tbuckley/cabot-search huggingface dataset:
Association of CpG island methylator phenotype with clear-cell renal cell carcinoma aggressiveness.
Authors: Gabriel Malouf, Jianping Zhang, Nizar M. Tannir, Erika Thompson, Jean-Philippe Spano, David Khayat, Xiaoping Su
Journal: Journal of Clinical Oncology (2014)

4574 Background: The key roles of epigenetic dysregulation of chromatin remodeling genes in clear-cell renal cell carcinoma (ccRCC) have been recently discovered through exome-sequencing which showed frequent mutations of PBRM1, SETD2 and UTX genes. However, the contribution and the prognosis impact of DNA methylation aberrations in ccRCC remain limited. Methods: We herein analyzed DNA methylation of 298 primary ccRCC samples, fully annotated for clinico-pathological features and profiled by the cancer genome atlas (TCGA) project using infinium 450K arrays. Furthermore, we established DNA methylation subtypes based on distinct signatures, and correlated them with clinico-pathological tumor features and copy-number alterations. Results: Unsupervised hierarchical clustering based on DNA methylation of promoters located in CpG islands (CGI) revealed three clusters of ccRCC. Cluster C1 (n=65) displays a CpG island methylator phenotype (CIMP+), while cluster C2 (n=53) and C3 (n=153) correspond to CIMP-low and CIMP negative subgroups, respectively. Tumors belonging to CIMP+ subgroup were more aggressive with higher pathological Fuhrman grade (p<0.00001), higher TNM stage (p<0.0001) and poorest overall survival (p=5.4e-9). After adjusting for classical clinico-pathoIogical prognostic factors using multivariate analysis, CIMP+ was not found to be independently associated with poor overall survival, suggesting that aberration DNA methylation might be acquired during tumor progression. Integration of DNA methylation with copy-number changes identified frequent gain of chr8q24.22 (p=0.0007) in CIMP+ subgroup, as well as losses of 9p23 (p=5.7E-09) and 9p21.3 (p=4.6E-07) regions. GSEA analysis reveals that promoters that gain DNA methylation in CIMP+ tumors were enriched for polycomb targets, and this was consistent with EZH2 increase (Fold change=1.5; p=0.05). Conclusions: Our study defines a novel genetically distinct CIMP subgroup in ccRCC associated with ccRCC aggressiveness and patient outcome. Furthermore, it provides evidence about the involvement of polycomb deregulation in ccRCC progression.
Azacitidine as induction therapy of elderly patients with acute myelogenous leukemia.
Authors: Cyrus Khan, James M. Rossetti, Christie Hilton, Santhosh Sadhashiv, Sanaullah Khalid, Arifa Abid, Victoria Fischer, Salman Fazal, Entezam A. Sahovic, Richard K. Shadduck, John Lister
Journal: Journal of Clinical Oncology (2012)

6620 Background: Effective alternative treatment of elderly patients (aged ≥ 60 years) with acute myelogenous leukemia (AML) remains challenging. Elderly patients with AML respond poorly to standard induction regimens and have high treatment related mortality. In a prior retrospective analysis of elderly patients with AML performed at our institution, azacitidine (AZA) showed an overall response rate (ORR) of 60% with limited toxicity. Methods: This is a prospective, phase II open-label study using AZA in patients ≥60 years with AML. Inclusion criteria: Newly-diagnosed non-M3 AML and ECOG ≤ 2. Patients with circulating blast count ≥30,000/mcl were treated with hydroxyurea until &lt; 30,000/mcl. AZA was administered at 100 mg/m2 subcutaneously for 5 consecutive days every 28 days until disease progression or significant toxicity. Results: In all, 15 patients were enrolled last follow-up being 8/2/11. The mean age of patients is 74 years (range: 64–82). Mean ECOG score was 1. Mean baseline bone marrow blast count was 52% (range: 25–92%). ORR was 46% (n=7) with complete response (CR) in 3 (20%) patients and partial response (PR) in 2 (13%) patients according to NCI response criteria, and hematologic improvement (HI) in 2 (13%) patients according to IWG response criteria. The mean number of days on treatment was 198 (range: 13–724). The mean time to best response among responders was 95 days (range: 44-279). The mean number of days hospitalized for diagnosis plus treatment or disease-related complication was 19 (range: 5–56), with the majority of therapy administered in an outpatient setting. Mean overall survival (OS) from diagnosis for all patients was 355 days (range: 13–908) and mean OS for responders was 532 days (range: 120–908). Non-hematological toxicity was limited to mild injection site skin reaction and fatigue in 73% (11/15). No treatment-related deaths were observed. The dose and schedule of AZA remained constant in a majority of the patients. Conclusions: This study suggests that a 5-day schedule of SC AZA at 100 mg/m2 to elderly patients with newly-diagnosed AML is a feasible, well-tolerated and effective alternative to standard induction chemotherapy.
Sexual function in adult cancer survivors.
Authors: Emily Jo Rajotte, K. Scott Baker, Leslie Heron, Karen Leslie Syrjala
Journal: Journal of Clinical Oncology (2017)

