tbuckley/cabot-search huggingface dataset:
Gefitinib and radiation therapy for elderly patients with esophageal squamous cell carcinoma: Preliminary results of a phase II study.
Authors: Yaping Xu, Xinmin Yu, Yuanda Zheng, Xiaojiang Sun, Wei Wu, Weimin Mao
Journal: Journal of Clinical Oncology (2014)

e15034 Background: To determine the safety and efficacy of Gefitinib combined with thoracic radiotherapy for elderly patients with esophageal squamous cell carcinoma (ESCC) who are not candidates for chemoradiation therapy. Methods: Patients > 65 years with ESCC who were not eligible for platinum-based treatment received Gefitinib daily for 2 months starting on day 1 of radiotherapy [50.4 Gy days 1–28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary end point of the study was the response rate, and the secondary end points were survival time and toxicity. Immunohistochemistry (IHC) was performed to analyze the expression of EGFR. The amplified refractory mutation system (ARMS) was performed to detect EGFR gene mutations using real-time PCR. The survival curves were calculated using the Kaplan–Meier method. Results: There were 5 complete responses, 13 partial responses who were treated with concurrent radiotherapy/Gefitinib. The overall response rate (CR + PR) was 90%, two (10%) had stable disease, no patient indicated progression. Median overall survival (OS) was 14.0 months (95% CI: 10.0-17.9 months) and median progression-free survival (PFS) was 7.0 months (95% CI: 0–17.2 months). Patients with good ECOG performance status, never smokers and EGFR mutation positive had the longest OS (14.0, 14.0 and 17.0 months, respectively). Treatment-related toxicities of grade 3/4 occurred in 5 patients. The most common toxicities were esophagitis (95%) and tracheitis (55%). No grade 3/4 impaired liver function or hematological toxicity was observed. Progression was locoregional (n = 7), distant (n = 5), recurrence of disease simultaneously in the primary tumor site and a distant area (n = 1). Estimated 1-year survival was 58.2%, Three patients with EGFR mutation all lived >12 months. Conclusions: Gefitinib with radiotherapy is tolerable and effective, further biomarker-driven evaluation is warranted in this population.
Visceral fat as a predictive marker of response to bevacizumab-based treatment in metastatic colorectal cancer.
Authors: Yuji Miyamoto, Yasuo Sakamoto, Masayuki Watanabe, Hideo Baba
Journal: Journal of Clinical Oncology (2013)

e14665 Background: A large amount of visceral adipose tissue might be correlated with high VEGF levels and with resistance to bevacizumab-based regimens in metastasic colorectal cancer (mCRC). The aim is to evaluate that abdominal obesity can be a predictive marker of response to bevacizumab-based therapy in mCRC. Methods: From January 2005 to December 2010, we performed a retrospective analysis of 74 consecutive patients with mCRC received bevacizumab-based first line treatment. Pretreatment CT was used to measure visceral fat volume (VFV), subcutaneous fat volume (SFV) an waist circumference (WC) in 74 patients with mCRC who received bevacizumab-based first-line treatment (bevacizumab group, n=37) or chemotherapy alone (chemotherapy group, n=37). Associations linkingVFV, SFV and WC to tumor response, progression free survival (PFS) and overall survival (OS) were evaluated. For all analyses, VFV, SFV and WC were dichotomized using the median as the cut-off point. Results: In the bevacizumab group, median follow-up lasted for 25 months (7-47). VFV, SFV and WC values were not associated with response or OS. PFS was shorter in patients with high VFV (12.8 vs 7.7 months; p=0.04). By multivariate analysis, high VFA was independently associated with PFS (HR=4.32, p=0.045). In the chemotherapy group, median follow-up lasted for 26 months (2-68). VFV, SFV and WC were not associated with response, PFS or OS. Conclusions: Visceral fat volume plays a role of predictive marker of PFS to bevacizumab-based therapy for Japanese patients with mCRC.
Vesicular monoamine transporter protein expression in neuroblastoma: A report from the Children’s Oncology Group.
Authors: Steven G. DuBois, William Temple, Lori Mendelsohn, Grace E. Kim, Erin Nekritz, Clay Gustafson, Lawrence Lin, Kathy Giacomini, Arlene Naranjo, Collin Van Ryn, Gregory A Yanik, Susan G. Kreissman, Michael D. Hogarty, Katherine K. Matthay
Journal: Journal of Clinical Oncology (2015)

