tbuckley/cabot-search huggingface dataset:
Updated efficacy and safety of the ALK inhibitor AP26113 in patients (pts) with advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC).
Authors: Scott N. Gettinger, Lyudmila Bazhenova, Ravi Salgia, Corey J. Langer, Kathryn A. Gold, Rafael Rosell, Alice Tsang Shaw, Glen J. Weiss, Narayana I. Narasimhan, David J. Dorer, Victor M. Rivera, Tim Clackson, Frank G. Haluska, D. Ross Camidge
Journal: Journal of Clinical Oncology (2014)

8047 Background: AP26113 is a novel orally-active tyrosine kinase inhibitor with preclinical activity against ALK and all 9 clinically-identified crizotinib-resistant mutants tested. Methods: The Phase (Ph) 2 portion of a Ph1/2 single arm, multicenter study in pts with advanced malignancies is underway. We report updated safety for all treated pts and efficacy data for ALK+ NSCLC pts previously treated with crizotinib. NCT01449461. Results: As of 16 Dec 2013, 114 pts were enrolled: 65 in Ph1 (30-300 mg) and 49 in Ph2 (180 mg). Baseline characteristics: 59% female, median age 57 yr; diagnoses: NSCLC n=106, other n=8. 66 pts remain on study; median follow-up for all pts is 3.6 mo (max= 21.4 mo, ongoing). The most common treatment-emergent AEs (≥20%) were nausea (38%), diarrhea (31%), fatigue (31%), cough (23%), and headache (20%), which were generally grade 1/2 in severity. Early onset of pulmonary symptoms (dyspnea with hypoxia and/or findings on imaging) observed in 6/45 (13%) pts at 180mg QD. These symptoms, requiring immediate medical attention, were not observed at 90mg QD (n=8) or in the lead-in dose cohort (n=19; initiated at 90mg QD, escalated to 180mg QD after 1 wk). Pts continue to be enrolled with this dose escalation scheme, and an additional cohort of 90mg QD without escalation will be added. Among 38 evaluable ALK+ NSCLC pts with prior crizotinib, 24 (63%) responded (23 partial response, 1 complete response). Duration of response was 1.6 - 14.7 mo (ongoing). 15 pts had confirmed responses; 5 await confirmation, 4 are unconfirmed. Among 42 evaluable pts with ALK+ NSCLC, median progression free survival is 47 wk. Independent radiological review conducted on 10 pts enrolled with untreated or progressing brain metastases showed 6/10 pts with response in brain, including 4 with undetectable brain metastases following AP26113; 2 pts had stable disease, 2 pts progressed; 8/10 remain on study (range 5-17 mo). Conclusions: AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized Ph2 trial evaluating 90 mg QD vs. 90mg QD escalating to 180mg QD in crizotinib-resistant ALK+ NSCLC will begin shortly. Clinical trial information: NCT01449461.
The behavior of colorectal liver metastases in the time frame between the end of preoperative chemotherapy and liver resection: A new selection criterion for technically resectable patients.
Authors: Luca Vigano, Shadya Sara Darwish, Lorenza Rimassa, Matteo Cimino, Carlo Carnaghi, Matteo Donadon, Fabio Procopio, Nicola Personeni, Daniele Del Fabbro, Armando Santoro, Guido Torzilli
Journal: Journal of Clinical Oncology (2017)