123 Background: Sexual dysfunction is a common treatment sequela across numerous cancer diagnoses and treatments, causing increased distress, discomfort and negatively impacting quality of life. Methods: Before their survivorship-focused clinic appointment, adult cancer survivors were asked to complete a comprehensive patient -eported outcomes survey that included detailed questions on their health status including sexual function. Results: Between April 2015 to July 2016, 94 patients completed the survey. They were 66% female, mean age 45 years (SD 16, range 21-82) and 34% leukemia/lymphoma, 18% breast cancer, and 12% genitourinary cancer survivors. Patients were a mean of 6.7 years (SD 7.9, range 0-42) from their cancer diagnosis at the time of clinic appointment. Nearly half (48%) were married or living with a partner and 49% were living alone (single, divorced, widowed). 70.2% reported being sexually active (alone or with a partner) in the last year: of these only half (55.3%) reported being sexually active in the last month. For those who were not sexually active the most commonly cited reasons included lack of interest (24.5%) and not having a partner (30.9%), with 12.8% reporting not being sexually active due to a physical problem. Survivors rated their sexual satisfaction in the past month as a 5.0 (SD 3.7; scale of 0-10, 0=not at all satisfying 10=extremely satisfying). An independent samples t-test revealed a statistically significant difference in sexual satisfaction between survivors under 45 years in age and ≥45 years in age (t=4.4, df=68.0, p &lt; 0.05). Older survivors (mean=3.71, SD=3.7) reported significantly lower levels of sexual satisfaction than did younger survivors (mean=7.11, SD=2.8). The most commonly reported sexual function issues for women included vaginal dryness (23.4%) and for men included difficulty getting an erection (7.4%). Conclusions: Sexual dysfunction is a common long-term effect of cancer across diagnoses and most treatments, warranting widespread implementation of targeted interventions to manage sexual dysfunction and improve quality of life for these survivors.
Croydon CCG stops funding IVF treatment to save £800 000 a year
Authors: Matthew Limb
Journal: BMJ (2017)

Campaigners fear that a hospital fertility centre could close after NHS commissioners in Croydon became the first in London to stop routine funding of in vitro fertilisation (IVF) treatment.

The NHS Croydon clinical commissioning group (CCG) said that it had taken the decision to help save over £800 000 a year, although 77% of people who responded to its consultation had opposed the closure. Agnelo Fernandes, a Croydon GP and the CCG’s assistant clinical chair, said, “This is one of the hardest decisions of my professional career, and I wish we were not in the position of having to make it.”

