tbuckley/cabot-search huggingface dataset:
Phase I study of erlotinib administered concurrently with and after irradiation (RT) in the treatment of children, adolescents, and young adults with newly diagnosed intracerebral high-grade glioma
Authors: A. Broniscer, S. J. Baker, T. E. Merchant, F. H. Laningham, M. Kocak, M. J. Krasin, L. E. Kun, A. Gajjar, C. F. Stewart
Journal: Journal of Clinical Oncology (2007)

9553 Background: High-grade gliomas are uncommon neoplasms in childhood that portend a poor prognosis. Because of the promising activity of erlotinib in adults with high-grade glioma, we conducted this Phase I study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of erlotinib administered concurrently with and after RT. Methods: Patients between 3 and 25 years of age with newly diagnosed high-grade glioma received erlotinib continuously once daily during and after RT for a maximum of 52 weeks. Pharmacokinetic studies of erlotinib and its metabolite OSI-420, and genotyping were performed during course 1 in consenting patients. Use of enzyme-inducing anticonvulsants was an exclusion criterion. Dose escalation followed a typical Phase I design (dosage levels of 70, 90, and 120 mg/m 2 per day). The DLT-evaluation period comprised the first 8 weeks of erlotinib. Results: Seventeen patients (median age 10.4 yrs; 10 males) were enrolled. Diagnoses consisted of glioblastoma (n=9), anaplastic astrocytoma (n=4), and other high-grade gliomas (n=4). Two of seven patients experienced reversible grade 3 hypokalemia / hypophosphatemia at the 70 mg/m 2 level. Once electrolyte abnormalities were excluded as DLT, only one of seven patients at the 120 mg/m 2 level has experienced grade 3 diarrhea so far. Pharmacokinetic studies were obtained in 14/17 patients. At the 70 mg/m 2 dosage level, the median (range) erlotinib and OSI-420 C max and T max were 1,405 ng/ml (937–2,180) and 4.1 hr (2.2–8.2) and 158.5 ng/ml (45–203) and 4.1 hr (2.2–7.9), respectively. Three patients have received erlotinib for more than 1 year with disease stabilization. Six patients have already experienced disease progression. Conclusions: Erlotinib administered concurrently with RT on this schedule has been well tolerated. Preliminary pharmacokinetic results are comparable to those observed in adults. Rather than continue to escalate erlotinib dosages, we plan to complete this study and open a phase II study of erlotinib and RT for this same patient population. No significant financial relationships to disclose.
Gene expression profile of pemetrexed and oxaliplatin response in a phase II induction trial in locally advanced head and neck squamous cell carcinoma
Authors: C. H. Chung, J. Aulino, J. Parker, A. J. Cmelak, J. Netterville, B. Burkey, R. Sinard, W. G. Yarbrough, B. A. Murphy, J. Gilbert
Journal: Journal of Clinical Oncology (2008)

6039 Background: To assess the efficacy and identify a biomarker of response, a phase II trial of pemetrexed (PT) and oxaliplatin (OX) as an induction regimen in locally advanced head and neck squamous cell carcinoma (HNSCC) was conducted. We hypothesized that the tumors with increased DNA repair and folate biosynthesis capacities would have resistance to the regimen. Methods: Patients (pts) were given PT 500 mg/m2 and OX 85 mg/m2 Q 2 weeks for 4 cycles. Response was assessed at the end of treatment by CT scan. Frozen and formalin-fixed paraffin-embedded tumors were collected for DNA microarray analysis. The gene expression data were queried using significance analysis of microarrays (SAM) for comparison of stable disease (SD) versus partial response (PR). Results: 15 pts have been enrolled (Male/female: 14/1, Median age: 57.3). ECOG PS: 0 (6), 1 (8) and 2 (1). Primary sites: oropharynx (5), oral cavity (6), larynx (2), hypopharynx (1) and unknown primary (1). Fourteen of the 15 pts were evaluable for response: 0 CR, 10 PR, 4 SD and 0 PD. Toxicity was minimal with grade (G) 3 toxicities in 2 pts for diarrhea and elevated AST. The most common toxicity was nausea (G1–2). Eight tumors (5 PR and 3 SD) and 3 adjacent normal mucosal epithelia were collected and evaluated using DNA microarray. SAM yielded 77 differentially expressed genes between PR vs. SD. The genes most significantly associated with PR were higher expression of TS, DHFR, CDKN2C and CDKN2A, and lower expression of GSTA1 and GSTA4. Because of the association of upregulated CDKN2A, DHFR and HPV infection, the data were queried with the 91-gene HPV signature and presence of the signature was associated with response. The HPV status was also confirmed with HPV E6 and E7 PCR. Conclusions: The combination of PT/OX is active in locally advanced HNSCC patients. Higher expression of genes involving folate biosynthesis and HPV infection may associate with better response to this regimen while no known DNA repair gene expressions were found to associate with the response. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology
Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia (CML) patients.
Authors: S. Soverini, S. Angelini, M. Barnett, M. Thornquist, E. Turrini, G. Rosti, P. Hrelia, T. Kalebic, M. Baccarani, G. Martinelli
Journal: Journal of Clinical Oncology (2010)

