tbuckley/cabot-search huggingface dataset:
Anthrax toxin receptor 1 is the cellular receptor for Seneca Valley virus
Authors: Linde A. Miles, Laura N. Burga, Eric E. Gardner, Mihnea Bostina, John T. Poirier, Charles M. Rudin
Journal: Journal of Clinical Investigation (2017)

Seneca Valley virus (SVV) is an oncolytic picornavirus with selective tropism for neuroendocrine cancers. It has shown promise as a cancer therapeutic in preclinical studies and early-phase clinical trials. Here, we have identified anthrax toxin receptor 1 (ANTXR1) as the receptor for SVV using genome-wide loss-of-function screens. ANTXR1 is necessary for permissivity in vitro and in vivo. However, robust SVV replication requires an additional innate immune defect. We found that SVV interacts directly and specifically with ANTXR1, that this interaction is required for SVV binding to permissive cells, and that ANTXR1 expression is necessary and sufficient for infection in cell lines with decreased expression of antiviral IFN genes at baseline. Finally, we identified the region of the SVV capsid that is responsible for receptor recognition using cryoelectron microscopy of the SVV-ANTXR1-Fc complex. These studies identify ANTXR1, a class of receptor that is shared by a mammalian virus and a bacterial toxin, as the cellular receptor for SVV.
Association of nuclear localization of SATB1 with adverse clinical outcome in breast cancer.
Authors: Weiming Duan, Kai Chen, Wei Li, Wei Liu, Min Tao, Zi-Xing Chen
Journal: Journal of Clinical Oncology (2016)

e12029 Background: Genome organizer SATB1 has been recently reported to associate with negative prognosis in several cancer forms.However, the role of SATB1 in breast cancer(BC) remains controversial.This study evaluated the expression of SATB1 and its role in predicting prognosis in BC. Methods: The SATB1 expression and its clinical significance were examined in 93 consecutive patients with invasive ductal breast carcinoma using immunohistochemistry. Kaplan-Meier survival analysis was used to estimate the prognostic relevance of SATB1 and the survival difference between groups was assessed by the log-rank test. Univariate and multivariate Cox regression analysis was performed to evaluate difference of all possible factors. Moreover, the sensitivity and specificity of the aforementioned biomarkers were identified by using receiver operating characteristic (ROC) curve. Results: Subcellular staining of SATB1 was heterogeneous, ranging from cytoplasmic to nuclear. SATB1 staining was strongly related to clinical stage, Ki67, ER and PR (all p < 0.05). When survival was analyzed according to SATB1 localization, we observed that patients with negative nuclear SATB1 staining and positive cytoplasmic staining had a similar better outcome compared with positive nuclear SATB1 staining samples, suggesting that cytoplasmic positive and nuclear negative SATB1 expression have a similar prognostic significance. Kaplan-Meier survival analysis revealed a correlation between higher SATB1 nuclear expression levels and shorter overall survival times (p < 0.001). Univariate and multivariate analyses revealed that SATB1 was an independent prognostic factor. Interestingly, analysis of survival in these patients classified according to Nottingham Prognostic Index (NPI) score as “good” or “poor” risk showed a significant difference in survival time in the NPI either good or poor score subgroups according to SATB1 expression. Furthermore, ROC curves showed that the AUC for SATB1, Ki67, c-erbB-2, ER and PR were 0.859,0.662,0.637,0.586 and 0.498, respectively. Conclusions: Nuclear localization of SATB1 is a robust independent biomarker for prognosis as compared to currently routinely used diagnostic parameters in BC.
Autoimmune Hematological Diseases Following Haploidentical Donor Hematopoietic Stem Cell Transplant Compared with Matched Sibling and Unrelated Donor
Authors: Weiran Lv, Qifa Liu, Zhiping Fan, Fen Huang, Na Xu, Li Xuan, Guopan Yu, Qianli Jiang, Hongsheng Zhou, Ren Lin, Jing Sun, Xin Zhang
Journal: Blood (2016)
Potential Influence of FDA-Sponsored Studies of Antiepilepsy Drugs on Generic and Brand-name Formulation Prescribing
Authors: Gregory L. Krauss
Journal: JAMA Neurology (2017)

