tbuckley/cabot-search huggingface dataset:
A phase II trial of gefitinib in patients with chemosensitive and chemorefractory relapsed neuroendocrine cancers. A Hoosier Oncology Group Trial
Authors: A. M. Moore, D. Estes, R. Govindan, J. Vinson, C. Calley, M. Yu, L. Einhorn, N. Hanna
Journal: Journal of Clinical Oncology (2005)

7160 Background: Gefitinib (Iressa) has demonstrated activity in patients (pts) with NSCLC. Tumor responses occurred in pts predominantly with adenocarcinoma, but responses have been observed in all histologies and regardless of the number of prior therapies. However, prior clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the EGFR. Although, EGFR is not over-expressed in SCLC, we postulated that gefitinib might affect tumor growth through other mechanisms. Methods: The primary objective was to assess the clinical control rate (CR, PR and SD > 90 days) of gefitinib in pts with chemoresistant and chemosensitive neuroendocrine tumors. Pts were to be recruited to the second stage if the disease control rate was 40% and 30% in chemo-sensitive or chemoresistant patients, respectively. Eligibility criteria included pathologic proof of a neuroendocrine tumor, ECOG PS 0–2, prior treatment with one or two prior chemotherapy regimens, and adequate end-organ function. Pts received gefitinib, 250 mg po daily until PD or intolerable side effects. Results: From April 2003 to March 2004, 19 pts were enrolled. Small cell lung cancer (SCLC) accounted for 18 of the 19 pts. 12 pts (63%) had chemosensitive disease, 7 (37%) had chemorefractory disease, 13 (68%) had one prior chemotherapy regimen and 6 (32%) had two prior chemotherapy regimens. Other pt characteristics: mean age 64 years (52–79); ECOG PS 0/1/2 = 7/9/3, M:F = 9:10. Grade 3 toxicities included: fatigue in 3 pts (15.8%), pulmonary toxicities in 3 pts (15.8%), and one pt (5.3%) each with hyperglycemia or pain. Four pts had grade 4 toxicities: one pt (5.3%) with fatigue and 3 pts (15.8%) with dyspnea. There were no pts with grade 3 or 4 rash or diarrhea. Two pts had stable disease (<90 days) and 17 had progressive disease. The continuing criterion for stage one was not met and therefore stage 2 was not performed. Median TTP was 50 days (95% CI = 21–58 days). One year OS was 21% (95% CI = 6–45.6%). Conclusions: Although gefitinib has activity in pts with NSCLC, this study failed to demonstrate activity in pts with SCLC. Further studies of this agent in SCLC are not warranted at this time. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Utilization of Oncotype DX testing in a community hospital system: How did this affect patient care?
Authors: Jennifer Snow, Deepa R. Halaharvi, Alyssa Pastorino, Meghan Wooster, Brian Dusseau, Mark H. Cripe
Journal: Journal of Clinical Oncology (2015)

19 Background: The Oncotype DX Breast Cancer Assay is a multigene assay which quantifies risk of distant recurrence at 10 years and predicts benefit of chemotherapy in women with stage I/II, lymph node negative, estrogen receptor positive breast cancer. This retrospective study examines utilization of Oncotype DX for appropriate patients in a community hospital system. We hypothesize that chemotherapy administration follows the Oncotype DX score recommendation that patients with low recurrence scores not receive chemotherapy and patients with high recurrence scores receive chemotherapy and intermediate recurrence scores receive chemotherapy half of the time. Methods: In this retrospective study, 302 female patients from 1/1/12 – 1/1/14, were identified by breast cancer ICD9 codes from the system’s cancer registry. Data including imaging findings, pathology, and treatment information was then compared using chi square tests for categorical variables and two sample t tests or Wilcoxon rank sum tests for continuous variables. Results: Three hundred two female patients with stage I/II, lymph node negative, HR+, HER2/neu, breast cancer from a community hospital system were identified as appropriate candidates by NCCN guidelines, for Oncotype DX testing between 1/1/12 - 1/1/14. In patients receiving Oncotype DX, mass sizes were larger and were a higher proportion of stage 2 cancers (p &lt; 0.001). Utilization of Oncotype DX in our CoC and NAPBC accredited hospital system was lower than hypothesized with only 73% of patients receiving testing. Following Oncotype DX testing, appropriate treatment ensued 94% of the time (low and high recurrence risk). Intermediate recurrence scores received treatment 36% of the time. Conclusions: In our CoC and NAPBC accredited hospital system, utilization of Onocotype DX testing was lower than hypothesized. For the patients who received testing, expected treatment was administered. Oncotype DX testing when performed influences patient care, however with 27% of patients not receiving testing and 25 % of the time this was due to patient preference, this observation supports that testing not be ordered reflexively, but rather with patient input and appropriate consent.
Controlling delayed vomiting: double-blind, randomized trial comparing placebo, dexamethasone alone, and metoclopramide plus dexamethasone in patients receiving cisplatin.
Authors: M G Kris, R J Gralla, L B Tyson, R A Clark, C Cirrincione, S Groshen
Journal: Journal of Clinical Oncology (1989)

