tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) of the angiogenesis inhibitor ABT-510 in healthy subjects
Authors: C. S. Karyekar, R. A. Carr, A. Andre, Q. Wang, I. Facey, K. Marsh, D. Daszkowski, R. Humerickhouse
Journal: Journal of Clinical Oncology (2004)

3080 Background: ABT-510 is a subcutaneously (SC) administered nonapeptide thrombospondin analogue in phase 2 clinical development for treatment of advanced malignancies. In mouse, rat, dog and monkey, t1/2 ranged from 0.2 h (mouse) to 1.3 h (monkey); metabolism was dominated by a single peptide bond cleavage yielding two inactive peptides (including M-1) which were rapidly excreted in bile and urine. Methods: To assess the safety, tolerability and PK of ABT-510, a first-time-in-man, single-escalating-dose, double-blind study was conducted in 43 healthy male subjects (mean±SD 34±12 yrs, 76±8 kg), randomly assigned to receive ABT-510 by SC bolus (10, 50, 75, 100 or 130 mg), SC infusion of 100 mg over 24 h, or 30-minute IV infusion (10, 50 or 100 mg); one subject per group received placebo. Samples for ABT-510 and M-1 assay were collected predose and over 24 h (blood) or 48 h (urine); concentrations were determined using a validated LC/MS/MS method. Results: PK results for SC bolus groups are shown below: ABT-510 PK were dose-proportional both for IV and SC regimens. Following IV dosing, CL, Vd and t1/2 were 35±8 L/h, 44±9 L and 0.9±0.1 h. SC doses were completely bioavailable relative to IV. The SC infusion produced a mean steady-state concentration of 150 ng/mL. M-1 plasma exposure averaged 50% greater than parent drug. About 78% of the dose was recovered as M-1 in urine. ABT-510 was generally well-tolerated, most AEs were mild in severity and resolved quickly. Conclusions: ABT-510 PK were linear in the range studied, interindividual variability was low. SC doses were rapidly absorbed and completely bioavailable relative to IV. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories
Continuous intrathecal chemotherapy with 5-fluoro-2'-deoxyuridine (FdUrd) in treatment of leptomeningeal carcinomatosis
Authors: H. Nakagawa, M. Tamura, Y. Fukushima, S. Majima
Journal: Journal of Clinical Oncology (2004)

1566 Background: Previously, we reported a good clinical treatment effect of intrathecal chemotherapy (ITC) by repeated bolus administration of 5-fluoro-2'-deoxyuridine (FdUrd) for leptomeningeal carcinomatosis (LMC). Moreover, there was no side effects and neurotoxicity detected despite the long-term repetition of intrathecal administration (IT). From these findings, continuous ITC with FdUrd for patients (pts) with LMC was attemted using a simple pump system. We evaluate the usefulness of continuous IT of FdUrd in treatment of LMC. Method: A total of 25 pts were enrolled in this study between January 2000 and April 2003. FdUrd 1.0 mg/day was administered using a balloon pump system. Continuous ITC was continued as long as possible changing the balloon pump containing FdUrd solution once every 7 days. Eight patients received whole brain irradiation (WBI, 3 Gy X 10 times) simultaneously with IT of FdUrd. The effects of the treatment were analyzed in terms of improvement in neurological signs and symptoms, the findings of ventricular and lumbar cerebrospinal fluid (CSF) after 2 and 4 weeks and MR images 2 months after continuous IT of FdUrd was initiated. Survival time was calculated as of August, 31, 2003. Results: No apparent toxicity has been observed to date. Evidence of CSF response was observed in 15 pts. Headache and nausea was improved in all pts and cranial nerve impairment was improved in 12 pts. MR image response was observed in only 2 patients. Overall response was observed in 15 pts when cases of stable disease were excluded from the responding cases. Survival times (mean ±sem days, n) were 251±30, 25. The survival times in pts with and without WBI were 182±37, 8 and 285±39, 17, respectively (p=0.057). Conclusion: This therapy may be useful, especially as a maintenance therapy of LMC, although WBI seems to cause adverse effects. No significant financial relationships to disclose.
Gene set comparison analyses of gene expression signatures for the acquired chemotherapy resistance.
Authors: H. K. Kim, I. J. Choi, C. G. Kim, J. E. Green
Journal: Journal of Clinical Oncology (2010)

