tbuckley/cabot-search huggingface dataset:
Everolimus (EVE) plus endocrine therapy in patients with estrogen receptor–positive (ER+), human epidermal growth factor receptor 2–negative (HER2<b>−</b>) advanced breast cancer (BC): First- and second-line data from the BOLERO-4 study.
Authors: Fatima Cardoso, Cristian Villanueva, Melanie Royce, Felipe Cruz, Marc Debled, Roberto Hegg, Tatsuya Toyama, Carla Isadora Falkson, Joon Jeong, Vichien Srimuninnimit, Mustafa Ozguroglu, William John Gradishar, Sergio J Azevedo, Christina H. Arce, Antonia Ridolfi, Chinjune Lin, Thomas Denis Bachelot
Journal: Journal of Clinical Oncology (2017)

1010 Background: Initial first-line (1L) data from the phase 2 BOLERO-4 (NCT01698918) study of EVE + letrozole (LET) in postmenopausal patients (pts) with ER+, HER2− metastatic BC (MBC) or locally advanced BC (LABC) have been previously reported. Here, we present updated 1L progression-free survival (PFS) data, plus new data describing second-line (2L) EVE + exemestane (EXE) in pts with disease progression after EVE + LET. Methods: Postmenopausal pts with ER+, HER2− MBC or LABC with no prior therapy for advanced disease received EVE 10 mg/day + LET 2.5 mg/day. After disease progression, pts could receive EVE + EXE 25 mg/day until further disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint: 1L PFS. Secondary endpoints: overall response rate (ORR), clinical benefit rate (CBR), 2L PFS, overall survival (OS), and safety (1L and 2L). Results: Among 202 pts (median age, 64 years) with 1L MBC (96%) or LABC (4%), median PFS (95% CI) was 21.7 (18.123.9) months, ORR was 43.6%, and CBR was 74.3%. 42 pts (median age, 62 years) with MBC (88%) or LABC (12%) who progressed on 1L EVE + LET received optional 2L EVE + EXE. 2L median PFS (95% CI) was 3.7 (1.89.1) months, ORR was 4.8%, and CBR was 21.4%. Common 1L adverse events (all grades, regardless of drug relationship) were stomatitis (69%), weight loss (44%), diarrhea (40%), nausea (37%), and anemia (35%); 2L adverse events included stomatitis (19%) and weight loss (19%). Median duration of follow-up from start of 1L to the data cutoff for these new analyses (17 June 2016) was 23.5 months. OS will be analyzed at a later data cut. Conclusions: EVE + LET is an effective regimen in 1L ER+, HER2− advanced BC. Thesedata support previously reported BOLERO-2 data demonstrating a PFS improvement from addition of EVE to an aromatase inhibitor. 2L data, although limited by the small number of pts, show preliminary evidence of EVE activity when continued beyond disease progression. No new safety signals were seen. Lower rates of stomatitis in 2L were noted. Clinical trial information: NCT01698918.
Detection of causative agents of tick-borne rickettsioses in Western Siberia, Russia: identification of Rickettsia raoultii and Rickettsia sibirica DNA in clinical samples
Authors: Y. Igolkina, E. Krasnova, V. Rar, M. Savelieva, T. Epikhina, A. Tikunov, N. Khokhlova, V. Provorova, N. Tikunova
Journal: Clinical Microbiology and Infection (2017)
Association of Sex with Risk of Kidney Graft Failure Differs by Age
Authors: Fanny Lepeytre, Mourad Dahhou, Xun Zhang, Julie Boucquemont, Ruth Sapir-Pichhadze, Heloise Cardinal, Bethany J. Foster
Journal: Journal of the American Society of Nephrology (2017)

