tbuckley/cabot-search huggingface dataset:
Abiraterone in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and MDV3100.
Authors: Ecaterina Ileana, Yohann Loriot, Laurence Albiges, Christophe Massard, Aurore Blesius, Mario Di Palma, Bernard J. Escudier, Pierre Blanchard, Alberto Bossi, Karim Fizazi
Journal: Journal of Clinical Oncology (2012)

4554 Background: Chemotherapy with docetaxel is the standard first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). In patients progressing after docetaxel, both abiraterone and MDV3100 have yielded improved survival for patients with mCRPC. The efficacy of abiraterone in patients pre-treated with MDV 3100 is unknown. Methods: We investigated abiraterone-prednisone in 24 patients with cancer progression after docetaxel followed by MDV3100. All patients received abiraterone 1000 mg/day plus prednisone 10mg/day. Prostate-specific antigen (PSA) response, symptom response, and time to progression were assessed. Results: Patient characteristics were as follows: median age: 74 years (53-84), median PSA: 108 ng/mL (2-2541), metastatic sites: bone: all 24 patients, liver/lung: 6 patients (25%), and lymph nodes : 9 patients (38%). Five patients (21%) had a PSA decrease on abiraterone-prednisone. Three patients (13%) achieved a PSA response, defined as a decrease of &gt;50% in PSA, confirmed after≥ 4 weeks. The duration of PSA response was 2, 3 and 4.5 months. Six patients (29%) had a symptomatic response on the pain score and analgesic consumption was decreased. Treatment was well tolerated. Abiraterone-prednisone was discontinued in one patient due to edema and hypokaliemia. Conclusions: This study shows preliminary evidence that abiraterone-prednisone yields activity in patients with mCRPC pretreated with docetaxel and MDV3100.
Can postoperative radiotherapy be omitted in localized standard-risk Ewing sarcoma? An observational study of the Euro-EWING Group.
Authors: Nathalie Gaspar, Bernadette Brennan, Lee Jeys, Uta Dirksen, Stephanie Foulon, Anna Cassoni, Beatrice M. Seddon, Line Claude, Perrine Marec-Berard, Anne Streitbuerger, Jeremy Whelan, Michael Paulussen, Robert Grimer, Marie-Cécile Le Deley, Heribert Jurgens
Journal: Journal of Clinical Oncology (2013)

10518 Background: Uncertainty exists on the most appropriate use of surgery, radiotherapy (RT) or both for treatment of primary Ewing sarcoma (ES). The objective of this study was to assess the impact of postoperative RT on local control in pts with localized ES and good (&lt;10% residual cells) histologic response to chemotherapy (CT). Methods: We analyzed data of all pts included in the EE99-R1 trial (comparing 2 consolidation CT regimens) undergoing surgery after induction CT. Local recurrence (LR) cumulative incidence (CI) was estimated using a competing risk approach. As local therapy was not randomized but tailored to the individual patient and tumor characteristics, impact of RT was assessed in multivariable models, adjusted for possible confounders: country, age, tumor type, site and volume, quality of resection and histologic response. We also evaluated the heterogeneity of RT effect by patient and tumor characteristics (interaction). Results: Among the 599 pts included from 1999 to 2009, 142 (24%) had received postoperative RT. With median follow-up of 6.2 yrs, disease failure was reported in 156 pts, including a LR in 67 (with concomitant metastases in 28), leading to an 8-yr LR-CI = 12% (se 1.4%). Overall survival = 21% (se 5%) 3 yrs after LR (31% in isolated LR). Controlling for possible confounders, the risk of LR was halved in pts treated by surgery + RT (HR=0.43, 95%CI, 0.21-0.88, p=0.02) compared to surgery alone. Postoperative RT had a rather homogeneous positive effect in all studied subgroups. The benefit of RT was very significant in pts with a tumor volume of &gt;200mL at diagnosis and 100% necrosis. Although not significant, we observed a trend for benefit associated with RT in terms of disease-free, event-free and overall survival. Conclusions: LR contributes significantly to disease failures in this standard risk group who experience few systemic failures. Outcome after LR is very poor. Postoperative RT appears to improve local control for all pts. Good histologic response and complete resection of residual mass may not be sufficient criteria to omit RT. Further study of RT in ES is required to assess the balance between benefit and risk (secondary malignancies, functional sequelae). Clinical trial information: NCT00020566.
Benign distal jejunal stricture treated by a partially covered esophageal stent with the use of spiral enteroscopy
Authors: Frances Onyimba, Vivek Kumbhari, Alan Tieu, Jennifer Cai, Ahmed Abdegelil, Aditi Reddy, Mouen Khashab, Patrick Okolo
Journal: Endoscopy (2015)