665 Background: Not all the patients with resectable colorectal liver metastases (CLM) benefit from liver resection (LR). To date, patients with disease progression during chemotherapy are excluded from surgery. The present study aims to elucidate if the CLM behavior in the interval between the end of chemotherapy and LR (stable disease vs. progression) impacts prognosis. Methods: All the consecutive patients undergoing LR for CLM between 2004 and 2014 after a tumor response or stabilization during chemotherapy were considered. The patients having received two separate imaging modalities after chemotherapy (one at the end of chemotherapy and one before LR) with an interval between the two &gt; 3 weeks were included. Any variation of CLM size was registered. Tumor progression was defined according to the RECIST criteria. Results: Overall, 130 patients were analyzed. One fourth of the patients with partial response or stable disease during chemotherapy had a disease progression after the end of chemotherapy before LR, 16% if the interval chemotherapy-surgery was &lt; 8 weeks. The risk of progression was not associated with the response to chemotherapy. Patients with progression after the end of chemotherapy had lower survival than patients with stable disease (5-year overall survival (OS) 19.0% vs. 27.6%; three-year recurrence-free survival (RFS) 6.7% vs. 21.3%, p &lt; 0.001 for both). Survival was extremely poor in case of early progression ( &lt; 8 weeks) (0% two-year RFS and OS). Progression was an independent prognostic factor of OS and RFS (HR = 3.243 and HR = 2.874, p &lt; 0.0001). Eleven patients had a complete radiologic response to chemotherapy and underwent LR at disease reappearance without further chemotherapy after a median delay of 8.7 months. They had excellent survival (five-year OS 39.0%, three-year RFS 36.4%). Conclusions: Early disease progression between the end of chemotherapy and LR occurs in ~15% of patients. It is associated with extremely poor survival and should be considered a contraindication to surgery. Patients with a complete radiologic response can be resected upfront at recurrence without further chemotherapy.
Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes
Authors: Eliana Mariño, James L Richards, Keiran H McLeod, Dragana Stanley, Yu Anne Yap, Jacinta Knight, Craig McKenzie, Jan Kranich, Ana Carolina Oliveira, Fernando J Rossello, Balasubramanian Krishnamurthy, Christian M Nefzger, Laurence Macia, Alison Thorburn, Alan G Baxter, Grant Morahan, Lee H Wong, Jose M Polo, Robert J Moore, Trevor J Lockett, Julie M Clarke, David L Topping, Leonard C Harrison, Charles R Mackay
Journal: Nature Immunology (2017)
Comparison of biochemical recurrence-free survival after radical prostatectomy among men in active surveillance following grade reclassification and men newly diagnosed with similar grade disease.
Authors: Clarissa P. Diniz, Ballentine Carter, Jonathan I. Epstein, Mufaddal Mamawala
Journal: Journal of Clinical Oncology (2017)

117 Background: Stakeholders in a Patient-Centered Outcomes Research grant questioned the clinical implications of biopsy grade reclassification (GR) while on active surveillance (AS). Methods: We conducted a retrospective analysis of men undergoing radical prostatectomy (RP) from 1995-2015 at Johns Hopkins and identified 4 groups; 76 men in AS underwent RP following GR from Gleason score (GS) 6 to GS 7(3+4) [grade group 2], 2947 men underwent immediate radical prostatectomy (IRP) following a diagnosis of grade group 2, 122 men in AS underwent RP following GR to GS ≥ 7(3+4) [grade groups ≥ 2], and 4433 men underwent IRP following a diagnosis of grade groups ≥ 2. Biochemical recurrence free survival (bRFS) was the outcome of interest that was assessed using Kaplan Meir curves and a multivariate Cox regression model. Results: Men on AS had a higher proportion of low volume cancer (p &lt;0.001; p &lt;0.001) as compared to the IRP groups for both biopsy grade group 2 and biopsy grade groups ≥ 2, respectively. On the Kaplan Meier curve, bRFS was higher for men in the AS cohort compared to IRP group for both biopsy grade group 2 (p = 0.071) and for biopsy grade groups ≥ 2 (p = 0.046). However, on the multivariate Cox model adjusting for age at treatment, cancer volume, and PSAD, the difference in bRFS between the AS and IRP group was no longer significant; HR = 0.61 (95% CI, 0.23 to 1.67) for biopsy grade 2, HR = 0.77 (95% CI, 0.41 to 1.46) for biopsy grades ≥ 2. Conclusions: AS patients that are reclassified to grade group 2 and those reclassified to grade group 2 or above have a higher chance of bRFS after treatment as compared to those undergoing IRP with similar grades. This could help inform decisions regarding the risk of entering an AS program. [Table: see text]
Cardiovascular Outcomes With Minute Ventilation–Targeted Adaptive Servo-Ventilation Therapy in Heart Failure
Authors: Christopher M. O’Connor, David J. Whellan, Mona Fiuzat, Naresh M. Punjabi, Gudaye Tasissa, Kevin J. Anstrom, Adam V. Benjafield, Holger Woehrle, Amy B. Blase, JoAnn Lindenfeld, Olaf Oldenburg
Journal: Journal of the American College of Cardiology (2017)