Prior studies of sex differences in kidney graft survival showed conflicting results. We hypothesized that the association between recipient sex and kidney graft failure risk differs by recipient age and donor sex. We evaluated 159,417 patients recorded in the Scientific Registry of Transplant Recipients database who received a first deceased-donor kidney transplant (1995-2013). We used time-varying Cox models to estimate the association between recipient sex and death-censored graft failure. Models, stratified on donor sex and adjusted for potential confounders, included a recipient sex by current age interaction term. Among recipients of male donors, females of all ages had significantly higher graft failure risks than males (adjusted hazard ratios 0-14 years: 1.51 [95% confidence intervals 1.19 to 1.90]; 15-24 years: 1.37 [1.18 to 1.59]; 25-44 years: 1.14 [1.03 to 1.26]; 45 years: 1.05 [1.01 to 1.09]). Among recipients of female-donor grafts, only female recipients aged 15-24 years had a significantly higher graft failure risk than their male counterparts had (1.28 [1.06 to 1.53]). Indeed, female recipients aged ≥45 years had a significantly lower graft failure risk than their male counterparts had (0.95 [0.91 to 0.99]). These observations might be explained by the combined influence of several factors, including recognition of sex-determined minor histocompatibility antigens, influence of sex hormones on immune activation, sex- and age-related differences in medication adherence, and sex-related differences in body size. Additional studies should determine whether sex- and age-specific immunosuppression strategies are warranted for kidney graft recipients.
Pathophysiology of Takotsubo Syndrome
Authors: Francesco Pelliccia, Juan Carlos Kaski, Filippo Crea, Paolo G. Camici
Journal: Circulation (2017)

Originally described by Japanese authors in the 1990s, Takotsubo syndrome (TTS) generally presents as an acute myocardial infarction characterized by severe left ventricular dysfunction. TTS, however, differs from an acute coronary syndrome because patients have generally a normal coronary angiogram and left ventricular dysfunction, which extends beyond the territory subtended by a single coronary artery and recovers within days or weeks. The prognosis was initially thought to be benign, but subsequent studies have demonstrated that both short-term mortality and long-term mortality are higher than previously recognized. Indeed, mortality reported during the acute phase in hospitalized patients is ≈4% to 5%, a figure comparable to that of ST-segment-elevation myocardial infarction in the era of primary percutaneous coronary interventions. Despite extensive research, the cause and pathogenesis of TTS remain incompletely understood. The aim of the present review is to discuss the pathophysiology of TTS with particular emphasis on the role of the central and autonomic nervous systems. Different emotional or psychological stressors have been identified to precede the onset of TTS. The anatomic structures that mediate the stress response are found in both the central and autonomic nervous systems. Acute stressors induce brain activation, increasing bioavailability of cortisol and catecholamine. Both circulating epinephrine and norepinephrine released from adrenal medullary chromaffin cells and norepinephrine released locally from sympathetic nerve terminals are significantly increased in the acute phase of TTS. This catecholamine surge leads, through multiple mechanisms, that is, direct catecholamine toxicity, adrenoceptor-mediated damage, epicardial and microvascular coronary vasoconstriction and/or spasm, and increased cardiac workload, to myocardial damage, which has a functional counterpart of transient apical left ventricular ballooning. The relative preponderance among postmenopausal women suggests that estrogen deprivation may play a facilitating role, probably mediated by endothelial dysfunction. Despite the substantial improvement in our understanding of the pathophysiology of TTS, a number of knowledge gaps remain.
CD99 suppresses KCMF1, a putative metastasis suppressor gene whose modulation is involved in the migratory ability of Ewing′s sarcoma cells
Authors: Michael Kreppel, Dave Nt Aryee, Karl-Ludwig Schaefer, Gabriele Amann, Reinhard Kofler, Christopher Poremba, Heinrich Kovar
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4305 

High CD99 expression levels and rearrangements of the EWS gene with ETS transcription factor genes characterize the Ewing’s sarcoma family of tumors (ESFT), the second most common tumors of bone and soft tissue in children. CD99 is a cell surface glycoprotein, highly expressed on hematopoietic precursor cells and ESFT, whose engagement with antibodies in hematopoietic cells has been implicated in cell proliferation as well as upregulation and transport of several transmembrane proteins. In ESFT, antibody-ligation of CD99 induces fast homotypic cell aggregation and cell death although its functional role in these processes remains largely unknown. Here, using an RNAi approach, we studied for the first time the consequences of modulated CD99 expression in six different ESFT cell lines, representing the most frequent variant forms of EWS gene rearrangement. CD99 suppression resulted in growth inhibition and reduced migration of ESFT cells. Among genes whose expression changes in response to CD99 modulation, the potassium-channel modulatory factor KCMF1 was consistently upregulated. In a series of 22 primary ESFT, KCMF1 expression levels inversely correlated with CD99 abundancy. Cells forced to express ectopic KCMF1 showed a similar reduction in migratory ability as CD99 silenced ESFT cells. Our results suggest that in ESFT, high CD99 expression levels contribute to the malignant properties of ESFT by promoting growth and migration of tumor cells and identify KCMF1 as a potential metastasis suppressor gene down-regulated by high constitutive CD99 expression in ESFT.Supported by grants from the Austrian Science Fund FWF (#16067-B04), the Austrian government (GEN-AU-Child, contract 200.071/2-VI/1/2001), and the European Commission (PROTHETS, contract LSHC-CT-2004-503036).
Abstract KP02: STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER
Authors: Ronny Drapkin
Journal: Clinical Cancer Research (2017)