The majority of patients receiving cisplatin at a dose of 120 mg/m2 experience delayed nausea and vomiting occurring between 24 and 120 hours after chemotherapy administration. Ninety-one patients who were receiving cisplatin (120 mg/m2) as initial chemotherapy were entered into this double-blind trial. All patients received intravenous (IV) metoclopramide, dexamethasone, and lorazepam for the control of acute emesis during the period from 0 to 24 hours after cisplatin. Patients were then randomized to one of three treatment regimens: placebo; oral dexamethasone, 8 mg twice daily for two days, then 4 mg twice daily for two days; or the combination of oral metoclopramide, 0.5 mg/kg four times daily for four days, plus oral dexamethasone administered as above. Forty-eight percent of individuals who received the two-drug combination of metoclopramide plus dexamethasone experienced delayed vomiting as opposed to 65% who were administered dexamethasone alone and 89% who received placebo (P = .006). Scores assessing the severity of delayed nausea and vomiting were consistently worse in individuals receiving placebo. The incidences of sleepiness, restlessness, heartburn, hiccoughs, loose bowel movements, insomnia, and acute dystonic reactions did not differ significantly among the three regimens and were mild and self-limited. The two-drug combination of oral metoclopramide plus dexamethasone is well tolerated, safe, and more effective than dexamethasone alone or placebo in controlling delayed vomiting following cisplatin.
Correlation of 11C-choline PET and PSA values in patients with prostate cancer and biochemical relapse after primary treatments
Authors: R. Vormola, C. Ortega, F. Montemurro, A. Capaldi, S. Cirillo, P. Gabriele, G. Muto, M. Aglietta
Journal: Journal of Clinical Oncology (2007)

5073 Background: 11C-choline PET has demonstrated promising results in the evaluation of suspected recurrence after a primary treatment in prostate cancer (PC) patients (pts). However in pts with asymptomatic biochemical relapse (BR), the timing of PET scan is a subject of controversy. Most authors argue against performing PET scan for rising PSA values &lt;5 ng/ml. Aim of our study was to evaluate if there is a PSA cut-off that significatively correlates to 11C-choline PET positivity. Methods: 68 pts with rising PSA after primary treatment underwent 11C-choline PET. Median age was 68 yrs (range 43–84). Median PSA at the time of PET scan was 2.91 ng/ml (range 0.12- 71.60). Primary treatments were: 27 (40%) radical prostatectomy (RP), 22 (32%) external-beam radiation therapy (EBRT), 13 (19%) RP + adjuvant EBRT, 6 (9%) hormonal therapy. Results: 11C-choline PET was positive in 39/68 pts (57%) and negative in 29/68 (43%). Median PSA values were 1.18 ng/ml (range 0.12–6.47) and 5.14 ng/ml (range 1.33–71.60) in pts with negative and positive PET scan respectively. Median PSA values were statistically different in positive and negative 11C-choline PET (Mann-Whitney U Test. p&lt; 0.001). No positive uptake was seen in pts with PSA &lt;1 ng/ml (12/68); all pts with PSA &gt;6.5 ng/ml had a positive finding; for PSA values between 1 and 6.5 ng/ml (33/68), 11C- choline PET showed a pathological uptake in 18 pts. The Receiver Operative Characteristic (ROC) analysis found that a PSA cut-off of 2.31 ng/ml has a sensitivity of 87% and a specificity of 83% in respect of 11C-choline PET positivity. Conclusions: For PSA values &gt; 2.3 ng/ml the probability to have a positive 11C-choline PET is high in order to recommend to perform the exam in clinical practice, even if further data are needed. On the contrary, we can’t suggest to perform PET scan in pts with PSA &lt;1 ng/ml. No significant financial relationships to disclose.
High Prevalence Of Extramedullary Relapse In Patients With Multiple Myeloma Treated With Novel Biological Agents
Authors: Silvia Mangiacavalli, Alessandra Pompa, Cristiana Pascutto, Virginia Ferretti, Lara Pochintesta, Federica Cocito, Marzia Varettoni, Mario Lazzarino, Mario Cazzola, Alessandro Corso
Journal: Blood (2013)
Abstract #5604: Bmi-1 protects human oral epithelial cells from ionizing radiation
Authors: Qinghua Dong, Roy Kim, No-Hee Park, Mo. K. Kang
Journal: Cancer Research (2009)