10043 Background: Vesicular monoamine transporters 1 and 2 (VMAT1 and VMAT2) are thought to mediate MIBG uptake in adult neuroendocrine tumors. VMAT expression has not been comprehensively investigated in neuroblastoma. Methods: We evaluated VMAT1 and VMAT2 expression by immunohistochemistry (IHC) in neuroblastoma tumors from 76 patients with high-risk disease treated on COG protocol A3973. All patients had baseline MIBG diagnostic scans centrally reviewed. IHC results were scored as the product of intensity grading (0-3+) and percent of tumor cells expressing the protein of interest. Association of VMAT1 and VMAT2 scores with clinical and biological features was tested using Wilcoxon rank sum tests. Results: Patient characteristics were typical of high-risk neuroblastoma, though the cohort was intentionally enriched for patients with MIBG non-avid tumors (n = 20). VMAT1 and VMAT2 were expressed in 62% and 75% of neuroblastoma tumors, respectively. VMAT1 and VMAT2 scores were both significantly lower in MYCN amplified tumors, non-adrenal primary tumors, and in tumors with high mitotic karyorrhectic index. MIBG avid tumors had significantly higher VMAT2 scores compared to MIBG non-avid tumors (median 216 vs. 45; p = 0.04). VMAT1 expression did not correlate with MIBG avidity. Conclusions: VMAT1 and VMAT2 are expressed in the majority of neuroblastomas. Expression correlates with clinical and biological features. Expression of VMAT2 but not VMAT1 correlates with avidity for MIBG.
Active surveillance: Do low-income patients adhere to the protocol?
Authors: Ryan Kraus, Lingyun Ji, Richard Jennelle, Susan Groshen, Leslie K Ballas
Journal: Journal of Clinical Oncology (2017)

53 Background: Use of active surveillance (AS) in low-risk prostate cancer (PC) is up from 10% in 2006 to 40% in 2013 according to the CaPSURE registry. The data that provides evidence for the use of AS were among patients adhering to follow-up schedules. There are no data illustrating if patients not on a study follow through with their AS. Based on our experience at a large safety-net hospital with a multi-ethnic, low-income population and a nearby university-based hospital, we hypothesize that AS patients at a safety-net hospital fail to follow-up more frequently than those at a university-based hospital. Methods: We performed a retrospective chart review of patients with non-metastatic prostate cancer who initiated AS at Los Angeles County Hospital (LAC) and Norris Cancer Center (NCC) between 1/1/2008-1/1/2015. Competing-risks regression analyses were used to examine the difference in the rates of AS patients being lost to follow-up (LTFU) between the two institutions, as well as the association between LTFU and patient characteristics, with patients who ended AS due to any reasons treated as competing risks. Results: We found 116 patients at LAC and 90 patients at NCC who met the AS criteria of this study. Patients at both hospitals had similar tumor characteristics. Patients at LAC and NCC differed, however, in median income, race, primary language spoken, median miles residing from hospital, and mean percent that graduated from high school in their zip code. There was a statistically significant difference between the rates of AS patients being LTFU at the two institutions. After two years, 48% of patients at LAC were LTFU vs. 16% of AS patients at NCC. Patients stay on AS for a median of 7.4 months at LAC vs. 22.8 months at NCC. On multivariable analysis (MVA), patients at NCC were more likely to be LTFU if they had a lower household income. At LAC, the MVA found that patients that lived further from LAC were significantly more likely to adhere to AS. Conclusions: Patients undergoing AS at LAC were LTFU at a high rate. AS can only be an effective strategy if patients actually undergo surveillance. We need further investigation to evaluate whether we should recommend AS at safety-net hospitals.
Chemotherapy-induced myelosuppression in ovarian cancer patients with germline <i>BRCA1/2</i> mutations: A case control study.
Authors: Alan Christie, Amalina Che Bakri, Patricia Roxburgh, Muhammad Imtiaz Khan, Yousuf Iqbal, Tzyvia Rye, Paul Mitchell, Ronald Rye, Fiona Nussey, Melanie J. Mackean, Nicholas Reed, Rosalind Margaret Glasspool, Michelle Ferguson, Charlie Gourley
Journal: Journal of Clinical Oncology (2013)