Croydon Health Services NHS Trust said that the future of the service at Croydon University Hospital was now “uncertain,” as the CCG was …
Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL
Authors: D R Howard, T Munir, L McParland, A C Rawstron, D Milligan, A Schuh, A Hockaday, D J Allsup, S Marshall, A S Duncombe, J L O'Dwyer, A F Smith, R Longo, A Varghese, P Hillmen
Journal: Leukemia (2017)
Gefitinib plus celecoxib in chemotherapy-naïve patients with stage IIIB/IV non-small cell lung cancer (NSCLC): A phase II study from the Hoosier Oncology Group
Authors: A. K. Agarwala, L. Einhorn, W. Fisher, D. Bruetman, J. McClean, D. Taber, M. Titzer, B. Juliar, T. Breen, N. Hanna
Journal: Journal of Clinical Oncology (2006)

7066 Background: Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) pathway, has single agent activity in NSCLC. Preclinical studies demonstrate significant interactions between the EGFR and cyclo-oxygenase 2 (COX-2) pathways and that simultaneous inhibition against NSCLC may have benefits over gefitinib alone. Methods: Eligibility required that pts were chemotherapy-naïve, had stage IIIb (with pleural effusion) or IV NSCLC and an ECOG PS 0–1. Pts received gefitinib 250mg orally daily plus celecoxib 400mg orally every 12 hours. Cycles consisted of 21 day treatment and continued until unacceptable toxicity or progression of disease. The primary objective of this single arm, two-stage, phase II study was to evaluate the overall response rate. If ≤ 10 out of 30 pts achieved a complete (CR) or partial response (PR), the study would be stopped early. If &gt;10 out of 30 pts had a CR or PR, enrollment would continue to 50 pts. Results: From 1/04 to 11/04, 31 pts were enrolled: male/female 13/18; median age 70.8 years (range, 19–93); 67.7% had adenocarcinoma; ECOG PS 0/1 13/18; stage IIIb/IV 2/29; 5 were current smokers, 9 were remote (&gt;30 years) or never smokers, 16 quit smoking &gt; 3 months ago. Median number of cycles was 4 (range, 0–16). 6 pts (19.4%) discontinued therapy due to toxicity, including 3 who died due to treatment. Select grade 3/4 toxicities included: pulmonary (6.5%), hepatic (6.5%), diarrhea (6.5%), skin (3.2%). Responses included PR 5 (16.1%), stable disease 8 (25.8%), and progressive disease 18 (58.1%). Median duration of response, progression free survival, and overall survival was 5.7, 2.8, and 7.2 months, respectively. All responders were females with adenocarcinoma, 2 were remote or never smokers and 3 were former smokers. Conclusion: Gefitinib plus celecoxib in an unselected population of chemotherapy naïve patients with advanced NSCLC and a PS of 0–1 has a lower response rate and overall efficacy compared with historical controls of chemotherapy. [Table: see text]
Clinical significance of ERCC2 haplotype-tagging single nucleotide polymorphisms in patients with unresectable non-small cell lung cancer treated with first-line platinum-based chemotherapy.
Authors: Seok-Hyun Kim, Gyeong-won Lee, Yi Yeong Jeong, Ho-Cheol Kim, Jong Deog Lee, Young Sil Hwang, In-Suk Kim, Suee Lee, Sung Yong Oh
Journal: Journal of Clinical Oncology (2013)

e19156 Background: DNA repair pathway is a crucial molecular mechanism potentially involved in resistance to platinum-based chemotherapy in the unresectable non-small cell lung cancer. Furthermore, single nucleotide polymorphisms (SNPs) and haplotypes in the ERCC2 gene are thought to be associated with the risk of developing lung cancer and clinical outcomes. Methods: We genotyped 8 ERCC2 htSNPs for 129 unresectable NSCLC (stage IIIA, 12; stage III, 36; stage IV, 82) cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, and predictive value of htSNPs in patient response, survival, and chemotherapy-related adverse events were analyzed according to each ERCC2 htSNP using chi-square test, Kaplan-Meier method, and Cox proportional hazard model. Results: No differences were observed in patient or disease characteristics and response according to ERCC2 htSNPs. In a survival analysis, rs50872 was significantly related to overall survival (OS) (log-rank test, p=0.014). The median survival duration of rs50872 G/G, A/G, and A/A genotypes was 35.75 (95% confidence interval [CI] 21.05-50.45), 36.07 (hazard ratio[HR] 1.02, 95% CI 25.20-46.94), and 16.75 (HR 3.49, 95% CI 5.73-27.77) months, respectively. A significant association was observed between grade 3-4 infections and poor survival: OS in patients with a grade 0-2 infection: 35.75 months (95% CI 28.15-43.35); OS in patients with a grade 3-4 infection: 12.86 months (95% CI 8.99-16.72, HR 3.57) (log-rank test, p&lt;0.001). In a subgroup analysis, rs238405 genotype was significantly related to OS in the taxane-based group. However, rs238416 genotype was significantly associated with OS in the gemcitabine-based group. Conclusions: ERCC2 htSNPs rs50872 (overall), rs238405 (taxane-based group), and rs238416 (gemcitabine-based group) and infection related to first-line chemotherapy were associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. However, additional large prospective studies focusing on the role of ERCC2 htSNPs in unresectable NSCLC are needed.
Rapid identification of drug-resistant BCR-ABL(+) leukemia.
Authors: Ronald J. Rieder, Zhihui Zhao, Alex Chalmers, Richard M. Stone, Ilene Galinski
Journal: Journal of Clinical Oncology (2013)