6554 Background: Imatinib mesylate (IM) is the first-choice treatment in CML, with excellent response rates. Major and complete molecular responses are the current goals of therapy, but not all patients (pts) achieve these milestones – hence the need to find biological predictors of response in order to guide therapy optimization. We investigated if single nucleotide polymorphisms (SNPs) influencing IM delivery may account for differences in response. Methods: We have genotyped a panel of 20 SNPs affecting the activity of the cytochrome p450 isoforms (CYP3A4, CYP3A5) and the transporters (ABCB1, ABCG2, hOCT1, OATP1A2, OCTN1) implicated in IM metabolism/transport in a subset of pts enrolled in the TOPS trial – a randomized phase III study of IM 400 mg/d vs IM 800 mg/d in newly diagnosed CML. A total of 189 pts were genotyped (156 white, 22 Asian and 11 non-white and non- Asian). Results: Comparison of genotype frequencies revealed differences between Asian and white pts. Among whites, but not other pts, the following SNPs and/or haplotypes correlated with cumulative incidence of major molecular response (MMR): a) OCTN1 rs1050152 number (no.) of major alleles (A) (p = 0.027); b) CYP3A4 rs2740574 no. of minor alleles (G) (p = 0.038); c) hOCT1 gene total no. of major alleles (rs72552763, rs12208357, rs683369, rs2282143) (p = 0.043); d) uptake (total no. of major alleles in hOCT1 rs72552763, rs12208357, rs683369, rs2282143, OCTN1 rs1050152, OATP1A2 rs11568563) (p = 0.005). In addition, the following SNPs and/or haplotypes correlated with cumulative incidence of complete molecular response (CMR): a) MDR1 rs60023214 no. of major alleles (C) (p = 0.005); b) uptake (total no. of major alleles in hOCT1 rs72552763, rs12208357, rs683369, rs2282143, OCTN1 rs1050152, OATP1A2 rs11568563) (p = 0.009). Conclusions: Our results suggest thatalthough ethnicity needs to be taken into account, pharmacogenetics of IM may be helpful in identifying pts who need treatment optimization. Confirmation in larger series is warranted to further test the predictive value of the SNPs identified in this study. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis
Virtual typing by people with tetraplegia using a self-calibrating intracortical brain-computer interface
Authors: Beata Jarosiewicz, Anish A. Sarma, Daniel Bacher, Nicolas Y. Masse, John D. Simeral, Brittany Sorice, Erin M. Oakley, Christine Blabe, Chethan Pandarinath, Vikash Gilja, Sydney S. Cash, Emad N. Eskandar, Gerhard Friehs, Jaimie M. Henderson, Krishna V. Shenoy, John P. Donoghue, Leigh R. Hochberg
Journal: Science Translational Medicine (2015)

Brain-computer interfaces (BCIs) promise to restore independence for people with severe motor disabilities by translating decoded neural activity directly into the control of a computer. However, recorded neural signals are not stationary (that is, can change over time), degrading the quality of decoding. Requiring users to pause what they are doing whenever signals change to perform decoder recalibration routines is time-consuming and impractical for everyday use of BCIs. We demonstrate that signal nonstationarity in an intracortical BCI can be mitigated automatically in software, enabling long periods (hours to days) of self-paced point-and-click typing by people with tetraplegia, without degradation in neural control. Three key innovations were included in our approach: tracking the statistics of the neural activity during self-timed pauses in neural control, velocity bias correction during neural control, and periodically recalibrating the decoder using data acquired during typing by mapping neural activity to movement intentions that are inferred retrospectively based on the user's self-selected targets. These methods, which can be extended to a variety of neurally controlled applications, advance the potential for intracortical BCIs to help restore independent communication and assistive device control for people with paralysis.
Extended exposure to alkylator chemotherapy: Delayed appearance of myelodysplasia
Authors: M. C. Chamberlain, J. Raizer
Journal: Journal of Clinical Oncology (2009)