10609 Background: A prospective, high-throughput transcriptional profiling study was performed using endoscopic biopsy samples from 22 metastatic gastric cancer patients who had partial response to cisplatin and fluorouracil (CF) combination chemotherapy. An acquired resistance signature was identified by comparing samples collected at progressive disease and pretreatment samples of these responders. Given that the activity of complex regulatory network in stem cells can be best detected by expression analysis of many genes, we performed several gene set comparison analyses comparing our acquired resistance signature with published embryonic stem (ES) cell signatures. Methods: The similarity of the acquired resistance signature to published ES cell signatures was tested using gene set comparison algorithms, which analyzed our acquired resistance signature for differential expression between ES cells and differentiated tissues. For each source dataset, a P value was computed for each gene for the differential expression between pre-defined classes. A summary statistic was computed that summarized these P values over the user-defined gene set; the summary statistic is average log(P) for the LS summary of how the P values differ from a uniform distribution for LS. Results: The acquired resistance gene signature was enriched for genes overexpressed in published ES cell signatures. Our acquired resistance signature was found to be highly enriched for genes over-expressed in at least 5/20 human ES cells profiling studies (LS P value=3.0 × 10-3). Even after the ES cell signature was modified to exclude genes listed in the “proliferation” category of Gene Ontology and the proliferation cluster of breast cancer, the overlap was still statistically significant. Notably, genes overlapping between ES cell signatures and the acquired resistance signature could segregate newly-diagnosed metastatic gastric cancer patients according to progression-free survival (adjusted P value, 0.011). Conclusions: This gene set comparison analysis demonstrates the signficant overlap between the ES cell signature and our drug resistance signatures. No significant financial relationships to disclose.
Antitumor activity of pemetrexed (Pem) in second-line advanced/metastatic osteosarcomas: A multicenter phase II study.
Authors: N. Bin Bui, G. Egerer, S. Ferrari, A. Comandone, A. Cioffi, H. Rassam, A. Michel, S. Ameryckx, S. Weitckus, F. Duffaud
Journal: Journal of Clinical Oncology (2010)

10076 Background: Osteosarcoma (OS) is the most common primary malignant bone tumor in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of OS treatment. The search for new agents in OS is mandatory. Pem is a multitargeted antifolate, with a mode of action similar to methotrexate, coupled with a broader range of action, which provided the rational for this study. Methods: This open-label, single-arm study enrolled patients (pts) with high-grade locally advanced/metastatic osteosarcoma, not amenable to surgery. Eligible pts had one prior chemotherapy regimen for advanced disease, and ECOG performance status 0 to 2. Pem 500 mg/m2 was given over 10 min on day 1 of a 21 day cycle with folic acid and vitamin B12 supplementation until progression. RECIST was used to evaluate response every two cycles. Primary endpoint was response rate (RR). At least five tumor responses over 32 were required to consider further investigations. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS) and safety profile. Results: Between September 07 and March 09 a total of 32 pts were entered, and received at least one cycle of Pem. Their mean age was 42.1 years, baseline ECOG performance status ≤1 in 93.8%, and 2 for one patient (3.1%). 90.6% of pts had metastatic sites in the lung. Median number of administered cycles was 2 [range 1 - 14]. Over 32 pts, one partial response was observed (RR: 3.1% (95% CI [0.1, 16.2])), 15.6% had stable disease. Most common possibly related grade 3/4 treatment-emergent adverse events were (N=32 pts): 9.4% asthenia, 9.4% elevated ALT, 9.4% leukopenia, 6.3% febrile neutropenia, 6.3% neutropenia, and 6.3% anemia. One patient died due to multiorgan failure possibly related to study drug. Conclusions: The response rate of Pem as a second-line treatment in advanced or metastatic osteosarcoma did not meet expectations required by the protocol. Patients are continuing in the follow-up period. PFS and OS will be analyzed at the end of the study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Novartis, PharmaMar Novartis Lilly
Importance of Radiation Oncologist Experience Among Patients With Head-and-Neck Cancer Treated With Intensity-Modulated Radiation Therapy
Authors: Isabel J. Boero, Anthony J. Paravati, Beibei Xu, Ezra E.W. Cohen, Loren K. Mell, Quynh-Thu Le, James D. Murphy
Journal: Journal of Clinical Oncology (2016)