7050 Background: Approximately 20% of patients with chronic myeloid leukemia and most patients with BCR-ABL-positive acute leukemia demonstrate resistance to imatinib mesylate resulting in treatment failure or suboptimal patient outcomes. We hypothesize that monitoring the development of cellular stress in BCR-ABL cells incubated with tyrosine kinase inhibitors (TKI) can be used as an early marker for determining the effects of the drugs on the cancer cells enabling rapid identification of drug-resistance and facilitating change to more effective therapies. Methods: The dielectric permittivities of non-leukemic peripheral blood mononuclear cells (PBMCs) and BCR-ABL cell lines known to be resistant (K562R and BaF3/T315I) or sensitive (K562 and HL60/BCR-ABL) to different TKIs were measured in the presence of imatinib (IMT), dasatinib (DAS), nilotinib (NIL), or ponatinib (PON) using the Z-Sense differential impedance sensing platform to record any changes in cellular stress. We also performed similar measurements on PBMCs from newly diagnosed CML patients exposed in vitro to the same TKIs. Results: Non-leukemic PBMCs showed no significant background levels when incubated with the following TKI concentrations: IMT (5 mg/mL), DAS (5 mg/mL), NIL (2.5 mg/mL), and PON (5 ng/mL). Normalized dielectric responses for all drug-resistant cell lines showed no change in value similar to control runs where no drugs were added. In contrast, all responses obtained for cell lines sensitive to these same TKIs were immediate and continuously decreased in value over time compared with resistant cell lines (p&lt;0.01). All sensitivities were confirmed by MTT assay. Notably, the response of BaF3/T315I cells to PON was easily distinguished from the responses to IMT, DAS, and NIL. Of significance, all responses of BCR-ABL(+) patient blood to the four TKIs measured prior to commencing therapy were qualitatively similar to sensitive cell line measurements and subsequently confirmed to respond to IMT therapy. Conclusions: Drug-sensitive BCR-ABL(+) cells can be readily distinguished from drug-resistant cells without cell culturing in less than 60 minutes by monitoring the development of cellular stress in response to TKI drugs using differential impedance sensing.
A retrospective analysis of the relationship between diabetes, metformin use, and survival in advanced endometrial cancer patients treated with chemotherapy.
Authors: Obiageli Chinaka Ezewuiro, Mohammed Issam Habis, Masha Kocherginsky, Jessica Hunn, Olufunmilayo I. Olopade, Tatyana A. Grushko, Iris L Romero, Gini F. Fleming
Journal: Journal of Clinical Oncology (2014)