Correction to: Benign distal jejunal stricture treated by a partially covered esophageal stent with the use of spiral enteroscopyEndoscopy 2015; 47(S 01): E117-E118DOI: 10.1055/s-0034-1391334
Optimizing the identification of anaplastic oligodendroglioma patients that benefit from adjuvant PCV chemotherapy using the Illumina platform: A further report from EORTC study 26951.
Authors: Martin J. Van Den Bent, Lale Erdem, Thierry Gorlia, Martin JB Taphoorn, Johan M Kros, Pieter Wesseling, Anouk Allgeier, Hendrikus J Dubbink, Ahmed Idbaih, Marc Sanson, Pim French
Journal: Journal of Clinical Oncology (2013)

2011 Background: Adjuvant PCV chemotherapy improves overall survival (OS) in 1p/19q co-deleted grade 3 gliomas. Analyses of EORTC 26951 and RTOG 9402 suggest that other molecularly defined subsets of grade III tumors benefit as well. We previously identified a CpG-Island Hypermethylated Phenotype (CIMP+) as a candidate biomarker. This was further explored in a larger series using snap frozen (SF) or formalin fixed paraffin embedded (FFPE) tumor material, and compared to the value of 1p/19q, IDH1/2 and MGMT status. Methods: Methylation profiles were assessed using the Infinium HumanMethylation 27 or 450 BeadChip (Illumina). MGMT promoter methylation was re-assessed with a logistic regression model (MGMT-STP27) using probes cg1243587 and cg12981137 of the platform as described (Bady et al, Acta Neuropathol 2012;124:547-60). These probes correspond to area’s of the promoter correlated to MGMT protein expression. Previously, MGMT promoter methylation had been assessed using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA). Results: Methylation profiling was conducted in 115 patients. CIMP status correlation between FFPE and SF was excellent (R 2 0.96). In multivariate analysis, 1p/19q co-deletion and CIMP status were independent prognostic factors. Although 1p/19q status and IDH mutational status identify subgroups with more benefit of PCV chemotherapy, tests for interaction remain negative (p 0.25 and 0.33 respectively); MGMTstatus (MS-MLPA) had no impact (p = 0.70). However, CIMP status was of borderline predictive significance (p= 0.07), and MGMT-STP27 was of statistical significance (p = 0.003; HR unmethylated 1.61, 95% CI [0.71, 3.66], HR methylated 0.37, 95% CI 0.23, 0.61]. Conclusions: CIMP status and MGMT promoter methylation assessed with Illumina HumanMethylation BeadChips appear the most informative tests for identifying grade III glioma patients benefitting from the addition of PCV to RT. Validation in an independent dataset is required. Clinical trial information: NCT00002840.
Plasma levels of carbonic anhydrase IX, cytokines, and angiogenic factors in testicular germ cell tumor patients.
Authors: Michal Chovanec, Miriam Zatovicova, Dana Cholujova, Paulina Gronesova, Vera Miskovska, Magdalena Vrestiakova, Daniela Svetlovska, Jana Obertova, Bibiana Vertakova-Krakovska, Vanda Usakova, Katarina Sevcikova, Stanislav Spanik, Dalibor Ondrus, Jozef Mardiak, Silvia Pastorekova, Michal Mego
Journal: Journal of Clinical Oncology (2014)

