tbuckley/cabot-search huggingface dataset:
Erratum: Thromboembolic risk in atrial flutter: Preliminary results of the Italian Multicenter Flasiec study (Circulation (October 27, 1998) 98:17 (I1-I1016))
Authors: G. Corrado, A. Sgalambro, F. Gentile, A. Mantero, M. Santarone, M. Gasparini, R. Bufalino, A. Morabito, K. Savino, R. Schlavina, R. Mangia
Journal: Circulation (1999)
The 70-gene signature to provide risk stratification and treatment guidance for patients classified as intermediate by the 21-gene assay.
Authors: Michaela L. Tsai, Sarah Untch, Tina Treece, Shelly S. Lo
Journal: Journal of Clinical Oncology (2016)

571 Background: The 21-gene assay (Oncotype DX) gives an intermediate recurrence score (RS 18-30 clinical range, 11-25 trial range) for 32-67% of tested patients. The clinical utility of the FDA-cleared 70-gene signature (MammaPrint) was evaluated in this population. Methods: This prospective study of MammaPrint in breast cancer patients with an intermediate recurrence score (PROMIS) was carried out at 58 US institutions, following NCCN guidelines. The trial included 831 ER+, LN- women with an intermediate RS between 18 and 30. The 70-gene signature (70-GS) was obtained to refine risk categorization. The recommended treatment plan was captured before and after receiving results for the 70-GS. Adjuvant treatment was started after obtaining results. The distribution of High Risk (HR) and Low Risk (LR) patients was evaluated, in addition to how the result affected physician adjuvant treatment decisions involving chemotherapy and physician confidence. Results: The 70-GS reclassified 831 intermediate patients to 45% LR and 55% HR. As a result of the 70-GS reclassifications, there were significant changes in chemo treatment decisions (p<0.001). 29% of the LR patients had chemo removed from their treatment recommendation, and 36% of the HR patients had chemo added to their treatment recommendation after receiving the 70-GS result. Due to the intended use population of the 21-gene assay (21-GA), 99% of patients were Luminal-type. There were LR and HR patients at every RS in the intermediate range. The 70-GS provided additional independent prognostic information (adjusted R-squared=0.13). Furthermore, a lack of correlation between the 70-gene index and 21-gene RS (r=-0.37) validates signature differences. Overall, 79% of physicians reported that they gained greater confidence in their treatment recommendation after receiving the 70-GS result. Conclusions: The PROMIS trial provides evidence that the 70-GS gives actionable results for patients classified as intermediate by the 21-GA, generating a 33% change in treatment decisions. Clinical trial information: NCT01617954.Treatment decision Post-70-GS-HR Post-70-GS-LR Chemo No Chemo Chemo No Chemo Chemo (Pre-70-GS) 234 2 33 108 No Chemo (Pre-70-GS) 165 57 1 231
Implementation of Treatment Protocols in the Diabetes Control and Complications Trial
Journal: Diabetes Care (1995)

