tbuckley/cabot-search huggingface dataset:
<i>MGMT </i>promoter methylation as a prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: First results from the randomized phase II DIRECTOR trial.
Authors: Ghazaleh Tabatabai, Wolfgang Wick, Joachim Peter Steinbach, Antje Wick, Oliver Schnell, Peter Hau, Ulrich Herrlinger, Michael Sabel, Hans-Georg Wirsching, Ralf Ketter, Oliver Baehr, Michael Platten, Joerg Tonn, Johannes Huesing, Guido Reifenberger, Michael Weller
Journal: Journal of Clinical Oncology (2014)

2015 Background: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after radiotherapy with concomitant and maintenance temozolomide (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying TMZ continuously or using 7/14 or 21/28 days schedules. Progression-free survival rates have been in the range of 10-30% without any major prognostic impact of O6-methylguanine DNA methyltransferase (MGMT). Methods: Glioblastoma patients at first progression after TMZ/RT→TMZ and at least 2 maintenance TMZ cycles were randomized to Arm A (one week on (150 mg/sqm TMZ per day) / one week off) or to Arm B (three weeks on (100 mg/sqm TMZ per day) / one week off). The primary end point was median time to treatment failure defined as progression, premature (< 12 months) TMZ discontinuation for toxicity, or death from any cause; 166 patients were deemed necessary to show a meaningful difference between arms. Results: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients.The outcomes in Arm A and Arm B for the primary endpoint of median time to treatment failure (56 days [95% CI 55-98] vs. 59.5 days [95% CI 56-105]) and for overall survival (OS) (298 days [95% CI 202-395] vs. 322 days, [95% CI 246-356]) were similar. These endpoints differed, however, by MGMT promoter methylation status, which was informative for all patients. Median time to treatment failure in patients with MGMT-methylated tumors was 98 days [95% CI 56-223] vs. 56 days [95% CI 56-60] in MGMT-unmethylated glioblastoma. PFS-6 was 39.7% vs. 6.9% with vs. without MGMT promoter methylation; OS with MGMT-methylated glioblastoma was 382 days [95% CI 300-531] vs. 241 days [95% CI 191-313] in MGMT-unmethylated glioblastoma. Hematological toxicity > grade 3 was similar (27% Arm A vs. 30.7% Arm B). Conclusions: TMZ rechallenge is an active treatment for MGMT promoter-methylated glioblastoma progressive after standard therapy. The best TMZ regimen remains to be defined. Alternative strategies are warranted for patients with progressive MGMT-unmethylated glioblastoma. Clinical trial information: NCT00941460.
Molecular Characterization By Immune Profiling of Paired Blood and Bone Marrow in Multiple Myeloma and Its Precursor States
Authors: Manisha Bhutani, David M. Foureau, Nury M Steuerwald, Sally Trufan, Fei Guo, Katherine Rigby, Elise Tjaden, Alicia Hamilton, Marina Leonidas, Aarin Berlin, Laura Johnson, Jordan Williams, Shebli Atrash, Ami P Ndiaye, James Symanowski, Peter M. Voorhees, Saad Z. Usmani
Journal: Blood (2018)
Age as an independent predictor of chemotherapy treatment decisions in 20 common cancers.
Authors: Peter Hall, Cat Handforth, Katie Spencer, David Jackson, Geoff Hall
Journal: Journal of Clinical Oncology (2014)

9550 Background: There have been recent concerns regarding ageism in oncological management. A debate is on-going as to what extent age alone influences the decision to offer a patient adjuvant or palliative chemotherapy, or whether apparent ageism is simply a reflection of correlation between age and other prognostic or predictive factors. This study aims to measure the independent effect of age on the decision to use chemotherapy in 20 common cancers. Methods: Patients with an ICD-10 coded diagnosis of cancer were identified within a regional cancer registry between 2000 and 2011. The data was linked to UK national diagnostic data (Hospital Episode Statistics) to provide information on comorbidity. The odds ratio for receiving chemotherapy dependent on age was estimated using logistic regression to adjust for stage, morphology, grade, socioeconomic status, surgery, radiotherapy, other treatments and 15 different comorbidities. Cox regression analysis on 10 year overall survival was used test for a predictive effect of age on benefit from chemotherapy, adjusted for these factors. Results: 96,165 patients were included in the study. The odds ratio for older patients receiving chemotherapy (age 70 or greater) was 0.03 (95% CI 0.03 - 0.04, p=<0.001) for early breast cancer; 0.10 (95% CI 0.05 – 0.20, p = <0.001) for metastatic breast cancer; 0.43 (95% CI 0.25-0.74, p=0.003) for ovarian cancer; 0.18 (95% CI 0.15 – 0.22, p=<0.001) for Dukes B and C colorectal cancer; 0.21 (95% CI 0.17 – 0.27, p<0.001) for metastatic colorectal cancer and significant for all other cancer types. For overall survival, the interaction between age and chemotherapy was significant (p<0.01) for many tumour types including early breast cancer, colorectal cancer, bladder cancer and pancreatic cancer. Conclusions: Age exerts an independent effect on the decision to treat with chemotherapy in all types of cancer studied. There is evidence that the size of this effect and the age cut-off for a likely decision to treat varies between cancer types. Age may be predictive of benefit from chemotherapy in many cancer types. Further research is needed to clarify to contribution of subjective attributes such as performance status, frailty and patient or clinician attitudes on treatment decisions.
Association of early venous thromboembolic events with worse prognosis in patients with lung cancer.
Authors: Taxiarchis Kourelis, Ewa Maria Wysokinska, Yi Wang, Ping Yang, Alfonso Tafur, Aaron Scott Mansfield
Journal: Journal of Clinical Oncology (2014)

