CBR radiation schedule after IC in patients with locally advanced SCCHN. Methods: All patients (AJCC Stage III -7% or IV -93%) were treated with IC (90% 3 cycles; 10% 1 or 2) using cisplatin/5-FU (PF), carboplatinum-F or DPF. Chemoradiotherapy (CRT) consisted of 4 weekly doses of D @ 20 or 25mg/M2 (15 patients/dose level) concurrently with the first 4 weeks of CBR (1.8 Gy qD X 18, 1.8/1.5 Gy bid X 12). Results: 31 patients were enrolled and 30 are evaluable. Median follow up is 21 months, (range of 6–40). Primary sites were: oropharynx 19, oral cavity 2, larynx/hypopharynx 5, unknown primary 4. 87% of patients had N2/N3 disease, 60% had T3/T4 disease. Only 20% of patients had a CR to IC and 50% had a CR to ST (IC, CRT, and Surgery) with 2 PD and 13 PRs. The 2 patients with PD died at 6 and 9 months. A total of 5 patients progressed (2 local, 1 local + distant, 2 distant) and died; another patient died of long-term toxicity. 19 of 26 patients presenting with neck disease had neck dissections. 7 did not; 5 were CRs, 1 had PD and one was inoperable. 7 of 19 (37%) dissections were positive and of these, two are dead of disease. Overall, 24 patients (80%) are alive, NED. No acute DLT was observed at either dose of D, but additional patients were added at 20 mg/M2 because of concerns regarding duration of PEG dependence at 25 mg/M2 and one patient dying late from respiratory arrest associated with severe fibrosis. Conclusions: This intensive ST regimen with concurrent D/CBR as CRT yields good local-regional control and survival in poor prognosis patients. Short term mucositis and late fibrosis are significant but may be justified by long term survival. Study accrual is complete and results of long term toxicity will be presented with additional follow up. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
First in human phase I study of MK-2461, a small molecule inhibitor of c-Met, for patients with advanced solid tumors
Authors: L. H. Camacho, S. L. Moulder, P. M. LoRusso, G. R. Blumenschein, P. J. Bristow, R. Kurzrock, S. Fu, K. Schlienger, D. A. Bergstrom
Journal: Journal of Clinical Oncology (2008)

14657 Background: MK-2461 is a potent small molecule inhibitor of c-Met, a receptor tyrosine kinase involved in tumor cell proliferation and motility. Over-expression of c-Met or Met gene amplification has been associated with poorer prognosis in several tumor types. Methods: Multicenter, open-label, phase I dose escalation study in patients with advanced solid tumors refractory to standard therapy. Drug was administered by mouth daily or twice daily (BID) for 28 days followed by a 14 day rest period during cycle 1. Patients received continuous dosing subsequently for 28-day cycles. Maximum tolerated dose (MTD) was determined using a standard 3+3 dosing design. PK analyses were performed on days 1 and 28 of cycle 1. Results: Fourteen patients (10 M/ 4 F), mean age 54 (range 19–76), have received 31 cycles (range 1–6). Dose levels tested include 60mg daily, 60mg BID, 120mg BID, and 180 mg BID. Toxicity data are available for 11 patients treated at the 60mg daily-120mg BID dosing cohorts. Ten patients (91%) have not experienced > Grade 1 drug-related toxicity. Dose limiting toxicity has not been reached and no objective antitumor responses have been observed. One patient with mucinous carcinoma of the appendix had stable disease for 6 cycles. Common drug related toxicities are outlined in the table below. Four patients experienced serious adverse experiences that were considered not related to MK-2461. PK analysis revealed a rapid Tmax (1–3 hr) across all dosing cohorts with a terminal half life of 6.3 hr following the final day of dosing for the QD dosing cohort. Conclusions: Twice daily administration of MK-2461 at the doses tested is well tolerated. Terminal t1/2 suggests acceptable drug plasma concentrations expected at BID dosing. Dose escalation continues. Toxicity Grade 1 (%) Grade 2 (%) Anorexia 2(18%) 0 Fatigue 1(9%) 1(9%) Nausea 1(9%) 0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Merck Exelixis, Merck
A cohort study of desired services and barriers to service access among informal caregivers of patients with advanced cancer
Authors: J. M. Ingham, J. Cullen, A. R. Ogdie, P. A. Mangan, K. L. Taylor
Journal: Journal of Clinical Oncology (2004)