OBJECTIVE To describe the methods used to implement intensive and conventional therapies in the Diabetes Control and Complications Trial (DCCT) and the metabolic results that occurred with the different treatment regimens. RESEARCH DESIGN AND METHODS The DCCT was a controlled clinical trial that demonstrated the beneficial effect of intensive therapy on the long-term complications of insulin-dependent diabetes mellitus (IDDM). A total of 1,441 volunteers with IDDM, aged 13–39, from 29 centers in the U.S. and Canada, were randomly assigned to conventional or intensive diabetes therapy. Intensive therapy, which used multiple daily injections (MDI) of insulin (≥3 injections/day) or continuous subcutaneous insulin infusion (CSI1), was implemented by a team that included diabetes nurses, dietitians, behavioral experts, and diabetologists. Volunteers in the intensive treatment group could use MDI or CSII, based on patient and clinic preference, and could switch between therapies over the course of the study. The volunteers were followed for a mean of 6.5 years (range 3–9 years). RESULTS A detailed analysis of implementation of the two treatments indicates that intensive and conventional treatment subjects adhered to their respective insulin injection regimens &amp;gt;97% of the time. Adherence to other elements of intensive treatment was similarly high and resulted in median HbAlc values between 6.7 and 7.2, compared with 8.7–9.2 with conventional therapy, over the course of the study. Severe hypoglycemia occurred three times more often in intensively treated subjects. Although subjects on intensive treatment were not randomly assigned to MDI or CSII, we compared those subjects who used either of these methods for &amp;gt;90% of the study time. CSIIy-treated patients maintained a mean HbAlc of 6.8 vs. 7.0 in MDI-treated subjects during the trial (P &amp;lt; 0.05). The frequency of hypoglycemia with coma and seizure and diabetic ketoacidosis was modestly higher with CSII than with MDI. CONCLUSIONS Intensive therapy was implemented successfully in the DCCT. The detailed description herein will serve to facilitate translation of the DCCT results to the clinical setting.
Preclinical anti-myeloma activity of EDO-S101, a new bendamustine-derived molecule with added HDACi activity, through potent DNA damage induction and impairment of DNA repair
Authors: Ana-Alicia López-Iglesias, Ana B. Herrero, Marta Chesi, Laura San-Segundo, Lorena González-Méndez, Susana Hernández-García, Irena Misiewicz-Krzeminska, Dalia Quwaider, Montserrat Martín-Sánchez, Daniel Primo, Teresa Paíno, P. Leif Bergsagel, Thomas Mehrling, Marcos González-Díaz, Jesús F. San-Miguel, María-Victoria Mateos, Norma C. Gutiérrez, Mercedes Garayoa, Enrique M. Ocio
Journal: Journal of Hematology & Oncology (2017)

Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylating activity. The efficacy of EDO-S101 was evaluated in vitro, ex vivo and in vivo, alone, and in combination with standard anti-myeloma agents. The underlying mechanisms of action were also evaluated on MM cell lines, patient samples, and different murine models. EDO-S101 displayed potent activity in vitro in MM cell lines (IC50 1.6–4.8 μM) and ex vivo in cells isolated from MM patients, which was higher than that of bendamustine and independent of the p53 status and previous melphalan resistance. This activity was confirmed in vivo, in a CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, leading to a significant survival improvement in both models. In addition, EDO-S101 was the only drug with single-agent activity in the multidrug resistant Vk12653 murine model. Attending to its mechanism of action, the molecule showed both, a HDACi effect (demonstrated by α-tubulin and histone hyperacetylation) and a DNA-damaging effect (shown by an increase in γH2AX); the latter being again clearly more potent than that of bendamustine. Using a reporter plasmid integrated into the genome of some MM cell lines, we demonstrate that, apart from inducing a potent DNA damage, EDO-S101 specifically inhibited the double strand break repair by the homologous recombination pathway. Moreover, EDO-S101 treatment reduced the recruitment of repair proteins such as RAD51 to DNA-damage sites identified as γH2AX foci. Finally, EDO-S101 preclinically synergized with bortezomib, both in vitro and in vivo. These findings provide rationale for the clinical investigation of EDO-S101 in MM, either as a single agent or in combination with other anti-MM drugs, particularly proteasome inhibitors.
Anthrax-toxin-receptor-directed angiogenesis inhibitors
Authors: Michael Rogers, Thomas Caldwell, Kenneth Christensen, Robert D'Amato
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