Abstract There is an emerging consensus that a majority of high-grade serous carcinomas, the most common type of ovarian cancer, are derived from PAX8-expressing cells in the distal fallopian tube. Careful histologic examination of fallopian tubes from BRCA1/2 mutation carriers has led to the identification of a morphological continuum that begins with a benign secretory cell, transitions to identifiable precursor lesions, and culminates in serous carcinoma. We have previously demonstrated the biologic plausibility of this hypothesis by showing that dysregulation of BRCA1/2 and TP53 in PAX8-expressing mouse or human fallopian tube secretory epithelial cells (FTSECs) can induce tumors that are genomically and phenotypically identical to human high-grade serous ovarian cancers. While PAX8 serves as the basis for many of the fallopian tube-based models we have developed, little is known about its role during neoplastic transformation. PAX8 is a lineage-defining transcription factor that directs the development of the Müllerian duct (the female reproductive tract). Its expression is retained by nearly all high-grade serous carcinomas but it remains unknown whether alterations in the PAX8 cistrome contribute to ovarian carcinomas. Using whole transcriptome shotgun sequencing (RNA-Seq) after PAX8 knockdown and ChIP-Seq, we show that FTSECs and high-grade serous carcinomas are distinguished by marked reprogramming of the PAX8 cistrome. Interestingly, the majority of PAX8 binding peaks are found in intronic and intergenic regions of the genome rather than promoters. Genes that are significantly altered between FTSECs and carcinoma lines are enriched near PAX8 binding sites. These sites are also near TEAD binding sites, and these transcriptional changes may be related to PAX8 interactions with the TEAD/YAP1 signaling pathway. These data suggest that transcriptional changes after transformation in ovarian cancer are closely related to epigenetic remodeling in lineage-specific transcription factors. Citation Format: Ronny Drapkin. STARING DOWN THE BARREL OF A TUBE AT THE ORIGINS OF OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr KP02.
Paclitaxel plus carboplatin versus paclitaxel plus epirubicin as first-line treatment for metastatic breast cancer: Efficacy and safety results of a randomized, phase III trial.
Authors: Zhongsheng Tong, Shufen Li, Yehui Shi, Xu Wang, Chen Wang, Chunfang Hao, Xiaorui Wang, Wenjin Meng, Li Zhang
Journal: Journal of Clinical Oncology (2017)

1087 Background: Paclitaxel/carboplatin combinations are highly active in metastatic breast cancer (MBC). We conducted a randomized, phase III, non-inferiority trial comparing paclitaxel/carboplatin (TP) with paclitaxel/epirubicin (TE) as first-line therapy for MBC. Progression-free survival (PFS) was the primary efficacy endpoint. Secondary endpoints included response rate, overall survival, tolerability, and quality of life (QoL). Methods: From June 2009 to January 2015, 231 patients were randomly assigned, 115 of whom were randomized to TP and 116 to TE. Baseline characteristics were relatively well-balanced in the two treatments. Results: After a median follow-up of 29 months, no significant difference was observed between the two treatments in objective response rate (ORR) (38.3% vs. 39.7%, respectively). Both the progression-free survival (p=0.158) and overall survival (p=0.369) were very similar between the two treatments. Both regimens were well tolerated. The main toxicities were myelosuppression, gastrointestinal reactions, and alopecia. TP showed higher grades 3–4 alopecia and higher nausea (p&lt;0.05). TE showed higher incidence of myelosuppression than TP (p&lt;0.05) (Table). Those patients whose epirubicin cumulative dose was more than 1000 mg/m 2 did not suffer worse cardiotoxicity. Conclusions: Our study suggests that TP arm is an effective therapeutic alternative for patients with MBC, especially in those previously exposed to epirubicin in the adjuvant setting. TP has some advantages, such as less cost and less side effects (myelosuppression and fatigue). Clinical trial information: NCT02207361. [Table: see text]
Targeted deep sequencing of solid tumors to predict response to therapy: A study in an Indian population.
Authors: Urvashi Bahadur, Mithua Ghosh, Vaijayanti Gupta, Soumya Rao, Manimala Sen, Satish Sankaran, Smita Agarwal, Vamsi Veeramachaneni, Gouri Deshpande, Manasa B.P., Jamuna Yadhav, Suman Kapoor, Ramesh Hariharan, Basavalinga S. Ajaikumar, Kalyanasundaram Subramanian
Journal: Journal of Clinical Oncology (2014)