Oral mucositis is a debilitating side effect of anti-cancer therapy that affects almost all patients exposed to therapeutic radiation. Pathogenesis of oral mucositis involves the direct genotoxic insult to the epithelial cells and the inflammatory response triggered by ionizing radiation (IR) or pro-inflammatory cytokines, such as TNF-\#945;. Epithelial tissue damage by IR is attributed to accumulation of DNA damage that leads to premature senescence. We previously showed that Bmi-1 enhances replication of normal human oral keratinocytes (NHOK). In the current study, we tested whether Bmi-1 could rescue NHOK from IR-induced premature senescence. Primary NHOK was infected with retroviral vector expressing Bmi-1or the empty vector (B0) to establish NHOK/Bmi-1 and NHOK/B0 cells, respectively. Three dimensional (3D) oral mucosal cultures were generated from these cells. We compared the phenotypic and molecular alternations of the cells and the reconstructs after exposure to IR or TNF-\#945;. The vast majority of NHOK/B0 cells underwent senescence within 5 days post-IR. These cells stopped proliferation and expressed senescence-associated \#946;-galactosidase (SA \#946;-Gal) activity. However, NHOK/Bmi-1 cells continued to proliferate, maintained the clonogenic properties, and exhibited reduced staining for SA \#946;-Gal even after 10 Gy IR. We then determined the role of Bmi-1 in DNA repair. NHOK/Bmi-1 demonstrated enhanced  in vitro  DNA end joining activity and  in vivo  double-strand break repair activity compared to those of NHOK/B0. Since oral mucositis is an inflammatory disorder, we determined the inflammatory signaling in NHOK/B0 and NHOK/Bmi-1. The pro-inflammatory signaling mediated by NF-\#954;B was significantly inhibited by Bmi-1. We determined the phenotypic responses of the 3D cultures exposed to IR or TNF-\#945; by histological examination and immunohistochemistry for proliferating cell nuclear antigen (PCNA), a cell proliferation marker. Upon exposure to either IR or TNF-\#945;, NHOK/B0 cells cultured in 3D models revealed disorganized epithelial structure and lost the expression of PCNA. However, NHOK/Bmi-1 cells retained the organized epithelial stratification and the proliferating basal cell layer. These results indicate that Bmi-1 protects oral epithelial cells from IR-induced mucositis by mitigating the genotoxic stress and pro-inflammatory signaling. This work was supported in part by grants (R01DE18295, K02DE18959, U19AI67769) from NIDCR/NIH.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5604.
Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression
Authors: F. S. Viola, A. Katz, A. Arantes, A. Gaiger, C. Vasconcellos, V. Passos, C. H. Barrios
Journal: Journal of Clinical Oncology (2007)

2056 Background: GBM are the most common primary brain tumors in adults. Despite available treatment they carry a poor prognosis with recurrences in most patients (pts) after initial therapy. PDGF signaling has been postulated to play a role in GBM transformation. We have demonstrated that PDGFRβ is expressed in tumor cells in 50% and in peritumoral endothelial cells in 65% of GBM (Barrios et al, abstract 11518, Proc ASCO 2006). Imatinib, an inhibitor of PDGFRa/β kinase activity could have therapeutic activity in these cases. Methods: We evaluated Imatinib in pts with recurrent GBM (previous radiation and chemotherapy) selected by PDGFR expression. Analysis of PDGFRa/β was performed by standard IHC. Positivity was considered in case of any qualitative expression. Pts were treated with 800 mg/day of Imatinib until tumor progression. All were on steroids and taking enzyme inducing antiepileptic drugs. Response was determined by MRI with spectroscopy and perfusion every 8 weeks according to RECIST criteria. Results: Twenty pts were enrolled (18 GBM, 2 AA). Median age: 51 (21–74), 7 were females. ECOG-PS at inclusion: 0 (3), 1 (10), 2 (7). All pts had expression of PDGFRa and 55% expressed PDGFRβ. Response data are available for all 20 pts. Main adverse events (all grade 1–2) were: edema (55%), nausea (50%), diarrhea and fatigue (35% each). We did not observe any PR but 13 pts (65%) showed disease stabilization. Median progression-free survival was 7.8 months with 60.8% of pts alive at 6 months; 6 months PFS was 52.2%. Conclusions: Imatinib was well tolerated in this group of poor prognosis highly pre-treated GBM pts demonstrating disease stabilization in a significant proportion of cases. These results, in a limited sample, compare favorably with historical data in similar populations. Selection of pts according to the specific molecular expression of their tumor may lead to better therapeutic results. No significant financial relationships to disclose.
Identification of drug sensitivity markers in lung cancer: an integrative genomics approach
Authors: Dimitri Semizarov, Ed Olejniczak, Charles Van Sant, Mark Anderson, Steve Tahir, Guido Sauter, Rick Lesniewski
Journal: Cancer Research (2007)