e15541 Background: Testicular germ-cell tumours (TGCTs) represent a model for the cure of cancer, nevertheless small proportion of patients experience tumor recurrence. Carbonic anhydrase 9 (CAIX) is a human transmembrane protein strongly associated with tumor hypoxia and cancer progression. In this study we investigated plasma CAIX in patients with TGCTs aimed to link the CAIX levels with patients`/tumor characteristics and plasma CAFs. Methods: In this ongoing translational study, plasma from 71 patients with TGCTs treated with first line of chemotherapy was collected. The concentrations of plasma CAIX were measured by enzyme-linked immunosorbent assay pretreatment (n = 71) and on day 22 (n = 65) of first cycle of chemotherapy. Plasma CAFs were measured using multiplex bead arrays (Human Group I and II cytokine panels and TGF beta by Bio-Plex 200 system). Results: Mean ± SEM plasma CAIX levels (pg/mL) pretreatment and on day 22 were 503.6 ± 116.8 and 478.5 ± 113.4, p = 0.2, respectively. We didn`t find any correlation between pretreatment plasma CAIX and patients` tumor characteristics and/or patients’ outcome. We observed inverse correlation between pretreatment lactate dehydrogenase and plasma CAIX. Patients with non-metastatic disease had significantly lower plasma CAIX after chemotherapy on day 22, compared to metastatic patients. We also observed inverse correlation between post-treatment CAIX and several plasma cytokines including IL-1RA, IL-4, IL-5, IL-7, IL-10, IL-17, FGF basic, IFN gama, MIP-1a, PDGF beta, TNF alfa. Conclusions: Our data suggest limited clinical value of plasma CAIX in TGCTs treated with first line chemotherapy. We suppose, that inverse correlation between post-treatment levels of plasma CAIX and CAFs could be related to tumor lysis due to chemotherapy with shedding of CAIX into the plasma and corresponding decrease of proinflammatory cytokines.
Proliferation heterogeneity in synovial sarcoma (SS) defines different patterns of clinical outcome: A retrospective study of 32 patients
Authors: S. Grisanti, F. Consoli, V. D. Ferrari, L. Bercich, V. Amoroso, G. Rangoni, G. L. Cetto, A. P. Dei Tos, F. Facchetti, G. Marini
Journal: Journal of Clinical Oncology (2009)

e21511 Background: SS is an aggressive soft tissue sarcoma (STS) characterized by a constitutive overexpression of the bcl-2 proteins and high proliferation rate (Ki67). The aim of the study was to evaluate prognostic value of proliferative activity and apoptosis in SS. Methods: A retrospective analysis of 32 patients treated at three oncology centers between January 2000 and August 2008 was conducted. Histologic diagnosis of SS was confirmed by FISH analysis of t(X;18). Bcl-2 and Ki67 were determined by immunohistochemistry at baseline and after neoadjuvant chemotherapy (CT). A cut-off value of 20% was established for Ki67. The bcl-2 gene status was evaluated by FISH in neoadjuvant subgroup. Treatment-induced pathological response (pCR) was defined as tumor necrosis of 100%. Endpoints were recurrence rate (RR), disease-free survival (DFS) and overall survival (OS). Clinical and pathological variables were considered in uni- and multivariate analysis. Results: 13/32 patients received an anthracycline/ifosfamide-based chemotherapy (CT) before surgery. 8 pts received concomitant radiotherapy. A median number of 3 cycles of neoadjuvant CT was administered. All patients underwent surgical resection and pathologic assessment of the coexpression of bcl-2 and Ki67 was evaluated in the resected specimens. At baseline, all samples showed immunoexpression of bcl-2 and 9/13 had Ki67 more than 20%. After neoadjuvant CT, Ki67 was downregulated &lt;20% in 11/13 samples and bcl-2 was negative in 4/13 pts. At FISH analysis, bcl-2 gene was neither rearranged nor amplified. After a median follow-up of 21 months (range 13–64 months), 9/13 pts without pCR experienced progression disease and 5 of them were dead of SS. At uni- and multivariate analysis, both pCR and downregulation of bcl-2 and Ki67 activity had a significant impact on DFS and OS (p=0.03). Conclusions: 1. Downregulation of bcl-2 and Ki67 index after treatment could be a predictor of recurrence and overall survival. 2. SS is characterized by cellular heterogeneity in which a high proliferative compartment coexists with low proliferative/anti-apoptotic compartment with different response to treatment. No significant financial relationships to disclose.
Early docetaxel-resistance in metastatic hormone-sensitive prostate cancer.
Authors: Nedal Bukhari, Kylea R. Potvin, D. Scott Ernst, Lori Sax, Eric Winquist
Journal: Journal of Clinical Oncology (2017)