e22059 Background: Massively parallel deep sequencing of genes involved in cancer can provide a comprehensive understanding of the processes that drive an individual's cancer and potentially provide personalized therapy options. Single gene sequencing based tests may provide an incomplete understanding of oncogenic pathways and response to therapy. We evaluated the utility of an NGS-multi-gene panel based approach in impacting treatment in a wide range of solid tumors from an Indian population of patients Methods: DNA from saliva and FFPE blocks of 30 tumor samples from varied tissue types (lung, colon, breast, ovary, glioblastoma, head and neck) was taken from consenting patients and subjected to deep sequencing using Illumina’s TSCAP 48 gene panel and the MiSeq technology. The average coverage across 220 hot spots was greater than 1000X in each sample. Data was processed using Avadis NGS™. Mutations identified in the tumor but not in the paired normal DNA were assessed for ‘actionability’ i.e. impact on prognosis and response to therapy. Results: Differential somatic alterations in the tumor were detected in 90% of the cases with TP53 being most frequently mutated. In half of the cases, variants were found with possible impact on prognosis or therapy. Notably, in 30% of the cases, somatic variants directly impacting therapy were found in genes encoding members in the growth factor signaling pathway. Variants with therapeutic relevance were found in PIK3CA, PTEN, KRAS and NRAS. Of these, variants in PIK3CA were the most frequent. Standard single gene testing would have identified only one KRASvariant. All the variants identified indicated resistance to conventional therapy (such as anti-EGFR, or anti-ERBB2) and suggested sensitivity to alternative targeted therapy, either approved or in clinical trials. These results thus have the potential to alter the course of therapy for these patients and open up new options of treatment. Conclusions: Our data from this pilot study suggest that targeted deep sequencing using a multi-gene panel approach can yield useful therapeutic insights in a wide range of tumor types. Ongoing work is aimed at expanding the range of genes examined in this test so as to increase therapeutic impact.
MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy
Authors: George W. Sledge, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Kenichi Inoue, Xavier B. Pivot, Olga Nikolaevna Burdaeva, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han A. Koh, Eva-Maria Grischke, Martin Frenzel, Yong Lin, Susana Barriga, Ian C. Smith, Nawel Bourayou, Antonio Llombart-Cussac
Journal: Journal of Clinical Oncology (2017)

1000 Background: Abemaciclib, an oral, selective inhibitor of CDK4 &amp; 6, dosed on a continuous schedule, demonstrated clinical activity as monotherapy in patients (pts) with treatment refractory hormone receptor positive (HR+) metastatic breast cancer (MBC). The tolerability and activity of abemaciclib + fulvestrant (F) supported Phase 3 evaluation. Methods: MONARCH 2 is a double-blind Phase 3 trial of abemaciclib + F vs placebo (P) + F in women with HR+/HER2- advanced breast cancer. Women who progressed on (neo)adjuvant endocrine therapy (ET), ≤12 months from end of adjuvant ET, or on first line ET for MBC and who had not received chemotherapy for metastatic disease were eligible. Pts were randomized 2:1 to receive abemaciclib at 150 mg Q12H (or 200 mg prior to amendment) or P plus F (500 mg, per label) and stratified by metastatic site (visceral, bone only, or other) and resistance to prior ET (primary vs secondary). Pre/perimenopausal pts received a gonadotropin-releasing hormone agonist. The primary objective was investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and other efficacy and safety endpoints. Assuming a hazard ratio (HR) of 0.703 in favor of abemaciclib + F, 378 events were needed for 90% power at one sided α=.025. Results: 669 pts were randomized to abemaciclib + F (N=446) and to P + F (N=223). 56% of pts had visceral disease, 72% had measurable disease, 25% had primary ET resistance, and 82% were postmenopausal. In the ITT population 379 PFS events were observed with a median PFS of 16.4 m for abemaciclib + F and 9.3 m for P + F (HR: 0.553; 95% CI: 0.449, 0.681, P&lt;.0000001 by log-rank test). In pts with measurable disease, the ORR was 48.1% (3.5% complete response [CR]) for abemaciclib + F and 21.3% (0% CR) for P + F. The most frequent treatment emergent adverse events for abemaciclib + F vs P + F were diarrhea (86.4% vs 24.7%), neutropenia (46.0% vs 4.0%), nausea (45.1% vs 22.9%), and fatigue (39.9% vs 26.9%). Conclusions: Abemaciclib + fulvestrant was an effective treatment in patients with HR+/HER2- advanced breast cancer who progressed on endocrine therapy with significantly improved PFS and ORR. Clinical trial information: NCT02107703.
Breast Cancer Index (BCI) prognostic and predictive classification in older versus younger patients with early-stage HR+ breast cancer (BC) and correlation with clinical risk factors.
Authors: Yuan Yuan, Yu Cao, Mason Israel, Junmei Liu, Catherine A. Schnabel, Arti Hurria
Journal: Journal of Clinical Oncology (2017)