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Treatment decision making and psychosocial outcomes associated with rapid genetic testing for BRCA1 and BRCA2 in women newly diagnosed with breast cancer.
Authors: Kelly A. Metcalfe, Steven Narod, Andrea Eisen, Jordan Lerner-Ellis
Journal: Journal of Clinical Oncology (2016)

1586 Background: For women with BRCA-associated breast cancer (BC), treatment with bilateral mastectomy improves survival, but most women do not know their BRCA status at the time of BC diagnosis. Rapid genetic testing (RGT) allows a woman to have genetic test results prior to treatment decision making, but it is unclear if RGT has an impact on treatment choices. It is unclear if provision of genetic testing at time of breast cancer diagnosis has an impact on psychosocial functioning. The objective of the current study was to assess the impact of RGT at the time of BC diagnosis on surgical decision-making and psychosocial functioning. Methods: Eligible women were referred from participating surgeons at BC diagnosis. Women completed baseline questionnaires assessing treatment preferences, cancer related distress, anxiety, and depression. All participants received in-person pre-test genetic counselling. BRCA genetic test results were given within 10 days. Participants completed surveys at 1 week and 1 year post-genetic testing to assess treatments and psychosocial functioning. Results: 495 women consented to participate, and 33 (6.7%) were identified with a BRCA mutation. Five of these women (15.2%) were not eligible for genetic testing based on provincial criteria for BRCA testing. Mean levels of cancer-related distress, anxiety and depression declined significantly from baseline to 1 year for all women (all p < .05), and there were no differences at any time point between those with and without a BRCA mutation. Of those identified with a BRCA mutation, 64.3% reported that their surgery choice changed; 75.9% of BRCA carriers had a bilateral mastectomy, and 10.3% were planning for a bilateral mastectomy after chemotherapy. Conclusions: Rapid genetic testing for BRCA1 and BRCA2 at the time of BC diagnosis does not have a negative impact on psychosocial functioning. There are no differences in cancer-related distress, anxiety or depression between women who receive a positive result compare to a negative genetic test result. Furthermore, surgical choice changed for many women identified with a BRCA mutation, with the majority electing for bilateral mastectomy.
Liposomal temozolomide drug delivery using convection enhanced delivery
Authors: Mirjam M. Nordling-David, Roni Yaffe, David Guez, Hadar Meirow, David Last, Etty Grad, Sharona Salomon, Shirley Sharabi, Yael Levi-Kalisman, Gershon Golomb, Yael Mardor
Journal: Journal of Controlled Release (2017)
Diffusion MRI Phenotypes Predict Overall Survival Benefit from Anti-VEGF Monotherapy in Recurrent Glioblastoma: Converging Evidence from Phase II Trials
Authors: Benjamin M. Ellingson, Elizabeth R. Gerstner, Marion Smits, Raymond Y. Huang, Rivka Colen, Lauren E. Abrey, Dana T. Aftab, Gisela M. Schwab, Colin Hessel, Robert J. Harris, Ararat Chakhoyan, Renske Gahrmann, Whitney B. Pope, Kevin Leu, Catalina Raymond, Davis C. Woodworth, John de Groot, Patrick Y. Wen, Tracy T. Batchelor, Martin J. van den Bent, Timothy F. Cloughesy
Journal: Clinical Cancer Research (2017)

Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine.
L'Association élastographie et injection de produit de contraste pour ultra-sons guidée par échoendoscopie(Ee) permet-elle de caractériser les masses du pancréas?
Authors: M Giovannini, E Bories, CH Pesenti, F Caillol, JR Delpero
Journal: Endoscopy (2006)

L'élastographie est une nouvelle technologie dans laquelle les modifications de contrainte des tissus sont employées pour détecter des tumeurs. Une tumeur cancéreuse est normalement 5–10 fois plus «rigide» que le tissu normal. Quand une compression mécanique est appliquée, la tumeur se déforme moins que le tissu environnant c.-à-d. La contrainte dans la tumeur est moindre que dans le tissu environnant. Cette propriété produit des images remarquablement claires. Par ailleurs, l'utilisation de produit de contraste pour US (Sonovue) permettrait de différencier les adénocarcinomes (généralement hypovascularisés) des autres masses du pancréas. Le but de cette étude a été d'appliquer ces 2 technologies à l'échoendoscopie pour le diagnostic de malignité des masses du pancréas.
A phase I study of safety and pharmacokinetics of NanoBB-1-Dox in patients with advanced solid tumors.
Authors: Olga Filon, Petr Krivorotko, Grigory Kobyakov, Viktoria Razjivina, Olga Maximenko, Svetlana Gelperina, Joerg Kreuter
Journal: Journal of Clinical Oncology (2017)