260 Background: The addition of docetaxel to standard androgen deprivation therapy (ADT) has been shown to improve the survival of men with metastatic hormone-sensitive prostate cancer (MHSPC) (Sweeney 2015, James 2016). We noticed PSA progression in some of our patients (pts) during docetaxel treatment and reviewed their outcomes. Methods: Men with MHSPC treated with docetaxel were identified from an electronic oncology pharmacy database. Eligible pts were prescribed docetaxel for metastatic adenocarcinoma of the prostate within 120 days of initiation of ADT. Pts with castration-resistant disease (CRPC), other histologies, and those without metastatic disease were excluded. Demographic, clinical, treatment and outcome data were extracted retrospectively from electronic medical records. Results: 31 eligible pts with MHSPC treated with docetaxel between August 2014 and July 2016 were identified. Median age was 65 years (53-83) and 28 (90%) had high-volume disease as defined by Sweeney et al (2015). Nadir PSA levels 6-7 months from ADT initiation were &lt; 0.2, 0.2-4, and &gt; 4 ng/mL in 29.0%, 36.7% and 36.7%, respectively. At median follow up of 85 weeks, 45.2% of pts had progressed to CRPC and 22.6% had died. Median time to CRPC was 59 weeks and median overall survival was 85 weeks. Seven pts with high-volume disease (25%) had PSA progression while receiving docetaxel treatment. The median overall survival of this group was 26 weeks (17 to 106+) and six have died. Three had visceral metastases. Nadir PSA was &lt; 0.2 (1 pt), 0.2-4 (2 pts) and &gt; 4 ng/mL (4 pts). After docetaxel 2 pts received BSC alone and 5 pts had 1 st -line CRPC therapy. No response to abiraterone/enzalutamide was seen (3 pts). Two pts who discontinued docetaxel immediately at PSA progression and were switched to alternative chemotherapy survived &gt; 1 year. Conclusions: A subset of men with MHSPC has lethal docetaxel-resistant disease characterized by early PSA rise. It is important to recognize these patients, but it is not clear if standard CRPC therapies are effective. An immediate early switch to alternative chemotherapy may be helpful. Further research to predict early docetaxel resistance, characterize response to current therapies and identify more effective treatment is needed.
Kinome reprogramming response to MEK inhibition: A window-of-opportunity trial in triple-negative breast cancer (TNBC).
Authors: Gary L. Johnson, Keith D. Amos, James S Duncan, Marty Whittle, Jon Zawistowki, Dan Goulet, Xiaping He, Jeanne Noe, Charles M. Perou, Shelton Earp, Lisa A. Carey
Journal: Journal of Clinical Oncology (2013)