Sleep apnea is common in hospitalized heart failure (HF) patients and is associated with increased morbidity and mortality. The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) trial investigated whether minute ventilation (MV) adaptive servo-ventilation (ASV) improved cardiovascular outcomes in hospitalized HF patients with moderate-to-severe sleep apnea. Eligible patients hospitalized with HF and moderate-to-severe sleep apnea were randomized to ASV plus optimized medical therapy (OMT) or OMT alone (control). The primary endpoint was a composite global rank score (hierarchy of death, cardiovascular hospitalizations, and percent changes in 6-min walk distance) at 6 months. 126 of 215 planned patients were randomized; enrollment was stopped early following release of the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial results. Average device usage was 2.7 h/night. Mean number of events measured by the apnea-hypopnea index decreased from 35.7/h to 2.1/h at 6 months in the ASV group versus 35.1/h to 19.0/h in the control group (p < 0.0001). The primary endpoint did not differ significantly between the ASV and control groups (p = 0.92 Wilcoxon). Changes in composite endpoint components were not significantly different between ASV and control. There was no significant interaction between treatment and ejection fraction (p = 0.10 Cox model); however, pre-specified subgroup analysis suggested a positive effect of ASV in patients with HF with preserved ejection fraction (p = 0.036). In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6-month cardiovascular outcomes. Study power was limited for detection of safety signals and identifying differential effects of ASV in patients with HF with preserved ejection fraction, but additional studies are warranted in this population. (Cardiovascular Improvements With MV ASV Therapy in Heart Failure [CAT-HF]; NCT01953874)
Validation of the web-based tool Adjuvant! in 5,381 Dutch breast cancer patients
Authors: S. Mook, M. K. Schmidt, A. O. van de Velde, O. Visser, E. J. Rutgers, L. J. van 't Veer, P. M. Ravdin
Journal: Journal of Clinical Oncology (2009)

11090 Background: Adjuvant! is a web-based tool that calculates individualized 10-year survival probability and estimates the benefit of adjuvant systemic therapy based on age, co-morbidity, tumor size, tumor grade, number of involved lymph nodes and estrogen-receptor status. The Adjuvant! model was constructed using observed overall survival (OS) for women diagnosed with breast cancer between 1988 and 1992 recorded in the US SEER registry (surveillance, epidemiology and end results) and has not yet been validated in any European series. It is of interest to see whether intrinsic characteristics of tumors and survival of Dutch patients may differ from those in the US. Methods: For this validation all patients who were treated at the Netherlands Cancer Institute for primary breast cancer between 1987 and 1998 were selected according to the following criteria: T1–3 tumor, N0–3, M0, definitive primary surgery, complete axillary staging, and no prior malignancies. Follow-up for OS was complete for &gt;99% of the patients until at least February 2007 (median follow-up 11.7 years). Clinicopathological characteristics as mentioned above and adjuvant treatment data were entered into Adjuvant! version 8.0 for each individual, blinded to the clinical outcome, to calculate predicted 10-year outcomes. Results: In this hospital-based cohort of 5381 patients, all known prognostic factors were significant predictors of overall survival. Across all patients, the 10-year OS was excellently predicted by Adjuvant! (predicted OS - observed OS=0.2%; p=n.s.). Also, for most relevant clinicopathological subgroups the differences between predicted and observed OS were within 2%. Adjuvant underestimated the OS in patients with tubular type of breast cancer (predicted - observed = -6.8; p&lt;0.01); presently, histology is not incorporated in Adjuvant!. Conclusions: Adjuvant! accurately predicts 10-year OS for common tumor types in this first large scale European validation study and is of use for adjuvant treatment-decision making. [Table: see text]
Development of Paroxysmal Nocturnal Hemoglobinuria in Children with Aplastic Anemia
Authors: Atsushi Narita, Hideki Muramatsu, Yusuke Okuno, Yuko Sekiya, Kyogo Suzuki, Motoharu Hamada, Shinsuke Kataoka, Rieko Taniguchi, Daisuke Ichikawa, Norihiro Murakami, Daiei Kojima, Eri Nishikawa, Nozomu Kawashima, Nobuhiro Nishio, Asahito Hama, Yoshiyuki Takahashi, Seiji Kojima
Journal: Blood (2016)
New clinical trial of DNA-based vaccines for patients with non-small cell lung cancer.
Authors: Edward P. Cohen, Jonathan M. Cohen
Journal: Journal of Clinical Oncology (2012)