8013 Background: Addressing emotional distress and unmet needs in informal caregivers (CGs) of cancer patients (PTs) is crucial to alleviate burden associated with advanced cancer. Multiple CG unmet needs (informational, social, practical, emotional and spiritual) have been reported but the barriers to addressing needs have rarely been explored. This exploratory study identified services that CGs believed would address their needs, and barriers to service receipt. Methods: CGs (N = 46) of out-PTs with advanced cancer completed a distress thermometer (DT; 0=no distress to10=extreme distress) and depression scale(CES-D). CGs identified desired services and potential barriers to service receipt from a list of 17 possible services (e.g., physician and nurse visits, counseling and spiritual services) each linked to a barriers checklist (e.g. finances, transportation, time constraints, privacy, confidence in the service, the PT's desires). Results: The mean age was 56.6 (range31–75) and 21.7% were male. The DT score was >5 in 43.4% and CES-D ≥16 in 37.0% of CGs. Frequently desired services were a “conversation alone with oncologist”(56.5%), “conversation alone with oncology nurse”(47.8%), personal physician for own care (47.8%), counselor/therapist (47.8%) and visiting nurse at home (39.1%). The barriers checklist revealed multiple barriers to service receipt. Lack of confidence in the quality of at least one service was cited by 41.3% of CGs, time constraints by 15% and PT barriers by 15%. No one service was clearly linked with one vs. another barrier. Conclusions: Caregivers are often not considered part of the unit of care but they need access to services for their own personal support and for PT care delivery at home. In this exploratory study, CGs commonly requested preferences for services that are not traditionally offered and for which system-based reimbursement barriers exist. Multiple barriers were identified by CGs and depression itself may be a barrier. This study sought to create awareness of a mismatch between desire for, and availability of CG services and of barriers to service receipt. Larger studies are needed on this topic. No significant financial relationships to disclose.
Nitric oxide inhibits intracellular adhesion molecule-1 expression in rat mesangial cells.
Authors: M Ikeda, U Ikeda, M Takahashi, K Shimada, S Minota, S Kano
Journal: Journal of the American Society of Nephrology (1996)

This study tested whether nitric oxide modulates the expression of intercellular adhesion molecule-1 (ICAM-1) expression in glomerular mesangial cells. In an enzyme-linked immunosorbent assay, interleukin 1 beta (IL-1 beta; 10 ng/mL) increased ICAM-1 molecule expression on cultured rat mesangial cell surface in a time-dependent manner. Addition of the nitric oxide donors 3-morpholino-sydnonimine (SIN-1) or sodium nitroprusside significantly suppressed IL-1 beta-induced ICAM-1 molecule expression in a dose-dependent manner. The inhibitory effect of SIN-1 was abolished in the presence of a nitric oxide scavenger hemoglobin, but not in the presence of superoxide dismutase or pyrrolidine dithiocarbamate. Addition of 8-bromo-cyclic GMP showed no significant effect on IL-1 beta-induced ICAM-1 expression. In Northern blot analysis, the expression of ICAM-1 mRNA was barely detected in unstimulated cells, whereas ICAM-1 gene transcripts were clearly expressed after exposure to IL-1 beta for 3 h, and addition of SIN-1 decreased IL-1 beta-induced ICAM-1 mRNA accumulation. These results suggest that nitric oxide suppresses ICAM-1 expression in IL-1 beta-stimulated mesangial cells, independent of cGMP formation.
Isolated nocturnal hypoxia in sickle cell disease (SCD)? Is it initial feature or separate entity?
Authors: Nadeem Maddekar, Rohit Saha, Bhagyashree Jayaraman, Tullie Yeghen, Tudor P. Toma
Journal: European Respiratory Journal (2011)

Introduction: Hypoxia is detrimental to patients with sickle cell disease (SCD) as it causes polymerisation of sickle haemoglobin. Whilst daytime oxygen saturations in patients with SCD are normal or near normal, overnight oxygen levels are not known and are not routinely assessed in these patients.

Aim: To evaluate and describe the prevalence and characteristics of nocturnal oximetry changes in patients with SCD.