e13537 Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier and delivery to the tumor inside the brain. Preclinical studies demonstrated that NanoBB-1-Dox enabled considerable growth inhibition of an intracranially implanted 101.8 glioblastoma in rats and long-term remission in &gt;20% animals, whereas the conventional doxorubicin formulation was only marginally effective. Methods: 21 patients with advanced solid tumors (18 with advanced breast cancer, 34 with GBM) were enrolled in the study. The objectives of the study were: 1) to evaluate the safety and pharmacokinetics (PK), 2) to determine the maximum tolerated dose (MTD). A standard “3 + 3” design with 7 dose levels (4, 24, 36, 48, 60, 75 and 90 mg/m 2 ) was used. Each patient received a single i.v. infusion of NanoBB-1-Dox. Doxorubicin serum concentrations were measured immediately before the infusion, and 2 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 168 h after the infusion. Results: The PK analysis demonstrated that AUC 0- t of doxorubicin after the NanoBB-1-Dox infusion increased in parallel with the dose level from 121.7 to 2054.4 h x ng/ml. T 1/2 varied from 45 to 75 h without dose dependence. NanoBB-1-Dox was well tolerated without dose limiting toxicity even at the highest dose of 90 mg/m 2 , so the MTD was not achieved. The most common AEs included leukopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, and alopecia. In general, the AE rate and intensity increased with the dose level reaching the maximum at a dose of 90 mg/m 2 . Only hematological AEs were severe according to CTCAE 4.03. No SAEs were reported. Conclusions: NanoBB-1-Dox after a single i.v. infusion in patients with advanced solid tumors is well tolerated and is characterized by a non-linear PK profile. NanoBB-1-Dox will be investigated in a phase II study in patients with GBM as a second line therapy. [Table: see text]
Retrospective review of safety and efficacy of checkpoint inhibition in refractory high-grade gliomas.
Authors: Samantha Reiss, Prakirthi Yerram, Lisa Modelevsky, Christian Grommes
Journal: Journal of Clinical Oncology (2017)

2033 Background: Treatment options for refractory high grade gliomas (HGG) are limited. Programmed cell death ligand-1 (PD-L1) expression has been reported in 0-61% of HGGs and therefore might be a suitable target in HGG. The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This IRB approved single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with an age ≥18 years who received a PD-1 inhibitor between 9/2014 and 10/2016 outside of a clinical trial. Results: Twenty five HGGs were identified. All patients received the PD-1 inhibitor pembrolizumab (pembro) as part of compassionate use. Median age was 49 years (range 30-72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Patients received a median of 4 prior lines of therapy (range 1-9). Nineteen (76%) previously failed bevacizumab. Median baseline KPS was 80 (range 50-100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1-14). Treatment toxicity and response was assessed in 24 patients. PD-1 inhibitor related adverse events (AEs) included LFT elevations (33%), hypothyroidism (17%), diarrhea (17%), myalgias/arthralgias (13%), and rash (8%). Other common AEs were hyperglycemia, fatigue, thrombocytopenia, lymphopenia, headache, and nausea in the setting of concomitant therapy and additional supportive care (dexamethasone). Grade 3 AEs included seizure (4%), headache (4%), nausea (4%), and vomiting (4%). Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 42 days (range 7-282) and median overall survival was 121 days (range 15-415). Three patients (12%) had a PFS &gt; 90 days; of these, 2 received single agent pembro. Conclusions: Patients with HGG had low response rates. However, a small number of patients had prolonged PFS. Pembro was tolerated with few serious AEs, even in patients receiving concomitant therapy.
Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+), HER2-negative (HER2–) advanced breast cancer (aBC): Phase Ib safety, preliminary efficacy and molecular analysis.
Authors: Dejan Juric, Pamela N. Munster, Mario Campone, Roohi Ismail-Khan, Laura García-Estevez, Erika Paige Hamilton, Carlos Becerra, Richard H. De Boer, Rina Hui, Anthony Goncalves, Yingbo Wang, Shyeilla V. Dhuria, Ghulam H. Kalimi, Karen Cristina Rodriguez Lorenc, Ingrid A. Mayer
Journal: Journal of Clinical Oncology (2016)