e13034 Background: We report a new immunotherapeutic trial for patients with non-small cell lung cancer (NSCLC). The trial to be conducted at the University of Pittsburgh Cancer Institute is a two-stage uncontrolled non-randomized Phase IB study designed to evaluate the safety, immunogenicity and feasibility of a new vaccine, consisting of human allogeneic fibroblasts transfected with DNA derived from the patient’s own tumor. The vaccine is prepared by transfer of genomic DNA-fragments (25 kb) from the patient’s tumor into MRC-5 cells, a human embryonic fibroblast cell line. The rationale is that numerous mutant and dysregulated genes in the tumor specifying an array of patient-specific tumor antigens are expressed in a highly immunogenic form by the DNA-transfected cells. A large body of preclinical studies in tumor-bearing mice supports this approach. An IND has been issued. Cohort 1 is underway without DLT. Methods: We plan to use a two-stage trial design. Initially, 15 early-stage patients with NSCLC will be enrolled. If there is no evidence of toxicity, and &gt;3 of the initial patients show an immunologic response, the second stage of the study will be opened for the accrual of 22 additional patients. A portion of the primary tumor removed at surgery will be obtained to serve as a source of tumor-DNA. Each vaccine will contain 1 X 10E7 DNA-transfected fibroblasts. The vaccine will be lethally irradiated before it is administered. It will be injected intradermally in the Outpatient Clinic. Immunologic responses to the vaccine and to the autologous tumor will be evaluated by IFN-g secretion in ELISPOT assays prior to and after vaccination for the frequency of T-cells responsive to the autologous tumor. Additional assays will include lymphocyte proliferation determinations in response anti CD3 and anti CD28 monoclonal antibodies and the effect of the immunizations on the proportion of myeloid-derived suppressor T cells in the patient’s peripheral blood. The patients will also be evaluated before and after immunization for the capacity of their T cells to respond to activating signals delivered via the T cell receptor (TcR). Results: Vaccines have been prepared. First patient has been enrolled. Conclusions: No data to report in this early trial.
Low-Dose, Occupational Exposure to the Leukemogen Benzene Induces Robust Changes in the Blood Transcriptome Associated with Altered Immune System Biology.
Authors: Cliona Mchale, Luoping Zhang, Qing Lan, Quilan Li, Alan Hubbard, Kristin Porter, Roel Vermeulen, Min Shen, Stephen Rappaport, Songnian Yin, Martyn T. Smith, Nathaniel Rothman
Journal: Blood (2008)
Neoadjuvant weekly nab-paclitaxel (wA), carboplatin (Cb) plus bevacizumab (B) with or without dose-dense doxorubicin-cyclophosphamide (ddAC) plus B in ER+/HER2-negative (HR+) and triple-negative (TN) breast cancer (BrCa): A BrUOG study.
Authors: Natalie Faye Sinclair, Maysa M. Abu-Khalaf, Tina Rizack, Kayla Rosati, Gina Chung, Robert Duffy Legare, Michael DiGiovanna, Mary Anne Fenton, Veerle Bossuyt, Rochelle Strenger, Bachir Joseph Sakr, Donald R. Lannin, Jennifer S. Gass, Lyndsay Harris, William M. Sikov
Journal: Journal of Clinical Oncology (2012)

1045 Background: High risk BrCa patients (pts) often receive weekly paclitaxel (wP) as well as ddAC. Switching to wA(Abraxane) or adding B or Cb may enhance its efficacy, especially in TN pts. Methods: Pts with clinical stage IIA-IIIC BrCa received wA 100 mg/m 2 , Cb AUC 6 + B 15 mg/kg q3wks x 12 wks only (cohort 1/Yale) or followed by ddAC + B x 4 (cohort 2/Brown). Endpoints: pathologic complete response (pCR) - absence of invasive BrCa in breast + axillary nodes, residual cancer burden (RCB), clinical CR/partial response (cCR/cPR), and toxicity. Correlative studies are being performed on biopsies obtained at baseline and after run-in doses of wA or B only. Post-op pts resume B for 34 wks; other systemic therapy, including ddAC in cohort 1, is at MD discretion. Results: 55 of 60 pts (median age 47, range 25-68; 31 HR+/29 TN) are evaluable for response (see table below). Median # doses wA 11,Cb 4, ddAC 4. Dose reductions: wA 25% for neutropenia (ANC), Cb 15% for thrombocytopenia (tcp). B 7% held for hypertension. Grade 3-4 toxicities (&gt;5%): ANC 85%, tcp 35%, anemia 25%. Serious adverse events during wA: 3 nausea/dehydration (N/D), 3 infection w/o neutropenic fever (FN), 2 GI bleed; during ddAC: 6 (21%) FN despite G-CSF, 3 N/D. Conclusions: The combination of wA, q3wk Cb + B was well tolerated, with cCR+cPR 84%. However, overall pCR was only 11% (27% in TN) after 12 wks of this regimen (cohort 1). Subsequent preop ddAC raised overall pCR to 54%, and 81% in TN, demonstrating that longer treatment duration or inclusion of anthracycline-based therapy improves responses. Results for cohort 2 compare favorably with those from I-SPY, GeparQuinto and NSABP B-40; the addition of Cb and/or B in TN is being evaluated in CALGB 40603. [Table: see text]
Biologic characteristics of breast cancer in male compared to female: SEER analysis.
Authors: Mohammed Shaik, Deimante Tamkus, Anas Al-Janadi
Journal: Journal of Clinical Oncology (2015)