e20623 Background: Venous thromboembolic events (VTE) are a leading cause of death in cancer patients. The timing of VTE may have additional prognostic significance. We hypothesized that early VTE (EVTE, within 3 months of diagnosis) in patients with lung cancer (LC) are associated with worse overall survival (OS). Methods: We identified 727 patients with LC that were treated at Mayo between 1998-2011. We excluded patients that were receiving anticoagulation at the time of LC diagnosis. Late VTE (LVTE) were defined as VTE occurring after 3 months from LC diagnosis and prior VTE (PVTE) as VTE occurring 3 to 12 months prior to their diagnosis of LC. Advance disease (AD) was defined as patients with Stage IV non-small cell lung cancer (NSCLC) or extensive stage small cell lung cancer (SCLC), and non-advanced disease (non-AD) was defined as ≤Stage III NSCLC or limited stage SCLC. Results: Out of 727 patients included in our review, 617 patients had NSCLC (85%), 94 (13%) SCLC and 16 (2%) low grade neuroendocrine tumors. Median follow-up was 15 months. Ninety five patients (13%) experienced VTE, 44 (6%) experienced an EVTE, 49 (7%) had a LVTE and 2 had a PVTE. Patients with EVTE were more likely to have AD (67% vs 39%, p<0.001), more likely to have received chemotherapy at LC diagnosis (55% vs 39%, p=0.04) and more likely to have a higher Charlson comorbidity index (8 vs 6, p=0.02). Patients with an EVTE had worse OS when compared to all other patients (medians 4 vs 17 months, p<0.0001). EVTE were associated with worse OS in patients with non-AD (medians 12 vs. 42 months, p=0.01) and AD (medians 4 vs 6 months, p=0.02). When considering patients with NSCLC only, EVTE were associated with worse OS in patients with stage I-III disease (medians 12 vs 46 months, p<0.001) as well as patients with stage IV disease (medians 3 vs 5 months, p<0.01). In a multivariate model that included age, stage, performance status>2 and Charlson comorbidity index, EVTE were an independent predictor of increased mortality (RR 2.3; 95% CI. 1.6-3.3). Conclusions: VTE are common in patients with LC. EVTE events are associated with worse OS, irrespective of stage of the disease. Our findings underscore the need for an efficient preventive strategy for VTE among patients with lung cancer.
Understanding the Cellular Origin and Pathogenic Transcriptional Programs in Multiple Myeloma (MM) and Light-Chain Amyloidosis (AL) through the Dissection of the Normal Plasma Cell (PC) Development
Authors: Daniel Alameda, Marco Vicari, David Lara-Astiaso, Marta Lasa, Noemi Puig, Maria Teresa Cedena Romero, Idoia Rodriguez, Diego Alignani, Amaia Vilas-Zornoza, Ibai Goicoechea, Sarai Sarvide, Enrique M. Ocio, Ramon Lecumberri, Alfonso García de Coca, Jorge Labrador, Esther González Garcia, Luis Palomera, Mercedes Gironella, Valentin Cabañas, Maria Casanova, Albert Oriol, Isabel Krsnik, Albert Pérez, Joaquin Martinez Lopez, Maria-Victoria Mateos, Juan-José Lahuerta, Felipe Prosper, Assaf Weiner, Ido Amit, Jesús F San-Miguel, Bruno Paiva
Journal: Blood (2018)
Identification and characterization of Urokinase substrates by screening one bead one compound (OBOC) combinatorial libraries
Authors: Pappanaicken R. Kumaresan, Aimin Song, Ruiwu Liu, Nin Yao, Kit S. Lam
Journal: Cancer Research (2006)