e13030 Background: Alkylator-based chemotherapy is recognized to be leukemogenic, however, it is infrequently described as a delayed consequence of anti-glioma treatment. Objective: A case series of gliomas treated with alkylator-based chemotherapy who subsequently developed myelodysplastic syndrome (tMDS) or acute myelocytic leukemia (AML). Methods: Seven patients (4 men; 3 women) ages 34–69 years (median 44), with gliomas (3 Grade 2; 4 Grade 3) were treated with surgery, all but one with involved-field radiotherapy and all with alkylator-based chemotherapy (temozolomide; 6 patients, nitrosoureas; 5 patients, both agents; 5 patients). Results: Exposure to alkylator-based chemotherapy ranged from 8 months to 30 months (median 24). The diagnosis of tMDS was determined by bone marrow biopsy in seven patients. Seven patients showed chromosomal abnormalities consistent with chemotherapy induced MDS. Three patients were diagnosed with AML as well (in two determined by bone marrow and one at autopsy). Interval from last chemotherapy exposure to diagnosis of tMDS/AML ranged from 3 months to 31 months (median 24 months). Two patients were treated with bone marrow transplantation and five received supportive care only. Five patients have died, two as a consequence of recurrent brain tumor, one as a complication of transplantation, and due due to AML. Conclusions: Although rare, induction of tMDS/AML following extended use of alkylator-based chemotherapy may become more relevant with the evolving practice to treat gliomas for protracted periods. Future work to determine at-risk patients would be important. No significant financial relationships to disclose.
Dynamic contrast enhanced MRI (DCE MRI) for Phase I anti-angiogenic trial: Comparison of the transfer constant (Ktrans) to blood flow and permeability derived by a distributed parameter model
Authors: C. H. Thng, S. Hartono, T. S. Koh, H. Rumpel, A. B. Ong, N. Sukri, B. C. Tai, R. A. Soo, R. Humerickhouse, B. C. Goh
Journal: Journal of Clinical Oncology (2008)

3514 Background: The distributed parameter (DP) model is a DCE-MRI model that enables derivation of blood flow and capillary permeability-surface area product (PS). We aim to compare the DP model to Ktrans in the assessment of angiogenesis assessment in a Phase I anti- angiogenic trial. Methods: Twenty-seven evaluable patients from a completed phase I trial (ABT-869) with 3 dose escalations formed the study population. All patients underwent DCE-MRI at baseline, Day 3 and Day 15 with temporal resolution of 4 seconds. Gadolinium concentrations were estimated using dual flip angle method. Ktrans, normalized IAUC60, permeability-surface area product derived from DP model (DP-PS), and blood flow derived from DP model, were calculated. Patients demonstrating progressive disease in first 2 evaluations scans (cycle 2 or 4) based on RECIST criteria were considered progressors and all other patients, non-progressors. Receiver operating curve (ROC) analysis was performed. Correlation with area under the curve extrapolated to infinity (AUCinf) was analyzed. Results: There is good correlation between DP-PS and drug exposure above threshold (threshold concentration 80 ng/mL; time threshold 3.5 hours) measured by AUCinf (Spearman's coefficient −0.556, p = 0.007). Although slightly weaker correlation is found with normalized IAUC60 (Spearman's coefficient −0.537, p = 0.01), the difference is not significant. (p = 0.9334) There is poor correlation for Ktrans (Spearman's coefficient −0.128, p = 0.570). ROC analysis for predicting progressors versus non-progressors showed a higher ROC area for DP-PS compared to Ktrans (0.869 versus 0.417, p < 0.001) and normalized IAUC60 (0.869 versus 0.643, p = 0.1543, not significant). Using a 29.45% drop from baseline at Day 15 to predict non-progressors, the sensitivity of DP-PS is 64.3% and the specificity is 100% whereas the sensitivity of Ktrans is 28.6% and the specificity is 66.7%. In 7 cases, DP-PS correctly predicted the eventual outcome whereas Ktrans predicted the direct opposite. Conclusion: Permeability-surface area product derived from DP model shows better correlation with drug exposure and may predict patient outcome better than Ktrans. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories
Gemcitabine, docetaxel, and capecitabine (GTX) in the treatment of metastatic pancreatic cancer (PC): A prospective phase II study
Authors: R. L. Fine, D. R. Fogelman, W. Sherman, S. Schreibman, A. Siegel, M. Mauer, J. Chen, K. Chu
Journal: Journal of Clinical Oncology (2006)