1106 

Anthrax toxin binds with high affinity to the cellular receptors known as capillary morphogenesis gene protein 2 (CMG2) and tumor endothelial marker 8 (TEM8). We have recently used non-toxic anthrax toxin receptor subunits to demonstrate that interfering with the normal function of anthrax toxin receptors inhibits angiogenesis. Thus, anthrax toxin receptors are useful targets for anti-angiogenic therapy. We have now developed, optimized, and performed pilot screening using homogeneous fluorescence resonance energy transfer assays to identify small molecules that inhibit the high affinity protein-protein interactions between PA and the anthrax toxin receptors, CMG2 or TEM8. Briefly, a PA cysteine mutant (PA E733C) was labeled with a donor fluorophore (Alexa Fluor 488) while soluble receptor binding domain truncation mutants were labeled with an acceptor fluorophore (Alexa Fluor 546). When mixed at equimolar ratios, significant energy transfer is observed. These assays have been optimized for reproducibility, robustness, stability, and sensitivity. Typical Z' values for these assays under screening conditions were >0.90. We have piloted this assay using a library of ~3000 bioactive compounds at Institute of Chemistry and Cell Biology Longwood (ICCB), and have begun more thorough screening of ICCB libraries. Compounds identified in these screens may have utility as anti-angiogenic agents. In addition, because the binding of anthrax protective antigen (PA) is required for anthrax pathogenicity, identification of small molecule inhibitors of PA-receptor binding may lead to anti-anthrax therapeutics for biodefense.
Very late relapse metastatic renal cell carcinoma: Characteristics and outcomes of patients with a disease-free interval of greater than 10 years.
Authors: John Ross Kucharczyk, Marc Ryan Matrana
Journal: Journal of Clinical Oncology (2016)

541 Background: Late relapse of renal cell carcinoma (RCC), or presentation with metastatic disease after a disease free interval of &gt;5 years, is a known behavior of RCC. Recent studies have concluded that late relapse RCC is associated with favorable patient and tumor characteristics as well as an improved response to targeted therapy (TT) when compared to early relapse patients. Less studied are patients who relapse very late, with a disease free interval &gt;10 years. We evaluated the clinical characteristics, response to TT and outcomes of this unique population. Methods: We collected data on consecutive patients with metastatic RCC who had disease recurrence &gt;10 years after nephrectomy. Outcomes were tabulated using basic statistical techniques; adverse events were graded using CTCAE v4.0 and treatment response graded using RECIST 1.1. Results: Among 720 RCC patients treated with nephrectomy, we identified 8 who developed recurrent metastatic disease after a &gt;10 year disease free interval (median: 16.7 years; range: 11.7-29.0). All patients presented with clear cell histology; 88% favorable IMDC and MSKCC risk subgroups. All patients presented with multiple metastases, with the most common sites being lung and bone, while unusual sites such as soft tissue, pancreas and adrenal were also detected. Median time on first-line TT was 20.1 months; 4, 3 and 1 patient received pazopanib (best response: PR), sunitinib (best response: SD) and cytokine (best response: PD) as first-line therapy, respectively. The median number of sequential TT received was 2 (range: 1-4). Four patients died, median OS was 46.6 months (range: 9.8-129), 3 year OS rate was 63%. Common adverse events to TT were fatigue (88%), anorexia (38%) and diarrhea (50%), 94% grade 1/2. Conclusions: Patients are at life-long risk of recurrence after resection of localized RCC as it is possible for metastases to present &gt;10 years after resection. Patients in our study had relatively large metastatic burden and a wide distribution of metastatic sites, insights that may be useful clinically during surveillance. Our cohort demonstrated favorable prognostic features and outcomes when compared to historical controls.
Trabectedin and indole-3-carbinol combination in heavily pretreated metastatic breast cancer: Results of a pilot clinical study.
Authors: Alberto Zambelli, Richard Tancredi, Sara Negri, Carlo Cattrini, Luisa Ponchio, Mara Frascaroli, Gian Antonio Da Prada, Vittorio Fregoni, Lorenzo Pavesi, Alberto Riccardi, Massimo Zucchetti, Ilaria Fuso Nerini, Maurizio D'Incalci
Journal: Journal of Clinical Oncology (2014)