5571 Background: Ovarian cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2) mutations frequently respond to multiple lines of chemotherapy. Having noticed significant myelosuppression during chemotherapy in gBRCA1/2 patients we wished to determine whether this was a chance finding or related to a heterozygous gene dosage effect in the bone marrow. Methods: gBRCA1/2 ovarian cancer patients from Edinburgh, Glasgow and Dundee were identified and matched for chemotherapy regimen, dose and age to controls from the Edinburgh Ovarian Cancer Database. Case notes and transfusion service records were analysed for chemotherapy details, haematology results, G-CSF use, red cell and platelet transfusions during first line chemotherapy. Results: Of 91 gBRCA1/2 patients, 35 patients were excluded who had previously received cytotoxic chemotherapy (mostly for breast cancer) or unusual chemotherapy regimens unable to be matched to controls. 56 were matched to controls. Baseline haematological indices were similar. There was a significant difference in the fall in haemoglobin levels from baseline to cycle 4 in gBRCA1/2 patients compared to controls (12.23% v 5.14%, p = 0.0005) and gBRCA1/2 patients had longer delays during their chemotherapy (mean 7.73 v 4.51 days, p = 0.0375) and more dose reductions for haemotoxicity (14 v 4 p = 0.0011). gBRCA1/2 were more likely to have a red cell transfusion (19 v 11, p = 0.099), and received more red cells (69 v 31 units, p = 0.0318). G-CSF was required in 3 BRCA patients versus 0 controls. Differences in platelet and white cell counts at cycle 4 were not significant. Conclusions: Patients with ovarian cancer and germline BRCA1/2 mutations were more likely to have significant falls in haemoglobin levels and require red cell transfusions and to experience delays during chemotherapy. This susceptibility to anaemia may be a hemizygous BRCA1/2 gene dosage effect manifest in the bone marrow and may have implications for the optimisation of cytotoxic and PARP inhibitor therapy in this patient group.
Health and Public Policy to Facilitate Effective Prevention and Treatment of Substance Use Disorders Involving Illicit and Prescription Drugs: An American College of Physicians Position Paper
Authors: Ryan Crowley, Neil Kirschner, Andrew S. Dunn, Sue S. Bornstein
Journal: Annals of Internal Medicine (2017)

Substance use disorders involving illicit and prescription drugs are a serious public health issue. In the United States, millions of individuals need treatment for substance use disorders but few receive it. The rising number of drug overdose deaths and the changing legal status of marijuana pose new challenges. In this position paper, the American College of Physicians maintains that substance use disorder is a treatable chronic medical condition and offers recommendations on expanding treatment options, the legal status of marijuana, addressing the opioid epidemic, insurance coverage of substance use disorders treatment, education and workforce, and public health interventions.
Histone H4 Acetylation Is Associated with Improved Relapse-Free Survival in Newly Diagnosed Patients with Acute Lymphoblastic Leukemia (ALL) Less Than 60 Years of Age without Poor Risk Cytogenetics.
Authors: Anjali S. Advani, Sarah Gibson, Tao Jin, Matt Kalaycio, Ronald Sobecks, Mikkael A. Sekeres, Ed Copelan, Shawnda Sungren, Eric D. Hsi
Journal: Blood (2007)
Correction: Combining Human and Rat Sequences in Her-2 DNA Vaccines Blunts Immune Tolerance and Drives Antitumor Immunity
Journal: Cancer Research (2010)

An early version of this article (Cancer Res 2010;70:119–28) under the title “Human Her-2 DNA Vaccines Containing Heterologous Rat Neu Sequence Overcome Immune Tolerance to Induce Elevated Antitumor Immunity” was published by mistake in the January 1, 2010 issue of Cancer Research (1). The correct version of the article appears online.
Preliminary results of a phase II study of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube
Authors: P. G. Rose, R. Drake, P. S. Braly, M. C. Bell, R. M. Wenham, J. H. Hines, A. Alvarez-Secord, E. Soltes-Rak, B. H. Childs, T. J. Herzog
Journal: Journal of Clinical Oncology (2009)