512 Background: Targeted therapy (Rx) in TNBC is challenging due to heterogeneity and cancer cell kinome “reprogramming” in response to targeted kinase inhibitors (Cell 149:307, 2012). In preclinical TNBC models specific kinases (e.g., DDR1/2, PDGFRbeta, VEGFR2, AXL) are activated in response to MEK inhibition. Our studies define unique kinome reprogramming in basal-like (BBC) versus claudin-low (CL). This study compared kinome profiles of TNBC pre- and post- MEK1/2 inhibition with GSK1120212 (trametinib, T) using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). Methods: Eligible patients (pts) with untreated TNBC received T (initial dose 1.5mg/d raised after interim analysis of kinome effects to 2mg/d) for 7 days preceding breast surgery. Fresh tumor tissue was obtained before and after T. Kinase activation state was analyzed as post:pre(-)treatment ratio; molecular subtype was by gene expression analysis. Results: Kinome response profiling was completed in 7 of 9 pts by abstract submission. Toxicities included grade 2 (2pts) or grade 1 (1pt) rash, grade 1 diarrhea (1pt), and grade 1 nausea (1pt). Two of the 9 pts profiled did not have sufficient pre-treatment tumor for kinome analysis. Molecular subtypes included 6 BBC patients (one of which was CL after T), 2 CL patients (one of which was BBC after T), and 1 normal-like patient (which was BBC after T). MEK1/2 inhibition and kinase reprogramming was seen in 6 of the 7 tumors where both pre- and post T samples could be analyzed. The results show kinome reprogramming in response to MEK1/2 inhibition occurs in human tumors similar to preclinical modeling in TNBC cell lines and credentialed engineered mouse models; the kinase reprogramming pattern differed between BBC and CL. Conclusions: MEK1/2 inhibition upregulates and activates specific receptor tyrosine kinases in BBC that are different from CL.A subset of BBC and CL may have plasticity, changing their molecular subtype and kinome profile, and responding heterogeneously to MEK1/2 inhibition. Analysis of kinome reprogramming identifies upregulation of druggable targets for individual patients that suggest rational combinations with MEK inhibition in TNBC. Clinical trial information: NCT01467310.
Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair
Authors: Aimee Bence Lin, Samuel C. McNeely, Richard P. Beckmann
Journal: Clinical Cancer Research (2017)

Abstract All cancers are characterized by defects in the systems that ensure strict control of the cell cycle in normal tissues. The consequent excess tissue growth can be countered by drugs that halt cell division, and, indeed, the majority of chemotherapeutics developed during the last century work by disrupting processes essential for the cell cycle, particularly DNA synthesis, DNA replication, and chromatid segregation. In certain contexts, the efficacy of these classes of drugs can be impressive, but because they indiscriminately block the cell cycle of all actively dividing cells, their side effects severely constrain the dose and duration with which they can be administered, allowing both normal and malignant cells to escape complete growth arrest. Recent progress in understanding how cancers lose control of the cell cycle, coupled with comprehensive genomic profiling of human tumor biopsies, has shown that many cancers have mutations affecting various regulators and checkpoints that impinge on the core cell-cycle machinery. These defects introduce unique vulnerabilities that can be exploited by a next generation of drugs that promise improved therapeutic windows in patients whose tumors bear particular genomic aberrations, permitting increased dose intensity and efficacy. These developments, coupled with the success of new drugs targeting cell-cycle regulators, have led to a resurgence of interest in cell-cycle inhibitors. This review in particular focuses on the newer strategies that may facilitate better therapeutic targeting of drugs that inhibit the various components that safeguard the fidelity of the fundamental processes of DNA replication and repair. Clin Cancer Res; 23(13); 3232–40. ©2017 AACR.
Bedaquiline as a potential agent in the treatment of <i>M. intracellulare</i> and <i>M. avium</i> infections
Authors: Silvan Vesenbeckh, Nicolas Schönfeld, David Krieger, Gudrun Bettermann, Torsten Thomas Bauer, Holger Rüssmann, Harald Mauch
Journal: European Respiratory Journal (2017)