e12015 Background: Trabectedin (T) is a DNA minor groove binder that modulates transcription regulation and modifies tumor microenvironment. It is currently used for the treatment of ovarian cancer and sarcoma and is under evaluation in metastatic breast cancer (mBC). The main toxicities of T are myelosuppression and reversible hepatotoxicity. High dose dexametasone (HD-Dex) reduces T-induced hepatotoxicity but is associated to adverse effects. Indole-3-Carbinol (I3C) was found to protect from T-related hepatotoxicity in pre-clinical models. This pilot study was designed to verify the preclinical findings in the clinic. Methods: 12 heavily pretreated mBC entered the study. Pts were divided in 3 cohorts, receiving dose-escalation of I3C (200, 400 and 600 mg/daily p.o) without HD-Dex pre-medication and T at a fixed dose of 1.3 mg/sqm (q.4wks, in 3hrs). Pts were randomized to receive or not I3C either during the first or the second-T cycle. Liver function, hematology and T-pharmacokinetics (Pk) were serially tested. Pts were evaluable for toxicity and response. Results: Overall, 3/12 discontinued the protocol due to severe side-effects. Universal transaminitis (AST/ALT peak G4) was found in pts receiving low-dose (200mg)I3C, while higher doses of I3C (400/600mg) caused hepatoprotection (AST/ALT peak G3).In spite of a mild neutropenia found at day +15, in all pts there was an early, selective effect on monocytes, with a dramatic decrease >70% from baseline at day +4, irrespectively of I3C/placebo. 3/12 pts obtained a good partial delayed response (>50%) that was not evident before 2 months after the last T administration. I3C does not seem to alter T Pk. Conclusions: The use of I3C, instead of HD-Dex, showed some hepatoprotectant activity when administered at the high-dose. The rapid and unpredicted effect of T on monocytes are in keeping with the recent preclinical observations that the drug down-regulates the Tumor Associated Macrophages. The peculiar delayed pattern of response to T in heavily pretreated mBC deserves further investigation.
A multicenter randomized study comparing 6 versus 12 months of trastuzumab in combination with dose-dense docetaxel following FEC as adjuvant treatment of women with axillary node–positive or high-risk, node-negative breast cancer overexpressing HER2.
Authors: Dimitrios Mavroudis, Nikolaos A. Malamos, Stylianos Kakolyris, Ioannis Boukovinas, Pavlos Papakotoulas, Nikolaos Ziras, Vassilis Georgoulias
Journal: Journal of Clinical Oncology (2014)

623 Background: Adjuvant trastuzumab in combination with chemotherapy improves outcome of women with HER2 positive early breast cancer. However, the optimal duration of treatment remains unknown. In this study we compared 6 versus 12 months of adjuvant trastuzumab. Methods: Axillary node positive or high risk node negative women with HER2 overexpressing or amplified early breast cancer were randomized following surgery to receive either 6 (arm A) or 12 (arm B) months of adjuvant trastuzumab in combination with dose dense G-CSF-supported Docetaxel (75mg/m2 every 14 days for 4 cycles) following FEC (5FU 700mg/m2, epirubicin 75mg/m2, cyclophosphamide 700mg/m2 every 14 days for 4 cycles). The primary endpoint of the study was the 3-year disease-free survival (DFS). Results: Four hundred eighty one patients were randomized; 240 on arm A and 241 on arm B. Of them 83 (34%) and 100 (41%) were premenopausal, 200 (83%) and 180 (75%) were node positive, 165 (69%) and 156 (65%) were hormone receptor positive in arm A and B, respectively. Chemotherapy was completed in 98% and 99% of patients while trastuzumab therapy in 96% and 100% of patients in arm A and B, respectively. After a median follow up of 43.5 and 42 months there were 26 (10.8%) and 15 (6.2%) (p=0.07) disease relapses and the median DFS has not yet been reached (p=0.08) while the 3-year DFS rate was 92.4% and 95.1% for arm A and B, respectively. Conclusions: Preliminary results of this study in terms of disease relapse and DFS are in favor of 12 months of adjuvant trastuzumab administration. Clinical trial information: NCT00615602.
Correlation between metastatic site and response to anti-<i>Programmed Death-1</i> (PD-1) agents in melanoma.
Authors: Simone M. Goldinger, Katy K. Tsai, Paul Tumeh, Omid Hamid, Adi Nosrati, Kimberly Loo, Barbara Grimes, Alain Patrick Algazi, Mitchell P. Levesque, Reinhard Dummer, Adil Daud
Journal: Journal of Clinical Oncology (2016)