14024 Background: We have found that the combination of gemcitabine, docetaxel, and capecitabine (GTX), when administered in a specific sequence, will induce a p53 independent pathway of cell death through the MAP kinase pathway. The sequence overcomes drug resistance in PC cells in vitro. We have begun a prospective, phase II trial of GTX in patients with metastatic PC as first-line therapy. Methods: 23 patients with metastatic PC, ECOG 0–2 were enrolled at either Columbia or a community practice. Each cycle was administered over a 21 days. Capecitabine was administered at 750 mg/m 2 twice daily for 14 days. Gemcitabine (750 mg/m 2 over 75 minutes) and docetaxel (30 mg/m 2 ) were administered on days 4 and 11. Responses were measured by CT (RECIST) and PET after every three cycles. A response by PET was defined as a 50% reduction in SUV while a CR was an absence of uptake. Results: Median age was 61, including 8 men and 15 women. Metastatic sites included liver (87%), abdomen (65%), and lung (17%). 70% of liver positive patients had at least five metastases. 22% had malignant ascites. 16 patients remain alive and 7 have progressive disease. Median survival has not yet been reached. Progression occurred at a median of 5.1 months. By CT, the response rate at metastatic sites was 39% (17% CR / 22% PR). Stable disease was observed in 48% at metastatic sites. PET showed a 53% response rate at metastatic sites. At the primary site, CT showed a 30% response rate including 17% complete responses. By PET criteria, there was a 31% response rate and a 26% CR rate at the primary site. In three patients, a PET response heralded a CT response by three cycles. In one patient, progressive disease on PET preceded progression on CT by two months. Toxicity: Grade 3 leukopenia and thrombocytopenia were 13% and 9%, respectively. There was no grade four hematologic toxicity. One patient experienced lung disease related to gemcitabine and withdrew from the study. A second patient experienced grade 4 mucositis, thrush, and sepsis which was presumed due to DPD deficiency. Grade 3–4 toxicities: HFS: 9%. There was no grade 3–4 diarrhea. Conclusions: GTX, elicits a promising response rate when used in metastatic P.C. PET detects a response and failure of chemotherapy earlier than CT scans. [Table: see text]
Fractional percentage of tumor volume removed is a predictor of outcome following cytoreductive nephrectomy for metastatic renal cell carcinoma
Authors: S. Collins, P. M. Pierorazio, J. M. McKiernan, M. C. Benson
Journal: Journal of Clinical Oncology (2006)

4599 Background: Metastatic renal cell carcinoma, (M+)RCC, is associated with poor overall survival with only 10–20% of patients alive at 2-years. The objective of this study is to determine if the fractional percentage of tumor volume (FPTV) removed at cytoreductive nephrectomy predicts disease specific survival (DSS). Methods: The Columbia Urologic Oncology Database was reviewed and 1,016 patients were identified that underwent renal surgery from 1988 to the present. A retrospective cohort of 93 patients were identified with (M+)RCC at the time of nephrectomy. The prospective database was reviewed to determine the FPTV removed and remaining following surgery. Patients were stratified to having greater or less than 90% of their cancer burden removed. Primary outcome was defined as DSS. Kaplan-Meier analysis with log-rank test was performed to determine survival advantage between groups. A Cox proportional hazard model was fit for PTR in both univariate and multivariate models. Secondary analyses were conducted to determine if the size of primary tumor affected outcome and if FPTV affected hospitalization time. Results: 63 of 77 patients had &gt;90% of their tumor burden removed. Median follow-up time was 8.6 months. Median DSS times were calculated to be 18.8 and 3.6 months for patients with &gt;90% and &lt;90% PTR respectively (p &lt; 0.001). The hazard ratio for death was 5.73 for patients with &lt;90% of tumor removed (p &lt; 0.001). Those with &gt;90% removed had larger primary tumors, 10.6cm vs. 7.2cm in the &lt;90% removed group (p = 0.01). Outcome analysis by size of primary tumor demonstrated no difference in survival. Patients with &lt;90% removed spent 13.6% of DSS time hospitalized compared to 6.3% for those with &gt;90% removed (p = 0.89). Conclusions: For patients with (M+)RCC, overall survival is limited but can be extended by cytoreductive nephrectomy. FPTV expected to be removed is a simple and available method to counsel patients regarding the benefits of surgical intervention. No significant financial relationships to disclose.
Operative morbidity and mortality in 54 consecutive patients undergoing operative cytoreduction and intraperitoneal chemotherapy for peritoneal mesothelioma
Authors: M. D. Kluger, R. N. Taub, L. Batista, C. M. DeRosa, M. DiGiorgi, M. E. Hesdorffer, J. Leinwand, J. A. Chabot
Journal: Journal of Clinical Oncology (2008)