Purpose Over the past decade, intensity-modulated radiation therapy (IMRT) has replaced conventional radiation techniques in the management of head-and-neck cancers (HNCs). We conducted this population-based study to evaluate the influence of radiation oncologist experience on outcomes in patients with HNC treated with IMRT compared with patients with HNC treated with conventional radiation therapy. Methods We identified radiation providers from Medicare claims of 6,212 Medicare beneficiaries with HNC treated between 2000 and 2009. We analyzed the impact of provider volume on all-cause mortality, HNC mortality, and toxicity end points after treatment with either conventional radiation therapy or IMRT. All analyses were performed by using either multivariable Cox proportional hazards or Fine-Gray regression models controlling for potential confounding variables. Results Among patients treated with conventional radiation, we found no significant relationship between provider volume and patient survival or any toxicity end point. Among patients receiving IMRT, those treated by higher-volume radiation oncologists had improved survival compared with those treated by low-volume providers. The risk of all-cause mortality decreased by 21% for every additional five patients treated per provider per year (hazard ratio [HR], 0.79; 95% CI, 0.67 to 0.94). Patients treated with IMRT by higher-volume providers had decreased HNC-specific mortality (subdistribution HR, 0.68; 95% CI, 0.50 to 0.91) and decreased risk of aspiration pneumonia (subdistribution HR, 0.72; 95% CI, 0.52 to 0.99). Conclusion Patients receiving IMRT for HNC had improved outcomes when treated by higher-volume providers. These findings will better inform patients and providers when making decisions about treatment, and emphasize the critical importance of high-quality radiation therapy for optimal treatment of HNC.
Lipid laden alveolar macrophages arise from airway reflux and aspiration
Authors: Yvette Hayman, Simon Hart, Alyn Morice
Journal: European Respiratory Journal (2011)

Introduction:  Lipid laden macrophages have previously been reported to be present in the diseased human airway, secondary to gastro-oesophageal reflux. We investigated the possibility that the lipid index (LI) system of scoring cellular lipid content by oil red o (ORO) staining could correlate with disease status and the Hull Airway Reflux Questionnaire (HARQ). We also investigated the hypothesis that lipid could be ingested directly from gastric contents by alveolar macrophages.   Methods:  Primary alveolar macrophages were obtained from bronchoalveolar lavage (BAL) fluid of patients undergoing diagnostic bronchoscopy. Patients were asked to fill in the HARQ prior to treatment. Lavage fluid was filtered and centrifuged (350xg;10min.) and cells transferred to glass slides using cytospin equipment. Cells were stained with ORO, counterstained with haematoxylin and macrophages scored according to the LI system. Meanwhile THP-1 cells stimulated to differentiate with phorbol myristate acetate (PMA;50μg/ml;24h) were incubated with varying concentrations of a high fat liquid meal and a fat free liquid meal as a control, at 37°C. The high fat meal contained a combination of canola and sunflower oil.   Results:  18 patients with a range of respiratory diseases had LI scores ranging from 4 to 309. LI score correlates (r = 0.86) with the HARQ but not to a particular disease group. PMA stimulated THP-1 cells showed maximal lipid accumulation by ORO staining with 10% v/v high fat liquid meal for 24h. No lipid accumulation was seen with the control feed.   Conclusion:  Macrophages were shown to be capable of lipid uptake directly from liquid meal and airway reflux correlates with the presence of lipid laden macrophages in the airway.
A prospective pharmacogenomic (PG), pharmacodynamic (PD), and pharmacokinetic (PK) study of determinants of erlotinib toxicity
Authors: C. M. Rudin, A. A. Desai, L. Janisch, M. Carducci, T. Karrison, W. Liu, G. F. Fleming, J. Ramirez, F. Innocenti, M. J. Ratain
Journal: Journal of Clinical Oncology (2006)