Methods: SCD patients referred by haematology for lung function testing also underwent overnight oximetry. Nocturnal oximetry findings were manually scored and results were correlated with lung function. Nocturnal hypoxia (NH) was defined as 30% total sleep time with SpO2 90%.

Results: Lung function testing showed that one patient had airway obstruction, while the rest had normal spirometry. The average KCO was Mean ± SD 91.63±20.54% predicted. The average daytime saturation in this group was 94.90±2.13%. However, the mean night time oxygen saturation in the group was 91.14±4.32.

NH was evident in 4/10 patients in this group and percentage of sleep time nocturnal desaturation was mean of 83.78±18.02 (SD). NH of < 85% was 7.92±13.10. None of the patients had a 4% oxygen desaturation index 10 events per hour.

Conclusion: Patients with SCD can have a normal gas transfer and a borderline normal daytime oximetry. However, during sleep, SCD patients can have long periods of moderate to severe hypoxia.

Our observation showed NH can be seen in SCD even in the abscence of OSA and COPD.

The pathophysiology of night time hypoxia in SCD and the possible therapeutic potential of night time oxygen for these patients deserve further studies.
Neutrophil dynamics and death in postchemotherapy septic neutropenia
Authors: N. A. Othieno-Abinya, G. W. Kiarie, Y. Mlombe, P. Wanzala
Journal: Journal of Clinical Oncology (2009)

e17579 Background: Mortality rates from septic neutropenia vary between studies, ranging from 7% to 30%. We observed the mortality rate for patients hospitalized for postchemotherapy septic neutropenia was 28.6% in one of our studies. Many deaths appeared to have occurred at the time of neutrophil recovery. We attributed this to immune reconstitution inflammatory syndrome akin to what is seen in HIV/AIDS. Methods: Records of patients who died during hospitalization with septic neutropenia. Results: Twenty one patients, 14 males (67%) and 7 females (33%) were included, age range 14–67 years. Six (28.6%) had World Health Organization (WHO) grade 0 neutropenia at the time of death, none had grade 1, one (4.8%) had grade 2, one (4.8%) grade 3, and 14 (67%) had grade 4. The last absolute neutrophil count (ANC) at death ranged between 0.005 and 6.3 x 109/litre. Ten patients (47.6%) died during neutrophil upswing and 11 (52.4%) during neutrophil decline. Thirteen patients (61.9%) also had grade 4 thrombocytopenia but no death was attributed to bleeding. Five of 18 (27.8%) had WHO grade 3 renal function impairment, and six (33.3%) had grade 2 impairment. The main cause for renal function disturbance was hypotension that was usually sudden and unexplained. There was no correlation between ANC and renal function impairment (p &gt; 0.5). Conclusions: Death from septic neutropenia could not be attributed to neutrophil dynamics and by extension immune reconstitution from this study. Neutropenia grade 4 still stood out as a major predictor of death. Larger prospective studies are required to address this issue. No significant financial relationships to disclose.
Typology of patient-patient assaults detected by videocameras
Authors: M L Crowner, F Stepcic, G Peric, P Czobor
Journal: American Journal of Psychiatry (1994)

Previous studies of inpatient assault have relied on reports by ward staff, data from which are often incomplete. The authors observed patient-patient assaults with videocameras, obtaining previously unavailable data. In this article they report a systematic method for assault description and classification.Assault was defined by behaviors such as hitting, kicking, and choking, with physical contact. Raters reviewed videotapes to make a global judgment of assailant intent to hurt; assault class was based on this judgment. At the same time the raters chose descriptors to better define classes. For external validation, the authors compared classes for resulting injuries, detection by incident reports, and patients' accounts of their motivations.Of 155 assaults detected, 21 were classified as least serious, 57 were in an intermediate group, and 76 were classified as most potentially hurtful. One assault could not be classified. Descriptor variables each made independent significant contributions to assault classification. Almost all assaults detected by incident report or resulting in injuries were in the most serious class. Assailants' claims that they were playing were significantly associated with the least serious class.With videocameras a variety of interactions between patients involving hitting, slapping, etc., were detected and documented. Some events seemed playful, others seemed intended to hurt, and some were of an intermediate type. This basic, descriptive work can lead to advances in the study of assault predictors.