568 Background: Ribociclib (cyclin dependent kinase 4/6 inhibitor; LEE) acts synergistically with letrozole (LET) in preclinical models of ER+ BC. LEE + LET in patients (pts) with ER+ aBC is being investigated in Arm 1 of a 3-arm, phase Ib study (NCT01872260). The Arm 1 recommended phase II dose (RP2D) was reported as LEE 600 mg QD (3 weeks [wks] on/1 wk off) + LET 2.5 mg QD (Juric et al.SABCS 2014;PD-19-24). Methods: Postmenopausal women with ER+, HER2− aBC received oral LEE + LET at the RP2D. Primary objective of expansion: safety and tolerability. Other objectives include efficacy, pharmacokinetics (PK), and biomarkers. Results: As of Aug 21, 2015, 47 pts received LEE + LET in Arm 1: 95% of 19 pts from the initial enrollment were previously treated for aBC (PT group) and 96% of 28 pts in expansion were treatment-naïve for aBC (TN group). Treatment was discontinued in 18 (95%) PT pts (progressive disease [PD], n = 16; adverse events [AEs], n = 1; physician decision, n = 1) and 10 (36%) TN pts (PD, n = 10). Median duration of exposure was 16 and 35 wks in PT and TN groups, respectively. Grade 3/4 AEs suspected to be drug-related included neutropenia (43%), lymphopenia (4%), and leukopenia (2%). Of the 47 evaluable pts, one complete response (CR; TN) was observed. Overall response rate (ORR; CR+partial response [PR]) was 5% (95%CI: 0–26%) for PT and 39% (95%CI: 22–59%) for TN groups. Clinical benefit rate (CBR; CR+PR+stable disease [SD] ≥ 24 wks) was 32% (95%CI: 13–57%) for 19 evaluable PT pts and 73% (95%CI: 50–89%) for 22 evaluable TN pts. PK data for LEE + LET in combination were consistent with historical single-agent data. PR was observed in tumors with PIK3CA alterations (3 PR) or CCND1 amplification (1 PR), which were present in tumor samples from 5 and 2 of 9 PT pts, and 6 and 1 of 10 TN pts, respectively. Conclusions: Based on these preliminary data, LEE + LET has an acceptable safety profile in pts with ER+, HER2– aBC and demonstrated clinical activity, particularly in the TN group (39% ORR; 73% CBR). LEE + LET may also provide benefit to pts with PIK3CA alterations or CCND1 amplification. A phase III study of LEE + LET in 1st line postmenopausal aBC has completed enrollment. Clinical trial information: NCT01872260.
Predictors of recurrence during years 5-14 in 46,138 women with ER+ breast cancer allocated 5 years only of endocrine therapy (ET).
Authors: Hongchao Pan, Richard G. Gray, Christina Davies, Richard Peto, Jonas C. S. Bergh, Kathleen I. Pritchard, Mitch Dowsett, Daniel F. Hayes
Journal: Journal of Clinical Oncology (2016)