5680   Cancer is a highly heterogeneous disease in terms of the genetic profile and the response to therapeutics. An early identification of a genomic marker in drug discovery may help select patients that would respond to treatment in clinical trials. Here we implemented a novel biomarker discovery strategy based on coupling compound screening with CGH analysis of the model systems to identify genomic correlates of sensitivity for subsequent use in clinical trials.  Two small-molecule inhibitors of Bcl-2 family proteins (ABT-263 and ABT-737) have recently been discovered at Abbott Laboratories and shown to induce regression of solid tumors. These compounds displayed selective potency against SCLC and lymphoma cells. We tested the compounds against a panel of 23 SCLC lines and identified sensitive (10 nM 10 μM) to the drug. The two compounds yielded a very similar inhibition profiles for the same 23 cell lines, while an enantiomer of ABT-737 was inactive in all lines, indicating that the observed response is mechanism-based.  We sought to identify genomic biomarkers of sensitivity to the Bcl-2 antagonists through genome-wide high-resolution CGH analysis of the panel of SCLC cell lines used to test the drugs. High-density SNP genotyping arrays were used for CGH analysis because of their high resolution and reproducibility. The data were analyzed using an in-house software package that identifies chromosomal aberrations that discriminate between two pre-defined groups. Our program tested for statistical significance using Fisher’s Exact Test to determine if a probeset (SNP) shows preferential gain/loss in the sensitive or resistant group. A previously unknown amplification was identified on 18q and associated with the sensitivity of SCLC cell lines to Bcl-2 antagonists. The region of gain contains Bcl-2 and NOXA, two apoptosis-related genes. Expression microarray profiling showed that the genes residing in the amplified region of 18q are also overexpressed in the sensitive lines relative to the resistant lines. FISH analysis of SCLC tumors revealed that Bcl-2 gain is a frequent event in SCLC. Our findings suggest that 18q21-22 copy number will be a clinically relevant predictor for sensitivity of SCLC to Bcl-2 family inhibitors. The 18q21-22 genomic marker may have a broader application in cancer, as Bcl-2 is associated with apoptosis evasion and chemoresistance.  Additionally, the CGH screen of the SCLC cell line panel revealed a number of novel recurrent gene copy number gains, which were also found in an independent dataset of 19 SCLC tumors and confirmed by real-time qPCR. Some genes in the gained regions may represent attractive drug targets in SCLC. Our findings validate the CGH-based methodology of biomarker discovery and reveal a mechanism-based marker of drug sensitivity for SCLC.
Abstract 20118: Defining the Sufficiency of Atg7 to Suppress Phenylephrine-induced Cardiac Hypertrophy
Authors: Marcus Tjeerdsma, Levi Froke, Jessica Freeling, Scott Pattison
Journal: Circulation (2014)

Introduction: Macroautophagy is a process of bulk protein degradation. Our prior work showed that Atg7 expression is sufficient to induce autophagic flux in vitro and in vivo . When Atg7 was co-expressed with CryAB R120G in the heart, cardiac hypertrophy was blunted in heart weight/body weight ratios and fetal gene expression markers. To determine if Atg7 expression is sufficient to limit hypertrophic growth in another model, we tested the effects of Atg7 overexpression with phenylephrine-induced hypertrophy both in vitro and in vivo . Hypothesis: Atg7 will blunt the hypertrophic effects of phenylephrine. Methods: Rat neonatal cardiomyocytes were infected with adenoviruses expressing either LacZ or Atg7 and treated with phenylephrine to induce cardiomyocytes hypertrophy. Osmotic pumps were surgically implanted into control mice and mice with cardiac-specific expression of Atg7 to infuse phenylephrine (PE) or vehicle (saline) for four weeks. Results: PE treatment significantly increased neonatal cardiomyocyte areas in LacZ-expressing cells, while Atg7-expressing cardiomyocytes showed no growth. In mice, all genotypes responded to PE treatment with significantly increased heart weight/body weight ratios and increased fiber size. However, Atg7-expressing hearts differed significantly from control hearts in normalized heart mass following PE delivery. Vehicle treated Atg7-expressing hearts had 17% smaller myofiber cross-sectional areas than those from control genotypes and had a reduced hypertrophic response to PE, relative to controls. Echocardiography showed that Atg7-expressing hearts had significantly elevated cardiac function (% fractional shortening) prior to and throughout the experiment over control hearts (33% vs. 29%). PE significantly increased fractional shortening) from 29% to 36% in control hearts, but failed to significantly elevate cardiac function in Atg7-expressing hearts further (33% vs 35%). Additional assays are underway to understand the Atg7-dependent adaptations to PE. Conclusion: Atg7 expression yields modestly smaller hearts with enhanced cardiac function which may protect them from hypertrophic stresses like phenylephrine.
Targeting Superficial Bladder Cancer by the Intravesical Administration of Copper-67–Labeled Anti-MUC1 Mucin Monoclonal Antibody C595
Authors: O.D. M. Hughes, M.C. Bishop, A.C. Perkins, M.L. Wastie, G. Denton, M.R. Price, M. Frier, H. Denley, R. Rutherford, P.A. Schubiger
Journal: Journal of Clinical Oncology (2000)