3080 Background: A strong but unexplained association between skin toxicity (rash) and survival from erlotinib therapy has been noted for patients with several epithelial malignancies. The correlation between rash and clinical benefit appears to extend across classes of epidermal growth factor receptor (EGFR)-targeted agents. Several hypothetical explanations for this association have been suggested including polymorphisms of the EGFR locus as well as PD and PK variability. Methods: We conducted this 80-subject prospective study in patients with lung (N=43), head and neck (N=9), and ovarian cancer (N=28) given erlotinib 150 mg daily to evaluate several of these hypotheses. Patients underwent toxicity monitoring, response assessment, skin biopsies pretreatment and after 28 days for immunohistochemical (IHC) analysis, as well as blood collection for PK analysis and evaluation of EGFR genetic polymorphisms reported to influence EGFR expression level. Results: 72/80 subjects are evaluable for toxicity. Response correlates with both worst grade diarrhea (p=0.003) and rash (p=0.044). Initial PK analysis suggests a positive association between d15 erlotinib trough level and both diarrhea (p=0.091) and rash (p=0.076). Controlling for d15 erlotinib level, EGFR intron 1 CA repeat length is also associated with rash (p=0.030). Polymorphisms in the EGFR promoter (216 G/T and 191 C/A) correlated with diarrhea (p=0.053 and 0.005 respectively) but not rash. IHC analyses including EGFR, p-EGFR, Akt, p-Akt, ERK, and p-ERK have been completed on 35 paired, pre-post treatment skin biopsies and demonstrate no strong correlations with toxicity. Conclusions: These data suggest that both interindividual PK variability and EGFR polymorphisms may contribute to erlotinib toxicity. Erlotinib effects on EGFR signaling in skin do not appear to correlate with toxicity. Samples obtained in this study are available for analysis of other candidate PG determinants of both toxicity and PK variability. [Table: see text]
ErbB1–4 expression in prostate cancer patients and its correlation to patients’ ethnicity and outcome
Authors: R. Ben-Yosef, I. Barnea, D. Sarid, A. Vexler, S. Marmor, A. Starr, Y. Greif, M. Inbar, N. Barak
Journal: Journal of Clinical Oncology (2006)

14615 Background: ErbB family is involved in both cancer progression and treatment response in solid tumors. Few inconclusive studies reported on ErbB over-expression in prostate cancer. We investigated ErbB1–4 expression in prostate cancer patients and its correlation to patients ethnicity and outcome. Methods: ErbB expression was evaluated by immunohistochemistry of prostate cancer specimen using polyclonal antibody (Santa Cruz, CA). The staining was recorded as negative (0/+1), moderately positive (+2) and highly positive (+3). Kattan nomogram was used to predict 5-yr progression-free probability, assuming that all patients received external beam radiation therapy (a total dose of 78 Gy) and hormonal manipulation. Origin was counted in all 43 patients: Ashkenazic patients were defined as those who immigrated from East/West Europe or North America and Sephardic patients - from Middle East and North Africa. Results: ErbB1 (+2/+3) was over-expressed in 12 and 7 patients for a total of 19/43 (44%). ErbB2 over-expression (+2/+3) was not found in all patients. ErbB3 over-expression of +2 was seen in 2 patients and none had +3 (2/43, 5%). ErbB4 over-expression (+2/+3) was seen in 5 and 11 patients for a total of 16/43 (37%). 22 patients were Ashkenazic and 21 - Sephardic. ErbB1 over-expression in Ashkenazic and Sephardic groups was 9/22 (41%) and 10/21 (48%). ErbB4 over-expression in the two groups was 7/22 (32%) and 9/21 (43%). Kattan score of &lt;80 was seen in 20/43 and &lt;60 in 7/43 patients. ErbB1 over-expression was noted in 11/20 and in 4/7 patients. ErbB4 over-expression was seen in 7/20 and in 4/7 patients. In both ErbB1 and ErbB4 over-expression and Kattan nomogram of &lt;80 and &lt;60 the Sephardic ethnicity dominated-7/11 (64%), 3/4 (75%), 5/7 (71%) and 3/4 (75%). Conclusions: ErbB1 and ErbB4 over-expression is presented in 43% and 37% patients while ErbB3 was over-expressed in 5%; no over-expression of ErbB2 was observed. Ashkenazic and Sephardic ethnicity were evenly distributed in the over-expressed ErbB1 and ErbB4 patients. However, a tendency to a worse prognosis, based on Kattan nomogram, was seen in over-expressed ErbB1 and ErbB4 patients from Sephardic ethnicity. Further studies on ethnicity and ErbB prevalence and prognosis are warranted. No significant financial relationships to disclose.
Diastolic Dysfunction Increases the Risk of Primary Graft Dysfunction after Lung Transplant
Authors: Mary K. Porteous, Bonnie Ky, James N. Kirkpatrick, Russell Shinohara, Joshua M. Diamond, Rupal J. Shah, James C. Lee, Jason D. Christie, Steven M. Kawut
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Primary graft dysfunction (PGD) is a significant cause of early morbidity and mortality after lung transplant and is characterized by severe hypoxemia and infiltrates in the allograft. The pathogenesis of PGD involves ischemia-reperfusion injury. However, subclinical increases in pulmonary venous pressure due to left ventricular diastolic dysfunction may contribute by exacerbating capillary leak.To determine whether a higher ratio of early mitral inflow velocity (E) to early diastolic mitral annular velocity (é), indicative of worse left ventricular diastolic function, is associated with a higher risk of PGD.We performed a retrospective cohort study of patients in the Lung Transplant Outcomes Group who underwent bilateral lung transplant at our institution between 2004 and 2014 for interstitial lung disease, chronic obstructive pulmonary disease, or pulmonary arterial hypertension. Transthoracic echocardiograms obtained during evaluation for transplant listing were analyzed for E/é and other measures of diastolic function. PGD was defined as PaO2/FiO2 less than or equal to 200 with allograft infiltrates at 48 or 72 hours after reperfusion. The association between E/é and PGD was assessed with multivariable logistic regression.After adjustment for recipient age, body mass index, mean pulmonary arterial pressure, and pretransplant diagnosis, higher E/é and E/é greater than 8 were associated with an increased risk of PGD (E/é odds ratio, 1.93; 95% confidence interval, 1.02-3.64; P = 0.04; E/é >8 odds ratio, 5.29; 95% confidence interval, 1.40-20.01; P = 0.01).Differences in left ventricular diastolic function may contribute to the development of PGD. Future trials are needed to determine whether optimization of left ventricular diastolic function reduces the risk of PGD.
Results of cisplatin-based chemotherapy in inoperable hepatoblastoma during last two years at a single institute
Authors: K. M. Patel, S. A. Shah, A. A. Patel, P. M. Shah, S. N. Shukla, B. J. Parikh, A. S. Anand, S. S. Talati, R. K. Srivastav, R. I. Dave
Journal: Journal of Clinical Oncology (2007)