15537 Background: The current standard of care for treatment of malignant peritoneal mesothelioma involves operative cytoreduction and intraperitoneal chemotherapy. Most centers favor aggressive operative cytoreduction to maximally resect gross disease, accepting high morbidity and mortality in the range of 25–50% and 1–10%, respectively. In our Phase I-II trials, patients underwent less extensive operative cytoreduction followed by intraperitoneal chemotherapy and radiation. Patients underwent a second-look cytoreduction operation with heated intraoperative intraperitoneal chemotherapy. We hypothesized this would result in lower operative morbidity and mortality with similar survival. Methods: Hospital electronic notes, discharge summaries, laboratory and radiography reports, and oncologist and surgeon office records were retrospectively reviewed to supplement a prospectively collected database. This database followed 54 patients with verified malignant mesothelioma consented for Phase I-II trials between 1997 and 2004. All documented 30-day morbidity and mortality were categorized; patients were not excluded from this analysis if they went off trial. Survival was defined as the time from first-look operation to death or last follow-up. Summary statistics and Kaplan Meier survival estimates were performed using Stata. Results: 54 first- look and 38 second-look operations were performed with 15% and 21% 30-day morbidity, respectively. There was no 30-day mortality. Respiratory (33%) and infectious (40%) complications comprised 73% of the morbidity. The median length of stay was 5 and 6 days for the first- and second-look operations, respectively. The mean length of stay for both operations combined was 13±9 days. Median follow-up was 32 months, with a median survival of 34 months, and 1, 3 and 5 year survival rates of 70%, 50% and 44%, respectively. Median survival for the epithelial subtype was 68 months. Conclusions: A less-aggressive approach to initial operative cytoreduction followed by perioperative chemotherapy and radiation offers similar survival to other equivalently sized trials with lower morbidity and mortality, and shorter total lengths of stay despite two operations. No significant financial relationships to disclose.
Short-course irradiation as adjuvant treatment of surgically resected single brain metastases
Authors: M. A. Alrefae, D. Roberge, L. Souhami
Journal: Journal of Clinical Oncology (2009)

2067 Background: Surgical resection followed by whole-brain irradiation is a standard treatment approach for patients with a single brain metastasis from solid tumours. As short-course hypofractionated irradiation has proven equivalent to more protracted schedules for the palliative treatment of brain metastasis, it has been commonly applied in the adjuvant setting. Methods: By reviewing our pathology database, we identified patients having undergone complete neurosurgical resection of a single brain metastasis followed by short-course (4–6 fractions) whole-brain irradiation. Irradiation was delivered using standard lateral-opposed megavoltage radiation portals. Local failure and new brain metastases were identified by chart and imaging study reviews. All outcomes were calculated actuarially. Results: Between March 2000 and August 2005, 50 patients received short-course whole-brain irradiation (20 Gy in 5 fractions in 41 of 50 cases) following complete surgical resection of a single brain metastasis. The most common primary malignancies were lung (66%), breast (14%), and cancer of unknown primary origin (10%). Median age was 60 years. Imaging studies were available for all patients and a preoperative MRI was reviewed in 94% of cases. Median follow-up for living patients was 30.0 months. The median overall survival was 10.92 months (29% at 2 years). Following radiation, failure at the surgical site was seen in 51% and 79% of patients at 1 and 2 years. New metastases elsewhere in the brain developed in 26% and 53% of these patients at 1 and 2 years. Conclusions: When calculated actuarially, local failure and new brain metastases were common following surgery and short-course whole-brain radiation therapy. In part, this may represent inefficacy of the short hypofractionated radiation scheme. Further investigation into the local and systemic treatment of these patients is warranted. No significant financial relationships to disclose.
P0277 : Enhanced and effective delivery of microrna by using ligand modified self assembled cationic dipeptide nanoparticles in hepatocellular carcinoma (HCC)
Authors: A. Varshney, J.J. Panda, A.K. Singh, S.B. Rooge, S. Biswas, S.K. Sarin, V.S. Chauhan
Journal: Journal of Hepatology (2015)