PURPOSE: More effective intravesical agents are required to limit the recurrence and progression of superficial bladder cancer. This study assessed the ability of copper-67 ( 67 Cu)-C595 murine antimucin monoclonal antibody to bind selectively to superficial bladder tumors when administered intravesically, with a view to its development for therapy. PATIENTS AND METHODS: Approximately 20 MBq of 67 Cu-C595 monoclonal antibody was administered intravesically to 16 patients with a clinical indication of superficial bladder cancer. After 1 hour, the bladder was drained and irrigated. Tissue uptake was assessed by imaging and by the assay of tumor and normal tissues obtained by endoscopic resection. RESULTS: Tumor was correctly identified in the images of 12 of 15 patients who were subsequently found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to-normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), this decreased to 4.3% of the injected dose per kilogram (SD = 2.9), with a tumor-to-normal tissue ratio of 1.8:1 (SD = 0.8). CONCLUSION: This study indicates a promising method for the treatment of superficial bladder cancer. Although the mean initial tumor uptake was high, effective therapy of bladder tumors will require an increased retention of the cytotoxic radionuclide in tumor tissue.
High incidence of symptomatic methemoglobinemia (metHb) in Asian patients (pts) treated with 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, triapine) and gemcitabine (GEM) in a second-line phase II trial of metastatic non-small cell lung cancer
Authors: B. Ma, E. H. Tan, T. Mok, K. C. Lam, R. Soo, S. S. Leong, L. Z. Wang, F. Mo, A. T. Chan, B. C. Goh
Journal: Journal of Clinical Oncology (2007)

18207 Background: Triapine (Vion Pharmaceuticals) is an inhibitor of ribonucleotide reductase that can enhance GEM uptake in GEM- resistant cell lines. Clinically significant metHb has been rarely reported with triapine &amp; G6PD-deficient pts maybe more susceptible. This multicenter study evaluated the activity &amp; safety of combined triapine-GEM in pts with metastatic NSCLC who had progressed despite prior response or disease stabilization to 1 st line platinum-GEM regimen. Methods: Eligible pts were treated with triapine (105mg/m 2 ) as 4-hr IV infusion, followed by GEM (1g/m 2 ) over 30-min on days 1, 8 &amp; 15, repeating every 28 days for 6 cycles. G6PD-deficient pts were excluded. Results: 6 males &amp; 6 female Asian pts (median age: 65 yrs) received a median no. of 2 cycles (range 1–6 cycles). At a median follow-up of 4.6 mos, no response was seen. 4 pts had stable disease. Median time to progression was 3 mos (95% CI: 1.7–9.1 mos). Gr 3–4 toxicities included neutropenia (gr 3, 2 pts), hypoxia (gr 3, 3 pts) &amp; dyspnea (gr 3, 1 pt). There were no treatment-related deaths &amp; all pts remained alive at analysis. 4 pts developed symptomatic metHb during, or ≤ 4 hrs of stopping triapine. This was manifested as dyspnea &amp;/or hypoxia, associated with an oxygen saturation of ≤90% at room air. Arterial metHb assay performed during the hypoxic episode showed a metHb level of up to 15% of total concentration of hemoglobin ([Hb]), which fell to &lt; 5% of [Hb] within 4–6 hrs of stopping triapine. All pts recovered with conservative treatment &amp; none required reversal with methylene blue. 3 out of the 4 pts were able to continue treatment after dose-reduction of triapine. Conclusions: The cause of the relatively high incidence of triapine-related symptomatic metHb was unclear in this Asian cohort. This study was terminated prematurely due to lack of response. No significant financial relationships to disclose.