20027 Background: Total surgical excision and adjunctive chemotherapy are cornerstones of treatment of hepatoblastoma in children. But many are unsuitable for radical surgery at diagnosis due to extensive intrahepatic and/or extra hepatic disease. We assessed 18 consecutive cases during the last two years, all of whom presented with unresectable tumor, treated in our center with neoadjuvant chemotherapy,in order to analyze the clinical profile and response to treatment. Methods: A retrospective analysis of patients who presented to our institute during January 2004 to January 2006 was carried out. All patients were biopsy proven hepatoblastoma. One patient was operated without anterior chemotherapy outside our institute .Two patients had lung metastasis. Rest all had stage 3 disease. All the patients were given cisplatin [90 mg/m 2 ] and continuous infusion doxorubicin [80 mg/m 2 over 4 days]. The response to therapy was assessed. Results: Mean age of presentation was 3 years and 4 months [range 1 year to 11 year]. M:F ratio was 4:1. Most common presenting complaint was an asymptomatic abdominal mass felt by the parent. All the patients had tumour in right lobe. Mean alpha fetoprotein level was 0.14 million and the range was from normal to 1.24 million. None of the patients were positive for hepatits B or hepatitis C. After three cycles of chemotherapy, seven of the seventeen patients had adequate down staging of the disease so as to undergo successful resection. There was one post operative mortality. All of them completed total of six cycles of chemotherapy. Ten patients had unresectable tumour even after six cycles of chemotherapy. All of them had reduction in the size of primary tumor and decreased alpha fetoprotein level .There was no chemotherapy related grade 3 or grade 4 toxicity. Conclusions: Hepatoblastoma occurs at a later age in Indian patients as compared to that seen in western countries. Cisplatin and adriamycin are quite effective in downstaging hepatoblastoma. Since these agents are cheap and have minimal toxicity they should be used frequently. No significant financial relationships to disclose.