1106  Uro-plasminogen activator (u-PA) interacts with its receptor UPAR and converts tissue plasminogen to plasmin. Plasmin plays a major role in destroying the extra-cellular matrix to metastasis cancer cells. Inhibitors for urokinase have shown to control the metastasis of cancer cells. However, efficient and metabolically stable small molecule inhibitors are much needed to control the disease. The goals of this project are to identify and characterize both urokinase substrates and inhibitors using the OBOC combinatorial chemistry methods. Several fluorescence resonance energy transfer (FRET) OBOC combinatorial libraries were constructed using 2-amino benzoic acid (fluorescence) and 2-nitrotyrosine (quencher) as the FRET pair. During library screening, freshly collected human plasma was incubated with the peptide libraries. The resulting fluorescent beads signify cleavage of the peptide or removal of the quencher from those beads. The fluorescent beads were removed and the remaining beads were then incubated with 500mU uPA for 1 hour. Over 20 fluorescent beads were isolated and microsequenced. These peptide leads can potentially be used substrates for the development of urokinase specific imaging agents as well as highly potent inhibitors for this enzyme.
On-demand CO release for amplification of chemotherapy by MOF functionalized magnetic carbon nanoparticles with NIR irradiation
Authors: Jizong Yao, Yao Liu, Jiawen Wang, Qin Jiang, Dejun She, Huishu Guo, Nianrong Sun, Zhiqing Pang, Chunhui Deng, Wuli Yang, Shun Shen
Journal: Biomaterials (2018)
Description of GCSF usage in oncology in five European countries.
Authors: Caroline Anger, Nina Schmidt, Carolina Ricarte
Journal: Journal of Clinical Oncology (2014)

e20718 Background: Granulocyte Colony-Stimulating Factors (GCSF) are used as supportive care in cancer management when patients receive chemotherapy. Purpose of this study was to describe the GCSF usage patterns in oncology across 5 European countries. Methods: For this study IMS Oncology Analyzer (OA) was used, a patient database collected through a quarterly physician panel survey. OA reports on patient case history information related to the treatment of patients across all cancer types. Most recent data (October 2012-September 2013) from France, Germany, Italy, Spain and UK were used. Results: From a total sample of 53,960 patients diagnosed with cancer, 34,106 patients were receiving a chemotherapy. Among them, 2,554 (7.5%) received a GCSF. 61% of them were ≥56 years old, with an even split between male and female. In GCSF treated population, non-hodgkin lymphoma was the most common cancer (NHL) (28%), followed by breast cancer (20%), hodgkin’s disease (7%) and non-small cell lung cancer (6%). Chemotherapies administered most often were anthracycline + alkylating agent (33%), platinum + antimetabolite (15%), platinum + taxane (10%), and taxane + anthracycline + alkylating agent (6%). Goal of chemotherapy was curative in 93% of patients. 38% of these treatments were prescribed by medical oncologists followed by haematologists (34%). In solid tumours, 53% of GCSF-treated patients received Pegfilgrastim, 36% Filgrastim and 10% Lenograstim. In liquid tumors those proportions changed to 38%, 48% and 12% respectively. 78% of GCSF administrations had a prophylactic intent, 18% were to treat 4% had both intents. Conclusions: Data from this study suggests that NHL and Breast cancer are the key cancers where more patients are treated with GCSF. Pegfilgrastim seems to be more used in solid tumours, whereas Filgrastim is the molecule used the most in liquid tumours. Around ¾ of the GCSF usage is prophylactic. Further research is needed to understand GCSF usage in specific tumours in different countries.
Relationship between type of therapeutic intervention and funding source in randomized clinical trials (RCTs) in oncology.
Authors: Fernando Costa Santini, Fabio Ynoe de Moraes, Everardo D. Saad, Artur Katz
Journal: Journal of Clinical Oncology (2014)