9549 Background: Antibodies against PD-1 have shown remarkable activity in the treatment of advanced melanoma. Clinical characteristics correlated with response have not yet been fully characterized. Previous work has shown that site of metastasis can correlate with treatment outcome. We sought to confirm these findings in a larger cohort of metastatic melanoma patients (pts). Methods: We conducted a multicenter retrospective study in a cohort of metastatic melanoma pts treated with anti-PD-1 agents. Relevant clinical data were retrieved from electronic medical records. Tumor responses were evaluated by RECIST v1.1. A multivariate regression model was used to investigate demographic and clinical variables associated with response. Results: We identified 337 pts who received pembrolizumab (2mg/kg or 10mg/kg Q3W) (N = 326) or nivolumab (3mg/kg Q2W) (N = 11) on clinical trials (N = 273) and early access programs (N = 64) at UCSF and USZ. In the multivariate model, pts who had liver metastasis (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.21-0.59) and prior ipilimumab (OR 0.39, 95% CI 0.24-0.64) were less likely to respond to treatment. Data for subgroup variables are shown (Table). Pts with lung metastasis were more likely to respond (OR 1.56, 95% CI 0.99-2.51). Conclusions: This multivariate model supports a significant correlation between liver metastasis and prior ipilimumab with poor response to anti-PD-1 therapy in melanoma pts. Presence of lung metastasis was correlated with improved response, though this just approached statistical significance. Efforts are ongoing to better identify clinical characteristics and biomarkers of response, and to further investigate the tumor microenvironment. Clinical trial information: NCT01295827, NCT01704287, NCT01721746, NCT02156804. Variable Odds ratio 95% CI p value Liver metastasis 0.35 0.21-0.59 < 0.0001 Prior ipilimumab 0.39 0.24-0.64 0.0002 Elevated LDH 0.64 0.40-1.04 0.07 ECOG 0.71 0.43-1.16 0.17 WBC 0.99 0.92-1.07 0.86 Brain metastasis 1 0.56-1.8 1 Lung metastasis 1.56 0.99-2.51 0.06
Anlotinib versus sunitinib as first line treatment for metastatic renal cell carcinoma (mRCC): Preliminary results from a randomized phase II clinical trial.
Authors: Ai-Ping Zhou, Jianhui Ma, Yuxian Bai, Yan Song, Hangzhong Li, Xiaodong Xie, Xiu-Bao Ren, Dingwei Ye, Jiyan Liu, Hong Luo, Xianzhong Bai, Shukui Qin, Cheng Fu, Jinwan Wang
Journal: Journal of Clinical Oncology (2016)