5607 Background: Pre-clinical data suggests that the diabetic medication, metformin, has anti-cancer effects. We hypothesized that advanced stage endometrial cancer (EC) patients who used metformin would have improved survival. Methods: We conducted a single institution retrospective review of women receiving chemotherapy in the setting of stage III, IV or recurrent EC or carcinosarcoma from 1992 to 2011. Results: We identified 418 pts with stage III, IV or recurrent EC, of whom 237 received chemotherapy, and 220 were included in the study. Median age at time of chemotherapy was 64.8 (range 21.1-87.0); race: 56% white, 40% African American (AA), 4% other. Histologies were 28% endometrioid, 28% serous, 16% carcinosarcoma, 7% clear cell and 21% other. Median OS was 24.5 months (95%CI: 20.1-28.5). AA pts had worse OS than whites (p=.02), with median OS of 16.9 (95%CI: 12.7-24.6) vs 28.5 (95%CI: 23.4-35.2) months, respectively. Older patients had worse OS (p=0.001). 43 pts had diabetes and 19 of them were taking metformin at the time of chemotherapy. Median OS for diabetics taking metformin, diabetics not taking metformin, and non-diabetics was 51.9 (95%CI: 17.9-127.5), 13.3 (95%CI: 8.0-24.6) and 24.2 (95%CI: 20.1-29.8) months. OS difference between the three groups was not statistically significant (p=0.12), but when comparing survival only among the diabetic groups, patients treated with metformin had a borderline statistically significant longer OS (p=0.066, logrank test). The difference was also borderline significant in the multivariate Cox regression model adjusted for race and age (HR=2.12, p=0.057). Conclusions: In this study of advanced EC, patients receiving chemotherapy who were concurrently treated with metformin had improved survival. Our study adds to the body of evidence suggesting potential anti-cancer effects of metformin and supports prospective testing of metformin added to standard chemotherapy for advanced EC. Supported by NCI K12CA139160 and CTSA-ITM CS UL1 RR024999 to TG, NCI 2K12HD00849-22 and University of Chicago Cancer Center to IR.
Analysis of Cardiac Myocyte Maturation Using CASAAV, a Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo
Authors: Yuxuan Guo, Nathan J. VanDusen, Lina Zhang, Weiliang Gu, Isha Sethi, Silvia Guatimosim, Qing Ma, Blake D. Jardin, Yulan Ai, Donghui Zhang, Biyi Chen, Ang Guo, Guo-Cheng Yuan, Long-Sheng Song, William T. Pu
Journal: Circulation Research (2017)

Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Previous studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation.
Exclusive chemoradiation with carboplatin-paclitaxel versus FOLFOX-4 in locally advanced esophageal cancer: A matched-pair analysis.
Authors: Joelle Miny, Aurelie Bertaut, Jean Francois Bosset, Jihane Boustani, Magali Rouffiac, Francois Ghiringhelli, Christophe Borg, Berardino De Bari, Gilles Crehange
Journal: Journal of Clinical Oncology (2017)

145 Background: The PRODIGE 5 trial has demonstrated the safety and the efficacy of FOLFOX-4 combined with exclusive 50Gy external RT while the CROSS trial showed an improvement in overall survival with Carboplatin-Taxol (C-TAX) when combined with 41.4Gy before surgery. We sought to determine the feasibility and efficacy of exclusive RT with C-TAX compared to FOLFOX-4 regimen. Methods: 46 patients with locally advanced esophageal cancer who were treated with exclusive chemoradiation were matched 1:1 : 23 patients were treated with FOLFOX-4 regimen (group A) and 23 patients with C-TAX (group B). Comparison between the 2 groups was performed using Mac Nemar test for paired data. All tests were two sided and Pvalues were considered significant when less than 0.05. Results: The mean age in group A was 69.4 years (12.5) and 72.4 years (12.6) in group B (p = ns). In each group, 11 patients had a stage III disease at diagnosis (47.8%) with only 2 stage IV in group A (8.7%) vs none in group B. The median delivered RT doses were 50Gy [14-60] in group A while it was 50Gy [20-70] in group B. 6 courses of chemotherapy were delivered in 12 patients in group A (52.2%) and 14 patients in group B (60.9%) (p = 0.51). After chemoradiation, G1 or higher esophagitis was observed in 5 patients (26.3%) in group A and 3 patients (13.0%) in group B of whom 0 vs 2 G3 were observed in group A and B, respectively. Four patients (21.1%) had a pulmonary infection in group A and 3 in group B (13.0%). Two patients (8.7%) vs 4 patients (17.4%) had G3 neutropenia, with only 0 and 2 neutropenic fever in group A and B, respectively. Neither G3 anemia, nor G3 thrombopenia occured. After a median follow-up of 17.7 months [0.0-46.9], 25 patients had died, 14 in group A (60.9%) and 11 in group B (47.8%). The median PFS rates were 14.0 months in group A [7.7-NR] vs 12.1 months [4.4-NR] in group B (p = 0.32). The median OS rates were 20.3 months in group A [6.2-39.3] vs 17.0 months [4.8-NR] in group B (p = 0.82). Conclusions: Exclusive chemoradiation with C-TAX seems feasible with similar toxicity and survival outcomes than FOLFOX-4. The safety and efficacy of the CROSS regimen needs to be tested prospectively with RT doses &gt; 41.4Gy in a phase II or III trial.
First-line pertuzumab (P), trastuzumab (H), and taxane therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC): Interim safety results (N=704) from PERUSE.
Authors: Thomas Denis Bachelot, Eva Ciruelos, Tamar Peretz-Yablonski, Fabio Puglisi, Andreas Schneeweiss, Mario Campone, Bruno P. Coudert, Bella Kaufman, Andrew M. Wardley, Lydie Bastiere-Truchot, Ulrich Freudensprung, Eleonora Restuccia, David Miles
Journal: Journal of Clinical Oncology (2014)