Recently in this journal, Salfinger and Migliori [1] discussed the accessibility of bedaquiline drug susceptibility testing and the analysis of minimum inhibitory concentrations (MICs) for strains of Mycobacterium tuberculosis . As the recommended treatments for diseases caused by M. avium , and especially M. intracellulare , have high failure rates [2, 3], we measured the MIC of bedaquiline in 20 clinical isolates of these species. Bedaquiline is a potential agent to treat severe or relapsing M. avium-intracellulare complex infections <http://ow.ly/n1eR308pERh>
Japanese nationwide multi-institutional cohort study of prostate cancer brachytherapy with permanent seed implantation.
Authors: Shiro Saito, Kazuto Ito, Atsunori Yorozu, Manabu Aoki, Hirofumi Koga, Takefumi Satoh, Toshio Ohashi, Naoyuki Shigematsu, Takashi Daimon, Shinsuke Kojima, Takushi Dokiya, Masanori Fukushima, Hidetoshi Yamanaka
Journal: Journal of Clinical Oncology (2013)

e16090 Background: Brachytherapy with permanent iodine-125 seed implantation (PI) has been approved in 2003 in Japan. Multi-institutional cohort study (Japanese Prostate Cancer Outcome Study of Permanent Seed Implantation; J-POPS, NCT00534196) assessing the treatment feature, efficacy, safety and health-related quality of life (QOL) has started in July 2005. Six thousand nine hundred and twenty-seven cases were enrolled to this study until December 2010 from 68 institutes around the country, which is approximately 40% of all the cases treated in Japan at that time. Methods: Patient’s background, cancer character, treatment feature such as combined therapy of external beam or hormone, post PI dosimetric information, treatment efficacy with PSA level, voiding symptoms with IPSS and treatment related adverse events according to NCI-CTCAE are investigated. PSA was measured every 3 months and symptoms accompanied to the treatment were assessed 3 to 6 months after the treatment. Backgrounds and treatment assessments of 2,341 patients enrolled in J-POPS during the initial 2 years are evaluated. Results: Patients’ age ranged from 45 to 89 (median 69) year-old and 99.0% of the cases were performance status 0 (ECOG criteria). Family history of prostate cancer was seen in 6.2%. PSA levels on cancer diagnosis were 1.60 to 42.0 (mean 6.80) ng/ml, clinical stage T2a or less was 89.9%, T2b was 5.2%, T2c was 2.9% and T3a-T3b was 0.8%. Gleason score (GS) less than 7 was 56.6%, GS 7 was 39.7%, and GS above 7 was 3.6%. According to NCCN risk classification, 44.2% was classified as low risk, 48.3% as intermediate risk and 5.7% as high risk. Androgen deprivation therapy (ADT) was performed in 48.5% of the patients and 23.4% was combined with external beam radiation therapy (EBRT). CT scan based first post therapeutic month dosimetry revealed that prostatic mean V100 and D90 for the cases treated with seed alone were 94.8% and 160.7 Gy, respectively. As for adequate control of radiation dose at rectum (mean R100 = 0.3 cc) and urethra (mean D5 = 223.4 Gy), high grade toxicities appeared very seldom. Conclusions: Outcomes of J-POPS will produce clinical evidence of PI that can be internationally accepted.
Is HbA1c &amp;lt;7% a Marker of Poor Performance in Individuals &amp;gt;65 Years Old?
Authors: Zachary T. Bloomgarden, Daniel Einhorn, Yehuda Handelsman
Journal: Diabetes Care (2017)

In this issue of Diabetes Care , Pogach et al. (1) raise reasonable concepts of the dangers of hypoglycemia as a criterion for assessing glycemic control, but the authors suggest a performance measure pertaining to glycemic control of persons with diabetes with which we disagree. They propose an out-of-range measure of having either HbA1c  9.0%, “for patients aged ≥65 years with diabetes and significant comorbid conditions taking antihyperglycemic agents other than metformin alone.” The presence of a “significant comorbid condition” was primarily driven by cardiovascular disease but also included persons with serum creatinine >1.7 mg/dL, cognitive impairment, diabetic retinopathy, major depression, and/or substance abuse. This out-of-range concept certainly merits discussion. Indeed, the notion has recently been put forward that HbA1c  9%, but 35.7% had HbA1c <7.0%; those deemed by Pogach et al. to be …