6621 Background: Pharmaceutical companies play an important role in drug development and approval in an environment where performing RCTs has become increasingly costly and complex. However, myriad questions about the impact of surgical and radiotherapy interventions equally require adequate hypothesis testing in RCTs. A potential lack of funding for non-drug related RCTs may lead to important gaps in clinical knowledge. Methods: We searched PubMed for all RCTs published between 01/2009 and 12/2013 in breast, prostatic, lung and colorectal cancers. All articles published in this period were manually screened for eligibility. We included only RCTs with clinical endpoints such as TTP, PFS, OS and response rate. Two investigators independently selected phase 2 and phase 3 RCTs with at least 50 patients published in English. We classified eligible trials according to the type of intervention (drugs, radiotherapy or surgery) and the stated funding source (industry versus nonprofit). Results: We retrieved 4,416 RCTs studies of which 709 (16%) were eligible. 578 (82%) of the RCTs evaluated drugs, 74 (10%) radiotherapy and 57 (8%) surgery. There was a significantly greater number of RCTs evaluating radiotherapy or surgery performed in colorectal and prostatic cancers compared to lung and breast. Overall, 470/709 (66%) RCTs were funded entirely or partially by industry (pharmaceutical and device companies) and 239/709 (34%) by nonprofit organizations (government, academic centers or foundations). There was a significant association between source of funding and type of intervention: 448/578 RCTs (77,5%) evaluating drugs were funded by industry, in comparison to only 22/131 (17%) of surgical and radiotherapy RCTs (p<0.0001). Conclusions: The vast majority of RCTs in oncology relates to drug development and is being funded by industry, while 83% of RCTs evaluating surgical or radiotherapy related questions are not industry funded. Even though drug development is of paramount importance, the extent to which clinically relevant issues are not being properly addressed by RCTs, at least in part due to lack of funding, should be considered and further evaluated.
Capridine-β, a new class of chemotherapeutic agents for prostate cancer.
Authors: Raj K Tiwari, Robert Suriano, Debabrata Banerjee, Jerzy Konopa, Jan Geliebter, Abraham Mittelman
Journal: Journal of Clinical Oncology (2014)

e16062 Background: Available targeted chemotherapy for prostate cancers (CaP) is limited. We are developing a nitroacridine (NA) derivative, 9-hydroxy-ethylamino-4-methyl-1 nitroacridine, C-1748 (Capridine-β) for CaP. Precursors of C-1748 have been used earlier as anti-malarial compounds and one such precursor, C-857, tested on the NCI panel of multiple cancer cell lines was determined to be CaP specific. Methods: In vitro inhibitory concentration, IC50, of Capridine-β in prostate, breast, colon, sarcoma and leukemia cancer cell lines was determined by XTT. Xenograft studies in nude mice were performed with CaP cells, LnCaP, DU-145, PC-3, JCA to define the in vivoanti-tumor efficacy doses. DNA intercalation, microarray gene profiling and western blot analyses were used to define Capridine’s targets in CaP. Hematological, renal, hepatic and cardiac toxicities were examined in rodents and dogs. Results: Of all the cell lines tested, the IC50 values of Capridine-β were the lowest in human prostate cancer cells (5-10 nM) and the highest in leukemia cells (over 100 nM). The drug had high anti-apoptotic activity against docetaxel resistant CaP cells. The differential anticancer activity between CaP and leukemic cells was validated by the observation of low myelotoxicity in rodent and dogs. In contrast to prevalent chemotherapeutic drugs, hematological, renal, hepatic and cardiac toxicities were minimal. Xenograft studies in nude mice using LnCaP, DU145, PC3 and JCA cells indicated that Capridine-β has anti tumor efficacy on both hormone dependent and independent CaP. The rodent tumor inhibitory dose extrapolated to humans suggests a very wide therapeutic window. Hormone independentCaP cells treated with capridine showed upregulation of a functional androgen receptor making them sensitive to anti-hormonal therapy. The cellular targets identified were the tumor suppressor protein p16, cell cycle molecule CDK4 and phosphorylated H2AXγ. Conclusions: Our in vitro, in vivo and toxicity profile studies suggests that C-1748 is a novel NA derivative that can potentially be useful in adjuvant chemotherapy for CaP, find a clinical niche in taxane resistant CaP, and used in combination with prevalent anti-hormonal therapy.
Cause-specific mortality among patients with Hodgkin lymphoma (HL) up to 40 years after treatment.
Authors: Michael Schaapveld, Anna M. van Eggermond, Cecile P.M. Janus, Augustinus D.G. Krol, John M. M. Raemaekers, Eefke J. Clevers-Petersen, Pieternella J. Lugtenburg, Jose M. Zijlstra, Gustaaf Willem Van Imhoff, Richard W.M. Van Der Maazen, Judith M. Roesink, Max L. Beijert, Philip M. Poortmans, Leontien C.M. Kremer, Marieke J. Louwman, Marnix Lybeert, J. P. De Boer, Berthe M.P. Aleman, Flora E. van Leeuwen
Journal: Journal of Clinical Oncology (2014)