4565 Background: Anlotinib is a potent oral, small molecular TKI with a favorable safety profile in phase I clinical trial which mainly targets VEGFR1/2/3, FGFR2. This multicenter randomized phase II trial (NCT02072031) compared efficacy and safety of anlotinib and sunitinib as first line treatment in mRCC patients with clear cell being the predominant component. Methods: Patients were randomized in 2:1 to receive anlotinib or sunitinib. Anlotinib was administered at dose of 12 mg once daily for 2 weeks followed by 1 week rest, sunitinib at dose of 50mg once daily for 4 weeks followed by 2 weeks off. The primary endpoint was progression free survival (PFS). Secondary end points included overall survival (OS), overall response rate (ORR), safety. Results: 133 (93 with anlotinib, 40 with sunitinib) patients were enrolled. Data cutoff was May 15, 2015. Both group had similar PFS (11.3 vs. 11.0 months (p = 0.30), ORR (24.4% vs. 23.3%), 6-week disease controll rate (97.8% vs. 93.0%, p = 0.33). OS for both group has not yet reached. Patients treated with anlotinib, as compared with those treated with sunitinib, had a significant less incidence of grade 3 or 4 side effects (28.9% vs. 55.8%, p = 0.0039), especially less grade 3 or 4 thrombocytopenia (0 vs. 11.6%, p = 0.003), neutropenia (0.0 vs. 9.3%, p = 0.009). As for all grades of side effects, anlotinib had less hand-foot syndrome (41.1% vs. 65.1%, p < 0.015), eyelid edema (2.2% vs. 25.4%, p < 0.0001), hair depigmentation (0.0% vs. 14.0%, p = 0.0009), skin yellowing (0.0 vs. 37.2%, p < 0.0001), neutropenia (3.3% vs. 44.2%, p < 0.0001), thrombocytopenia (11.1% vs. 58.1%, p < 0.0001), anemia (4.4% vs. 34.9%, p < 0.001). Also, anlotinib had a trend of less hypertension (50% vs. 67.4%, p = 0.0647), increase of creatinine (14.4% vs. 27.9%, p = 0.095), hypophosphatemia (13.3% vs. 27.9%, p = 0.085). Whereas, anlotinib had a trend of higher incidence of hypercholesterolemia (25.6% vs.11.6%, p = 0.073) than sunitinib. Conclusions: Anlotinib was shown to have similar efficacy to sunitinib with favorable safety profile in patients with metastatic RCC. Clinical trial information: NCT02072031.
ERASE: Elimination of recurring artifacts and stochastic errors: An NGS analysis approach and its application to liquid biopsy samples.
Authors: Nicholas Kamps-Hughes, Tony Tran, Reynolds Brobey, Robert J. Amato, Ajjai Shivaram Alva, Pamela Paris, Terence W. Friedlander, Gayatri Premasekharan, Cristian Ionescu-Zanetti
Journal: Journal of Clinical Oncology (2016)

e13002 Background: Next generation sequencing (NGS) of blood-derived nucleic acids is an emerging paradigm for determining the mutational status of cancer patients over time. Circulating tumor cells (CTC) and cell-free circulating DNA have been proposed as possible sample types for extracting tumor DNA. A number of sequencing and approaches (i.e. barcoding) have been proposed for increasing sensitivity/specificity for somatic mutation detection but require specialized chemistry and informatics; here we present a novel methodology that is compatible with routine sequencing lab workflows and functions well at allelic frequencies below 1%. Methods: Analytical sensitivity / specificity was determined by DNA spikes and cell spikes into whole blood resulting in mutation at allelic frequencies down to 0.4%. For validation using clinical samples, a number of cancer patient blood samples were enriched for circulating tumor cells (CTCs) using the IsoFlux System. Matched samples were enumerated to determine the CTC load. Cells were lysed andDNA amplified by whole genome amplification. Targeted libraries were sequenced using the NextSeq platform (Illumina) and analyzed using the ERASE algorithm (Elimination of Recurring Artifacts and Stochastic Errors). VarSeq software (Golden Helix Inc.) was used for variant functional interpretation. Results: Analytical DNA spiking experiments demonstrated a detection limit of 0.5%, with no false positives detected across a standard amplicon set aimed at somatic mutation detection. Comparisons of the ERASE methodology results with standard sequencing demonstrates a drastic reduction of a number of different classes of errors by accounting for the statistical significance of the sample mutations compared to background at each position. Clinical samples demonstrated variant detection in a majority of samples, and concordance for the biological replicates tested. Conclusions: The ERASE approach is compatible with routine amplicon based sequencing, and increases the detection floor from about 5% to 0.5% for such samples. It enables detection of somatic variants from liquid biopsy samples.