599 Background: Male (Ma) breast cancer (BC) is a rare disease and information about tumor biomarkers(ER,PR and HER2) is lacking. Since HER2 status was not routinely collected in the population-based cancer registries for patients (pts) before 2010,in this study we aim to evaluate the expression of tumor biomarkers in MaBC compared to female (F) BC. Methods: Using SEER database we analyzed 917(0.84%) MaBC and 108,669 (99.16%) FBC (2010-2011). Data including age, sex, grade, stage, ER/PR status(HR), and HER2 status was used in analysis. These variables were compared between MaBC and FBC. Chi-square and t-test were used for categorical and numerical variables, respectively. Results: The median age for MaBC and FBC was 68 and 61, respectively. Majority were whites followed by blacks and others(81%, 14%, and 5% vs. 80%, 11% and 9%, respectively) in both MaBC and FBC. Stages(0, I, II, III and IV) in MaBC vs. FBC were 2.6%, 35.1%, 38.1% ,17.5% and 6.4% vs. 3%, 47%, 33.6%, 11.5%, and 4.7%, respectively. Tumor biomarkers in MaBC vs. FBC were HR+ 96.7%, HER2+ 12.5% and triple negative(TN) 2% vs. HR+ 83%, HER2+ 15% and TN 12%, respectively (Table). Conclusions: Overall prevalence of MaBC was 0.84%, diagnosed at older age and the most were of luminal subtype. Prevalence of HER2+ve in MaBC was slightly lower compared to FBC(12.5% vs 15%, p = 0.03). TN phenotype in MaBC was uncommon (2%). More favorable tumor biomarker profile was seen in MaBC as compared with FBC. However, HER2 +ve BC represented a significant proportion of MaBC in our study. MaBC should be included in future studies to evaluate HER2 targeted therapies. Comparison of MaBC and FBC. Variable MaBC(%) FBC(%) p-value Median Age (yrs) 68 61 < 0.0001* Race White 742 (81%) 87037 (80%) 0.01 Black 128 (14%) 11635 (10.7%) Others 47 (5%) 9997 (9.3%) Receptor status HR+/HER2+ 105 (11.4%) 11285 (10.3%) < 0.0001** HR-/HER2+ 10 (1.09%) 5133 (4.7%) HR+/HER2- 783 (85.3%) 79145 (72.8%) HR-/HER2- 19 (2.07%) 13105 (12%) HER2 Status HER2+ve 115 (12.5%) 16418 (15%) 0.03*** HER2-ve 802 (87.5%) 92250 (85%) Stage *** 0 23 (2.6%) 3212 (3%) < 0.0001** I 310 (35.2%) 49548 (47%) II 336 (38%) 35455 (33.6%) III 155 (17.5%) 12169 (11.5%) IV 57 (6.4%) 4961 (4.7%) * t test; ** chi-square test; *** data missing for 3307 pts.
Biodegradation behavior of magnesium and ZK60 alloy in artificial urine and rat models
Authors: Shiying Zhang, Yanze Bi, Jianye Li, Zhenguo Wang, Jingmin Yan, Jiawang Song, Haibo Sheng, Heqing Guo, Yan Li
Journal: Bioactive Materials (2017)

In this work, the biodegradable and histocompatibility properties of pure Mg and ZK60 alloy were investigated as new temporary implants for urinary applications. The corrosion mechanism in artificial urine was proposed using electrochemical impedance spectroscopy and potentiodynamic polarization tests. The corrosion potential of pure magnesium and ZK60 alloy were −1820 and −1561 mV, respectively, and the corrosion current densities were 59.66 ± 6.41 and 41.94 ± 0.53 μA cm−2, respectively. The in vitro degradation rates for pure Mg and ZK60 alloy in artificial urine were 0.382 and 1.023 mm/y, respectively, determined from immersion tests. The ZK60 alloy degraded faster than the pure Mg in both artificial urine and in rat bladders (the implants of both samples are ø 3 mm × 5 mm). Histocompatibility evaluations showed good histocompatibility for the pure Mg and ZK60 alloy during the 3 weeks post-implantation in rat bladders, and no harm was observed in the bladder, liver and kidney tissues. The results provide key information on the degradation properties and corrosion mechanism of pure Mg and ZK60 alloy in the urinary system.