548^ Background: Combining P with 1st-line H + docetaxel (DOC) in pts with HER2-positive mBC significantly improved progression-free survival (PFS) and overall survival (OS) in the randomized phase III CLEOPATRA trial. PERUSE is assessing the safety of 1st-line P + H + investigator’s chosen taxane in routine oncology practice. Methods: In the ongoing multicenter single-arm phase IIIb PERUSE study, pts with HER2-positive LR/mBC, ECOG PS ≤2 and no prior systemic therapy for LR/mBC (except endocrine therapy) receive P (840→420 mg q3w), H (8→6 mg/kg q3w) and a taxane (DOC, paclitaxel [PAC] or nab-PAC) until disease progression (PD) or unacceptable toxicity. Pts will be followed until 45 mo after last pt enrollment. The primary endpoint is safety, including grade (G) ≥3 AEs. Secondary endpoints include PFS, OS, objective response rate and QoL. We report a prespecified interim analysis reviewed by the Independent Data Monitoring Committee. Results: As of 13 Sep 2013, 704 of the planned 1500 pts had completed ≥6 weeks’ follow-up. Baseline characteristics: median age 55 y (range 26–87); 26% ≥65 y; 76% Caucasian; 61% ECOG PS 0; 32% stage IV at 1st diagnosis; 73% visceral metastases; 67% ER and/or PgR positive; 29% prior (neo)adjuvant H; 43% prior (neo)adjuvant chemotherapy. The initial taxane was DOC in 320 pts (45%), PAC in 331 (47%) and nab-PAC in 45 (6%). The median number of cycles was 9 (range 1–23) for P, 8 (1–23) for H and 6 (1–21) for each taxane; 81% of pts are still receiving ≥1 study therapy. Therapy was discontinued most often for PD (P 7%, H 7%, taxane 4%) and for AEs in 4% (each agent). Conclusions: The safety profile of P + H + investigator’s choice of taxane in this interim safety analysis is consistent with previous clinical experience of P + H + DOC. No unexpected safety signals were seen. Safety data by taxane will be reported. Clinical trial information: NCT01572038. AEs in >15% (any G) or >1% (G ≥3) AE, % of pts All G G ≥3 Diarrhea 65.1 7.5 Alopecia 41.8 0 Nausea 28.0 0.4 Fatigue 27.6 2.1 Asthenia 25.0 1.8 Peripheral neuropathy 19.5 1.1 Mucosal inflammation 18.6 1.4 Rash 18.0 0.4 Epistaxis 16.8 0 Vomiting 15.2 0.6 Dysgeusia 15.2 0.1 Anemia 13.9 1.6 Neutropenia 13.1 8.7 Dyspnea 11.1 1.1 Febrile neutropenia 4.4 4.4