9517 Background: HL treatment is associated with high risk of treatment-related morbidity, including second cancers and cardiovascular diseases. However, only few studies examined excess mortality after prolonged follow-up up to 40 years. Methods: We studied cause-specific mortality in a multicenter cohort comprising 3,575 5-year HL-survivors, diagnosed before age 51 and treated between 1965 and 1995. Follow-up was complete until at least January 2010 for 96% of the patients. For 93% of deaths, the cause was known. Mortality after HL was compared with mortality in the general population by calculating standardized mortality ratios (SMRs) and absolute excess mortality (AEM), expressed per 10,000 person-years. Treatment-specific SMRs were compared by Poisson regression. Results: After a median follow-up of 21.6 years since HL treatment 1,328 patients had died (19.5% from HL, 32.5% from solid tumors (ST), 15.5% from cardiac diseases (CD), 7.0% from NHL/leukemia). The SMR for causes other than HL was 8.2-fold that of the general population. The cohort experienced 149.2 excess deaths per 10,000 patients per year. The SMR and AEM for causes other than HL increased throughout follow-up: after ≥35 years the SMR was 19.2, translating into 505.9 excess deaths per 10,000 patients per year. ST accounted for the largest part of the excess mortality (overall SMR 5.6, AEM 56.1). While the SMR for ST remained stable, the SMR for CD (overall SMR 9.8, AEM 29.4) increased during follow-up (SMR at ≥35 years 28.8, ptrend<0.001)). Adjusted for sex, age and follow-up time, risk of death from CD was increased for patients treated with supradiaphragmatic radiotherapy (RT) (Relative Risk (RR) 4.8, p<0.001) or anthracyclines (RR 1.5, p=0.044), independently. The SMR for infectious causes (2.9% of all deaths, including deaths due to influenza/pneumonia) was 6.5-fold increased. Both splenectomy (2.1, p=0.041) and spleen RT (RR 3.2, p=0.001) were associated with increased risk of death due to infectious causes compared to patients not receiving such treatment. Conclusions: Even after ≥35 years since treatment, HL patients experienced elevated SMRs and AEMs from ST and CD. Both splenectomy and spleen RT increased mortality due to infections.
Retrospective evaluation of prophylactic cranial irradiation in patients with limited-stage small cell lung cancer with stereotactic radiotherapy: A multi-institutional study.
Authors: Yuichi Ozawa, Minako Omae, Masato Fujii, Masato Kato, Kazuhiro Asada, Shinya Sagisaka, Masato Karayama, Takashi Matsui, Toshihiro Shirai, Kazumasa Yasuda, Yutaro Nakamura, Naoki Inui, Kazunari Yamada, Koshi Yokomura, Takafumi Suda
Journal: Journal of Clinical Oncology (2014)

7591 Background: The benefits of prophylactic cranial irradiation (PCI) on survival time have been repeatedly reported especially in patients with limited stage small cell lung cancer (LS-SCLC). However, almost all such studies were performed decades ago and whether PCI is still beneficial in conjunction with pre-symptomatic brain screening and stereotactic radiotherapy (SRT) in patients with brain metastasis (BM) remains unknown. Methods: The data of all patients with pathologically proven SCLC from 1/1/2006 to 6/31/2013 were collected from 4 designated cancer care hospitals in Japan, all of which were equipped with or had access to SRT, and thoroughly reviewed. LS disease at diagnosis and who were estimated as CR or good PR after the first treatment were enrolled. All possible patients were periodically screened for BM by CT or MRI and patients with BM were preferentially considered for SRT. The effects of PCI and SRT were analyzed by Kaplan-Meier method and Cox proportional hazards model. Results: Of all 418 patients with SCLC, 124 matched our criteria. The 124 patients were divided into a PCI (P) group (n=29) and non-PCI (NP) group (n=95). Patient backgrounds were similar with the exception of median age (65 v 73; p<0.001) and stage (1/2/3) at diagnosis (1/4/24 v 31/15/49; p=0.001). Neither the cumulative occurrence of BM at 2 years (COB) (45.5 v 29.9%; p=0.250) nor the median survival time (MST) (25.5 v 34.5 months (m); p=0.312) showed statistically significant differences between the two groups. Even when only stage 3 cases were analyzed, no statistically significant differences in COB or MST were found between the two groups (43.1 v 53.7%; p=0.437, 25.5 v 26.5 m, p=0.546, respectively). 10 patients in P group and 25 in NP group developed BM. Survival time after BM detection was significantly longer in NP group (8.0 v 20.2 m, p=0.050). Furthermore, SRT was significantly associated with longer survival after BM detection when adjusted for age and stage (hazard ratio; 0.468, p=0.045). Conclusions: PCI does not benefit patients with LS-SCLC in conjunction with periodical brain screening and SRT. A prospective study is currently underway.