505 Background: For operable ER+ breast cancer, 5 years of ET with tamoxifen and/or aromatase inhibitors reduces breast cancer mortality in years 0-4 and years 5-14 by about a third. Extending ET past year 5 further reduces risks in years 5-14, but has further side-effects. Knowledge of the effects of prognostic factors on absolute risks of distant recurrence and death in years 5-14 if ET stops at year 5 could help decide whether to extend ET after year 5 for lower-risk patients. Methods: Data on 46,138 individual patients with ER+ disease (diameter T1 or T2 only, pathological nodal status N0, N1-3 or N4-9 only) in trial groups allocated 5 years only of ET yielded the effects on outcomes in years 5-14 of tumor diameter, nodal status and, if available, grade, Ki-67, PR and HER-2 status. Cox regression analyses of each factor were adjusted for age, trial group, and the other factors. Results: In ER+ disease, recurrence rates continued steadily throughout the first 20 years. Distant recurrence rates in years 5-14 still depended on initial N-stage (N1-3 vs N0: RR = 2.08, 95%CI 1.87 – 2.32), T-stage (T2N0 vs T1N0: RR = 1.73, 1.53 – 1.95), grade (T1N0, high vs low: RR = 2.02, 1.44 – 2.83) and Ki67 ( ≥ 20% vs 0-13%: RR = 1.63, 1.23 – 2.16). Similar associations were seen for breast cancer mortality, but contralateral cancer rates (0.3%/year) were little related to these risk factors. For T1N0 disease of low, moderate, and high grade, the risks in years 5-14 were, respectively, 5%, 8%, and 10% for distant recurrence (Table) and 12%, 15% and 17% for any recurrence. Conclusions: Even after 5 years of ET, ER+ recurrence risk continued steadily over years 5-14. Although this risk was less for patients with favorable TN status and grade, even those with low-grade T1N0 disease had an appreciable risk of distant recurrence. Distant recurrence in years 5-14 in ER+ disease allocated 5 years only of endocrine therapy. No. of women Annual, Years 5-9 Rate (%), Years 10-14 Cumulative risk (%), years 5-14 Trend P Nodes: N0 23,870 1.0 1.1 9.8 1-3 16,630 2.0 1.5 15.6 4-9 5,638 4.1 2.6 27.7 < 0.0001 Diameter, N0 only: T1 16,286 0.7 0.9 7.9 T2 7,584 1.6 1.3 13.6 < 0.0001 Grade, T1N0 only: Low 2,996 0.4 0.7 5.4 Moderate 6,120 0.8 0.9 8.1 High 2,135 1.0 1.2 10.0 < 0.0001
Reply to Saeid Safiri and Erfan Ayubi's Letter to the Editor re: Nicholas J. Giacalone, William U. Shipley, Rebecca H. Clayman, et al. Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience. Eur Urol 2017;71:952–60. Methodological Issues to Avoid Misinterpretation
Authors: Nicholas J. Giacalone, Andrzej Niemierko, William U. Shipley, Jason A. Efstathiou
Journal: European Urology (2017)
Prognostic impact of progesterone receptor status in 3030 Chinese estrogen receptor positive early breast cancer patients.
Authors: Zhenchuan Song, Nan Yao, Xinle Wang, Shan Yang, Heng Song
Journal: Journal of Clinical Oncology (2016)

e12002 Background: Estrogen receptor (ER) and progesterone receptor (PR) have been used as indicators of endocrine system since the mid-1970s in the breast cancer. The predictive role of ER in endocrine therapy is undisputed, but the prognostic value of PR is still debated.The objective of this study was to investigate the clinical characteristics and prognosis of ER+ early breast cancer in different PR expression. Methods: A population cohort of 3030 ER+ primary invasive breast cancer with curative intent patients presenting to a single Cancer Centre over 6 years (2004–2010) underwent surgery and received adjuvant endocrine therapy. Age, menopausal status, tumor size, histology, lymph node status, PR status, Her-2, and Ki-67 were collected. The follow-up data for disease-free survival (DFS) and overall survival (OS) was obtained and distribution of factors was compared using the standard Chi-Square test. Univariate Cox hazard models were used to assess the effects of treatment and predictive factors on clinical outcomes. Results: The patients with low PR expression ( ≤ 25%) were more frequent in older (aged 50 and above, 62.9% vs. 46.9%, P< 0.001), postmenopausal (55.2% vs. 38.0%, P< 0.001), larger size (57.8% vs. 51.8%, P= 0.014), lymph node metastasis (24.8% vs. 19.7%, P= 0.004), higher Ki-67 level (53.7% vs. 46.7%, P= 0.007), HER-2 expression (25.3% vs. 14.0%, P< 0.001) than those with high PR expression ( > 25%). The median follow-up period was 70 months (range 42-125). 425 patients had recurrence and metastasis and 329 died. Multivariate analyses demonstrated that low PR expression was significantly associated with poorer prognosis for DFS [P= 0.014; HR = 0.781 (95% CI: 0.641-0.950)] and OS [P= 0.002; HR = 0.699 (95% CI: 0.560-0.873)]. Furthermore, in low PR expressing patients who received chemotherapy had better DFS [P= 0.002; HR = 0.449 (95% CI: 0.268-0.751)] and OS [P＜0.001; HR = 0.341 (95% CI: 0.192-0.606) than those who didn’t received chemotherapy. Conclusions: ER+ invasive early breast cancer patients with low PR-expressing tumors have worse outcomes and benefit less from adjuvant endocrine therapy, but more from chemotherapy than those with high PR-expressing tumors.