546 Background: Older patients with HR+ BC may present distinct challenges for treatment decision-making. BCI is a validated gene expression assay for pts with early stage HR+ BC that provides 2 results: BCI Predictive, based on HoxB13/IL17BR (H/I ratio), reports a prediction of likelihood of benefit from extended endocrine therapy (EET); BCI Prognostic, based on the combination of H/I and proliferation-based genes, reports individualized risk of late distant recurrence (DR). Here, the predictive and prognostic value of BCI results across the aging spectrum ( &lt; 64y, 65-74y, ≥75y) and correlation with clinical risk factors were examined. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains &gt; 50 clinicopathologic and molecular variables from cases submitted for BCI in clinical practice (N = 14,463). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. Chi-squared tests were used to compare BCI results between age groups and clinical subsets. Results: Analyses included LN- pts (N = 3,395): median age 59.1y; 5.5% ≥75y (N = 188), 24.0% 65-74y (N = 814), 70.5% ≤64y (N = 2,393). BCI Prognostic had a wide distribution of individual risk assessments in all age groups. The proportion of pts classified as high risk was similar between age groups (48.4%, 48.4% and 49.8% in ≥75y, 65-74y and ≤64y; p = 0.76). The proportion of pts with high risk results increased with increasing tumor size and grade in all age groups (P &lt; 0.05 for all). Notably, in pts ≥75y, BCI identified 31.9% of T1a/b and 21.1% of Grade 1 tumors as high risk of late DR. BCI Predictive (H/I) also identified similar proportions as High H/I across age groups (42.0%, 41.8%, and 40.6% in ≥75y, 65-74y, and ≤64y; p = 0.81). Similar proportions of pts ≥75y were identified as high H/I across size and grade subsets (P = 0.702, P = 0.193, respectively). Conclusions: BCI identifies pts with high risk disease and who may benefit from EET across the aging spectrum. Individualized decisions for EET also must include life expectancy, competing comorbidities and potential toxicities from therapy.
Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis
Authors: Cumali Efe, Hannes Hagström, Henriette Ytting, Rahima A. Bhanji, Niklas F. Müller, Qixia Wang, Tugrul Purnak, Luigi Muratori, Mårten Werner, Hanns-Ulrich Marschall, Paolo Muratori, Fulya Gunşar, Daniel Klintman, Albert Parés, Alexandra Heurgué–Berlot, Thomas D. Schiano, Mustafa Cengiz, Michele May-Sien Tana, Xiong Ma, Aldo J. Montano-Loza, Thomas Berg, Sumita Verma, Fin Stolze Larsen, Ersan Ozaslan, Michael A. Heneghan, Eric M. Yoshida, Staffan Wahlin
Journal: Clinical Gastroenterology and Hepatology (2017)
Monocyte Subpopulation Recovery and Outcomes Following Hematopoietic Cell Transplantation
Authors: Lucie M. Turcotte, Qing Cao, Elias Krahn, Julie Curtsinger, Ashley M. Yingst, Sarah Cooley, Claudio G Brunstein, Margaret L. MacMillan, Shernan G. Holtan, John E. Wagner, Daniel J. Weisdorf, Bruce R. Blazar, Jeffrey S. Miller, Michael R. Verneris
Journal: Blood (2016)
Prx II(Peroxiredoxin II) Activity Has Important Roles As a New Mechanism to Control ABL Tyrosine Kinase Activity in STIs(Signal Transduction Inhibitor) Treated CML Patients
Authors: Eun-Sun Yoo, Yeung-Chul Mun, Jee-Young Ahn, Jung-Won Huh, Chu-Myong Seong
Journal: Blood (2016)