5546 Background: Objectives are to estimate efficacy and safety of a novel taxane/platinum chemotherapy doublet in combination with bevacizumab (B), as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube (FT), after initial debulking surgery. Methods: Eligibility criteria included histological confirmation of primary disease, previous debulking surgery, and normal renal, hepatic, hematological, and neurological function. Subjects were treated with 6 cycles of oxaliplatin (85 mg/m2), docetaxel (75 mg/m2) and B (15 mg/kg) Q3W, followed by maintenance B (15 mg/kg Q3W) to complete one year of therapy. The primary endpoint is progression-free survival (PFS) of pts with measurable disease at 1 year. Results: A total of 110 subjects are included in safety and 95 in efficacy analyses (55 with measurable disease). Median age was 58 years. Tumors were mostly ovary as primary site (84%), poorly differentiated (65%), serous adenocarcinoma pathology (73%) and FIGO stage IIIC (68.2%) or IV (14.6%). 61% of subjects were optimally debulked. 95 (86%) of subjects had completed the chemotherapy cycles with 87 of the 95 having started on the B-only maintenance cycles. 85 (77%) subjects have stopped study treatment [including 33 completed study treatment, 29 disease progression, 15 adverse event (AE), 8 other reasons]. The most common grade 3–4 AEs were: neutropenia (39%), leukopenia (11%), hypertension (9%), and fatigue (7%) Grade 3–4 peripheral sensory neuropathy (PSN) occurred in 2 patients (1.3%). There was one case of colonic perforation associated with B. Investigator-determined best overall confirmed response rates were: complete response 32.8%; partial response, 29.1%; stable disease 32.7%; and progressive disease (PD), 1.8%. The 1-year PFS probability is 70.1% (95% C.I., 56.8%-83.4%) in the 55 patients with measurable disease. Conclusions: This preliminary data supports feasibility of this novel regimen, with an acceptable safety profile and a low incidence of PSN and colonic perforation. Preliminary 1-year PFS is promising. The trial completed accrual to 132 patients in August 2008. Updated results will be presented. [Table: see text]
A novel targeted oral insulin-like growth factor-1 receptor (IGF-1R) inhibitor and its implications for patients with non-small cell lung cancer (NSCLC): A phase I clinical trial.
Authors: Simon Ekman, Johan Harmenberg, Jan-Erik Frödin, Stefan Bergström, Cecilia Wassberg, Staffan Eksborg, Olle Larsson, Magnus Axelson, Åsa Hedlund, Carina Alvfors, Birgitta Ståhl, Michael Bergqvist
Journal: Journal of Clinical Oncology (2012)

7539 Background: The small-molecule IGF-1R inhibitor picropodophyllin (PPP) is the active compound in the oral suspension AXL1717. PPP has shown extensive preclinical antitumor effects against a wide range of cancers supporting its use as a single agent treatment. Methods: The clinical phase Ia/b study on advanced progressive cancer patients with various solid tumors and without remaining treatment options aimed at establishing the recommended phase II dose (RPTD) and the maximum tolerated dose (MTD) of AXL1717. Phase Ia consisted of single day dosing and phase Ib multiday dosing (to an accumulated total of 28 days of treatment; 2*28 days following amendment) with 3 weeks intermission between treatments. Non-progressing patients could continue treatment in the extension study without time limitation (treated 119 weeks). PK samples were obtained at 10 different time-points after the morning dose when appropriate. Results: Phase Ia included 16 patients treated with 78 BID doses ranging from 5-2900 mg AXL1717 BID without any dose-limiting toxicity. Phase Ib included 39 patients treated with doses between 290-930 mg BID in periods between 7-28 days, totally for 147 weeks. Phase Ib showed that AXL1717 was well tolerated and neutropenia was the only detected dose-related, reversible, dose-limiting toxicity (DLT). RPTD dose was set at 390 mg BID to minimize neutropenia. Although the study was not designed for efficacy assessment, some patients, mainly with NSCLC, showed signs of clinical benefit, including 3 partial responses and 12 patients with stable disease. The 15 patients with NSCLC and treatment duration of more than 2 weeks with single agent AXL1717 in 3rd or 4th line showed a median time to progression of 31 weeks and a survival time of 60 weeks with 4 patients being alive at cut-off. Down-regulation of IGF-1R on granulocytes and increases of serum IGF-1 were seen. The systemic exposure of AXL1717 was dose-dependent and sufficient for antitumor effects. Conclusions: AXL1717 has a good safety profile and demonstrated promising clinical benefits in this severely ill and heavily pretreated patient cohort, especially in patients with NSCLC.
Linking kinases to adverse events through kinase inhibitors.
Authors: Afsheen Iqbal, Shan Zhao, Sonia Evelyn Reichert, Robert G. Maki
Journal: Journal of Clinical Oncology (2013)

e13524 Background: Small molecule oral kinase inhibitors (SMOKIs) are anticancer agents with unique activity and toxicity. We sought to determine if specific kinases blocked by SMOKIs could be linked to specific adverse events (AEs). Methods: We identified studies in which cancer indications for SMOKIs were compared to placebo or other therapy, and collected prevalence data of grade 3, 4, and 5 AEs for each study arm. Targets of each SMOKI were screened from existing data on kinase specificity, selecting Kd&lt;500nM. Each SMOKI was mapped to its respective kinases. We compared the frequency of AEs from all studies when the kinase of interest was involved to AE frequency when the kinase was not involved, and computed the probabilities for attributed risk for each kinase and the significance of association between AE and drug of interest via t-test. We evaluated the significance in a pair-wise manner, computing the difference in probability for a single AE for each study independently, and then evaluating the significance of the average probability, assuming unequal variance across studies. Results: 67 trials fit our criteria, and led to the identification of AEs associated with varying number of kinases, e.g. diarrhea (45 kinases), asthenia (43), hypertension (30), rash (30), thrombocytopenia (plts, 29), and neutropenia (21). Most associations, while statistically significant, had low attributable risk (≤5%), except diarrhea (24 kinases), hand-foot syndrome (19), and plts (13). BRAF (5.4% attributable risk) and VEGFR1 (4.9%) inhibition were most strongly associated with hypertension; AXL (5.3%), FGFR3 (5.3%), MAP4K5 (5%), and YES1 (5%) were associated with neutropenia; and TNIK (5.4%), PLK4 (5.3%), STK16 (5.3%), RPS6KA1 (5.1%), and FGFR3 (5%) were associated with asthenia. Conclusions: Certain AEs are common to many SMOKIs and thus many kinases. Other AEs such as neutropenia and asthenia were more tightly linked to specific kinases. By developing SMOKIs that block the target of interest but not kinases identified from these data, it may be possible to decrease the toxicity burden of future generations of SMOKIs.
Neoadjuvant administration of radiation therapy and intratumoral autologous dendritic cells in patients with localized high-risk soft tissue sarcomas.
Authors: Shailaja KS Raj, Daniel Joseph Indelicato, Alberto Chiappori, Anthony Paul Conley, Ricardo Gonzales, Randy Heysec, Douglas D. Letson, Dmitry Gabrilovich, Marilyn M Bui, Steven Finklestein, Scott Joseph Antonia
Journal: Journal of Clinical Oncology (2014)

10519 Background: Patients with high grade, large (<5 cm) soft tissue sarcomas (STS) can develop metastases after surgical therapy with no proven benefit to adjuvant chemotherapy. Our in vivo murine model demonstrated that standard external bean radiation therapy with experimental intratumoral injection of dendritic cells (DC) produces tumor-directed immunity. Our protocol, established that preoperative RT +DC regimens safe in patients with large high grade STS with a significant anti autologous tumor cell immune response. We hypothesize that release of tumor antigens to the intratumoral dendritic cells results in the cross priming of an effector anti tumor cell response. Methods: 32 patients were enrolled in two (phase I & II) trials given radiation neoadjuvantly, up to 50Gy,5days a week, combined with intratumoral injection of dendritic cells, followed by surgery and compared to 54 historic controls treated at Moffitt Cancer Center during the same period with radiation. Dendritic cells were prepared using culture of mononuclear cells with granulocyte-macrophage colony stimulating factor GM-CSF and interleukin-4. Results: 9/17 patients on the phase I developed tumor-specific immune responses, which lasted from 11 to 42 weeks. The remaining immunological results will be presented at the meeting. In multivariate analysis using Cox-proportional hazards model, tumor size (>=10cm) was associated with poorer OS (p=0.028; HR=3.6 with 95%CI=1.1-11.4) and with DFS (p=0.021; HR=2.8 with 95%CI=1.2-6.9). A trend to better overall survival (OS) and progression free survival (DFS) of the patients, in the dendritic cell vaccine arm was seen, when compared to the historic controls but this was not statistically significant by univariate analysis (OS: p=0.29; DFS: p=0.24). Conclusions: Neoadjuvant therapy with radiation and intratumoral autologous dendritic cells in high risk soft tissue sarcoma patients is safe. Tumor specific immune responses were seen with CD4 positive T cells in the earlier group of patients. Clinical trial information: 16441.